Hemophilia A & B Inheritance X-linked recessive Clinical features Delayed/prolonged bleeding after mild trauma Hemarthrosis, intramuscular hematomas Gastrointestinal or genitourinary tract bleeding Intracranial hemorrhage Complications: hemophilic arthropathy Laboratory findings ↑ Activated PTT Normal platelet count & PT Absent or ↓ factor VIII (hemophilia A) or factor IX (hemophilia B) activity Treatment Factor replacement Desmopressin for mild hemophilia A Abnormal bleeding following tooth extractions or other surgical procedures can signify a quantitative or qualitative platelet defect, coagulopathy, or abnormal fibrinolysis.  This patient's male sex and family history of hemarthrosis in a maternal male relative suggest an X-linked coagulopathy such as hemophilia A (factor VIII deficiency) or hemophilia B (factor IX deficiency, Christmas disease).  Hemophilia A and B are indistinguishable clinically as both demonstrate similar symptoms and inheritance patterns.  Both conditions are characterized by isolated prolongation of partial thromboplastin time due to defects in the intrinsic coagulation pathway.  Prothrombin time [PT] and thrombin time [TT] are normal in patients with hemophilia. When endothelial injury occurs, platelets are activated and form a hemostatic plug first, followed by activation of the coagulation cascade.  Patients with hemophilia have normal platelet function and can form a platelet plug, so bleeding after procedures can be delayed rather than immediate, in contrast to patients with platelet disorders.  Manifestations include intramuscular hemorrhage, hemarthrosis, and prolonged or delayed bleeding after surgical procedures. (Choice A)  Low haptoglobin is a sign of hemolytic anemia.  Other associated findings include increased indirect bilirubin and lactate dehydrogenase. (Choice B)  This patient's hemoglobin level is likely normal since the oozing began recently and he has no history of chronic or recurrent bleeding. (Choice D)  Signs of thrombocytopenia include easy bruisability, petechiae, and mucocutaneous hemorrhage (eg, recurrent epistaxis, gingival hemorrhage).  The absence of petechiae and the delayed bleeding onset make a platelet disorder unlikely. (Choice E)  The platelet function analyzer (PFA-100) test monitors the time needed for a patient's blood to form a platelet-based hemostatic plug in an in vitro environment.  Abnormal results are seen in von Willebrand disease, inherited/acquired platelet dysfunction (eg, NSAID use), and thrombocytopenia. (Choice F)  PT reflects the extrinsic clotting pathway, which involves tissue factor, fibrinogen, and factors II, V, VII, and X.  Vitamin K deficiency and warfarin anticoagulant therapy are common causes of isolated PT prolongation as they lead to decreased activity of factors II, VII, IX, and X.  Inherited deficiencies of these clotting factors are very rare. (Choice G)  The TT measures the rate of conversion of fibrinogen to fibrin.  It is prolonged in patients with deficient or defective fibrinogen, which can be congenital or acquired.  The most common cause of acquired dysfibrinogenemia is liver disease. Educational objective: Hemophilia is an X-linked recessive coagulopathy that presents with intramuscular hemorrhage, hemarthroses, and delayed bleeding after procedures.  Laboratory results show partial thromboplastin time prolongation; other tests of hemostatic function are generally normal. Convert this UWorld question into ultra high-yield USMLE notes: 1. Diagnosis: 2. Key clue from question stem (1 line): 3. Why correct answer (max 2 lines): 4. Why others wrong (1 line each): 5. Buzzword trigger: 6. Trap / trick tested: 7. One-liner memory hook: Make it extremely concise. No paragraphs. use this formal everytime

Pure red cell aplasia Etiology Autoimmune-mediated destruction of erythrocyte precursors in bone marrow → complete cessation of erythrocyte production → severe anemia (eg, exercise intolerance, severe pallor)   Causes: Neoplasm: thymoma, lymphoproliferative disorder Medication: antimicrobials, immunosuppressants Infection: parvovirus B19 Laboratory findings Blood cells: Normocytic, normochromic erythrocytes Normal quantity & morphology of platelets & leukocytes Severe reticulocytopenia Normal hemolysis markers (eg, LDH, schistocytes, bilirubin) Normal iron studies Diagnosis Bone marrow biopsy: normocellular bone marrow with dramatic erythrocytopenia This patient has severe anemia with normal platelet and leukocyte counts.  Because 2 of the 3 cell lines produced by the bone marrow are intact (ie, platelets and leukocytes), it is unlikely that this patient has a disorder that affects the entire bone marrow, such as neoplastic tumor infiltration (Choice A). The next step is to determine whether the anemia is due to impaired production or increased loss of erythrocytes.  The bone marrow normally releases immature erythrocytes (reticulocytes) in response to severe anemia to compensate for lost oxygen-carrying capacity.  For this reason, a high reticulocyte count suggests the anemia is due to a process outside the bone marrow, such as acute bleeding or hemolysis (eg, intravascular or splenic erythrocyte destruction) (Choice D).  In contrast, an inappropriately low reticulocyte count (as in this case) suggests a problem with the production of red blood cells in the bone marrow, which may be caused by 1 of the following: Low erythropoietin (EPO):  EPO is primarily produced in the cortical peritubular cells of the kidneys.  It travels to the bone marrow, where it stimulates the division and differentiation of erythroid progenitor cells.  A low level of EPO is primarily caused by fibrosis of the peritubular cells due to chronic renal failure.  This patient with a normal creatinine level is very unlikely to have low EPO (Choice B). Lack of nutrients (eg, vitamin B12, folate, iron):  Efficient erythropoiesis requires adequate levels of vitamin B12, folate, and iron.  Significant deficiencies in these nutrients usually alter the size of mature erythrocytes, leading to changes in mean corpuscular volume (MCV).  Low vitamin B12 or folate eventually causes macrocytosis (high MCV), and low iron eventually causes microcytosis (low MCV). Destruction of erythrocyte precursors:  Viruses (eg, parvovirus B19), medications, and autoantibodies can destroy erythrocyte progenitor cells, leading to severe anemia with morphologically normal platelets and leukocytes (ie, red cell aplasia).  This condition is common with certain tumor types, namely lymphoproliferative disorders (eg, chronic lymphocytic leukemia) and thymoma.  Thymoma often causes mediastinal mass with pulmonary symptoms (eg, persistent nonproductive cough) due to infringement on adjacent airways. Educational objective: Pure red cell aplasia is a rare form of bone marrow failure characterized by severe anemia with reticulocytopenia and morphologically normal platelets and leukocytes.  It is most common with thymoma, lymphocytic leukemia, and parvovirus B19 infection. same as above

A 55-year-old woman is being evaluated for persistent nonproductive cough.  She also has had worsening exercise intolerance and fatigue for the past 4 weeks.  Physical examination shows conjunctival pallor.  Laboratory results are as follows: Complete blood count Hemoglobin 6.2 g/dL Mean corpuscular volume 90 µm3 Reticulocytes 0.1% Platelets 280,000/mm3 Leukocytes 6,700/mm3 Serum chemistry and kidney function test results are normal.  Iron studies and serum vitamin B12 and folic acid levels are within normal limits.  Chest imaging reveals an anterior mediastinal mass.  Which of the following is the most likely cause of this patient's hematologic disorder? this question stem

no above is also good notes combine 2 ntes and make a new one

A 7-year-old boy comes to the office for follow-up.  A week ago, the patient began having episodes of bloody diarrhea that have since resolved.  His current laboratory studies show elevated blood urea nitrogen and serum creatinine levels.  Complete blood count reveals anemia and thrombocytopenia.  Coagulation studies are within normal limits.  His peripheral blood smear is shown in the image below. the clinical presentation and the peripheral blood smear shown are typical of hemolytic uremic syndrome (HUS).  Most cases of childhood HUS are preceded by bloody diarrhea, often caused by Shiga-like toxin released from enterohemorrhagic Escherichia coli (particularly strain O157:H7).  Undercooked ground beef is a common cause of HUS. The smear contains classic schistocytes (fragmented red cells) and few platelets.  Schistocytes are diagnostic of a traumatic mechanism and indicate either microangiopathic hemolytic anemia (eg, HUS, thrombotic thrombocytopenic purpura [TTP], disseminated intravascular coagulation [DIC]) or mechanical damage (eg, prosthetic valve, severely calcified valves).  HUS and TTP lie on a spectrum.  Unlike in DIC, the coagulation system is not activated in HUS-TTP; therefore, coagulation studies (prothrombin time and partial thromboplastin time) are normal, as seen with this patient. (Choice A)  Autoimmune hemolytic anemia (AIHA) is due to an altered immune response and the production of antibodies against erythrocytes.  AIHA can occur following infections with Mycoplasma pneumoniae and Epstein-Barr virus but not usually following a diarrheal illness.  In addition, thrombocytopenia and renal failure are not associated with AIHA. (Choice B)  Erythropoietin deficiency results in normocytic, normochromic anemia; neither schistocytes nor decreased platelets are present.  In addition, erythropoietin deficiency is usually seen in chronic renal failure; this patient has acute renal failure. (Choice C)  Glucose-6-phosphate dehydrogenase (G6PD) deficiency causes hemolytic anemia due to oxidative stress.  It is not associated with thrombocytopenia or renal failure.  The peripheral smear usually shows bite cells. (Choice D)  Leukoerythroblastic peripheral smears (ie, nucleated red cells and immature white cells) are usually seen when the marrow is replaced with fibrosis (or metastatic cancer).  The red cells can be squeezed while passing through fibrous strands and appear on the peripheral smear as characteristic teardrop cells. Educational objective: Schistocytes suggest microangiopathic hemolytic anemia (eg, hemolytic-uremic syndrome [HUS], thrombotic thrombocytopenic purpura [TTP], disseminated intravascular coagulation [DIC]) or mechanical damage [eg, prosthetic valve]).  In childhood, HUS is often preceded by bloody diarrhea.  Coagulation studies (prothrombin time and partial thromboplastin time) are normal in HUS-TTP but abnormal in DIC

1) Diagnosis: Typical HUS (Shiga toxin–associated; EHEC O157:H7) 2) Key clue (1 line): Child + bloody diarrhea 1 week ago → now AKI (↑BUN/Cr) + anemia + thrombocytopenia with normal PT/PTT 3) Why correct (≤2 lines): Shiga-like toxin damages endothelium → platelet microthrombi → MAHA (schistocytes) + thrombocytopenia + renal failure. Coags normal (not DIC). 4) Why others wrong (1 line each): AIHA: spherocytes/Coombs+, no thrombocytopenia or AKI; not post-diarrhea. EPO deficiency: chronic CKD → normocytic anemia only; no schistocytes/low platelets. G6PD deficiency: bite cells/Heinz bodies; no thrombocytopenia or AKI. Leukoerythroblastic smear: teardrop cells + immature cells from marrow infiltration/fibrosis; not MAHA. 5) Buzzword trigger: “Undercooked ground beef” + “bloody diarrhea” + “schistocytes” + “↑Cr” + “normal PT/PTT” 6) Trap / trick tested: Differentiate HUS/TTP vs DIC → HUS/TTP: normal coags; DIC: ↑PT/↑PTT. 7) One-liner memory hook: “EHEC → Shiga toxin → shred RBCs (schistocytes) + chew platelets + crush kidneys; coags OK.” thi sis my notes create like thi stoo , like for exampole in clues i wrote Inc.BUn?Creat - AKi like that now combine 2 and make notes

i liked yours too i want both combined becoz i want all hy notes

A 5-year-old boy is brought to the office by his parents who say that he "looks yellow" and has been uncharacteristically tired lately.  He has had upper respiratory tract infection symptoms for the past 3 days, including cough, rhinorrhea, sneezing, and sore throat.  The parents say that "a lot of kids at daycare have been sick lately."  The patient has no prior medical problems.  He is consistently at the 50th percentile for height and weight.  He takes no medications, and his immunizations are up to date.  Pallor, scleral icterus, and palpable splenomegaly are seen on examination.  Laboratory results are as follows: Complete blood count Hemoglobin 9 g/dL Reticulocytes 10.8% Platelets 218,000/mm3 Leukocytes 7500/mm3 Liver studies Total bilirubin 3 mg/dL Direct bilirubin 0.3 mg/dL Alkaline phosphatase 95 U/L Aspartate aminotransferase (AST) 18 U/L Alanine aminotransferase (ALT) 15 U/L The patient recovers spontaneously after a few weeks.  Peripheral smear of the boy's blood after recovery is shown in the exhibit.  Which of the following is the most likely cause of this patient's condition? Explanation Hereditary spherocytosis Genetics Autosomal dominant inheritance (most cases) Pathogenesis RBC membrane defect (eg, spectrin, ankyrin) Spherocytes with ↓ deformability sequestered in spleen Extravascular hemolysis Clinical presentation Hemolytic anemia Jaundice Splenomegaly Laboratory findings ↑ MCHC Spherocytes on peripheral blood smear Negative Coombs test ↑ Osmotic fragility Treatment Splenectomy Complications Pigmented gallstones Aplastic crisis (with parvovirus B19 infection) RBC = red blood cell; MCHC = mean corpuscular hemoglobin concentration. This patient's peripheral smear shows spherocytes (small, round, hyperchromic red cells that lack central pallor), a finding consistent with hereditary spherocytosis (HS), an autosomal dominant hemolytic anemia caused by a red cell membrane cytoskeletal defect.  The mutation in HS most often affects the plasma-membrane scaffolding proteins spectrin and ankyrin.  Without this scaffolding, spherocytes are less deformable than normal RBCs and are prone to sequestration and subsequent accelerated destruction in the spleen. Clinical manifestations include hemolytic anemia, jaundice (increased RBC destruction results in greater bilirubin production), and splenomegaly (spherocytes have difficulty passing through the cords of Billroth and accumulate in the spleen).  Concurrent infections (often routine febrile viral illnesses) can increase splenic sequestration and RBC destruction, causing a hemolytic crisis with worsening anemia and jaundice and an elevated reticulocyte count. This is distinct from parvovirus B19–induced aplastic crisis, which causes abrupt anemia due to temporary bone marrow suppression and is associated with a low reticulocyte count. (Choice A)  Glucose-6-phosphate dehydrogenase (G6PD) enzyme deficiency anemia usually follows oxidative stress.  Common triggers include drugs (sulfonamide or antimalarial agents), fava beans, and infections (viral hepatitis, pneumonia, or typhoid).  Unlike this case, peripheral smears of G6PD deficiency anemia show bite cells and Heinz bodies. (Choice B)  An imbalance between alpha globin and beta globin chain production results in thalassemia.  In this patient, the peripheral smear has no morphologic variants associated with thalassemia, such as target cells or hypochromic microcytes. (Choice C)  A nuclear maturation defect due to defective DNA synthesis is the pathophysiologic mechanism of megaloblastic anemia, which is most commonly caused by vitamin B12 and folic acid deficiencies.  Enlarged oval cells and hypersegmented neutrophils would be expected on peripheral smear. (Choice D)  Polymerization of hemoglobin occurs in sickle cell anemia.  A missense mutation in the beta globin chain leads to the production of hemoglobin S, which has the capacity to polymerize in deoxygenated states.  This polymerization leads to red blood cell membrane injury and deformation to a "sickle" shape seen on peripheral smear. Educational objective: Hereditary spherocytosis results from red cell cytoskeleton abnormalities, most commonly spectrin and ankyrin.  Hemolytic anemia, jaundice, and splenomegaly are classic manifestations.  Spherocytes are seen on peripheral blood smear.

A 59-year-old woman comes to the office due to progressive fatigue and occasional heart palpitations over the last 6 months.  The patient has been under a lot of stress recently due to problems at work.  She has no dietary restrictions, eats out at restaurants frequently, and drinks 2 or 3 cans of beer on the weekends.  The patient is postmenopausal and has not noticed any uterine bleeding, dark stools, or bleeding with bowel movements.  Her BMI is 25 kg/m2.  Hemoglobin is 8.5 g/dL.  Peripheral blood smear reveals pale, microcytic erythrocytes.  Which of the following is the most likely underlying cause of this patient's abnormal laboratory findings? Fatigue and heart palpitations are common manifestations of all forms of anemia.  This patient's peripheral smear findings indicate hypochromic, microcytic anemia, which most often arises in the setting of iron deficiency.  The primary, and most dangerous if overlooked, mechanism of iron deficiency is blood loss, and it should be excluded first.  Women of childbearing age are commonly iron deficient due to menstruation.  Men (especially over the age of 60) or postmenopausal women have no physiologic reason to be iron deficient and therefore should be evaluated for blood loss in the gastrointestinal (GI) tract (eg, due to malignancy).  GI blood loss is often occult, so the lack of dark or bright red stools in this patient should not rule out GI hemorrhage.  Iron studies (including ferritin) should be obtained, and the patient will likely require endoscopic evaluation. (Choice A)  Ingestion of the more commonly abused drugs is not associated with microcytic anemia. (Choice B)  Hematologic malignancies (eg, leukemia, lymphoma, multiple myeloma) tend to be associated with normochromic, normocytic anemia.  The decrease in erythropoiesis seen in these patients results from hypersplenism or tumor replacement of bone marrow mass. (Choice C)  Hemolysis often presents with a normochromic, normocytic anemia.  Spherocytes or schistocytes are often seen on peripheral blood smear. (Choice D)  The anemia of chronic liver disease is usually normocytic or slightly macrocytic with target cells on the peripheral blood smear.  Microcytic anemia occurs in <25% of cases, and most patients have only mild anemia with a hemoglobin level of 10-11 g/dL. (Choice F)  This patient has a normal BMI and no factors predisposing her to malnutrition (eg, dietary restrictions, chronic alcohol use).  A normal Western diet provides 6 mg of iron for every 1,000 calories, and the recommended intake for individuals age >50 is 8 mg per day.  As a result, men and postmenopausal women (ie, not menstruating, pregnant, or lactating) usually have no dietary iron shortage. Educational objective: Hypochromic, microcytic anemia is most commonly due to iron deficiency.  Blood loss, especially occult loss from the gastrointestinal tract, must be ruled out in a patient with iron deficiency anemia.

A 3-year-old boy diagnosed with thalassemia major receives multiple transfusions to maintain his blood hemoglobin level.  On physical examination, his liver and spleen are mildly enlarged.  He also has glucose intolerance as demonstrated by an oral glucose tolerance test.  Which of the following therapies would prevent congestive cardiac failure in this patient? Many hemolytic diseases (eg, thalassemia major) require frequent, regular treatment with red blood cell transfusions for the maintenance of an adequate hemoglobin level.  Over time, these chronic red blood cell transfusions cause iron to accumulate within the reticuloendothelial system and organs such as the liver and heart.  Because iron cardiotoxicity may result in arrhythmias and congestive heart failure, it is important to implement chelation therapy within one to two years of beginning red blood cell transfusions. Chelation therapy allows for the removal of excessive iron from the body, and can delay or prevent the development of cardiac disease.  Deferoxamine is one of the more effective and safe iron chelators, as it complexes with ferric ions to form ferrioxamine, which is removed by the kidneys. (Choices A, B, D, and E)  Erythropoietin induces erythropoiesis and reticulocyte release from the bone marrow.  It is commonly used to treat the anemia of chronic kidney disease.  Cobalamin (vitamin B12) is necessary in the treatment of pernicious anemia.  Ascorbic acid (vitamin C) is used in the treatment of scurvy.  Digoxin causes increased cardiac contractility, enhanced vagal tone, and decreased ventricular rate.  As such, it is used in the treatment of congestive heart failure and supraventricular arrhythmias. None of these therapies are capable of preventing congestive heart failure secondary to iron cardiotoxicity, however. Educational objective: Chelation therapy with deferoxamine should be implemented in patients receiving chronic red blood cell transfusions.  Deferoxamine prevents iron-induced cardiotoxicity and congestive heart failure from developing in this patient population.

A 2-week-old girl is brought to her primary care provider for a routine visit.  The patient was born by normal spontaneous vaginal delivery at 39 weeks gestation.  The mother is breastfeeding exclusively, and the infant has regained her birth weight.  Newborn screening results from hemoglobin electrophoresis are as follows: Hemoglobin F 70% Hemoglobin A 20% Hemoglobin S 10% The patient's mother has sickle cell trait, and a maternal cousin has sickle cell anemia.  Examination shows a well-appearing infant with no pallor or splenomegaly.  Which of the following is most likely true about this patient? Explanation Sickle cell trait Clinical features Usually no symptoms of sickle cell anemia More prevalent in African, Middle Eastern & Mediterranean countries; African American & Hispanic individuals No change in overall life expectancy Diagnosis Normal hemoglobin, reticulocyte count, RBC indices & morphology Hemoglobin electrophoresis shows both Hb A & Hb S, with the amount of Hb A greater than Hb S Hb A = hemoglobin A; Hb S = hemoglobin S; RBC = red blood cells. This patient's hemoglobin electrophoresis from her newborn screen is most consistent with sickle cell trait.  At birth, infants who are heterozygous for sickle cell trait typically have the greatest amount of fetal hemoglobin (Hb F), followed by hemoglobin A (Hb A), and the smallest amount of hemoglobin S (Hb S).  Hb A continues to be higher than Hb S throughout the lifetime of these patients as Hb F naturally declines, offering protection from sickle cell anemia, aplastic crises, and splenic sequestration.  Patients with sickle cell trait are usually asymptomatic with normal hemoglobin level, reticulocyte count, and red blood cell (RBC) indices.  However, they may develop hematuria, priapism, and increased incidence of urinary tract infections.  Splenic infarction at high altitudes has also been reported. Patients with sickle cell trait have relative protection from Plasmodium falciparum (malaria), resulting in lower rates of severe malaria and hospitalization than seen in the general population.  Possible mechanisms include increased sickling of parasitized sickle cell trait RBCs and accelerated removal of these cells by the splenic monocyte-macrophage system.  These patients are not immune to malaria, however, and those visiting malaria-endemic areas should still receive prophylaxis. (Choice A)  Life expectancy of patients with sickle cell trait is no different than that of the general population.  Patients who are homozygous for the sickle cell mutation have a decreased life expectancy due to significant complications of disease (eg, acute chest syndrome, infection from encapsulated organisms). (Choices B and C)  Patients with sickle cell trait typically have normal RBC indices and reticulocyte counts.  Individuals with sickle cell anemia (eg, no normal Hb A) will have an elevated reticulocyte count but will maintain a normal mean corpuscular volume. (Choice E)  It is unlikely that this patient will develop painful crises as she is protected by the predominance of Hb A (normal hemoglobin) over Hb S.  Vaso-occlusive pain crises that develop in patients with sickle cell anemia are thought to occur when Hb S polymerizes and causes the RBCs to assume a sickle shape, typically in response to a trigger (eg, cold weather, dehydration). Educational objective: Patients with sickle cell trait are typically asymptomatic and have relative protection from malaria caused by Plasmodium falciparum.  These patients usually have normal hemoglobin, reticulocyte, and red blood cell index values.  Life expectancy is the same as that of the general population.

A 53-year-old man comes to the clinic due to frequent headaches and dizziness.  The patient has a history of hypertension and peptic ulcer disease.  His medications include daily chlorthalidone and antacids as needed.  Temperature is 37 C (98.6 F), blood pressure is 146/92 mm Hg, pulse is 89/min, and respirations are 16/min.  BMI is 26 kg/m2.  Physical examination shows facial plethora and moderate splenomegaly.  Laboratory results are as follows: Complete blood count Hemoglobin 21.5 g/dL Hematocrit 64% Erythrocytes 7.6 million/mm3 Mean corpuscular volume 90 μm3 Mean corpuscular hemoglobin 31 pg/cell Mean corpuscular hemoglobin concentration 33% Hb/cell Red blood cell distribution width 14.0% (n = 10.3%-14.1%) Platelets 545,000/mm3 Leukocytes 15,500/mm3 This patient most likely has a mutation affecting which of the following types of protein? this patient's striking elevation in hemoglobin concentration (> 18.5 g/dL) is most likely due to polycythemia vera, a myeloproliferative disorder characterized by uncontrolled erythrocyte production.  Patients frequently experience nonspecific symptoms (eg, headache, dizziness); more specific symptoms include aquagenic pruritus and facial plethora/splenomegaly (vascular congestion).  Complications include peptic ulcer disease (altered mucosal blood flow due to increased viscosity) and gouty arthritis (higher erythrocyte turnover).  Laboratory studies show increased erythrocyte mass and low erythropoietin levels; thrombocytosis and leukocytosis are also characteristic of polycythemia vera.  Erythrocyte indices are usually normal. Polycythemia vera is caused by abnormal transduction of erythropoietin growth signals.  The erythropoietin receptor has no intrinsic kinase activity and must interact with Janus kinase 2 (JAK2), a non-receptor tyrosine kinase found in the cytoplasm, to initiate downstream signaling.  Almost all patients with polycythemia vera have a mutation in JAK2 that causes constitutive activation of the protein's kinase domain, resulting in clonal proliferation of myeloid cells.  JAK2 mutations have also been implicated in essential thrombocythemia, primary myelofibrosis, and other myeloproliferative disorders. (Choice A)  Burkitt lymphoma is characterized by translocation of the Myc oncogene on chromosome 8 to the Ig heavy chain region on chromosome 14.  This translocation results in constitutive expression of Myc, a growth-stimulating transcription factor. (Choice C)  Receptor tyrosine kinases are transmembrane receptors with intrinsic kinase activity that autophosphorylate and induce a downstream signaling cascade upon ligand binding.  Examples include the receptors for insulin, insulin-like growth factor, and epidermal growth factor.  Mutations causing excessive epidermal growth factor receptor activity occur in many solid tumors. (Choice D)  Mutations in the p53 tumor suppressor are associated with Li-Fraumeni syndrome, an autosomal dominant disorder that predisposes to various cancers, particularly sarcomas and tumors of the breast, brain, and adrenal cortex. (Choice E)  Expression of vascular endothelial growth factor (VEGF) is required for tumor angiogenesis, a critical step during tumor growth and metastasis.  VEGF upregulation occurs in most cancers. Educational objective: Polycythemia vera is a myeloproliferative disorder characterized by uncontrolled erythrocyte production.  Almost all patients with polycythemia vera have a mutation in the JAK2 gene, which encodes a non-receptor (cytoplasmic) tyrosine kinase associated with the erythropoietin receptor.

A 28-year-old man starts taking a prophylactic medication before leaving on a business trip to Costa Rica.  Five days later, he comes to the emergency department due to jaundice and dark urine.  Laboratory results are as follows: Hemoglobin 8.2 g/dL Reticulocytes 8% Total bilirubin 3.5 mg/dL Direct bilirubin 0.5 mg/dL Lactate dehydrogenase 342 U/L Haptoglobin 42 mg/dL (normal: 50-150) A peripheral smear shows red blood cells with dark inclusions when stained with crystal violet, a supravital stain.  This patient's condition most likely demonstrates which of the following inheritance patterns? Glucose-6-phosphate dehydrogenase deficiency Epidemiology Hemolytic anemia due to oxidative stress (infection, sulfa drugs, fava beans) X-linked: Asian, African, or Middle Eastern descent Manifestations Pallor & fatigue Dark urine, jaundice & icterus Abdominal/back pain Laboratory findings Hemolysis: ↓ hemoglobin, ↓ haptoglobin, ↑ bilirubin & LDH, ↑ reticulocytes Peripheral smear: bite cells & Heinz bodies Negative Coombs test ↓ G6PD activity level (may be normal during attack) Management Remove or treat responsible agent/condition Provide supportive care G6PD = glucose-6-phosphate dehydrogenase; LDH = lactate dehydrogenase. This patient developed acute hemolytic anemia (eg, jaundice, dark urine, low haptoglobin) after taking a new medication, suggesting glucose-6-phosphate dehydrogenase (G6PD) deficiency.  G6PD catalyzes production of NADPH in erythrocytes; loss of G6PD function limits regeneration of reduced glutathione, impairing the ability of erythrocytes to handle increased oxidative stress (eg, foods, medications).  The trigger in this case was likely primaquine prescribed for malaria prophylaxis. Manifestations of G6PD deficiency typically begin within 2-5 days and often include pallor, dark urine, and jaundice.  Laboratory evaluation reveals signs of erythrocyte lysis such as elevated bilirubin, elevated lactate dehydrogenase, and low haptoglobin (protein that binds free heme).  The bone marrow responds by releasing young erythrocytes, leading to reticulocytosis.  Peripheral smear will demonstrate signs of denatured hemoglobin precipitation such as intraerythrocytic dark inclusions (Heinz bodies). G6PD deficiency is an X-linked recessive disorder; males (46,XY) who carry the mutation are affected because all erythrocytes have the defective G6PD gene.  Females (46,XX) who carry a copy of the defective gene (heterozygous) are usually unaffected because random inactivation of the X chromosome (lyonization) results in ~50% of erythrocytes with the normal gene.  However, heterozygous females can develop acute hemolysis when lyonization is skewed toward expression of the mutated gene. (Choice A)  Most structural erythrocyte abnormalities (eg, hereditary spherocytosis) are inherited in an autosomal dominant manner.  Although jaundice from hemolysis can be seen, peripheral smear would not show Heinz bodies. (Choice B)  In contrast to G6PD deficiency, most other erythrocyte enzyme deficiencies (eg, pyruvate kinase [PK] deficiency) are inherited in an autosomal recessive pattern.  PK catalyzes the last step in glycolysis; because erythrocytes rely solely on glycolysis for ATP production (due to a lack of mitochondria), patients develop chronic (not episodic) hemolysis. (Choice C)  Mitochondrial DNA is of maternal origin.  Mitochondrial diseases generally limit cellular ATP generation due to impaired oxidative phosphorylation and often present with neuromuscular dysfunction.  Heinz bodies would not be seen; in addition, hemolysis following medication exposure indicates likely G6PD deficiency. (Choice D)  X-linked dominant disorders affect males and females equally.  Nearly all cases of symptomatic G6PD deficiency occur in males, indicating an X-linked recessive inheritance pattern. Educational objective: Glucose-6-phosphate dehydrogenase deficiency is an X-linked recessive disorder that causes acute hemolysis after exposure to oxidizing medications, foods, or acute infection.  Nearly all affected persons are male, but heterozygous females can become symptomatic due to skewed lyonization.

G6PD Deficiency — Ultra High-Yield USMLE Notes 1. Diagnosis: Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency — X-linked recessive; triggered by primaquine (malaria prophylaxis) 2. Key clue (1 line): 28M + travel to Costa Rica + new medication (primaquine) + jaundice + dark urine + ↓Hgb + ↑retics + ↑LDH + ↑indirect bili + ↓haptoglobin + Heinz bodies (dark inclusions on crystal violet stain) 3. Why correct (≤2 lines): G6PD deficiency → ↓NADPH → ↓reduced glutathione → RBCs cannot neutralize oxidative stress → hemoglobin denatures → Heinz bodies → splenic macrophages bite them out → bite cells → intravascular + extravascular hemolysis within 2–5 days of trigger. X-linked recessive → nearly all symptomatic patients are male; heterozygous females protected by lyonization (~50% normal RBCs). 4. Why others wrong (1 line each): Autosomal dominant (HS): Hereditary spherocytosis → spherocytes, not Heinz bodies; chronic not episodic hemolysis Autosomal recessive (PK deficiency): Pyruvate kinase deficiency → chronic hemolysis (not episodic/drug-triggered); no Heinz bodies Mitochondrial inheritance: Maternal transmission; causes neuromuscular/ATP disorders; no Heinz bodies or drug-triggered hemolysis X-linked dominant: Would affect males AND females equally; G6PD overwhelmingly affects males → X-linked recessive pattern 5. Buzzword triggers: Travel to malaria region + primaquine/dapsone/sulfonamides → G6PD deficiency Fava beans + hemolysis → G6PD deficiency Heinz bodies (crystal violet/supravital stain) → denatured Hgb precipitates → G6PD Bite cells (regular stain) → splenic removal of Heinz bodies → G6PD Episodic hemolysis (not chronic) + oxidative trigger → G6PD (vs PK deficiency = chronic) G6PD activity level: may be falsely normal during acute attack (old deficient RBCs already lysed; young retics have higher G6PD) Negative Coombs → not immune-mediated hemolysis 6. Trap / trick tested: G6PD level may be normal during acute attack — test after recovery when retic count normalizes; young RBCs have higher G6PD masking true deficiency Heinz bodies ≠ bite cells — Heinz bodies seen on supravital stain (crystal violet); bite cells seen on regular peripheral smear; both indicate G6PD Heterozygous females CAN be symptomatic if lyonization skewed toward mutant X — not always protected PK deficiency vs G6PD: PK = chronic hemolysis + autosomal recessive; G6PD = episodic + X-linked recessive 7. One-liner memory hook: "Primaquine/Sulfa/Fava → oxidative stress → G6PD gone → no NADPH → no glutathione → Hgb denatures → Heinz bodies → bite cells → episodic hemolysis in males." All of the choices represent mechanisms for anemia.  The key to answering this question is this patient's history and peripheral smear.  Red blood cell (RBC)fragments and helmet cells (a type of schisctocyte with crescent shapes) are consistent with traumatic hemolysis, which can result from either microangiopathic hemolytic anemia or mechanical damage (eg, prosthetic valve). Prosthetic valves produce excessive shear and turbulence in the cardiac circulation, causing mechanical trauma to the RBCs and schistocytes. (Choice A)  Microvascular thrombi are the pathophysiologic mechanism for microangiopathic hemolytic anemia, which causes thrombocytopenia.  In this patient, platelet count is normal. (Choice B)  Cytoskeleton abnormalities describe an intracorpuscular defect characteristic of a group of anemias that includes hereditary spherocytosis, hereditary elliptocytosis, and hereditary stomatocytosis.  Respectively, spherocytes, elliptocytes, or stomatocytes are characteristically seen in the peripheral blood smear. (Choice C)  Impaired DNA synthesis is the pathophysiologic mechanism for megaloblastic anemia.  Ovalo-macrocytes are the associated morphologic RBC variant seen in this group of anemia.  In addition, hypersegmented neutrophils are also characteristic. (Choice D)  Gastrointestinal blood loss results in hypochromic, microcytic anemia due to iron deficiency. (Choice E)  Mutation of the beta globin chain results in beta thalassemia; target cells are the RBC morphologic variant commonly seen. (Choice F)  Paroxysmal nocturnal hemoglobinuria is an episodic hemolysis caused by a complement-mediated mechanism.  Leukopenia and thrombocytopenia (pancytopenia) are commonly associated. Educational objective: Red blood cell fragments and helmet cells are associated with either microangiopathic hemolytic anemia or mechanical red cell destruction. In patients with prosthetic valves, red blood cells are exposed to excessive shear and turbulence in the circulation, causing damage from mechanical trauma.

A 23-year-old African American man comes to the emergency department due to back and lower extremity pain for 2 days.  He has had several similar episodes over the last 15 years that have required hospitalization.  His pain is not responsive to over-the-counter analgesics, and review of his prior records shows that he has needed treatment with opioids for adequate pain relief.  The patient does not use tobacco, alcohol, or illicit drugs.  On physical examination, he has scleral icterus and tenderness over his lower back and long bones of his thighs.  Laboratory evaluation shows a hemoglobin level of 6.7 g/dL. Item 1 of 2 Histopathologic evaluation of this patient's spleen is most likely to reveal which of the following? patient with frequent episodes of bony pain likely has sickle cell disease (SCD), an autosomal recessive condition characterized by hemolytic anemia and vaso-occlusion.  The hemolytic anemia causes jaundice (due to unconjugated hyperbilirubinemia) and promotes formation of pigmented gallstones.  Vaso-occlusion by sickled red blood cells occurs in various tissues, causing hypoxia and acidosis (vaso-occlusive pain episodes).  Microvascular occlusion nearly always affects the spleen due to the trapping of sickle cells by the rigid splenic cords; autoinfarction begins in early childhood and can precipitate splenic sequestration crisis in infants.  However, repeated infarction eventually leads to significant scarring, fibrosis, and atrophy of the spleen, which would likely be present in this adult patient. Asplenic patients are more susceptible to infections with encapsulated bacteria (eg, group B Streptococcus, Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis, Salmonella typhi). (Choice A)  Splenic congestion occurs during a splenic sequestration crisis (marked hemoglobin decrease, rapidly enlarging spleen), which develops due to vaso-occlusion within the cords of Billroth and splenic pooling of erythrocytes.  However, repeated infarction leads to functional asplenia and autosplenectomy (splenic atrophy) by late childhood/adolescence. (Choices B and D)  Splenic cyst formation typically occurs due to infection.  Splenic infiltration can be seen with metastatic neoplasms but is not a feature of SCD. (Choice E)  The white pulp of the spleen is composed of lymphoid tissue.  Lymphoid hyperplasia may represent infection or malignancy. Educational objective: Sickle cell disease is characterized by repeated splenic infarctions that ultimately result in splenic atrophy and fibrosis, a process that is typically complete by late childhood/adolescence.  After autosplenectomy, patients are predisposed to infections with encapsulated bacterial organisms.

The patient is admitted to the hospital and receives opioid analgesics and intravenous fluids.  He has no evidence of active infection.  His hemoglobin electrophoresis results are consistent with sickle cell disease (hemoglobin SS).  Further laboratory evaluation shows a mean corpuscular volume of 113 µm3 and a reticulocyte index of 1.5, which is low given the patient's severe anemia.  Which of the following is the most likely cause of this patient's macrocytosis? patient has macrocytic anemia (mean corpuscular volume [MCV] >100 µm3).  Severe macrocytosis (MCV >110 µm3) is usually due to megaloblastic anemia, a subtype of macrocytic anemia caused by impaired DNA synthesis.  Cytoplasmic components then accumulate within the slowly dividing erythrocytes, producing cells that are larger than normal (macrocytes). Patients with sickle cell disease (SCD) or other hemolytic anemias have increased folic acid requirements due to increased erythrocyte turnover.  As such, they are prone to developing relative folic acid deficiency and megaloblastic anemia. (Choice A)  Extramedullary erythropoiesis can occur in SCD and lead to an elevated reticulocyte count and MCV, as the reticulocytes produced are larger than those released by the bone marrow.  However, this patient's low reticulocyte index (representing the reticulocyte percentage corrected for the degree of anemia) suggests an inadequate response to anemia and a lack of erythropoiesis. (Choice C)  Patients with SCD may receive multiple transfusions for treatment of severe or symptomatic anemia.  Transfusion related iron overload can cause severe liver disease, but would be unlikely to produce an MCV >110 µm3. (Choice D)  Macrocytosis can occur in liver failure due to an increase in circulating phospholipids and cholesterol that adsorb onto erythrocytes, resulting in membrane expansion.  However, liver-associated macrocytosis is generally mild (<110 µm3) and this patient does not have any findings to suggest advanced liver disease (eg, ascities/edema, bleeding). (Choice E)  A disease of the elderly, myelodysplastic syndrome can cause macrocytic anemia.  In the setting of a young patient with SCD and hemolytic anemia, however, folic acid deficiency is much more likely. Educational objective: An MCV >110 µm3 is highly suggestive of megaloblastic anemia, such as that caused by folic acid or vitamin B12 deficiency.  Patients with chronic hemolytic anemia have increased folic acid requirements due to increased erythrocyte turnover and are predisposed to developing macrocytosis.

A 35-year-old woman comes to the office due to reduced energy and fatigue.  She reports heavy menstrual bleeding over the past 6 months.  The patient is found to have hypochromic microcytic anemia.  Iron supplementation is prescribed.  A week later, a peripheral blood smear shows numerous enlarged red blood cells that have a bluish hue on Wright-Giemsa staining.  The bluish color of these red blood cells is best explained by the presence of which of the following? this patient has iron deficiency anemia (most likely due to menstrual blood loss), characterized by the presence of microcytic (ie, small), hypochromic (ie, pale) red blood cells (RBCs).  Patients with iron deficiency anemia who receive iron replacement therapy experience enhanced erythropoiesis and accelerated release of reticulocytes into the bloodstream as the bone marrow attempts to correct the anemia. Reticulocytes (immature RBCs) are anucleate (like mature RBCs) but are enlarged and have a blue-gray hue on Wright-Giemsa staining.  This bluish color (ie, polychromatophilia) is due to the presence of large amounts of ribosomal RNA necessary for adequate hemoglobin synthesis.  The ribosomal RNA can be distinguished using a supravital stain that binds RNA (eg, new methylene blue) and appears as a blue, reticular (ie, net-like) substance. Ribosomal RNA is gradually degraded as the reticulocyte matures.  After spending a day or more in the bloodstream, the maturation process is complete, and the reticulocyte transforms into a mature RBC, which has a lifespan of approximately 120 days. (Choices A and D)  Young reticulocytes contain organelles necessary for cell development, including mitochondria and remnants of Golgi apparatus, which are also removed as the reticulocyte matures.  However, it is the ribosomal RNA that imparts the bluish color on Wright-Giemsa staining. (Choice B)  Heinz bodies consist of denatured hemoglobin precipitate and are associated with glucose-6-phosphate dehydrogenase deficiency.  They cannot be seen on Wright-Giemsa staining but appear as round, peripheral RBC inclusions using a supravital stain. (Choice C)  Histone proteins are found in the nucleus.  During erythropoiesis, the erythroblast ejects its nucleus, forming a reticulocyte; because the reticulocyte does not have a nucleus, it does not contain histones. (Choice E)  Howell-Jolly bodies are nuclear remnants visible on Wright-Giemsa staining as purple, round, peripheral RBC inclusions.  They are associated with asplenia or hyposplenia because the spleen typically removes these nuclear remnants. Educational objective: Reticulocytes (immature red blood cells) appear as blue-gray (ie, polychromatophilic) red blood cells on Wright-Giemsa staining due to the presence of ribosomal RNA.  In patients with iron deficiency anemia, iron supplementation results in increased bone marrow erythropoiesis and accelerated release of reticulocytes into the bloodstream.

A 22-year-old woman comes to the office due to worsening dyspnea and heart pounding with exercise for the last week.  She has no chronic medical conditions but reports aches and pains over the past several weeks.  The patient takes ibuprofen as needed but no other medications.  Temperature is 37.2 C (99 F), blood pressure is 138/86 mm Hg, and pulse is 90/min.  BMI is 18 kg/m2.  Physical examination shows an erythematous rash in sun-exposed regions.  The lungs are clear to auscultation.  A midsystolic click and systolic murmur are heard best at the apex without radiation.  There is mild tenderness of joints.  Laboratory results are as follows: Hemoglobin 7.8 g/dL Reticulocytes 6% Platelets 205,000/mm3 Leukocytes 11,200/mm3 Creatinine 1.4 mg/dL Which of the following is the most likely cause of this patient's hematologic findings? his patient with dyspnea and heart pounding with exercise has symptomatic anemia.  Her other findings, including the presence of joint pain, a photosensitive rash, and mild renal insufficiency, raise suspicion for systemic lupus erythematosus (SLE), an autoimmune disease primarily seen in young women.  SLE frequently causes anemia due to a combination of factors, including chronic inflammation (anemia of chronic disease), gastrointestinal serositis (iron deficiency from bleeding), and/or autoimmune hemolytic anemia (AIHA). Approximately 10% of patients with SLE develop AIHA due to immune dysregulation, which results in the formation of IgG autoantibodies against the erythrocyte membrane.  Erythrocytes coated with IgG are subsequently identified by the Fc-receptor on splenic macrophages and partially or wholly phagocytized, leading to extravascular hemolysis.  Laboratory assessment typically reveals elevated reticulocyte count (ie, reticulocytosis) because interstitial fibroblasts in the kidney sense tissue hypoxia and increase the release of erythropoietin; this drives the bone marrow to increase erythrocytosis, leading to the presence of immature red cells in the peripheral blood (normoblasts, reticulocytes). (Choices A and C)  The presence of significant reticulocytosis (eg, >4-5%) rules out causes of anemia associated with an impaired bone marrow response, including bone marrow suppression from cancer or infection (eg, parvovirus), anemia of chronic disease (cytokine-mediated retention of iron), and vitamin deficiency (eg, vitamin B12 deficiency from intrinsic factor antibodies, iron deficiency). (Choice D)  A normal platelet count effectively rules out anemia due to a microangiopathic process associated with intravascular platelet consumption (eg, thrombotic microangiopathy). (Choice E)  Although traumatic intravascular hemolysis can occur with a mechanical heart valve or severe aortic stenosis, it is uncommon in otherwise healthy young individuals.  Furthermore, this patient's heart murmur is most consistent with mitral valve prolapse, which is common in patients with SLE but rarely causes traumatic hemolysis. Educational objective: Anemia with an elevated reticulocyte count (ie, reticulocytosis) indicates that the bone marrow is responding appropriately to the anemia by generating new erythrocytes.  Reticulocytosis is commonly seen in patients with hemolysis or acute bleeding.  Many other causes of anemia are associated with low reticulocyte count, including bone marrow suppression (eg, parvovirus), iron deficiency anemia, vitamin B12/folate deficiency, and anemia of chronic disease.

A 16-year-old girl comes to the office due to fatigue for the past few months.  She attends high school and plays on the school soccer team but says that her endurance has decreased.  The patient sleeps 9 hours a night and has been a vegetarian for the past 6 months.  She reached menarche at age 13 and has had regular menses for the past 6 months.  Blood pressure is 110/60 mm Hg, pulse is 70/min, and BMI is 21 kg/m2.  Physical examination shows a well-nourished teenage girl with pale conjunctivae.  Hemoglobin is 9.2 g/dL.  Which of the following sets of additional laboratory findings are most likely to be seen in this patient? Serum ferritin Circulating transferrin Mean corpuscular volume Hypersegmented neutrophils Serum folate  A. Normal Normal 74 None Normal  (1%)  B. Low High 76 None Normal  (55%)  C. Low Low 84 None Normal  (7%)  D. High Low 95 None Normal  (1%)  E. Normal Normal 108 Present Normal  (15%)  F. Normal Normal 115 Present Low  (18%) his girl with fatigue, conjunctival pallor, and a low hemoglobin level has anemia.  Women of childbearing age are at risk for iron-deficiency anemia due to menstrual cycle blood loss, especially teenage girls who have higher iron requirements due to growth.  In this patient, decreased consumption of dietary iron (eg, vegetarianism) is an additional risk factor.  As iron deficiency develops, the following sequence can be seen: Decreased bone marrow iron stores (ferritin and hemosiderin) Decreased serum ferritin Increased serum total iron-binding capacity, reflecting increased transferrin (Choice C) Decreased serum iron concentration Decreased hemoglobin Appearance of microcytic, hypochromic red blood cells (low mean corpuscular volume [MCV]) Ferritin is an intracellular iron-storage protein that is used as a serum marker of total body iron stores.  It is decreased in iron deficiency and elevated in iron overload or during infection/inflammation (acute phase reaction).  Transferrin transports iron through the plasma.  When iron levels are normal, approximately one third of circulating transferrin is bound to iron.  In iron deficiency, hepatic synthesis of transferrin increases but transferrin saturation drops due to decreased release of iron into the plasma from intracellular stores. (Choice A)  The earliest signs of iron deficiency are low serum ferritin and high serum transferrin, which manifest before overt anemia develops.  This pattern of findings is more consistent with α- or β-thalassemia, which usually cause microcytic anemia with normal ferritin and transferrin levels. (Choice D)  Low hemoglobin in the setting of a normal MCV, low circulating transferrin, and high serum ferritin is suggestive of anemia of chronic disease, which is often associated with infections and inflammatory conditions.  Other acute phase reactants (eg, C-reactive protein, sedimentation rate) are usually elevated in these patients. (Choices E and F)  Hypersegmented neutrophils are characteristic of megaloblastic anemias, which can be caused by folate and vitamin B12 deficiency.  Folate deficiency is unlikely in this patient, as folate is found in many vegetable products.  Although vegetarians are at risk for vitamin B12 deficiency, depletion of hepatic B12 stores takes several years, and this patient has been a vegetarian only for the past 6 months. Educational objective: Anemia in women of childbearing age is typically caused by iron deficiency secondary to menstrual blood loss.  Iron deficiency is associated with decreased serum ferritin, increased total iron-binding capacity (transferrin), and microcytic, hypochromic red blood cells.

A 20-year-old woman comes to the emergency department due to bloody stools.  Approximately an hour ago, the patient had a bowel movement that appeared grossly bloody.  For the past month, she has also had decreased energy.  Temperature is 37 C (98.6 F), blood pressure is 110/60 mm Hg, pulse is 110/min, and respirations are 20/min.  The patient appears tired.  Cardiopulmonary examination reveals mild tachycardia.  The abdomen is soft without organomegaly.  Skin examination shows pallor and scattered bruises in various stages of healing throughout the trunk.  Complete blood count results are as follows: Hemoglobin 7.2 g/dL Mean corpuscular volume 90 µm3 Platelets 10,000/mm3 Leukocytes 1,050/mm3 Neutrophils 5% Lymphocytes 95% Which of the following is the most likely cause of this patient's condition? Explanation Causes of pancytopenia Bone marrow aplasia Aplastic anemia Infection (eg, parvovirus, HIV, viral hepatitis) Nutritional deficiency (eg, vitamin B12/folate) Medications (eg, hydroxyurea) Bone marrow infiltration Cancer (eg, hematologic, metastatic) Myelofibrosis Infection (eg, tuberculosis, fungal infection) Mature blood cell destruction Intravascular (eg, DIC, TTP) Extravascular (eg, hypersplenism) DIC = disseminated intravascular coagulation; TTP = thrombotic thrombocytopenic purpura. This patient has gastrointestinal bleeding and ecchymosis secondary to thrombocytopenia; although anemia (eg, pallor) would be expected with significant bleeding, her low leukocyte count indicates pancytopenia, which is generally caused by one of the following: Bone marrow aplasia: Hematopoietic stem cells in the bone marrow are unable to proliferate and differentiate into mature blood cells due to aplastic anemia, nutritional impairment, infection (eg, parvovirus, HIV), or cytotoxic medications. Bone marrow infiltration: Cancer, fibrosis, or infection (eg, tuberculosis) fills the bone marrow and crowds out hematologic cells, thereby preventing blood cell replication and maturation. Mature blood cell destruction: Circulating mature blood cells may be destroyed due to disseminated intravascular coagulation or thrombotic thrombocytopenic purpura; extravascular mature blood cells may be destroyed or sequestered in the spleen due to hypersplenism. Based on this patient's laboratory and physical examination results, several answer choices can be eliminated.  The presence of a normal MCV makes vitamin B12 or folate deficiency unlikely because these are associated with macrocytic (not normocytic) anemia (Choice E).  Hypersplenism is also unlikely because abdominal examination would show significant splenomegaly (Choice C).  Chronic myelogenous leukemia, an infiltrative cancer associated with constitutively active tyrosine kinase, is also unlikely because this condition is usually associated with dramatic leukocytosis (not leukopenia) (Choice B). Therefore, the most likely cause of this patient's pancytopenia is aplastic anemia (AA).  Although AA is linked to certain medications, infections, toxins, or radiation, most cases are idiopathic and thought to be caused by autoimmune-induced loss of multipotent hematologic stem cells.  In idiopathic AA, an underlying insult (eg, mutation, virus) causes alteration of surface antigens on multipotent stem cells, making them appear foreign and triggering a cytotoxic T-cell response.  Cytokines released by T-helper cells (type 1 cytokines) also contribute to the pathogenesis, most notably interferon-gamma, which triggers apoptotic cell death due to the stimulation of a destructive cytokine cascade and the increased expression of the Fas receptor on the hematologic stem cell surface. (Choice D)  Autoantibodies against glycoprotein IIb/IIIa cause immune thrombocytopenia, which is marked by thrombocytopenia and no change in the other cell lines. Educational objective: Aplastic anemia is a form of bone marrow failure in which patients have decreased production of all cell lines (platelets, erythrocytes, and leukocytes).  It is primarily caused by the autoimmune destruction of multipotent hematologic stem cells due to an alteration in their surface antigens, leading to a cytotoxic T-cell response and release of interferon-gamma from T-helper cells (triggers apoptotic cell death).

Aplastic Anemia — Ultra High-Yield USMLE Notes 1. Diagnosis: Aplastic Anemia (AA) — autoimmune destruction of multipotent hematopoietic stem cells → pancytopenia 2. Key clue (1 line): 20F + bloody stools + bruising + fatigue + ↓Hgb + ↓↓platelets (10k) + ↓↓WBC (1050) + normal MCV + lymphocyte predominance → pancytopenia = aplastic anemia 3. Why correct (≤2 lines): Idiopathic AA: altered HSC surface antigens → cytotoxic T-cell attack + IFN-γ release from Th1 cells → Fas receptor upregulation → HSC apoptosis → all 3 cell lines fail (↓RBC + ↓WBC + ↓platelets) with normocytic anemia (no DNA synthesis defect). Bone marrow biopsy confirms: hypocellular marrow replaced by fat cells (hallmark). 4. Why others wrong (1 line each): CML (tyrosine kinase mutation): Causes dramatic leukocytosis (not leukopenia); BCR-ABL constitutive activation; not pancytopenia Hypersplenism: Requires significant splenomegaly on exam; abdomen soft + no organomegaly → rules out ITP (anti-GpIIb/IIIa autoantibodies): Causes isolated thrombocytopenia only; WBC and RBC normal → not pancytopenia B12/folate deficiency: Causes macrocytic anemia (↑MCV) + hypersegmented neutrophils; MCV 90 (normal) here → rules out 5. Buzzword triggers: Pancytopenia + normal MCV + hypocellular marrow → Aplastic anemia AA causes: idiopathic (most common) > drugs (chloramphenicol, sulfonamides, NSAIDs, carbamazepine) > radiation > infections (parvovirus, HIV, hepatitis) > toxins (benzene) Pancytopenia causes: aplasia / infiltration / destruction — determine by marrow biopsy AA pathogenesis: mutated HSC surface antigen → CD8+ T-cell attack + IFN-γ → Fas/apoptosis AA treatment: allogeneic HSCT (young, matched donor) or immunosuppression (ATG + cyclosporine if no donor) AA → ↑risk of PNH and MDS later (clonal evolution) Fanconi anemia: congenital AA + short stature + thumb anomalies + café-au-lait spots 6. Trap / trick tested: Normal MCV in pancytopenia → aplastic anemia (not B12/folate); macrocytosis expected with megaloblastic cause Lymphocyte predominance (95% lymphocytes) in differential is a relative finding — absolute lymphocyte count is actually low; lymphocytes appear dominant only because neutrophils are destroyed preferentially ITP vs AA: both present with bleeding/bruising — key difference = other cell lines: ITP = isolated ↓platelets; AA = ↓ALL three lines Pancytopenia + hypercellular marrow → infiltration (leukemia, myelofibrosis); Pancytopenia + hypocellular marrow → aplastic anemia 7. One-liner memory hook: "Aplastic anemia = T-cells kill the stem cell factory → empty marrow (fat cells) → no RBCs + no WBCs + no platelets; normal MCV + pancytopenia = think aplastic, not B12." Causes of polycythemia Etiology Plasma volume RBC mass SaO2 EPO Relative Dehydration ↓ Normal Normal Normal Absolute Primary Polycythemia vera (ie, JAK2 mutation)* Normal ↑ Normal ↓ Secondary Physiologic response to hypoxemia Normal ↑ ↓ ↑ Inappropriate (eg, EPO-producing tumor, testosterone excess) Normal ↑ Normal ↑ *Polycythemia vera accounts for ~95% of primary polycythemia cases, with rare mutations other than JAK2 accounting for the remainder. EPO = erythropoietin; RBC = red blood cell; SaO2 = oxygen saturation. Polycythemia vera (PV) is a clonal myeloproliferative disease of pluripotent hematopoietic stem cells.  Approximately 95% of patients with PV have a V617F mutation involving the JAK2 gene, a signal transduction molecule that stimulates cell growth.  This mutation replaces a valine with phenylalanine, allowing constitutive proliferation of hematopoietic cells independent of circulating growth factor (eg, erythropoietin, thrombopoietin) levels. PV presents with increased RBC mass and low erythropoietin levels.  Additional manifestations can include an elevated platelet and/or WBC count, thrombotic events (from blood hyperviscosity), peptic ulceration and aquagenic pruritus (due to histamine release from basophils), and gouty arthritis (from increased cell turnover). Physical examination typically shows a plethoric, reddened face and splenomegaly.  Diagnosis is established by confirming low serum erythropoietin levels and cytogenetic studies showing a JAK2 mutation.  Treatment involves serial phlebotomy as necessary to keep the hematocrit < 45%. (Choice A)  Dehydration or excessive diuresis can also cause elevated hematocrit, mild leukocytosis, and thrombocytosis due to low effective circulating volume.  However, splenomegaly and symptoms such as pruritus would not be seen. (Choice B)  Hypoxia is a strong stimulus for erythropoietin production.  SaO2 < 92% (PaO2 < 65 mm Hg) appears to be the threshold for the development of (physiologic) secondary polycythemia.  Conditions such as chronic obstructive pulmonary disease and obstructive sleep apnea can cause secondary polycythemia.  However, these will not cause leukocytosis, thrombocytosis, or splenomegaly. (Choice D)  Increased red cell life span would not be expected to cause leukocytosis and thrombocytosis. (Choice E)  EPO-producing tumors (eg, renal cell carcinoma, hepatocellular carcinoma) can cause secondary polycythemia due to abnormal erythropoietin production.  Workup will show an elevated erythropoietin level.  However, the combination of multiple elevated cell lines and splenomegaly is unlikely to result from a process causing secondary polycythemia. Educational objective: Polycythemia vera (PV) is a clonal myeloproliferative disease characterized by an increased RBC mass and low erythropoietin levels.  PV can be differentiated from secondary polycythemia by the presence of leukocytosis, thrombocytosis, and/or splenomegaly.  The majority of patients with PV have a JAK2 mutation causing hematopoietic stem cells to proliferate uncontrollably.

A 6-year-old boy is brought to the emergency department due to bleeding after a dental extraction earlier this morning.  The patient's past medical history is significant for painful swelling of his knee joints after minor trauma.  Aspiration of the joints during several occasions yielded frank blood, and he was diagnosed with hemarthrosis.  He has no known allergies.  Currently, hemostasis in this patient most likely can be achieved by the administration of which of the following? history of prolonged bleeding following procedures (eg, dental extractions, surgeries) and spontaneous hemorrhages into the joints (hemarthrosis) is typical for hemophilia, an X-linked recessive bleeding disorder due to decreased levels of factor VIII (hemophilia A) or factor IX (hemophilia B). Factors VIII and IX are components of the intrinsic coagulation pathway and activate factor X; activated factor X (Xa) then catalyzes the conversion of prothrombin (factor II) into thrombin as part of the final common pathway.  In the absence of factors VIII or IX, activation of factor X and subsequent conversion of prothrombin into thrombin do not occur.  Administration of thrombin, however, will make up for the deficiency and lead to blood clotting.  In practice, prothrombin complex concentrates (containing factors II, VII, IX, and X, which lead to thrombin formation) were used for management of hemophilia B, although thrombogenic risks have limited their application. In both types of hemophilia, the bleeding time and platelet count are normal.  The prothrombin time (PT) is also normal as it tests the extrinsic clotting pathway and reflects the function of factors II, V, VII, and X (mnemonic: PeT).  However, the activated partial thromboplastin time (PTT) is prolonged as it assesses the activity of factors II, V, VIII, IX, X, XI and XII, the intrinsic clotting pathway (mnemonic: PiTT).  Diagnoses of hemophilia A and B are made by measuring plasma levels of factors VIII and IX, respectively. (Choice A)  Factor XII (Hageman) is synthesized by the liver and is activated by endothelial injury.  It triggers the intrinsic coagulation pathway by activating factor XI.  The addition of factor XII does not clot the blood of patients with hemophilia because the downstream clotting factors VIII or IX are deficient. (Choice B)  Fibrinogen is a protein synthesized by the liver.  Thrombin mediates cleavage of fibrinogen to form fibrin, the main component of thrombi; therefore, without thrombin, fibrinogen administration alone would not be helpful. (Choice C)  Protein C is a vitamin K-dependent factor synthesized in the liver.  It is a physiologic anticoagulant that degrades factors Va and VIIIa. (Choice E)  Urokinase is a thrombolytic agent used for treatment of myocardial infarction and pulmonary embolism.  It acts by converting plasminogen to plasmin, which then breaks down fibrinogen and fibrin into their respective degradation products.  The addition of urokinase would prevent thrombosis. Educational objective: Bleeding after a tooth extraction and history of hemarthrosis are suggestive of hemophilia.  Decreased levels of factor VIII or IX lead to failure to convert prothrombin into thrombin and deficient thrombus formation.  The addition of thrombin to the blood of a patient with hemophilia results in clotting.

his patient's presentation is consistent with paroxysmal nocturnal hemoglobinuria (PNH), a disorder due to complement-mediated hemolysis.  PNH is usually due to a mutated phosphatidylinositol glycan class A (PIGA) gene, which helps synthesize the glycosylphosphatidylinositol (GPI) anchor protein.  This protein helps attach several cell surface proteins (eg, CD55 decay accelerating factor, CD59 MAC inhibitory protein) that inactivate complement.  Absence of these proteins leads to uncontrolled complement-mediated hemolysis. Manifestations of PNH include the following: Fatigue and jaundice due to hemolytic anemia (elevated bilirubin and lactate dehydrogenase, low haptoglobin, hemoglobinuria [which may be nocturnal]) Thrombosis at atypical sites (eg, hepatic, portal, or cerebral veins) possibly due to the release of prothrombotic factors from lysed red blood cells and platelets (mesenteric vein thrombosis may explain this patient's abdominal pain) Pancytopenia due to stem cell injury Chronic hemolysis with breakdown of iron-containing erythrocytes can also lead to iron deposition in the kidney (hemosiderosis), which can interfere with proximal tubule function and cause interstitial scarring and cortical infarcts.  The hemosiderosis combined with microvascular thrombosis can increase the risk of chronic kidney disease. (Choices A and C)  Cast nephropathy is usually seen in multiple myeloma and is due to large amounts of monoclonal free chain deposition in the kidney.  Interstitial nephritis (inflammation in the area surrounding the renal tubules) is most commonly due to drugs (eg, analgesics, antibiotics), recent infection, or systemic conditions (eg, sarcoidosis). (Choices D and E)  Membranous glomerulonephritis can be associated with systemic lupus erythematosus, drugs (eg, nonsteroidal anti-inflammatory drugs [NSAIDs]), hepatitis B and C, or solid tumor malignancies (eg, lung, prostate, gastrointestinal).  Minimal change disease can be associated with drugs (eg, NSAIDs), hematologic malignancies (eg, lymphoma, leukemia), or allergens (eg, fungi). Educational objective: Paroxysmal nocturnal hemoglobinuria is due to a gene defect that leads to uncontrolled complement-mediated hemolysis.  The classic triad includes hemolytic anemia (hemoglobinuria), pancytopenia, and thrombosis at atypical sites.  Chronic hemolysis can cause iron deposition in the kidney (hemosiderosis). A 63-year-old man comes to the emergency department due to abdominal pain.  Physical examination shows abdominal tenderness without guarding or rebound.  His laboratory test results are as follows: Hemoglobin 8.9 g/dL Platelets 134,000/mm3 Total bilirubin 6.3 mg/dL Lactate dehydrogenase 740 U/L Haptoglobin Low On further investigation, magnetic resonance angiography of the abdomen reveals mesenteric vein thrombosis.  Flow cytometry shows absence of CD55 on the surface of red blood cells.  Which of the following is the most likely pathologic renal finding in this patient ?

A 25-year-old woman comes to the office due to significant fatigue.  Several weeks ago, the patient had a weeklong episode of intermittent fever and severe body aches.  Over the last 2 weeks, she has been too tired to complete her normal jogging routine in the mornings and has had to take naps after returning home from work.  The patient has no chronic medical conditions and takes no medications.  Temperature is 37.2 C (99 F), pulse is 110/min, and respirations are 20/min.  Examination shows pale lips and conjunctivae.  The abdomen is soft and there is no hepatosplenomegaly.  Examination of the extremities is unremarkable, and no lymphadenopathy is present.  Laboratory results are as follows: Hemoglobin 7.0 g/dL Mean corpuscular volume 90 μm3 Reticulocytes 0.1% Platelets 40,000/mm3 Leukocytes 2,000/mm3 PT 13 sec PTT 30 sec Peripheral blood smear reveals normocytic, normochromic red blood cells, and other cell types appear morphologically normal.  This patient's bone marrow biopsy would most likely show which of the following patterns? Explanation Aplastic anemia Pathogenesis Multipotent hematopoietic stem cells are destroyed by cytotoxic T cells or direct cytotoxic injury → bone marrow aplasia/hypoplasia → lack of circulating peripheral blood cells Common triggers Autoimmune Drugs: cytotoxic chemotherapy, immunosuppressants, idiosyncratic reactions Ionizing radiation & toxins Viral infections (eg, viral hepatitis, HIV) Manifestations Anemia (eg, fatigue, weakness, pallor) Thrombocytopenia (eg, bleeding, bruising) Leukopenia (eg, recurrent infections) Diagnosis Bone marrow biopsy: hypocellular marrow with abundance of stromal & fat cells This patient with pancytopenia has inappropriately low reticulocyte count, morphologically normal cell lines on peripheral smear, and no splenomegaly on physical examination, raising strong suspicion for aplastic anemia. Aplastic anemia is a form of bone marrow failure caused by direct toxic injury or cytotoxic T-cell destruction of multipotent hematopoietic stem cells in the bone marrow.  Because these stem cells generate progenitor cells that produce all blood cells, damage results in a dramatic reduction of immature and mature blood cells in the bone marrow and peripheral blood.  This is reflected on bone marrow biopsy as marked hypocellularity with an abundance of fat cells and other marrow stroma; aspiration classically produces a "dry tap." Although aplastic anemia is usually idiopathic (no clear cause), it can be triggered by viral infection (eg, hepatitis, HIV), chemical or radiation exposure, or medications (eg, carbamazepine).  Patients typically have manifestations of pancytopenia such as severe fatigue and pale mucous membranes (anemia), bleeding/bruising (thrombocytopenia), or infection (eg, leukopenia).  No significant extramedullary hematopoiesis occurs (eg, no splenomegaly) because few hematopoietic stem cells continue to function. (Choice A)  Acute leukemias (eg, acute myeloid leukemia) are usually associated with a hypercellular marrow with increased blasts.  Although anemia and thrombocytopenia may be present, most patients have mild leukocytosis.  In addition, blasts would be seen on peripheral smear. (Choice B)  Chronic myeloid leukemia, a myeloproliferative neoplasm of granulocytes associated with the BCR-ABL fusion gene, is marked by a hypercellular marrow with increased granulocytes and megakaryocytes.  Patients typically have significant peripheral leukocytosis and thrombocytosis; in addition, hepatosplenomegaly is generally present. (Choice D)  Myelofibrosis, a chronic hematopoietic neoplasm, is marked by hypocellular marrow with extensive fibrosis.  Although pancytopenia is typically present, peripheral blood smear usually shows teardrop-shaped and nucleated erythrocytes; significant extramedullary hematopoiesis also occurs, so dramatic splenomegaly is usually present. (Choice E)  Acute promyelocytic leukemia is associated with promyelocytes with Auer rods (rod-shaped cytoplasmic inclusions).  This type of acute myeloid leukemia is characterized clinically by disseminated intravascular coagulation (acquired hypercoagulability and bleeding), which is not seen in this patient (normal PT and PTT); immature leukocytes would also be seen on peripheral smear. Educational objective: Aplastic anemia is a form of bone marrow failure due to destruction of multipotent hematopoietic stem cells.  It is marked by pancytopenia and profound hypocellularity of the bone marrow with an abundance of fat cells and stroma.  Impaired reticulocytosis and an absence of splenomegaly are important features.

A 56-year-old man is evaluated for increased fatigability.  His past medical history is significant for diabetes mellitus, osteoarthritis, and severe aortic stenosis that required aortic valve replacement.  His peripheral blood smear is shown on the slide below. he fragmented erythrocytes shown on the slide above are called schistocytes or helmet cells.  They are formed by mechanical trauma to erythrocytes as they circulate through the vasculature.  This patient's schistocytes are most likely due to erythrocyte damage caused by his aortic valve prosthesis.  Artificial (mechanical) valves are more traumatic for RBCs than porcine prostheses and frequently cause hemolysis.  Schistocytes can also be formed from narrowing of the microvascular spaces, as seen in disseminated intravascular coagulation, hemolytic-uremic syndrome, and thrombotic thrombocytopenic purpura. Hemolytic anemia due to intravascular erythrocyte destruction results in laboratory findings similar to those in other types of hemolytic anemias, including an increase in serum indirect bilirubin.  Intravascular erythrocyte damage also results in free hemoglobin in serum (hemoglobinemia) and urine (hemoglobinuria) as well as increased serum lactate dehydrogenase (LDH).  Haptoglobin is a serum protein that binds to free hemoglobin and promotes its uptake by the reticuloendothelial system.  Haptoglobin levels decrease when significant quantities of hemoglobin are released into the circulation, as occurs with intravascular hemolysis. (Choice A)  Increased serum iron occurs in hemochromatosis most classically, but increased serum iron can also be iatrogenic.  Hemochromatosis does not cause anemia, but it is associated with cirrhosis and increased incidence of hepatocellular cancer.  Hemolysis does not usually have a significant effect on serum iron because the iron released from lysed RBCs remains bound to hemoglobin. (Choice C)  Increased mean corpuscular volume (MCV) occurs in megaloblastic anemia (eg, folate/vitamin B12 deficiency) due to the presence of enlarged ovoid erythrocytes.  Increased MCV may also occur with other forms of anemia due to a reactive increase in reticulocytes (large, immature RBCs); however, anemia caused by mechanical erythrocyte trauma usually results in decreased MCV due to the presence of small RBC fragments (schistocytes). (Choice D)  A decreased reticulocyte count in the presence of anemia is characteristic of aplastic anemia.  In hemolytic anemias, the reticulocyte count is increased to compensate for the increased destruction of RBCs. (Choice E)  A decreased serum albumin level is associated with cirrhosis (decreased production), nephrotic syndrome (urinary loss), and protein-wasting enteropathy (bowel loss). Educational objective: Schistocytes (helmet cells) are fragmented erythrocytes.  They occur secondary to mechanical trauma from microangiopathic hemolytic anemias or prosthetic cardiac valves (macroangiopathic).  Intravascular hemolytic anemias are characterized by decreased serum haptoglobin levels as well as increased LDH and bilirubin.

A 24-year-old man comes to the clinic due to 2 weeks of progressive generalized weakness.  He has also had significant bruising on his trunk that developed spontaneously without trauma.  The patient has no known medical conditions and takes no medications.  Temperature is 37.1 C (98.8 F), pulse is 120/min, and respirations are 20/min.  Conjunctival pallor is present.  Cardiac examination reveals mild sinus tachycardia with no murmurs.  Skin examination shows truncal ecchymoses but is otherwise normal.  Laboratory results reveal a hemoglobin of 6.8 g/dL and a normal creatinine.  Bone marrow aspiration is grossly pale and histologically appears diluted due to high lipid content.  Which of the following laboratory patterns is most likely present in this patient? Erythropoietin Reticulocytes Mean corpuscular volume Haptoglobin  A. ↑ ↑ Normal Low  (11%)  B. ↑ ↓ Normal Normal  (60%)  C. ↑ ↓ ↓ High  (16%)  D. ↓ ↑ ↓ Low  (4%)  E. ↓ ↓ Normal Normal  (7%) Aplastic anemia Pathogenesis Multipotent hematopoietic stem cells are destroyed by cytotoxic T cells or direct cytotoxic injury → bone marrow aplasia/hypoplasia → lack of circulating peripheral blood cells Common triggers Autoimmune Drugs: cytotoxic chemotherapy, immunosuppressants, idiosyncratic reactions Ionizing radiation & toxins Viral infections (eg, viral hepatitis, HIV) Manifestations Anemia (eg, fatigue, weakness, pallor) Thrombocytopenia (eg, bleeding, bruising) Leukopenia (eg, recurrent infections) Diagnosis Bone marrow biopsy: hypocellular marrow with abundance of stromal & fat cells This patient with a low hemoglobin level has several symptoms of anemia, including generalized weakness, tachycardia, and conjunctival pallor.  The presence of spontaneous bruising in the absence of trauma likely indicates thrombocytopenia.  Bone marrow aspirate reveals an abundance of lipids instead of cells, which is usually seen with bone marrow aplasia or hypoplasia.  This constellation of findings is highly suggestive of aplastic anemia (AA). AA is a form of bone marrow failure primarily caused by cytotoxic T-cell destruction of multipotent hematologic stem cells.  Because multipotent stem cells produce all mature blood cells, patients usually develop pancytopenia (not just anemia as the name suggests) and have manifestations of anemia, thrombocytopenia, and/or leukopenia (eg, infections). As with most forms of anemia, anemia-induced tissue hypoxia stimulates interstitial cells in the kidney to increase the release of erythropoietin.  However, in AA, erythropoietin is unable to stimulate significant new red blood cell production due to the reduced population of functioning hematologic stem cells; therefore, reticulocytes are inappropriately low.  Because the blood cells produced by the remaining undamaged hematopoietic stem cells are normal in morphology, erythrocytes are normal in size and appearance; therefore, mean corpuscular volume is normal.  Because there is no intravascular hemolysis, haptoglobin (binds free hemoglobin in the blood) is also normal. Educational objective: Aplastic anemia (AA) is a form of bone marrow failure associated with pancytopenia and bone marrow aplasia/hypoplasia.  Although erythropoietin levels are high, reticulocytes remain low because the production of new erythrocytes is impaired by a paucity of bone marrow stem cells.  However, the blood cells produced by the remaining stem cells are normal in morphology and red cell indexes (eg, mean corpuscular volume) are usually normal.

A 20-year-old man is evaluated for recurrent episodes of jaundice.  He was separated from his parents at a young age and is unaware of his family medical history.  The patient resided in several foster homes throughout his childhood but currently lives alone.  Temperature is 36.7 C (98.1 F), blood pressure is 120/80 mm Hg, and pulse is 72/min.  Physical examination shows pallor, icterus, and mild splenomegaly.  There is no lymphadenopathy or hepatomegaly.  The remainder of the physical examination is normal.  Laboratory results are as follows: Hemoglobin 9 g/dL Platelets 198,000/mm3 Leukocytes 6,500/mm3 Lactate dehydrogenase increased Total bilirubin 3.4 mg/dL Direct bilirubin 0.2 mg/dL Aspartate aminotransferase (SGOT) 25 U/L Alanine aminotransferase (SGPT) 30 U/L Direct Coombs test negative When the patient's red blood cells are incubated in a hypotonic saline solution, hemoglobin is released.  The control sample does not release hemoglobin.  This patient is at greatest risk for developing which of the following complications? Hereditary spherocytosis Genetics Autosomal dominant inheritance (most cases) Pathogenesis RBC membrane defect (eg, spectrin, ankyrin) Spherocytes with ↓ deformability sequestered in spleen Extravascular hemolysis Clinical presentation Hemolytic anemia Jaundice Splenomegaly Laboratory findings ↑ MCHC Spherocytes on peripheral blood smear Negative Coombs test ↑ Osmotic fragility Treatment Splenectomy Complications Pigmented gallstones Aplastic crisis (with parvovirus B19 infection) RBC = red blood cell; MCHC = mean corpuscular hemoglobin concentration. This patient's anemia, elevated lactate dehydrogenase (LDH), and indirect hyperbilirubinemia is suggestive of hemolytic anemia.  Red cell lysis (ie, hemoglobin release) when incubated in hypotonic saline describes a positive osmotic fragility test, a diagnostic test for hereditary spherocytosis (HS). HS is the most common form of hemolytic anemia caused by an RBC membrane defect.  HS mutations most often affect spectrin and ankyrin (plasma-membrane scaffolding proteins), producing an unstable plasma membrane that loses fragments over time.  As a result, the RBCs acquire an inflexible, spheroid shape (ie, spherocytes).  Because spherocytes have a decreased surface area/volume ratio, they are more prone to rupture when incubated in hypotonic saline (ie, increased osmotic fragility). Patients with HS have the classic findings of chronic extravascular hemolysis, including anemia, jaundice, and splenomegaly (due to increased splenic macrophages and congestion).  They are also at risk for pigmented gallstones (due to increased bilirubin precipitating as calcium bilirubinate in the gallbladder) and aplastic crises with parvovirus B19 infection. (Choice A)  Autoimmune hemolytic anemia (AIHA) results in findings similar to those seen in HS (eg, indirect hyperbilirubinemia, elevated LDH, spherocytes).  In contrast to HS, patients with AIHA have a positive direct antiglobulin (Coombs) test and a propensity for developing other autoimmune disease (eg, systemic lupus erythematosus). (Choices B and C)  The abnormal adhesion of sickled RBCs to the endothelium and the subsequent obstruction of small blood vessels lead to various injuries, including splenic autoinfarction and femoral avascular necrosis.  Although sickle cell disease causes hemolysis (eg, indirect hyperbilirubinemia, elevated LDH), a positive osmotic fragility test classically describes HS. (Choice D)  Hemochromatosis (ie, iron overload) is a potential complication of beta-thalassemia due to ineffective erythropoiesis (stimulates iron absorption) and treatment-related blood transfusions.  Hemolysis is often less severe in HS, and most patients do not develop iron overload. Educational objective: Hereditary spherocytosis results from red blood cell cytoskeleton abnormalities, most commonly in the proteins spectrin and ankyrin.  The diagnosis can be confirmed with a positive osmotic fragility test.  Hemolytic anemia, jaundice, and splenomegaly are classic manifestations.  Complications include pigmented gallstones and aplastic crises.

A 9-year-old boy with beta-thalassemia major is brought to the office for a routine red blood cell transfusion.  He was diagnosed at age 6 months and has since received numerous blood transfusions.  The patient has tolerated each transfusion well with no immediate reactions.  Vital signs are normal.  On physical examination, the patient has mild frontal bossing, hepatosplenomegaly, and jaundice.  A recent liver biopsy showed Kupffer cells containing coarse, yellow-brown cytoplasmic granules.  The granules are most likely composed of which of the following? Patients with chronic hemolytic anemia (eg, beta-thalassemia major) depend on recurrent red blood cell (RBC) transfusions to maintain an adequate hemoglobin level.  Iron overload (hemosiderosis) from increased iron absorption is a common complication resulting from both the primary condition (eg, hemolysis) and its treatment (frequent RBC transfusions). Circulating iron is carried by transferrin.  Once deposited in cells, iron binds to apoferritin to form ferritin micelles.  Because iron is used poorly in patients with thalassemia and cannot be excreted actively, the ferritin micelles accumulate in macrophages of the reticuloendothelial system.  The resulting iron-storage complex is known as hemosiderin and microscopically appears as brown or yellow-brown pigments in either granular or crystalline form.  Hemosiderin can be confirmed histologically with Prussian-blue staining.  In the liver, hemosiderin is typically seen in Kupffer cells (hepatic macrophages that line the walls of the sinusoids and participate in RBC breakdown). Eventually, the iron burden will overwhelm the reticuloendothelial cells' capacity to sequester iron, resulting in parenchymal iron overload in the liver, myocardium, skin, and pancreas (eg, "bronze diabetes").  Patients receiving regular transfusions should undergo routine iron chelation therapy to reduce the overall iron load within the body and improve survival. (Choice A)  Amyloid protein appears as an amorphous, pink, extracellular material that shows apple-green birefringence under polarized light after Congo red staining.  Hepatic amyloid can be seen in primary (eg, multiple myeloma) or secondary (eg, chronic inflammation) amyloidosis. (Choice B)  Bilirubin is the primary pigment found within bile, which has a brown, yellow, or green appearance microscopically.  Accumulation in hepatocytes and canaliculi (ie, cholestasis) is associated with defects in bile production or flow (eg, duct obstruction). (Choice C)  Copper accumulation is seen in Wilson disease, an autosomal recessive disease characterized by cirrhosis and neurologic complications. (Choice D)  Glycogen appears as clear cytoplasmic vacuoles and stains pink-purple with the periodic acid-Schiff reaction.  Glycogen is abundant in the liver shortly after a meal. (Choice E)  Patients with Gaucher disease (glucocerebrosidase enzyme deficiency) have pancytopenia, hepatosplenomegaly, and pathologic fractures.  Gaucher cells, macrophages laden with cerebrosides and other glycolipids, have a "wrinkled tissue paper" appearance microscopically. (Choice G)  Lipofuscin is an insoluble yellow-brown pigment composed of lipids and phospholipids complexed with proteins.  This pigment accumulates with age (ie, typically seen in adults) and "wear and tear" of multiple organs. Educational objective: Iron overload (hemosiderosis) is a common and serious complication of chronic hemolytic anemia and frequent blood transfusions.  Accumulation of yellow-brown hemosiderin pigment is the cardinal histologic finding.  Chelation therapy is indicated to reduce parenchymal iron deposition.

A 4-year-old boy is admitted to the hospital due to shock and subsequently dies from overwhelming sepsis.  Examination during autopsy shows hepatosplenomegaly.  Clumps of erythroid precursor cells are seen in the liver and spleen.  The presence of these precursor cells is most likely due to which of the following underlying conditions? e presence of erythroid precursor cells in this patient's liver and spleen is indicative of extramedullary hematopoiesis (EMH).  EMH is characterized by the formation and maturation of blood cell precursors (ie, hematopoiesis) outside of the bone marrow, commonly in response to increased destruction of blood cells (eg, severe chronic hemolysis). Throughout fetal development, hematopoiesis normally occurs in the yolk sac, followed by the liver, spleen, and bone marrow; after birth, the bone marrow is the primary hematopoietic site.  However, in response to uncompensated, severe, chronic hemolytic anemia (eg, beta thalassemia, sickle cell disease), elevated erythropoietin can cause some hematopoietic stem and progenitor cells to leave the bone marrow, migrate to other organs (often those involved in fetal hematopoiesis such as the liver and spleen), and initiate compensatory erythropoiesis. EMH can cause enlargement of the involved organs (eg, hepatosplenomegaly).  In some patients, extensive splenic infiltration can impair the spleen's filtration and immune capabilities, increasing the risk for severe infections (eg, sepsis). (Choice B)  Deficiency of cobalamin (vitamin B12), which is required for DNA synthesis, results in megaloblastic anemia; it is not typically associated with EMH. (Choice C)  Erythropoietin deficiency (eg, chronic kidney disease) is associated with anemia but does not cause EMH, since EMH is driven by increased levels of erythropoietin. (Choice D)  Red blood cell transfusions limit EMH by reducing hypoxia and erythropoietin release.  Patients with severe chronic hemolysis often receive regular transfusions to improve anemia and suppress EMH. (Choice E)  Deficiency of iron, which is necessary for hemoglobin production, results in a relative depression of erythropoietic activity; it is not typically associated with EMH. (Choice F)  Patients with primary immunodeficiency disorders may be susceptible to overwhelming sepsis, but these disorders are not frequently associated with severe chronic hemolysis, and EMH is not expected. Educational objective: The presence of erythroid precursors in the liver and spleen is indicative of extramedullary hematopoiesis (EMH), a condition characterized by erythropoietin-stimulated formation and maturation of blood cells outside of the bone marrow.  EMH frequently occurs in response to severe chronic hemolytic anemia (eg, beta thalassemia).

A 70-year-old female presents to your office complaining of easy fatigability, exertional dyspnea and weight loss.  She also complains of frequent falls.  Physical examination reveals symmetrically decreased vibratory sensation to the lower extremities.  Her hemoglobin is 7.8 g/dL and a peripheral blood smear shows hypersegmented neutrophils.  Which of the following is the best treatment for this patient? Deficiencies of folic acid and vitamin B12 are the most important causes of megaloblastic anemia.  Both of these vitamins are required for DNA synthesis in erythropoiesis.  When there is a deficiency of either of these vitamins, cell division is delayed, though the cytoplasm develops normally.  Thus, the cells enlarge (megaloblasts) but do not divide.  The bone marrow is hypercellular in megaloblastic anemia, but the megaloblastic erythroid precursor cells are rapidly destroyed in the bone marrow and few differentiated large RBCs are released into the circulation.  In severe megaloblastic anemia, 90% of erythroid precursors are destroyed without ever entering the circulation. Vitamin B12 and folic acid deficiencies cause similar hematological pictures.  However, neurological dysfunction is only seen in patients with vitamin B12 deficiency.  This is because B12 deficiency also causes axonal demyelination and degeneration.  In late disease, the neurological dysfunction may be irreversible.  The main sites of neurological involvement include the peripheral nerves, spinal cord (posterior and lateral columns), and the cerebrum.  Decreased vibratory and position sense are early signs of vitamin B12 deficiency.  Patients experience ataxia and recurrent falls because of compromised proprioception.  Importantly, neurologic abnormalities can occur in vitamin B12 deficiency in the absence of frank anemia.  Treating megaloblastic anemia due to vitamin B12 deficiency with folate alone could worsen the neurological dysfunction. An RBC mean corpuscular volume (MCV) of more than 100 fL is suggestive of megaloblastic anemia.  However, RBC macrocytosis can also occur in liver disease, hypothyroidism, and alcohol-induced liver disease.  MCVs greater than 110 fL are typically seen only with vitamin B12 and folic acid anemias.  On peripheral blood smear, there is macrocytosis (large RBCs), hypersegmented neutrophils, and large bizarrely shaped platelets.  The presence of even a single neutrophil with more than 6 lobes should raise the suspicion of megaloblastic anemia. The medications listed in the other answer choices are not used for the treatment of megaloblastic anemia. Educational Objective: Vitamin B12 and folic acid deficiencies cause similar hematological pictures.  However, neurological dysfunction is only seen in patients with vitamin B12 deficiency.  If megaloblastic anemia due to vitamin B12 deficiency is mistakenly treated with folate alone, the neurologic dysfunction can worsen. options : iron preparation, pyridoxine , vit.c , folic acid, EPO, Filgrastim, Il-2 , Antithymocyte globin

A 45-year-old man comes to the office for progressive weakness and fatigue over the last year.  The patient was adopted and does not know his family history.  After a comprehensive physical examination and laboratory evaluation, the patient undergoes genetic testing.  A loss of expression mutation is identified in a gene coding for a protein found on the basolateral surface of hepatocytes and enterocytes.  The protein is known to interact with the transferrin receptor.  Which of the following conditions is this patient at greatest risk of developing? Primary hemochromatosis (ie, hereditary hemochromatosis) is most commonly caused by mutations affecting the HFE protein.  This protein normally interacts with the transferrin receptor to form a complex that functions as a sensor of iron stores.  Mutations that inactivate the HFE protein cause enterocytes and hepatocytes to detect falsely low iron levels.  This increases iron accumulation in the body through the following 2 mechanisms: Enterocytes respond by increasing apical expression of divalent metal transporter 1 (DMT1), increasing iron absorption from the intestinal lumen Hepatocytes respond by decreasing hepcidin synthesis; low hepcidin levels result in increased ferroportin expression on the basolateral surface of enterocytes.  This allows increased iron secretion into the circulation, leading to iron overload When body iron levels exceed 20 g, patients typically develop the classic triad of micronodular cirrhosis, diabetes mellitus, and skin pigmentation (ie, "bronze diabetes").  These patients are at an increased risk for hepatocellular carcinoma, congestive heart failure, and testicular atrophy/hypogonadism. (Choice A)  Basal ganglia atrophy is a potential complication commonly seen in Wilson disease (ie, hepatolenticular degeneration). (Choice B)  Exocrine pancreatic function is usually preserved in patients with hemochromatosis.  Therefore, fat malabsorption and osteoporosis (due to decreased vitamin D) would not typically be seen. (Choice C)  Iron deficiency anemia is a potential complication of blood loss, lack of dietary iron, or an inability to absorb iron (eg, celiac disease).  Hemochromatosis results in iron overload, not iron deficiency. (Choice E)  Pulmonary emphysema is a potential complication of alpha-1 antitrypsin deficiency. Educational objective: HFE protein mutations are the most common cause of primary hemochromatosis.  Inactivation of the HFE protein results in decreased hepcidin synthesis by hepatocytes and increased DMT1 expression by enterocytes, leading to iron overload.  Patients with hemochromatosis are at an increased risk for liver cirrhosis and hepatocellular carcinoma.

what is HFE

compress more small and simple concept undersy=tanding

A 34-year-old man with obesity comes to the office due to fatigue, daytime sleepiness, and occasional headaches.  When asked to describe his sleeping habits, he reports that he sleeps in a separate room from his wife because she finds his snoring annoying.  Blood pressure is 160/90 mm Hg and pulse is 80/min.  The abdomen is soft and nontender.  The liver span is 9 cm, and the spleen is not palpable.  Laboratory results are as follows: Hematocrit 58% White blood cells 9,000/mm3 Platelets 190,000/mm3 Decreased arterial oxygen content, sensed by which of the following organs, is primarily responsible for this patient's elevated hematocrit? his patient with daytime sleepiness, recurrent headaches, and snoring most likely has obstructive sleep apnea (OSA).  Excess tissue around the extrathoracic upper airways (eg, from obesity) can predispose to upper airway collapse during sleeping.  As a result, patients with OSA may have up to 500 episodes of asphyxia per night. In adults, the main response to hypoxemia is coordinated by the kidneys.  In the renal cortex, peritubular fibroblasts sense hypoxia using the transcription factor hypoxia-inducible factor 1-alpha (HIF-1α).  When oxygen is readily available, HIF-1α is marked for proteasomal degradation.  Under low oxygen conditions, intracellular levels of HIF-1α accumulate, substantially increasing erythropoietin (EPO) production. EPO is secreted into the bloodstream, acting on the bone marrow to accelerate erythrocyte precursor maturation (Choice A).  The rapid rise in the number of mature erythrocytes leads to secondary polycythemia (eg, elevated hematocrit).  As a result, the oxygen-carrying capacity of blood rises, helping to compensate for chronic hypoxemia. (Choice B)  The brain does not regulate erythropoiesis in response to hypoxemia.  Instead, severe cerebral hypoxia drives increased sympathetic tone, increasing respiration, cerebral perfusion pressure, and oxygen delivery. (Choice C)  In response to hypoxemia, the liver helps supply iron (by suppressing hepcidin and upregulating transferrin) to support EPO-driven red blood cell production.  However, iron mobilization alone is insufficient to increase erythropoiesis.  For this reason, patients with severe chronic kidney disease (low EPO production), even when chronically hypoxemic, often have anemia and fail to develop secondary polycythemia. (Choice D)  With OSA, the lungs do not receive adequate oxygen delivery due to recurrent upper airway collapse.  In response to chronic alveolar hypoxemia, HIF-1α activation in the lungs contributes to sustained pulmonary vasoconstriction and pulmonary hypertension.  However, the lungs do not participate in erythropoiesis. (Choice F)  The spleen is the major site of erythrocyte destruction, not production.  In states of chronic hypoxemia, severe anemia, or bone marrow dysfunction, tissues with resident hematopoietic stem cells (eg, spleen, liver) can respond by participating in erythropoiesis (ie, extramedullary hematopoiesis). Educational objective: The kidneys respond to chronic hypoxemia (detected by the transcription factor hypoxia-inducible factor 1-alpha) by substantially increasing production of erythropoietin.  This hormone circulates to the bone marrow, where it accelerates the maturation of erythrocyte precursors, resulting in an elevated hematocrit (secondary polycythemia).

A 10-year-old boy comes to the office for a first visit.  His family recently came to the United States as political refugees.  The patient's mother says that he has required several blood product transfusions due to anemia, but she does not have prior records available with her.  On examination, the patient's temperature is 37.1 C (98.8 F).  BMI is 21 kg/m2.  Examination is notable for conjunctival pallor and moderate splenomegaly.  Laboratory results are as follows: Hemoglobin 9.4 g/dL Platelets 240,000/mm3 Enzyme assays performed on circulating blood cells demonstrate low pyruvate kinase activity.  Which of the following is the most likely cause of this patient's splenomegaly? Pyruvate kinase is a glycolytic pathway enzyme that converts phosphoenolpyruvate to pyruvate, resulting in the generation of a molecule of ATP.  Allosteric stimulation of pyruvate kinase (by fructose 1,6-bisphosphate) stimulates glycolysis.  Mature red blood cells (RBCs), which do not contain mitochondria, rely on lactate as the main metabolite for glycolysis. Most of the ATP produced is used for transport of cations against a concentration gradient in the RBC membrane.  Therefore, pyruvate kinase deficiency, which results in insufficient ATP production, disrupts this gradient, leading to water and potassium loss, defective maintenance of membrane architecture (echinocyte formation), and hemolysis.  As reticuloendothelial cells in the splenic red pulp are involved in removal of damaged RBCs, their increased activity in the setting of pyruvate kinase deficiency causes them to undergo hyperplasia, resulting in splenomegaly. (Choice A)  The spleen is important in fighting infectious pathogens in the body; therefore, many acute and chronic infections lead to enlargement of the spleen due to proliferation of lymphoid tissue. (Choice B)  Disorders such as leukemia and lymphoma result in splenomegaly from neoplastic proliferation of lymphoid tissue within the spleen. (Choice C)  Passive congestion of the spleen with blood occurs in the setting of portal hypertension, splenic vein thrombosis, or congestive heart failure.  Resultant splenic sinusoid dilation can lead to splenomegaly. (Choice D)  In infective endocarditis, circulating immune complexes can deposit in the kidneys and the spleen, likely contributing to splenomegaly. (Choice F)  Splenomegaly in the lysosomal storage diseases Niemann-Pick disease and Gaucher disease is due to the accumulation of sphingomyelin and glucocerebrosides, respectively. Educational objective: Pyruvate kinase deficiency causes hemolytic anemia due to failure of glycolysis and resultant failure to generate sufficient ATP to maintain erythrocyte structure.  In this case, splenic hyperplasia results from increased work of the splenic parenchyma, which must remove these deformed erythrocytes from the circulation.

A 12-year-old girl is brought to the emergency department due to several days of worsening exertional dyspnea and lethargy.  The patient has a history of sickle cell disease and takes hydroxyurea.  Physical examination shows mucosal pallor and a systolic ejection murmur.  Laboratory studies reveal a hemoglobin level of 5.6 g/dL.  Bone marrow biopsy is performed and demonstrates decreased erythroid precursors and giant pronormoblasts containing inclusions, as shown below. this patient's symptomatic anemia (lethargy, exertional dyspnea, mucosal pallor, ejection murmur) and bone marrow biopsy showing decreased erythropoiesis (reduced erythrocyte precursors) raise suspicion for transient aplastic crisis due to acute parvovirus B19 infection. Parvovirus is a small, nonenveloped, DNA virus transmitted via the respiratory route that primarily attacks erythroid progenitor cells due to tropism for an erythrocyte cell surface receptor (P blood group antigen).  Infection of erythroid progenitor cells prevents red blood cell maturation, leading to formation of abnormal giant pronormoblasts (several times larger than surrounding red blood cells) with glassy, intranuclear viral inclusions.  The drop in red cell production often leads to a transient (1-2 week) drop in hematocrit.  Although many patients are asymptomatic, individuals with underlying hemoglobin disorders (eg, sickle cell anemia) sometimes develop symptomatic anemia. (Choice B)  Folate deficiency can be seen in patients with sickle cell disease due to increased erythropoiesis in response to chronic anemia.  However, folate deficiency is characterized by macrocytic anemia and hypersegmented neutrophils; giant pronormoblasts with inclusions would not be seen. (Choice C)  Hydroxyurea can sometimes interfere with normal erythropoiesis and result in macrocytic anemia.  However, it is not associated with giant pronormoblasts with intranuclear inclusions. (Choice D)  Patients with sickle cell disease who require repeated blood transfusion can sometimes develop secondary iron overload.  Bone marrow biopsy would show increased iron stores. (Choice E)  Exposure to toxic chemicals (eg, industrial solvents/chemicals, insecticides) can lead to aplastic anemia.  However, bone marrow biopsy would show hypocellular marrow with a decrease in all cell types; the remaining hematopoietic cells would be morphologically normal. Educational objective: Parvovirus B19 infection can cause transient aplastic crisis, particularly in those with underlying hemoglobin disorders such as sickle cell anemia.  Patients develop symptomatic anemia (eg, exertional dyspnea, fatigue, low hematocrit) due to inhibition of erythropoiesis by the virus.  Bone marrow examination will show giant pronormoblasts with glassy, intranuclear viral inclusions.

A 12-year-old boy is brought to the emergency room due to high fever, chest pains, and dyspnea.  Medical history is significant for 2 prior hospitalizations for abdominal pain that resolved with analgesics and hydration.  Evaluation today shows a hematocrit of 23% and reticulocyte count of 9%.  Several hours after being admitted to the hospital, the patient dies.  At autopsy, the spleen is small and firm.  This patient's autopsy finding is most likely related to which of the following Sickle cell disease Pathophysiology β-globin mutation (Glu → Val) → HbS Deoxygenation → HbS polymerization → sickled RBCs → hemolysis & vasoocclusion Clinical features Hemolysis Chronic hemolytic anemia Aplastic crisis* Vasoocclusion Pain Acute chest syndrome† Stroke Avascular necrosis Splenic sequestration crisis‡ (early childhood), autosplenectomy Infection (eg, osteomyelitis) Laboratory findings ↓ Hematocrit ↑ Reticulocyte count Peripheral smear: sickled RBCs Hemoglobin electrophoresis: ↑ HbS, ↓ HbA  *Aplastic crisis: temporary arrest of erythropoiesis due to infection (eg, parvovirus B19). †Acute chest syndrome: pulmonary infiltrates, fever, chest pain, hypoxemia, and dyspnea due to pulmonary vasoocclusion. ‡Splenic sequestration crisis: worsening anemia with enlarging spleen due to splenic vasoocclusion and RBC pooling. HbA = hemoglobin A; HbS = hemoglobin S; RBCs = red blood cells. This patient's hematologic findings (eg, anemia, reticulocytosis) and medical history (eg, recurrent episodes of abdominal pain that resolved with analgesics and hydration) are suggestive of sickle cell disease (SCD).  SCD is a hemoglobinopathy characterized by sickle hemoglobin (HbS), an abnormal hemoglobin that can polymerize in deoxygenated conditions.  HbS polymerization leads to sickle-shaped erythrocytes that can occlude small vessels.  This patient's most recent presentation (eg, fever, chest pain, dyspnea) was most likely due to small-vessel occlusion localized to the pulmonary vasculature (ie, acute chest syndrome). Vascular occlusion can also cause splenic infarctions.  Repeated infarctions produce a shrunken, fibrotic spleen.  By adulthood, most patients with SCD have undergone autosplenectomy and have a small, scarred splenic remnant.  As a result, these patients have functional asplenia and are susceptible to infection with encapsulated organisms (eg, Streptococcus pneumoniae). (Choice A)  Extramedullary hematopoiesis (EMH) can develop in patients with hemolytic anemias (eg, beta-thalassemia, SCD) or myeloproliferative neoplasms (eg, primary myelofibrosis) and typically occurs in the liver and spleen.  Splenic EMH would result in splenomegaly, not splenic atrophy. (Choice B)  Splenic follicular hyperplasia can be seen with systemic infections and can result in an enlarged, not small and firm, spleen. (Choice C)  Intrasplenic lipid accumulation may occur in lysosomal storage disorders such as Gaucher disease.  Although such patients can have bone pain and anemia, they typically have splenomegaly. (Choice D)  Pressure atrophy of the splenic parenchyma can be seen when a lesion (eg, a cyst) compresses the spleen, which would likely have been detected during autopsy. Educational objective: In patients with sickle cell disease, repetitive splenic infarctions caused by microvessel occlusion result in a small, firm splenic remnant (ie, autosplenectomy).

A 23-year-old man comes to the emergency department due to 4 days of cramping abdominal pain.  He has been feeling weak for the past 2 weeks.  The patient tried over-the-counter antacids without relief.  He is an industrial laborer with no significant medical history or known allergies.  The patient lives in Massachusetts.  The patient's parents have hypertension, and his siblings are healthy.  Temperature is 37.1 C (98.8 F).  Physical examination is unremarkable.  The patient's peripheral blood smear is shown in the image below: This patient likely has lead poisoning.  Lead poisoning (ie, plumbism) is often a pediatric condition that results from children ingesting lead-containing paint chips.  However, lead poisoning can also occur in adults.  Affected individuals are usually miners or industrial workers (especially those in battery manufacturing) who inhale particulate lead while working. Adults with lead poisoning experience weakness, abdominal pain, and constipation.  In severe cases, there may be neurologic manifestations (eg, headache, cognitive symptoms, peripheral neuropathy).  On physical examination, patients may have blue "lead lines" at the junction of the teeth and gingivae. The classic findings on peripheral blood smear are coarse basophilic stippling and hypochromic, microcytic anemia.  Basophilic stippling results from impaired degradation of ribosomal RNA, which is normally degraded and eliminated during reticulocyte maturation.  Lead inhibits an enzyme involved in this process, resulting in ribosomal precipitates that appear as dark blue-purple granules throughout red blood cells (RBCs).  Hypochromic microcytic anemia results from inhibition of delta-aminolevulinate dehydratase (delta-ALA dehydratase) and ferrochelatase, which are involved in heme synthesis.  This causes decreased hemoglobin synthesis, which gives the RBCs a pale appearance. (Choice A)  Acute intermittent porphyria is characterized by reduced activity of porphobilinogen deaminase (an enzyme in the heme synthesis pathway) in the liver, causing buildup of neurotoxic heme pathway intermediates.  It can cause attacks of abdominal pain (without abdominal tenderness) due to autonomic neuropathy.  Erythropoiesis is not affected, and the peripheral blood smear is normal. (Choice B)  Myeloblasts containing cytoplasmic Auer rods on peripheral blood smear are a characteristic finding of acute myeloid leukemia, which typically presents with complications of pancytopenia (eg, bruising from thrombocytopenia, infection from neutropenia). (Choice C)  Autoimmune destruction of gastric parietal cells causes atrophic gastritis, which can lead to pernicious anemia (a type of megaloblastic anemia) due to vitamin B12 malabsorption.  Megaloblastic anemia is characterized by hypersegmented neutrophils and macro-ovalocytes (large, oval RBCs). (Choice E)  Babesiosis is endemic in the northeastern United States and commonly presents with fever, fatigue, and myalgia.  Although it can be detected in a peripheral blood smear, Babesia typically appears as a ring or tetrad form (ie, Maltese cross) within RBCs. (Choice F)  Patients with splenic dysfunction (eg, functional asplenia, splenectomy) may have Howell-Jolly bodies (nuclear remnants normally removed by the spleen), which typically appear as solitary, dark blue-purple inclusions at the periphery of RBCs. Educational objective: Coarse basophilic stippling (dark blue-purple granules throughout red blood cells) and hypochromic, microcytic anemia are common peripheral blood smear findings in lead poisoning.  High-risk groups include young children ingesting paint chips and industrial workers inhaling particulate lead.

A 37-year-old man comes to the emergency department due to blood-tinged vomiting and abdominal discomfort.  Six months ago, he lost his job as an investment banker and began drinking large amounts of whiskey on a daily basis.  He has since been hospitalized several times with alcohol intoxication.  His temperature is 36.7 C (98 F), blood pressure is 110/70 mm Hg, pulse is 84/min, and respirations are 18/min.  Physical examination shows a firm, enlarged liver.  Peripheral blood smear results show neutrophils with 6-8 nuclear lobes.  Which of the following is the most likely explanation for this patient's abnormal hematologic findings? lcohol use disorder is one of the most common causes of folate deficiency anemia due to poor dietary intake and impaired folate absorption, utilization, and enterohepatic recycling.  A normal individual with a folate-deficient diet can maintain normal red blood cell (RBC) production for months due to folate recycling, whereas a patient who consumes large amounts of alcohol will experience anemia within a few weeks. A reduced form of folic acid, tetrahydrofolic acid, is necessary for the synthesis of amino acids, thymidine, and purines.  Impaired nucleotide synthesis leads to defective DNA production in blood cell precursors, resulting in abnormal cell division and megaloblastic hyperplasia of the bone marrow.  The peripheral blood smear shows pancytopenia and hypersegmented neutrophils containing nuclei with >5 lobes.  RBC abnormalities include ovalocytosis and macrocytosis, with a mean corpuscular volume (MCV) >100 µm3. (Choice A)  Lipid abnormalities such as extreme hypertriglyceridemia can cause acute pancreatitis. (Choice B)  Chronic blood loss causes iron deficiency anemia, which is not characterized by hypersegmented neutrophils. (Choice C)  Chronic alcohol use can deplete vitamin B12 levels; however, depletion would take place over a period of years, not weeks (in contrast to folate deficiency).  In addition, this patient does not have any of the classic neurologic symptoms that accompany B12 deficiency (eg, subacute combined degeneration). (Choice E)  Myelodysplasia is a premalignant condition that manifests with pancytopenia, impaired blood cell differentiation, and clonal expansion of mutated hematopoietic cells in the bone marrow.  Elevated MCV can be present, but hypersegmented neutrophils are not commonly seen. Educational objective: Folic acid deficiency anemia commonly occurs in alcoholism.  It is a megaloblastic anemia that can develop within weeks.  Peripheral blood smear shows macrocytosis, ovalocytosis, and neutrophils with hypersegmented nuclei.

A 32-year-old man comes to the office due to progressive fatigue, easy bruising, and recurring episodes of gum bleeding.  Physical examination shows several ecchymoses in his lower extremities.  Laboratory studies are as follows: Complete blood count     Hemoglobin 7.8 g/dL     Platelets 65,000/mm3     Leukocytes 3,000/mm3 Coagulation studies     Prothrombin time 22 sec     Activated partial thromboplastin time 53 sec     Plasma fibrinogen 134 mg/dL (normal: 200-400 mg/dL)     D-dimer 4.1 µg/dL (normal: <0.5 µg/dL) Bone marrow biopsy is performed and fluorescence in situ hybridization studies reveal a balanced translocation between the long arms of chromosomes 15 and 17.  Which of the following proteins is most likely to be abnormal in the hematopoietic cells of this patient? cute myelogenous leukemia (AML), characterized by failure of immature myeloid precursors (myeloblasts) to differentiate into mature granulocytes, is divided into 8 types (M0 through M7).  Acute promyelocytic leukemia (APML), the M3 variant of AML, is associated with the t(15;17) cytogenetic translocation involving the promyelocytic leukemia (PML) gene on chromosome 15 and the retinoic acid receptor alpha (RARA) gene on chromosome 17.  Fusion of these 2 genes produces PML/RARA, a chimeric gene (illustrated in this fluorescence in situ hybridization image) that codes for an abnormal retinoic acid receptor, which then inhibits myeloblast differentiation.  Abnormal promyelocytes and Auer rods are seen on the smear. The clinical manifestations of AML, including anemia (fatigue, pallor), thrombocytopenia (petechiae, hemorrhages), and neutropenia (fever, opportunistic infections), result from marrow replacement by leukemic cells.  As seen in this patient, APML is associated with disseminated intravascular coagulation (DIC), which is characterized by activation of the coagulation cascade.  Laboratory findings seen in DIC include thrombocytopenia, elevated D-dimer due to fibrinolysis, and prolonged coagulation profile times (eg, prothrombin time, activated partial thromboplastin time) and low fibrinogen due to consumption. All-trans retinoic acid is used for treatment of APML. (Choice A)  Mutations in the genes that code for the epidermal growth factor receptors are associated with certain lung (ERBB1), breast (ERBB2, also known as HER2/neu), ovarian, and gastric tumors. (Choice B)  GTP-binding proteins are involved in cellular signal transduction. (Choice C)  A defective platelet-derived growth factor receptor plays a role in the pathogenesis of several cancers, including ovarian cancers. (Choice D)  An abnormal RB gene predisposes to development of retinoblastoma and osteosarcoma. Educational objective: The cytogenetic defect t(15;17) is associated with acute promyelocytic leukemia (APML).  A translocation involving the retinoic acid receptor alpha (RARA) gene from chromosome 17 and the promyelocytic leukemia (PML) gene on chromosome 15 leads to the formation of PML/RARA, a fusion gene whose product inhibits differentiation of myeloblasts and triggers the development of APML.

A 34-year-old man with an unremarkable past medical history is evaluated for an enlarged lymph node in his anterior cervical chain that measures 4 cm in diameter.  The patient first felt the lymph node several weeks ago and states that it has been steadily increasing in size.  He is concerned about whether or not he “has cancer.”  The patient is referred to a specialist for surgical removal of the enlarged node.  Biopsy reveals abnormal lymph node architecture and numerous lymphocytes.  Which of the following, if present, would be most consistent with malignancy in this patient? ymphadenopathy can represent inflammatory changes within the lymph node (reactive hyperplasia) or malignant transformation.  Reactive hyperplasia is a broad term that encompasses all benign, reversible enlargement of the lymphoid tissue secondary to an antigenic stimulus.  The nodal response to antigenic stimuli is highly variable and can be classified as follicular hyperplasia, sinus hyperplasia, or diffuse hyperplasia.  Follicular hyperplasia occurs when the follicles increase in size and number, whereas sinus hyperplasia occurs when the sinuses enlarge and fill with histiocytes.  Diffuse hyperplasia is observed when the nodal architecture is diffusely effaced by sheets of lymphocytes, immunoblasts, and macrophages.  When malignant transformation occurs (as in lymphomas), the normal lymph node architecture is distorted or effaced by the proliferation of malignant lymphoid cells, often to a greater extent than that seen with reactive hyperplasia.  Malignancy-associated effacement of nodal architecture may be follicular or diffuse. Reactive lymphoid hyperplasia is polyclonal in that it consists of a proliferation of many different cell types within the lymph node.  For each type of lymphocyte responding to an antigenic stimulus, multiple genetically-distinct cells of that variety undergo limited monoclonal expansion, leading to an overall polyclonal response.  Malignant transformation, in contrast, is monoclonal in that it results from the unchecked proliferation of a single genetically unique cell from only one cell line. Evaluation for monoclonality of the lymphocyte population is important when lymphoma is suspected.  The clonality of a T-cell population is assessed by molecular methods, such as PCR, that examine the rearrangement of T-cell receptor (TCR) genes.  If a single allele for the V region of the T-cell receptor predominates in a lymphocytic population, monoclonal proliferation is suspected.  The same principle applies when assessing B-cell clonality.  Monoclonal rearrangement of the genes for immunoglobulin variable regions is suggestive of a B-cell lymphoma.  Of the choices given, monoclonal TCR gene rearrangement is most indicative of malignant processes, especially in the context of appropriate clinical features (i.e., weight loss, night sweats, fever, anorexia). (Choices A, B, & C)  Pleomorphism, increased mitoses, and nuclear changes are all commonly seen in the lymphocytes of a reactive hyperplastic lymph node.  These findings do not automatically classify the specimen as malignant. (Choice E)  An admixture of several lymphoid cell types in a lymph node is suggestive of a benign process.  A predominantly monomorphic cell population is indicative of malignancy and is characteristic of non-Hodgkin’s lymphoma.  Hodgkin’s lymphoma does demonstrate an admixture of several lymphoid cell types within the lymph nodes; however, this finding does not distinguish Hodgkin’s lymphoma from reactive hyperplasia.  Additionally, genetic analysis of Reed-Sternberg cells most often reveals monoclonal characteristics. Educational objective: Benign lymph node enlargement in response to antigenic stimulation is associated with a polyclonal proliferation of lymphocytes.  A monoclonal lymphocytic proliferation is strong evidence of malignancy.

A 15-month-old boy is brought to the clinic for evaluation of recurrent mouth ulcers.  Over the past 5 months, his mother has noted that he has had periodic episodes of mouth pain and oral ulcers.  She says the episodes usually last for a couple of days and then resolve without intervention.  The boy has no known medical conditions and takes no medications.  Vital signs are normal.  Examination shows mucositis.  The rest of the examination is unremarkable.  Complete blood count (CBC) reveals an absolute neutrophil count of 390/mm3.  Hemoglobin level and platelet count are normal.  Serial CBC results are documented over the next 6 weeks, revealing the pattern shown below: his patient has isolated, severe neutropenia defined by an absolute neutrophil count (ANC) <500/mm3.  It resolves and recurs in a predictable pattern, a finding characteristic of cyclic neutropenia.  Cyclic neutropenia occurs due to a mutation in the gene encoding neutrophil elastase.  This enzyme is normally packaged within neutrophil granules and plays a role in the degradation of virulence factors on bacterial pathogens. Misfolded neutrophil elastase increases endoplasmic reticulum stress, causing a portion of the neutrophil precursors in the bone marrow to undergo apoptosis.  Bone marrow aspirate would show myeloid progenitor cells with features characteristic of apoptosis (eg, nuclear fragmentation, membrane blebbing).  The depressed ANC is thought to transiently upregulate granulocyte colony-stimulating factor (G-CSF), which stimulates neutrophil production from the hematopoietic stem cells that did not undergo apoptosis.  As neutrophil numbers normalize, G-CSF production decreases, allowing neutrophil counts to decline again. Clinical manifestations of cyclic neutropenia correlate with neutrophil nadirs, which typically occur every 3 weeks, and include recurrent episodes of fever, fatigue, and mucositis (eg, gingival ulcers, inflammation) in young children.  Life-threatening infection in cyclic neutropenia is rare due to the brief duration of neutropenic periods, and patients are typically asymptomatic between episodes.  Serial ANC measurements over 6-8 weeks showing predictable oscillations support the diagnosis, and genetic testing is confirmatory. (Choice A)  Increased adipocytes and stroma relative to hematopoietic cells describes aplastic anemia, in which severe, chronic neutropenia can occur but would be accompanied by other cytopenias (eg, anemia, thrombocytopenia). (Choice B)  Hypersegmented neutrophils and megaloblastic erythroid cells are characteristic of vitamin B12 or folate deficiency.  Neutropenia is common but would be persistent.  In addition, a macrocytic anemia would be expected. (Choice C)  Lymphoid cells with eccentrically located round nuclei and pale perinuclear area describes plasma cells seen in multiple myeloma.  Neutropenia can occur due to bone marrow infiltration but would be nonoscillating, and anemia is usually present.  Moreover, this diagnosis is extremely unlikely in patients age <40. (Choice D)  A hypercellular marrow revealing myeloblasts with open chromatin and prominent nucleoli is seen in acute myeloid leukemia.  Persistently low, not oscillating, ANCs are often seen along with anemia and/or thrombocytopenia. Educational objective: Cyclic neutropenia occurs as a result of a mutation in the gene encoding neutrophil elastase.  This leads to accelerated apoptosis of neutrophil precursors with characteristic bone marrow findings of nuclear fragmentation and membrane blebbing.  Cyclic neutropenia is characterized by episodic (every 3 weeks), severe neutropenia that causes recurrent fever and mucositis.

A 42-year-old previously healthy woman comes to the office due to fever and sore throat.  She has no cough.  Physical examination shows tonsillar exudate and a nontender cervical lymph node that measures 3.5 cm in diameter.  Oral antibiotic therapy is started and on a follow-up visit a week later, the patient reports that her symptoms have resolved.  The previously enlarged cervical lymph node has decreased slightly in size.  On several follow-up visits over the following year, the patient remains asymptomatic and the size of the lymph node fluctuates but does not disappear completely.  Referral to a surgeon is made and excisional biopsy of the lymph node is performed.  Which of the following is the most likely diagnosis? his patient with persistent fluctuating lymphadenopathy, who may have had an unrelated pharyngitis (treated with antibiotics) on initial presentation, most likely has follicular lymphoma.  Follicular lymphoma is the most common indolent non-Hodgkin lymphoma (NHL) in adults and the second most common NHL overall (after diffuse Large B cell lymphoma).  It derives from germinal center B cells and typically has a long, waxing and waning clinical course. The condition most often presents in middle-aged patients with painless lymph node enlargement or abdominal discomfort from an abdominal mass.  Histology is notable for a nodular pattern, and the neoplastic follicles are composed of a mixture of centrocytes (cleaved cells) and centroblasts (noncleaved cells).  The majority of tumors exhibit a t(14;18) translocation, resulting in overexpression of the BCL2 oncogene that blocks programmed cell death. (Choice A)  Acute lymphoblastic leukemia/lymphoma is the most common malignancy in children.  It presents with lymphadenopathy, hepatosplenomegaly, fever, bleeding, and bone pain.  Neoplastic cells are pre-B or pre-T cells (lymphoblasts). (Choice B)  Burkitt lymphoma is a highly aggressive (but generally chemotherapy-responsive) B-cell NHL associated with chronic Epstein-Barr virus infection and/or deregulation of the MYC proto-oncogene.  Patients typically develop rapidly growing tumor masses in the facial bones, jaw, or abdomen.  Tumor doubling time is very rapid and spontaneous tumor lysis can occur. (Choice C)  Diffuse large B-cell lymphoma typically presents with a rapidly enlarging nodal (neck, abdomen, mediastinum) or extranodal symptomatic mass.  The Waldeyer's ring (oropharyngeal lymphoid tissue) and gastrointestinal tract are commonly involved, and systemic "B" symptoms (fever, weight loss, drenching night sweats) can also be seen. (Choice E)  Hairy cell leukemia, a mature B-cell neoplasm, presents with splenomegaly and pancytopenia most often in older men.  Lymph node enlargement is not characteristic.  Leukemic cells have hairlike cytoplasmic projections and are positive for tartrate-resistant acid phosphatase (TRAP). (Choice F)  Mycosis fungoides is a cutaneous T-cell lymphoma.  Proliferating CD4+ atypical lymphocytes infiltrate the dermis and epidermis, where they form Pautrier microabscesses.  This condition manifests with plaques (often on trunk or buttocks) that may be confused with eczema or psoriasis.  Generalized erythema and scaling and thickening of the skin (erythroderma) may result. Educational objective: Follicular lymphoma is the most common indolent non-Hodgkin lymphoma in adults.  It is of B-cell origin and presents with painless waxing and waning (ie, fluctuating) lymphadenopathy.  The cytogenetic change t(14;18) is characteristic and results in overexpression of the BCL2 oncogene.

A 36-year-old man presents to your office with persistent fever, bleeding gums, and a sore throat.  Peripheral blood microscopy findings are shown in the image below. his peripheral blood smear shows myeloblasts, which are large myelogenous cells with abundant basophilic cytoplasm and large nuclei that can be folded or bilobed.  Myeloblasts often have a number of coarse rod/needle-shaped intracytoplasmic granules (eg, Auer rods) that stain positive for myeloperoxidase.  Auer rods indicate myeloid differentiation. Acute promyelocytic leukemia (APL) is a variant of acute myeloid leukemia (AML), in which immature cells of myeloid origin are unable to differentiate and mature.  They proliferate in the bone marrow and suppress the growth and multiplication of other hematopoietic precursors.  The clinical manifestations of APL, such as anemia (fatigue, pallor), thrombocytopenia (petechiae, hemorrhages), and neutropenia (fever, opportunistic infections), result from marrow replacement by leukemic cells. (Choice A)  Major basic protein is found in eosinophil granules and helps to defend against parasites. (Choice C)  Platelet-derived growth factor receptor mutations play a role in gastrointestinal stromal tumors. (Choice D)  Hairy cell leukemia stains positively for tartrate resistant acid phosphatase (TRAP).  The neoplastic cells are mature B cells and are CD20+.  Hairy cell leukemia presents with splenomegaly, fatigue ,and pancytopenia. (Choice E)  Terminal deoxynucleotidyl transferase (TdT) is responsible for adding nucleotides to the V, D and J regions of the antibody gene for antibody diversity.  It is a marker of immature lymphocytes, both B and T cells.  Neoplastic cells in acute lymphoblastic leukemia (ALL) are TdT positive.  ALL mainly affects children. Educational Objective: Auer rods are deformed azurophilic granules found in the cytoplasm of myeloblasts that stain positively for myeloperoxidase.  Auer rods are found in abundance in AML M3 (acute promyelocytic leukemia).

A 60-year-old man undergoes lymph node biopsy due to persistent cervical lymphadenopathy.  Histologic examination reveals a population of small lymphoid cells arranged in a follicular pattern.  The cells demonstrate overexpression of the BCL2 gene.  The protein encoded by this gene normally inhibits which of the following processes? poptosis (ie, programmed cell death) is a strictly controlled method of cell death that allows for the degradation and removal of cells without evoking an inflammatory response.  BCL2 protein functions as an inhibitor of the intrinsic (ie, mitochondrial) apoptotic pathway. Apoptosis involves triggering a cascade of proteolytic caspase enzymes.  In the mitochondrial pathway, caspase activation occurs via the movement of cytochrome c protein from the mitochondrial intermembrane space to the cytoplasm.  The BCL2 protein family regulates the ability of cytochrome c to permeate the mitochondrial outer membrane.  This protein family includes both proapoptotic members (eg, BAX, BAK), which increase the permeability of the membrane via pore formation, and antiapoptotic members (eg, BCL2, BCL-XL), which preserve membrane integrity and prevent the release of cytochrome c. The characteristic cytogenetic abnormality associated with follicular lymphoma, a mature B-cell lymphoma, is a translocation involving the BCL2 gene on chromosome 18 and the immunoglobulin heavy-chain gene on chromosome 14 [t(14;18)].  This results in overexpression of BCL2 protein, which allows the neoplastic cells to evade apoptosis. (Choice B)  Mutations of genes responsible for DNA mismatch repair (eg, MSH2) can be seen in disorders such as hereditary nonpolyposis colon cancer (ie, Lynch syndrome).  This condition is characterized by a familial predisposition to colon cancer and other visceral malignancies (eg, endometrial cancer). (Choice C)  Retinoblastoma (Rb) is a tumor suppressor protein that regulates cell cycle progression.  When active, Rb binds E2F transcription factors, prevents transcription, and blocks progression through the G1/S checkpoint. (Choice D)  RAS protein is a component of the mitogen-activated protein (MAP) kinase pathway, a signaling system that regulates cell proliferation via transmission of stimuli from the cell surface receptor to the nucleus.  Neurofibromin, encoded by the NF1 gene, is a tumor suppressor protein that inhibits RAS function. (Choice E)  Telomeres are DNA sequences found at the ends of chromosomes that are shortened with cellular division, eventually leading to growth arrest.  Telomerase is an RNA-dependent DNA polymerase that prevents shortening of telomeres.  The majority of cancer cells show increased telomerase activity, thereby avoiding growth arrest and facilitating continuous cell proliferation. Educational objective: BCL2 protein inhibits apoptosis by blocking the release of proapoptotic factors (eg, cytochrome c protein) from the mitochondria.  BCL2 is overexpressed in follicular lymphoma secondary to the t(14;18) translocation involving BCL2 and immunoglobulin heavy-chain genes.

A 15-year-old boy is brought to the emergency department due to progressive shortness of breath.  The patient has no chronic medical conditions.  Temperature is 37.1 C (98.8 F), pulse is 130/min, and respirations are 32/min.  Pulse oximetry is 94% on room air.  Lung examination demonstrates diffusely diminished breath sounds.  Clusters of enlarged cervical lymph nodes are palpable bilaterally.  A large mediastinal mass is visualized on chest x-ray.  The leukocyte count is elevated, and a peripheral blood smear shows abnormal white blood cells, as shown in the image below: his patient's peripheral blood smear demonstrates blast cells characterized by large nuclei, scant cytoplasm, visible nucleoli, and immature (ie, fine) chromatin.  These early hematologic precursors normally comprise a small percentage in the bone marrow but, with malignant transformation, can proliferate and be detected in peripheral blood (eg, acute leukemia). The presence of myeloperoxidase (MPO) helps determine whether blasts are lymphoid or myeloid in origin.  Because MPO is an enzyme involved in microbial killing by myeloid derivatives (eg, neutrophils), it is absent in lymphoid cells.  In addition, positive terminal deoxynucleotidyl transferase (TdT) indicates lymphoblasts; TdT is a DNA polymerase involved in V(D)J recombination, which generates antigen receptor diversity during early lymphoid maturation.  Therefore, negative MPO and positive TdT confirm that these are lymphoblasts. Lymphoblasts are further differentiated by markers unique to B (eg, CD19) or T (eg, CD3) cells.  This patient's CD3-positive lymphoblasts indicate T-lymphoblastic leukemia (T-ALL).  Unlike B-lymphoblastic leukemia (B-ALL), which usually occurs in early childhood, T-ALL is most common in adolescence.  Tumors classically develop in the thymus, the site of T-cell development, and often result in the formation of a mediastinal mass that compresses the airway, causing cough and dyspnea, or the nearby blood vessels, causing superior vena cava syndrome. (Choice A)  Acute myeloid leukemia arises from myeloid precursors (myeloblasts), and cells therefore express MPO, not CD3 and TdT. (Choice B)  B-ALL, the most common ALL subtype, expresses TdT.  However, expression of B-cell surface markers (eg, CD19) would be expected.  In addition, presentation usually involves signs of bone marrow failure (eg, pallor, bruising) in young children, not a mediastinal mass in an adolescent. (Choice C)  Burkitt lymphoma, a malignancy derived from mature B cells, can present with disseminated disease involving the bone marrow.  An enlarging mass can be seen, but it is usually in the abdomen or jaw, not the mediastinum.  Cells express B-cell, not T-cell, markers.  Because Burkitt lymphoma is composed of mature B cells, TdT is negative. (Choice D)  Hodgkin lymphoma can present with a mediastinal mass and painless lymphadenopathy.  Circulating blasts are not typical.  Instead, Reed-Sternberg cells (large cells with multilobated nuclei and eosinophilic nucleoli) within lymph nodes are characteristic.  Because they arise from mature germinal or post–germinal center B cells, TdT is negative. Educational objective: T-lymphoblastic leukemia (T-ALL) is characterized by circulating lymphoblasts that express terminal deoxynucleotidyl transferase (TdT) and CD3.  T-ALL often presents in adolescents/young adults with a mediastinal mas

A 24-year-old, previously healthy woman comes to the hospital due to a 3-day history of fever, dyspnea, and cough productive of yellow sputum.  Temperature is 38.8 C (101.8 F), blood pressure is 110/66 mm Hg, and pulse is 110/min.  The patient has bronchial breath sounds and crackles over the right lower lung.  Laboratory results are as follows: Hemoglobin 13 g/dL Platelets 350,000/mm3 Leukocytes 54,000/mm3     Neutrophils 65%     Band forms 10%     Myelocytes 3%     Metamyelocytes 1%     Lymphocytes 15% The leukocyte alkaline phosphatase test score is elevated.  Which of the following is the most likely finding on this patient's peripheral blood smear? his patient most likely has pneumonia with sepsis and an associated leukemoid reaction, a significant leukocytosis (may exceed 50,000/mm3) that occurs in response to an underlying inflammatory condition (eg, severe infection, hemorrhage, solid tumors).  Release of colony-stimulating factors and inflammatory mediators into the circulation causes the bone marrow to increase the production of leukocytes, resulting in leukocytosis. Blood smear typically shows numerous mature neutrophils, which may have reactive morphologic features, such as Döhle bodies (blue cytoplasmic inclusions of rough endoplasmic reticulum), toxic granulation, and cytoplasmic vacuoles.  Increased neutrophil precursors (eg, bands, metamyelocytes, myelocytes) are also typically present (referred to as "left shift") due to early release from the marrow in response to the increased demand of the inflammatory condition. Assessment of leukocyte alkaline phosphatase (an enzyme found in maturing neutrophils) can be used to distinguish marked leukocytosis due to leukemoid reaction from chronic myeloid leukemia (CML).  Values are typically normal or increased in leukemoid reaction; in contrast, they are usually low in CML because the abnormal maturing neutrophils have decreased levels of this enzyme. (Choice B)  Basophilic stippling refers to small, blue granules (ribosomal precipitates) in the cytoplasm of red blood cells.  It is most often seen in thalassemia, alcohol use disorder, and lead/heavy metal poisoning.  This patient's acute presentation and laboratory results are more consistent with leukemoid reaction. (Choice C)  Hypersegmented neutrophils show ≥6 nuclear lobes and are a feature of megaloblastic anemia, often due to vitamin B12 or folate deficiency.  This patient's normal hemoglobin makes this unlikely. (Choice D)  The presence of numerous blasts with cytoplasmic Auer rods (fused azurophilic granules) in the blood smear would be concerning for acute myeloid leukemia.  This patient's laboratory results show mainly mature neutrophils with increased neutrophil precursors (eg, bands, metamyelocytes, myelocytes) but not blasts. (Choice E)  Small lymphoid cells with cleaved nuclei are seen in certain types of lymphoma, particularly follicular lymphoma, a mature B-cell neoplasm.  This patient's clinical symptoms and neutrophilia with left shift are more consistent with leukemoid reaction. Educational objective: Leukemoid reaction is a significant leukocytosis (may exceed 50,000/mm3) that occurs in response to an underlying condition, commonly severe infection.  Blood smear often shows neutrophilia with reactive features (eg, Döhle bodies), as well as increased neutrophil precursors (eg, bands, metamyelocytes, myelocytes).  The leukocyte alkaline phosphatase score is normal or increased.

A 65-year-old man comes to the office due to 4 months of worsening fatigue.  The patient feels tired with simple household chores.  He has a 15-pack-year smoking history and drinks 2 or 3 beers daily.  Temperature is 37 C (98.6 F), blood pressure is 134/86 mm Hg, and pulse is 76/min.  Physical examination reveals a late systolic ejection murmur with a soft S2.  The lungs are clear to auscultation.  The abdomen is soft and nontender with no hepatosplenomegaly.  There are no focal neurological deficits.  Laboratory testing reveals hemoglobin is 9 g/dL and mean corpuscular volume is 93 µm3.  Peripheral blood smear is shown below: his patient's peripheral blood smear shows rows of erythrocytes stacked on one another like coins (rouleaux formation).  This occurs due to elevated levels of circulating proteins, which disrupts the repulsive electrostatic charge on the erythrocyte surface and causes stacked aggregation.  Although rouleaux formation can be seen with inflammatory conditions (eg, infection, rheumatic disease) that increase acute-phase reactants (eg, fibrinogen), it is classically linked to lymphoproliferative/plasma cell disorders such as multiple myeloma and Waldenstrom macroglobulinemia, which generate high levels of monoclonal paraprotein (immunoglobulins). Multiple myeloma is a plasma cell malignancy often associated with normocytic anemia, osteolytic bone lesions, and hypercalcemia due to proliferation of neoplastic cells in the bone marrow.  Patients also frequently have renal insufficiency (due to immunoglobulin light-chain cast nephropathy) and nonspecific symptoms (eg, fatigue).  Diagnosis is generally made using serum/urine protein electrophoresis (monoclonal M-spike) and bone marrow biopsy. (Choice A)  Chronic gastrointestinal blood loss is a leading cause of iron-deficiency anemia, which usually results in microcytosis and hypochromia on peripheral smear (sometimes with target cells).  Rouleaux formation and normocytic erythrocytes would be atypical. (Choice B)  Cold agglutinins are cross-reactive IgM antibodies that form with some infections (particularly Mycoplasma pneumoniae) and hematologic malignancies.  Cold agglutinins typically cause clumping agglutination (not stacked-coin agglutination) and hemolysis. (Choice D)  Mechanical erythrocyte injury is common in patients with damaged or artificial heart valves.  Although this patient has a cardiac murmur that indicates possible aortic stenosis, mechanical erythrocyte injury is usually associated with schistocytes on peripheral blood smear, not rouleaux formation. (Choice E)  Vitamin B12 deficiency causes abnormal hematologic cell nuclear maturation, which leads to macrocytic anemia and hypersegmented neutrophils on peripheral blood smear. Educational objective: Multiple myeloma is associated with elevated circulating paraproteins (monoclonal immunoglobulins), which causes erythrocytes to stack like coins (rouleaux formation).  Patients classically have normocytic anemia, hypercalcemia, bone pain, and renal insufficiency.

rouleux formation seen in what all other DD

A 59-year-old man comes to the office due to 3 months of progressive fatigue and back pain.  The back pain occurs mainly with movement or positional changes.  Physical examination reveals midline tenderness over the middle and lower back.  Laboratory evaluation shows a hemoglobin level of 10.2 g/dL and serum calcium level of 12 mg/dL.  A bone marrow aspirate is performed, and the histopathologic findings are shown below. his patient's bone marrow aspirate shows numerous plasma cells, which can be identified by abundant basophilic cytoplasm, eccentric nuclei, well-developed Golgi apparatus (perinuclear paleness), and "clock-face" (peripheral) chromatin.  A bone marrow sample with >10% plasma cells is strongly suggestive of multiple myeloma (MM), a clonal plasma cell malignancy. In MM, neoplastic plasma cells: Replicate in the bone marrow and choke out normal hematopoiesis, leading to normocytic, normochromic anemia (impaired erythropoiesis) and increased risk of infection (impaired B-cell lymphopoiesis). Secrete osteolytic cytokines, leading to bone pain, osteolytic (radiolucent) bone lesions, and hypercalcemia. Produce large quantities of monoclonal immunoglobulin (paraprotein) composed of heavy and light chains (eg, IgG, IgA) or light chains alone.  Light chains can deposit in the renal tubules, leading to light-chain cast nephropathy, which is usually characterized by mild renal insufficiency and waxy, laminated urinary casts (Bence Jones). Light chains can also form insoluble fibrils and deposit in major organs, leading to amyloid light-chain amyloidosis.  This can contribute to the already elevated risk of renal failure as well as heart failure and neurologic dysfunction.  Amyloidosis can often be identified on biopsy using hematoxylin and eosin stain (eosinophilic extracellular deposits) or Congo red stain viewed under polarized light (apple-green birefringence). (Choice B)  Cardiac tamponade can be associated with some neoplasms (eg, lung, breast) due to tumor invasion of the pericardium.  MM does not typically cause pericardial disease; therefore, it is not associated with cardiac tamponade. (Choice C)  Hepatic failure is most often linked to viral hepatitis or chronic alcohol use.  It occasionally occurs due to malignant infiltration of the liver (eg, lymphoma, breast cancer); however, risk of hepatic failure with MM is low; amyloidosis is a far more common complication. (Choice D)  Hyperthyroidism is most often due to Graves disease, an autoimmune disorder that generates TSH-receptor antibodies.  It can also be seen with medications (eg, lithium) and tumors that produce TSH (eg, pituitary adenoma).  MM is not linked to hyperthyroidism. (Choice E)  Meningeal carcinomatosis is a rare condition associated with some solid tumors (eg, breast cancer, lung cancer, melanoma).  Tumor spread to the leptomeninges can cause mass effect (eg, headache, hydrocephalus), cranial/spinal nerve dysfunction, and focal neurologic issues.  MM does not typically spread to the leptomeninges. (Choice F)  Atraumatic splenic rupture can occur with leukemia and lymphoma due to massive splenomegaly from extramedullary hematopoiesis and/or underlying tumor infiltration.  MM does not typically cause significant extramedullary hematopoiesis and usually replicates in the bone marrow, not the spleen. Educational objective: Amyloid light-chain amyloidosis is associated with multiple myeloma and other monoclonal plasma cell dyscrasias due to the deposition of insoluble immunoglobulin light-chain fibrils in major organs (eg, kidneys, heart, neurologic system).  A bone marrow sample with >10% plasma cells is strongly suggestive of multiple myeloma.

A 63-year-old man comes to the office due to fatigue and easy bruising.  He has no lymphadenopathy on physical examination.  Laboratory results are as follows: Complete blood count     Hemoglobin 8.0 g/dL     Platelets 40,000/mm3     Leukocytes 20,500/mm3 The patient's peripheral blood smear is shown in the image below: this patient's peripheral blood smear shows very large nucleated cells (see red cell size for comparison) with scant cytoplasm.  These are blast cells, the finding of which makes acute leukemia likely.  Closer examination of the smear reveals linear, purple-red inclusions in some of the cells, called Auer rods.  These represent fused granules and may be single or multiple within immature myeloid precursors.  Auer rods are highly suggestive of acute myeloid leukemia (AML) but not of acute lymphoblastic leukemia (ALL) (Choice A).  Although Auer rods are most commonly associated with the M1, M2, and M3 subtypes of AML, they may be found in any type of AML. The vast majority of AML cases occur in adults, with a median age of 65 and median white blood cell count of about 15,000/mm3 at diagnosis.  Most patients present with complications of pancytopenia (eg, fatigue from anemia, bruising/bleeding from thrombocytopenia, infection from functional neutropenia [despite leukocytosis]).  Diagnostic criteria generally require the presence of >20% myeloblasts in the bone marrow or peripheral blood. (Choices C and D)  Chronic leukemia causes a prevalence of mature cells in the peripheral blood.  In chronic myeloid leukemia (CML), peripheral smears usually show many mature granulocytes and few blasts (generally <2%).  In chronic lymphocytic leukemia (CLL), smears show many mature lymphocytes. (Choice E)  Patients with hairy cell leukemia have splenomegaly, cytopenias, and circulating hairy cells.  On peripheral blood smear, hairy cells take the appearance of small- to medium-sized lymphoid cells with circumferential "hairy" projections. (Choice F)  Patients with Hodgkin lymphoma generally present with a mass (eg, mediastinal mass, enlarged lymph nodes).  The finding of circulating neoplastic cells is extremely rare.  Histologically, Reed-Sternberg cells are characteristic.  These are large cells with abundant basophilic cytoplasm and >2 nuclear lobes or nuclei. (Choice G)  Patients with infectious mononucleosis have fatigue, lymphadenopathy, and splenomegaly.  Thrombocytopenia can be a complication of this infection.  Peripheral blood smear will show few circulating atypical lymphocytes, not numerous blasts. Educational objective: The finding of Auer rods (linear purple-red inclusions within immature myeloid precursors) is helpful in making the diagnosis of acute myeloid leukemia.  Auer rods are not found in acute lymphoblastic leukemia.  In chronic myeloid leukemia, there are more mature cells and fewer blasts.

A 30-year-old man comes to the emergency department due to rapidly increasing abdominal distention and anorexia.  The patient has a history of HIV infection and intravenous drug use.  CT scan of the abdomen shows ascites and a large mass involving the small intestine.  Biopsy of the mass reveals sheets of uniform, round, medium-sized tumor cells with basophilic cytoplasm and a very high rate of proliferation and apoptosis.  Which of the following infectious agents is most closely associated with the development of this patient's condition? this patient with rapidly increasing abdominal distention and abdominal mass has histopathology consistent with Burkitt lymphoma (BL), an aggressive B-cell malignancy.  Epstein-Barr virus (EBV) is the infectious agent most strongly associated with BL pathogenesis. EBV infects B cells via the CD21 complement receptor.  Infected cells produce viral proteins that stimulate signaling pathways (eg, JAK/STAT), triggering proliferation.  This proliferation of infected B cells is usually limited by T cells, but some B cells may reduce production of EBV antigens and escape recognition.  An impaired immune response (eg, HIV, persistent malaria) can also enable continuous B-cell division.  Proliferating B cells are more likely to acquire genetic abnormalities (eg, chromosomal translocations), resulting in a neoplastic clone.  BL cells harbor the translocation t(8;14), which causes MYC overexpression, uncontrolled cell growth, and rapid enlargement. Nonendemic BL often involves the gastrointestinal tract, which can present as an enlarging abdominal mass with ascites (due to lymph obstruction) and distention.  Histopathology shows uniform, medium-sized lymphoid cells with basophilic cytoplasm and numerous mitotic figures (indicating high proliferation rate) and apoptotic bodies.  Scattered macrophages, which digest the apoptotic debris, produce the characteristic "starry sky" appearance. (Choice B)  Helicobacter pylori is associated with gastric lymphoma (eg, marginal zone lymphoma of mucosa-associated lymphoid tissue [ie, MALT lymphoma]).  Gastrointestinal MALT lymphomas may cause abdominal discomfort but are typically indolent and slow growing (ie, would have lower proliferation rate).  Rapid abdominal distention would be unusual. (Choice C)  Chronic hepatitis B can cause hepatocellular carcinoma.  Although patients may have abdominal distention and ascites, imaging would reveal a liver mass, not an intestinal lesion.  Histopathology often shows thickened plates of malignant hepatocytes (eg, polygonal cells, eosinophilic cytoplasm). (Choice D)  Human herpesvirus 8 can cause Kaposi sarcoma (KS), a vascular tumor seen in HIV-positive individuals.  Although it can involve the gastrointestinal tract in later stages, KS typically presents initially with cutaneous lesions.  Histopathology often shows spindle-shaped endothelial cells and slit-like vascular spaces. (Choice E)  High-risk human papillomavirus types (eg, 16, 18) have been identified in cervical squamous cell carcinoma.  Histopathology often shows invasive nests of malignant cells with squamous differentiation (eg, intercellular bridges). Educational objective: Burkitt lymphoma, an aggressive B-cell malignancy, can be associated with Epstein-Barr virus infection.  It typically presents as a rapidly growing mass (eg, abdomen).  Histopathology shows sheets of uniform, medium-sized lymphoid cells with numerous mitotic figures (ie, high proliferation rate) and apoptotic bodies.

A 15-year-old girl is evaluated due to persistent fever, fatigue, and sore throat.  Physical examination reveals splenomegaly and symmetric posterior cervical lymphadenopathy.  Peripheral blood smear results are shown in the image below: his patient's fever, fatigue, sore throat, splenomegaly, symmetric posterior cervical lymphadenopathy, and atypical lymphocytosis are characteristic of infectious mononucleosis (IM).  After entering the bloodstream through the pharyngeal mucosa and tonsillar crypts, the Epstein-Barr virus (EBV) preferentially infects B lymphocytes by binding to CD21 cell surface receptors.  EBV-infected B lymphocytes then activate cytotoxic T lymphocytes (CD8+) through the presentation of viral antigens on major histocompatibility complex class I molecules.  These reactive (atypical) CD8+ T lymphocytes are the primary immune response to EBV and clonally expand to destroy virus-infected cells. Atypical lymphocytes make up more than 10% of the cells in a peripheral blood smear in IM, and most (>95%) of those cells are CD8+ T lymphocytes.  They classically appear much larger than quiescent lymphocytes, with abundant basophilic cytoplasm and a cell membrane that conforms to the borders of neighboring cells.  Although activated CD21+ B lymphocytes and CD4+ helper T lymphocytes can have a similar appearance in response to EBV infection, they make up <5% of the atypical lymphocytes in the peripheral circulation (Choices A and D). (Choice C)  Monocytosis can be seen with chronic infections and may be associated with persistent fever, fatigue, and splenomegaly; however, monocytes typically have vacuolated, grayish cytoplasm. (Choice E)  Activated plasma cells appear as ovoid cells with abundant cytoplasm and an eccentric nucleus with a spoke-wheel chromatin pattern.  A zone of perinuclear clearing within the cytoplasm may also be noted, corresponding to the active Golgi body. Educational objective: The primary immune response to Epstein-Barr virus is mediated by CD8+ T lymphocytes, which are activated through the presentation of viral antigens on infected CD21+ B lymphocytes.  These reactive (atypical) CD8+ T lymphocytes can be observed in the peripheral blood smears of patients with infectious mononucleosis.

A 28-year-old previously healthy man comes to the office due to episodic fevers, night sweats, and weight loss for several months.  He emigrated from Kenya with his family at age 14.  He does not use tobacco, alcohol, or illicit drugs.  The patient works as a driving instructor and volunteers at a homeless shelter.  His temperature is 37.2 C (99 F).  Physical examination is normal with the exception of cervical lymphadenopathy.  A lymph node biopsy is performed, and histopathologic findings are shown in the image below. his patient most likely has classic Hodgkin lymphoma (HL).  The typical presentation is either nontender lymphadenopathy or lymphadenopathy incidentally detected on routine chest x-ray.  Many patients develop associated systemic B symptoms (fevers, night sweats, weight loss).  HL has a bimodal age distribution with a peak in the 20s (or younger in some countries) and another in the 60s.  The complete blood count and peripheral blood smear are usually unremarkable. A lymph node biopsy can distinguish HL from benign causes of lymphadenopathy.  The key to diagnosing classic HL is detecting the characteristic Reed-Sternberg (RS) cell on hematoxylin and eosin preparation.  RS cells have ample cytoplasm, a multilobed nucleus or multiple nuclei, and inclusion-like nucleoli.  RS cells are seen against a background of lymphocytes, histiocytes, and eosinophils in classic HL. (Choice A)  Burkitt lymphoma often presents as a mass in the abdomen/pelvis (or the jaw in the endemic [African] form, which has a peak incidence in boys around age 5).  However, histology would show a monotonous population of medium-sized lymphoid cells with many tingible body macrophages, giving a "starry sky" appearance.  High numbers of mitotic cells and apoptotic bodies would be seen. (Choice B)  Follicular lymphoma shows aggregates of closely packed, neoplastic lymph node follicles.  Two major cell types, centrocytes (small cleaved cells) and centroblasts (large noncleaved cells), are observed.  Older adults tend to be affected.  Waxing and waning painless lymphadenopathy (typically without B symptoms) is common. (Choice D)  Large B-cell lymphoma is characterized by diffuse sheets of large, atypical lymphoid cells with nuclei at least 5 times the size of small lymphocytes.  RS cells against a background of mixed inflammation is not a characteristic histologic feature of large B-cell lymphoma. (Choice E)  Multiple myeloma, a plasma cell dyscrasia characterized by proliferation of clonal plasma cells, is predominantly a disease of the elderly.  It is characterized by osteolytic lesions, although spread to nodal and extranodal sites can occur. (Choice F)  Tuberculosis is on the differential diagnosis for this patient, who is from Kenya, volunteers at homeless shelters, and has had night sweats and weight loss.  However, histology in tuberculosis would show caseating granulomas, not RS cells. Educational objective: The presence of Reed-Sternberg (RS) cells on lymph node biopsy is a diagnostic feature of classic Hodgkin lymphoma.  RS cells have abundant cytoplasm, a multilobed nucleus or multiple nuclei, and inclusion-like nucleoli.

A 45-year-old man comes to the office due to a week of purulent nasal discharge, headache, sore throat, and nonproductive cough.  He has no significant past medical history except for an episode of infectious mononucleosis at age 22.  The patient smokes a pack of cigarettes daily.  His temperature is 38 C (100.4 F).  He has maxillary sinus tenderness, pharyngeal erythema, and tender anterior cervical lymphadenopathy.  Laboratory results are as follows: Leukocytes 58,000/mm3     Neutrophils 42%     Myelocytes 30%     Metamyelocytes 8%     Band forms 1%     Blast cells 1%     Eosinophils 6%     Basophils 4% is patient with sinusitis is found to have a markedly elevated white blood cell (WBC) count with an increase in myeloid precursor forms on peripheral blood smear.  The differential diagnosis is chronic myelogenous leukemia (CML) (uncontrolled mature granulocyte production, mostly neutrophils but also basophils and eosinophils) or leukemoid reaction (over-exuberant WBC response associated with bacterial infection or malignancy, among others).  Both cause an elevated WBC count (>50,000/mm3) with an increase in precursor forms (eg, bands, metamyelocytes, myelocytes).  However, the enzyme leukocyte (neutrophil) alkaline phosphatase is decreased in CML (as seen in this patient) because the WBCs are cytochemically abnormal; by contrast, it is normal or elevated in a leukemoid reaction (Choice I). Other clues to the diagnosis of CML are the predominance of myelocytes compared to more mature forms such as metamyelocytes ("myelocytic bulge") and the absolute basophilia and eosinophilia.  CML is confirmed by demonstration of the Philadelphia chromosome (translocation between chromosomes 9 and 22) or the BCR-ABL1 fusion gene or mRNA.  Immature blast cells (eg, myeloblasts, promyelocytes) are typically <2%.  Management generally includes a tyrosine kinase inhibitor. (Choice A)  This patient has an abnormality of myeloid (not lymphoid) cells and his smear shows only 1% blasts.  In general, >25% bone marrow lymphoblasts are seen in acute lymphoblastic leukemia, which is much more common in young children. (Choice B)  Acute myelogenous leukemia is the most common acute leukemia in adults.  However, the mean age at diagnosis is around 65, and most patients will have a WBC count of about 15,000-20,000/mm3 with a significant increase in blast cells (eg, >20%) rather than the 1% seen in this patient. (Choices C, F, and G)  Follicular lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma cause lymph node and/or soft-tissue (not peripheral blood) abnormalities.  In addition, these cancers are all lymphoid, not myeloid, in nature. (Choice D)  Patients with chronic lymphocytic leukemia have increased circulating mature lymphoid cells, not increased myeloid cells. (Choices H and J)  Parasitic superinfection (which can lead to eosinophilia) and fungal infection would not explain the predominance of myeloid neutrophil precursor forms in this patient. Educational objective: Chronic myelogenous leukemia (CML) and leukemoid reaction can have presentations similar to leukocytosis; however, leukocyte (neutrophil) alkaline phosphatase level is normal or elevated in a leukemoid reaction but decreased in CML.  The definitive diagnosis of CML requires demonstration of the Philadelphia chromosome t(9;22) or BCR-ABL fusion gene or mRNA.

A 52-year-old man comes to the office due to a progressively enlarging neck mass, fatigue, and weight loss over the past 2 months.  Physical examination shows enlarged, firm, and nontender cervical lymph nodes.  The patient also has enlarged tonsils, bilateral axillary lymphadenopathy, and splenomegaly.  Excisional lymph node biopsy reveals diffuse sheets of atypical, large B cells that have replaced the normal tissue architecture.  In situ hybridization of the tissue specimen is positive for Epstein-Barr virus.  Which of the following risk factors is most strongly associated with development of this patient's condition his patient likely has non-Hodgkin lymphoma (NHL).  Depending on the subtype, NHL may present with a rapidly progressive mass, lymphadenopathy, splenomegaly, and B symptoms (eg, night sweats, weight loss).  Diagnosis is typically made with excisional lymph node biopsy, which usually demonstrates a loss of normal tissue architecture with expansion of abnormal lymphocytes (most often B cells, as in this patient with large, atypical B cells). Lymphoma is frequently associated with Epstein-Barr virus (EBV), a ubiquitous herpesvirus that primarily infects B lymphocytes and causes persistent latent infections.  Although viral reactivation is uncommon, the latent EBV genome still transcribes viral gene products that can result in malignant transformation of infected cells.  EBV is particularly associated with nasopharyngeal carcinoma, Hodgkin lymphoma, and some forms of NHL (eg, Burkitt lymphoma). Patients with HIV are at greatest risk for EBV-associated lymphomas (risk is up to 60-fold greater).  This is likely due to HIV-related immune dysregulation, which decreases recognition of EBV-infected cells and promotes B-cell proliferation.  Some types of NHL (eg, primary central nervous system lymphoma) are considered AIDS-defining conditions and can sometimes be the presenting manifestation of HIV infection. (Choice B)  Aspirin and nonsteroidal anti-inflammatory drugs may decrease the risk of colorectal cancer.  Their use is not linked to an increased risk of NHL. (Choice C)  Cigarette smoking is a strong risk factor for the development of many types of cancer (eg, lung, bladder, pancreas) but is not closely linked with the development of NHL. (Choice D)  The link between radiation exposure and the development of NHL is controversial.  However, most studies indicate that this is not a strong risk factor. (Choice E)  Although lower socioeconomic status may be associated with worse outcomes in patients with NHL, this marker has not been closely linked with the development of NHL. Educational objective: Patients with HIV have much higher rates of lymphoma than the general population.  Many cases are due to underlying Epstein-Barr virus infection, which acts synergistically with HIV to promote uncontrolled B lymphocyte proliferation.

A 46-year-old smoker presents to your office with a three week history of low-grade fever, weakness and neck swelling. Biopsy of the affected tissue reveals the following histologic findings: order to answer this question, you must be able to recognize the characteristic histology.  The tissue biopsy shows numerous lymphocytes (small cells with dark, round nuclei and a small rim of cytoplasm), meaning that it was most likely taken from a lymph node.  The key finding is the giant binucleated cell, a Reed-Sternberg (RS) cell, in the center of the slide.  RS cells are derived from germinal center B-lymphocytes and are the neoplastic cells of Hodgkin lymphoma (HL).  RS cells must be present in order to make the diagnosis of HL.  The two mirror-image nuclei of RS cells are often described as having the appearance of "owl's eyes." (Choice A)  The respiratory epithelium is a pseudostratified columnar ciliated epithelium that extends down to the level of the bronchioles.  At the bronchioles, the epithelium gradually becomes cuboidal and then transitions to a flat, single-celled alveolar lining of Type I pneumocytes. (Choice B)  A goiter may cause neck swelling.  Histologically, Hashimoto thyroiditis has the appearance of lymphocytes infiltrating between thyroid follicles. (Choice D)  Reed-Sternberg cells are not associated with leukemia.  The classic finding in patients with leukemia is a peripheral blood smear with leukemic cells, leukocytosis and thrombocytopenia. (Choice E)  Both melanoma and squamous cell carcinoma can metastasize from the skin causing lymphadenopathy.  The cells on this tissue biopsy show no evidence of squamous or melanocytic differentiation, however. Educational Objective: Reed-Sternberg cells are large binucleated cells with an "owl's eyes" appearance that appear on a background of lymphocytic infiltrates.  Reed-Sternberg cells must be present histopathologically in order to make the diagnosis of Hodgkin lymphoma.

A 6-year-old boy is brought to the clinic due to recurrent nosebleeds over the last couple of weeks.  The patient has no chronic medical conditions and takes no medications.  Vital signs are normal.  On physical examination, there is conjunctival pallor.  The nares have dried, crusted blood with no active bleeding.  The oropharynx is clear.  Neck examination shows enlarged, palpable lymph nodes bilaterally.  Cardiopulmonary examination is unremarkable.  The abdomen is soft and nontender, with the liver measuring 4 cm below the costal margin.  There are scattered petechiae along the trunk.  Complete blood count is as follows: Hemoglobin 9.0 g/dL Platelets 20,000/mm3 Leukocytes 35,500/mm3 Flow cytometry of the peripheral blood demonstrates a distinct population of cells that express terminal deoxynucleotidyl transferase (TdT), CD10, and CD19.  Myeloperoxidase (MPO) is negative.  Which of the following is the most likely diagnosis? his child with marked leukocytosis has lymphadenopathy, hepatomegaly, and signs of bone marrow failure (eg, pallor from anemia, bleeding/petechiae from thrombocytopenia).  These findings are concerning for acute leukemia, which occurs due to clonal expansion of hematopoietic progenitor cells (ie, blast cells).  Blasts may be either lymphoid or myeloid in origin.  Immunophenotyping (eg, flow cytometry) is used to characterize blast cells and classify acute leukemia. This patient's cells are lymphoid in origin.  Lymphoid cells typically lack myeloperoxidase (MPO), an enzyme involved in microbial killing by myeloid derivatives (eg, neutrophils).  Immature lymphocytes (lymphoblasts) can be differentiated from mature lymphocytes by the presence of terminal deoxynucleotidyl transferase (TdT); TdT is a DNA polymerase involved in V(D)J recombination, which generates antigen receptor diversity during early lymphoid maturation.  Therefore, this patient has acute lymphoblastic leukemia (ALL). ALL can be subdivided into B-lymphoblastic leukemia (B-ALL) or T-lymphoblastic leukemia (T-ALL) based on the following markers: B lymphoblasts:  CD10, CD19, CD20, CD22, CD79a (typically CDs ≥10) T lymphoblasts:  CD2, CD3, CD4, CD5, CD7, CD8 (typically CDs <10) This patient's cells express both CD10 and CD19, findings consistent with B-ALL. (Choice A)  Acute promyelocytic leukemia (APML), a type of acute myeloid leukemia, can also present with bone marrow failure.  However, APML would not express TdT, CD19, and CD10.  Blast features that indicate a myeloid lineage include the expression of MPO and presence of Auer rods (needle-like cytoplasmic structures representing fused granules). (Choice C)  Burkitt lymphoma can present with lymphadenopathy and disseminated disease, including bone marrow failure.  Although the malignant cells express B-cell markers (eg, CD19), they do not express TdT because the cell of origin is a mature, not a progenitor, B cell. (Choice D)  Mature T-cell leukemia is derived from mature or postthymic T cells, and immunophenotyping would reveal the presence of T-cell markers (eg, CD3) and the absence of TdT.  Moreover, this is an uncommon neoplasm typically seen in adults, not young children. (Choice E)  Immunophenotyping of cells in T-ALL, which typically presents in adolescents with a mediastinal mass, would show expression of TdT but would also express T-cell, not B-cell, markers. Educational objective: Acute lymphoblastic leukemia typically presents with signs/symptoms of bone marrow failure (eg, bleeding due to thrombocytopenia).  Immunophenotyping by flow cytometry establishes the specific subtype; B-lymphoblastic leukemia shows expression of terminal deoxynucleotidyl transferase (TdT) (marker expressed in lymphoblasts) and B-cell markers (eg, CD10, CD19).

A 64-year-old man is brought to the hospital by ambulance after being found unresponsive by his brother.  Despite resuscitative efforts, he dies shortly thereafter.  The family reports that the patient had 2 months of progressive fatigue and an unintentional weight loss prior to the episode.  Autopsy examination reveals a massive pulmonary embolus, and a cross-section of the liver shows the following: he cross-section of the liver shows a large, solid, yellow-green nodule with multiple smaller nodules, consistent with hepatocellular carcinoma (HCC).  Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections dramatically increase the risk of HCC.  Ongoing infection with either virus leads to increased hepatocyte turnover, which increases the risk for genetic mutations and malignant transformation.  However, HBV has several additional mechanisms that promote HCC, including the following: Integration into the host genome – Nearly 90% of patients with chronic HBV who develop HCC have evidence of HBV DNA in the chromosomes of tumor cells.  HBV is a partially double-stranded DNA virus that is repaired to form a closed circular DNA strand.  HBV DNA is often inserted into the cellular genome, although this is not required for viral replication (unlike HIV).  Integration into regions that control cell growth and differentiation can result in tumorigenesis. Production of oncogenic viral proteins – HBV produces a viral protein called HBx that is a transcriptional activator of several genes associated with cellular growth.  It also interferes with the function of p53, an important tumor-suppressor protein. (Choices A and C)  Cytomegalovirus and Epstein-Barr virus are members of the Herpesviridae family.  Both have double-stranded DNA genomes and cause acute infection followed by latent infection.  Cytomegalovirus is not particularly associated with cancer, but Epstein-Barr infection is linked to nasopharyngeal carcinoma and hematologic malignancies.  However, neither virus is strongly associated with development of HCC. (Choice B)  Entamoeba histolytica is a protozoal infection that is typically acquired by ingesting contaminated food or water in developing countries.  A minority of patients develop invasive disease with liver abscess.  This usually presents with fever and right-upper quadrant pain; the organism does not incorporate its genome into host cells. (Choice E)  Chronic HCV infection dramatically increases the risk of HCC.  However, HCV is an RNA virus (that does not have reverse transcriptase) and is unable to integrate into the host genome. (Choice F)  Human papilloma virus is a double-stranded DNA virus of the papillomavirus family.  HPV produces oncogenic proteins and is able to integrate into the host chromosome.  However, HPV is not linked with liver cancer; it typically causes cervical and oropharyngeal cancer. Educational objective: Both hepatitis B (HBV) and hepatitis C virus infections increase the risk of hepatocellular carcinoma due to chronic hepatic inflammation and cell turnover.  HBV is also carcinogenic due to the production of oncogenic proteins and the insertion of the HBV genome into host chromosomes.

A 43-year-old man comes to the hospital due to recurrent episodes of fever and sore throat despite multiple antibiotic courses.  For the past several months, he has also felt "run down" and fatigued all the time.  His wife adds that he bruises easily and has had bleeding gums on several occasions.  Temperature is 37.8 C (100.2 F).  On physical examination, he has mucosal pallor, pharyngeal erythema, and multiple ecchymoses on his extremities.  Peripheral blood smear is shown in the image below: his patient has recurrent infections (likely reflecting neutropenia), pallor (anemia), and ecchymoses (thrombocytopenia), with a peripheral blood smear that shows several abnormal myeloid precursors containing rod-shaped intracytoplasmic granules called Auer rods.  This presentation is characteristic of acute myeloid leukemia (AML).  The M3 variant of AML, acute promyelocytic leukemia (APML), is characterized by the presence of abnormal promyelocytes on smear, typically containing abundant cytoplasmic granules, multiple Auer rods, and bilobed nuclei. Affected cells exhibit the cytogenetic abnormality t(15;17).  This cytogenetic change represents a translocation between the retinoic acid receptor alpha (RARα) gene on chromosome 17 and the promyelocytic leukemia (PML) gene on chromosome 15.  Fusion of these 2 genes produces a chimeric gene product, PML/RARα, which codes for an abnormal retinoic acid receptor.  This abnormal fusion gene inhibits promyelocyte differentiation and triggers the development of APML. APML is associated with disseminated intravascular coagulation (ie, bleeding, thrombocytopenia, prolonged prothrombin and activated thromboplastin time).  Prompt management with all-trans retinoic acid is essential. (Choice A)  Burkitt lymphoma is associated with t(8;14).  This translocation between the MYC protooncogene on chromosome 8 and the Ig heavy chain region on chromosome 14 leads to increased production of the MYC oncoprotein.  In the blood smear, the neoplastic cells show basophilic cytoplasm with lipid vacuoles. (Choice B)  Translocation of the ABL1 gene from chromosome 9 to chromosome 22 is characteristic of chronic myeloid leukemia.  t(9;22) forms the Philadelphia chromosome and results in the formation of a new gene, BCR-ABL1, whose product has constitutive tyrosine kinase activity.  Blood smear typically shows numerous mature and immature myeloid cells. (Choice C)  Mantle cell lymphoma is a B-cell malignancy associated with t(11;14).  This translocation results in activation of the cyclin D1 gene.  Blood smear shows lymphoid cells with irregular nuclei. (Choice E)  Deletion of 13q is one of the molecular defects seen in chronic lymphocytic leukemia, which is characterized by small, mature lymphocytes as well as smudge cells in the blood smear. Educational objective: The presence of rod-shaped intracytoplasmic inclusions (known as Auer rods) is characteristic of many forms of acute myeloid leukemia (AML).  The M3 variant of AML, acute promyelocytic leukemia, is associated with the cytogenetic abnormality t(15;17) and typically shows abnormal promyelocytes with abundant cytoplasmic granules, multiple Auer rods, and bilobed nuclei.

A 54-year-old, previously healthy man comes to the clinic due to progressive, generalized weakness and easy fatigability that started 2 months ago.  He also describes abdominal discomfort and early satiety.  The patient works as a security advisor and has not traveled recently.  He is afebrile, and other vital signs are normal.  Examination is significant for pallor, abdominal distension, and massive splenomegaly with the spleen tip crossing the midline.  No peripheral lymphadenopathy is present.  Peripheral blood cell count shows pancytopenia.  Bone marrow aspiration is attempted, but no marrow can be obtained.  Which of the following findings is most likely to be seen in this patient? Explanation Hairy cell leukemia Epidemiology Indolent mature B-cell neoplasm Middle-aged men Pathogenesis BRAF activating mutation → ↑ cell survival & proliferation Clinical manifestations Pancytopenia (due to bone marrow fibrosis) Fatigue & weakness Recurrent infections Bleeding & bruising Splenomegaly (may be massive) Diagnosis Peripheral blood: lymphocytes with hair-like cytoplasmic projections Bone marrow biopsy with flow cytometry This patient's presentation is concerning for hairy cell leukemia (HCL), an indolent B-cell neoplasm predominantly diagnosed in middle-aged men.  Most cases are due to a BRAF activating mutation that increases B-cell survival, leading to increased cellular proliferation and infiltration of the bone marrow and reticuloendothelial system. Bone marrow infiltration and cytokine production cause fibrosis and bone marrow failure, resulting in pancytopenia.  Bone marrow aspiration is usually unsuccessful (ie, dry tap), but peripheral blood smear often shows neoplastic lymphocytes with characteristic cytoplasmic projections (ie, hairy cells).  Splenic red pulp infiltration can result in massive splenomegaly (ie, crossing midline or extending into the left lower quadrant).  Common manifestations include left upper quadrant pain as well as fatigue, recurrent infections, and bleeding (due to pancytopenia). The diagnosis is made using bone marrow biopsy along with immunophenotyping by flow cytometry.  These studies can distinguish HCL from other causes of massive splenomegaly and marrow fibrosis, such as primary myelofibrosis (a myeloproliferative neoplasm that shows circulating immature neutrophils, nucleated erythrocytes, and teardrop cells).  Flow cytometry has generally replaced tartrate-resistant acid phosphatase (TRAP) activity testing. (Choice A)  Intraerythrocytic ring forms are seen in malaria, which may cause splenomegaly.  However, this patient has no travel history and no fever to suggest malaria. (Choice C)  Myeloid cells with azurophilic rod-like granules (Auer rods) can be found in acute myeloid leukemia (AML).  Although AML often presents with pancytopenia, it does not typically cause splenomegaly. (Choice D)  Heterophile antibodies are found in most patients with Epstein-Barr virus–induced infectious mononucleosis, which commonly affects young adults and presents with low-grade fever, pharyngitis, and cervical lymphadenopathy.  Mild hepatosplenomegaly may be present; massive splenomegaly is uncommon. (Choice E)  Ring sideroblasts are abnormal erythrocyte precursors characterized by mitochondrial iron accumulation surrounding the nucleus; they can be found in myelodysplastic syndrome (MDS).  Patients with MDS typically have petechiae, weakness, and recurrent infections due to pancytopenia, but splenomegaly is uncommon. Educational objective: Hairy cell leukemia is an indolent B-cell neoplasm predominantly found in middle-aged men.  It is characterized by bone marrow failure and infiltration into the reticuloendothelial system, causing massive splenomegaly.  Other typical features include a dry tap (unsuccessful bone marrow aspiration) and the presence of lymphocytes with cytoplasmic projections.

Certain patients with non-small cell lung cancer develop constitutive tumor kinase activity due to the production of echinoderm microtubule-associated protein-like 4 - anaplastic lymphoma kinase (EML4-ALK), a fusion protein that contributes to carcinogenesis.  This is most similar to the molecular pathophysiology of which of the following disorders?  A. Burkitt lymphoma  (11%)  B. Chronic myelogenous leukemia  (66%)  C. Follicular lymphoma  (8%)  D. Li-Fraumeni syndrome  (8%)  E. Mantle cell lymphoma  (5%) proximately four percent of patients with non-small cell lung carcinoma (NSCLC) have an inversion of the short arm of chromosome 2 that creates a fusion gene between EML4 (echinoderm microtubule-associated protein-like 4) and ALK (anaplastic lymphoma kinase).  This results in a constitutively active tyrosine kinase that causes malignancy.  Interestingly, patients who harbor this gene fusion are usually young non-smokers, often with adenocarcinoma, who lack mutations in either the epidermal growth factor receptor gene or the K-ras gene.  The kinase activity of this fusion protein is a target of the protein kinase inhibitor, crizotinib. The pathophysiology of EML4-ALK NSCLC is most similar to the pathophysiology of chronic myelogenous leukemia (CML).  In CML, the classic and most common cause is a translocation between chromosomes 9 and 22.  The ABL proto-oncogene is transported from chromosome 9 to chromosome 22 where it is placed adjacent to the BCR gene.  The resulting oncogene, BCR-ABL, codes for a fusion protein with constitutive tyrosine kinase activity.  This protein stimulates the proliferation of granulocytic precursors and leads to the development of CML.  The kinase activity of this fusion protein is a target of the protein kinase inhibitor, imatinib. (Choice A)  Burkitt lymphoma is characterized by a translocation of the c-myc oncogene on the long arm of chromosome 8 to the Ig heavy chain region on chromosome 14.  This causes constitutive overproduction of c-myc, a nuclear phosphoprotein that functions as a transcription activator. (Choice C)  Patients with follicular lymphoma have a t(14;18) translocation that causes overexpression of the antiapoptotic BCL2 gene product. (Choice D)  Li-Fraumeni syndrome is an autosomal dominant predisposition to a variety of cancers, particularly sarcomas and tumors of the breast, brain, and adrenal cortex.  This syndrome is associated with a mutation of the tumor suppressor gene, p53. (Choice E)  Translocation between the cyclin D1 locus on chromosome 11 and the immunoglobulin heavy chain locus on chromosome 14 is characteristic of mantle cell lymphoma.  This abnormality results in increased production of cyclin D1, a promoter of the G1 to S-phase transition during the cell cycle. Educational objective: Some patients with non-small cell lung carcinoma (NSCLC) harbor a chromosomal rearrangement that creates a fusion gene between EML4 (echinoderm microtubule-associated protein-like 4) and ALK (anaplastic lymphoma kinase).  This results in a constitutive active tyrosine kinase that causes malignancy.

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An 8-year-old boy comes to the office due to a mass in the right mandible.  His family first noticed it a few months ago, and it has grown rapidly.  He has had no fevers, chills, cough, or weight loss.  The patient and his family recently immigrated to the United States from East Africa.  He has no known medical problems.  Temperature is 37 C (98.6 F).  Physical examination shows a large tumor on the right mandible with palpable regional lymphadenopathy.  A biopsy of the lesion is performed.  Histopathologic examination shows a diffuse infiltrate of lymphoid cells with numerous mitotic figures; interspersed macrophages with clear cytoplasm are also seen.  These lymphoid cells most likely have a chromosomal translocation that directly alters which of the following processes? his patient likely has the endemic African form of Burkitt lymphoma, which primarily affects children and typically presents as a maxillary or mandibular mass.  This type of lymphoma is strongly associated with Epstein-Barr virus (EBV) infection. On histopathologic examination, Burkitt lymphoma consists of monomorphic, intermediate-sized lymphoid cells with round nuclei, multiple nucleoli, and basophilic cytoplasm.  A high mitotic index and high cell death rate are typically seen.  Benign macrophages that phagocytize the resulting cellular debris ("tingible body macrophages") are distributed throughout the malignant tissue.  The clear cytoplasm of the macrophages contributes to the characteristic "starry sky" appearance of Burkitt lymphoma. Most Burkitt lymphomas demonstrate a translocation between the c-Myc oncogene on the long arm of chromosome 8 and the Ig heavy chain region on chromosome 14 [t(8;14)]; this results in Myc overexpression due to the highly active immunoglobulin promoter in B cells.  The product of c-Myc is a nuclear phosphoprotein that functions as a transcription activator, stimulating cell growth and proliferation. (Choice A)  Follicular lymphoma is often characterized by a translocation between the long arm of chromosome 18 near the BCL2 gene and the Ig heavy chain gene on chromosome 14 [t(14;18)].  This translocation leads to overexpression of the apoptosis inhibitor protein Bcl-2. (Choice B)  Mutations of DNA repair enzymes (eg, BRCA1, BRCA2) are associated with breast cancer, ovarian cancer, Lynch syndrome, xeroderma pigmentosum, Fanconi anemia, and many other diseases. (Choice C)  Translocation between the cyclin D1 locus on chromosome 11 and the Ig heavy chain locus on chromosome 14 [t(11;14)] is characteristic of mantle cell lymphoma.  This abnormality results in increased production of cyclin D1, a promoter of G1 to S-phase transition during the cell cycle. (Choice E)  Translocation of the ABL gene from chromosome 9 to 22 [t(9;22)] results in the Philadelphia chromosome, a typical finding in chronic myeloid leukemia.  BCR-ABL, the resulting fusion gene, encodes a protein with increased tyrosine kinase activity that inhibits apoptosis while promoting mitogenesis. Educational objective: Burkitt lymphoma is characterized by aggressive rapid growth and a "starry sky" microscopic appearance.  Translocation between the c-Myc oncogene on the long arm of chromosome 8 with the Ig heavy chain region on chromosome 14 leads to overexpression of Myc, a nuclear phosphoprotein that functions as a transcription activator.

A 42-year-old man is hospitalized due to fever and persistent sore throat.  Temperature is 38.3 C (100.9 F), blood pressure is 120/80 mm Hg, pulse is 94/min, and respirations are 16/min.  There are several bruises on his trunk, and blood oozes from his intravenous catheter venipuncture sites.  Blood fibrinogen level is 110 mg/dL (normal: 150-400).  Bone marrow aspirate shows a predominance of immature myeloid cells with numerous azurophilic, needle-shaped cytoplasmic granules.  Chromosomal analysis of these immature cells is most likely to show which of the following abnormalities? Explanation Chromosomal translocations associated with hematologic malignancies Malignancy Pathogenesis Acute promyelocytic leukemia t(15;17) involving PML & RARA → PML-RARα oncoprotein → myeloid differentiation inhibited RARα: nuclear receptor involved in myeloid differentiation PML: fusion forms receptor with dominant negative activity Burkitt lymphoma t(8;14) involving MYC & IGH → MYC overexpression → cell growth MYC: transcription factor regulating cell growth IGH: immunoglobulin heavy chain (high expression in B cells) Chronic myeloid leukemia t(9;22) involving ABL1 & BCR → BCR-ABL1 oncoprotein → cell proliferation ABL1: nonreceptor tyrosine kinase BCR: fusion leads to activation Follicular lymphoma t(14;18) involving IGH & BCL2 → BCL2 overexpression → apoptosis evasion BCL2: antiapoptotic protein Mantle cell lymphoma t(11;14) involving CCND1 & IGH → cyclin D1 overexpression → cell cycle progression Cyclin D1: regulates cell cycle This patient with a predominance of immature myeloid cells containing numerous azurophilic, needle-shaped cytoplasmic granules likely has acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia.  Acute leukemia can present with persistent fever and sore throat due to increased risk of infection conferred by fewer functional leukocytes. APL is microscopically characterized by abnormal promyelocytes (immature myeloid cells) that may contain numerous needle-shaped cytoplasmic inclusions known as Auer rods (fused lysosomal granules) and often have bilobed nuclei.  Cytogenetic studies show t(15;17) chromosomal translocation, which causes fusion of the retinoic acid receptor-alpha (RARA) gene to the promyelocytic leukemia (PML) gene. A classic presentation of APL is bleeding in the setting of disseminated intravascular coagulation (DIC) (eg, oozing at venipuncture sites), as the malignant cells express prothrombotic factors (eg, tissue factor) that lead to widespread consumptive coagulopathy.  DIC is characterized by decreased fibrinogen levels, increased fibrin degradation products, prolonged PT and PTT, and thrombocytopenia that is generally not low enough to result in spontaneous bleeding by itself.  Prompt treatment of APL with all-trans retinoic acid is essential. (Choice A)  t(8;14) occurs in approximately 80% of cases of Burkitt lymphoma and results in movement of the MYC protooncogene from chromosome 8 to a region near the immunoglobulin promoter site on chromosome 14.  In blood and bone marrow, Burkitt lymphoma cells often have basophilic, vacuolated cytoplasm. (Choice B)  t(9;22) forms the Philadelphia chromosome associated with chronic myeloid leukemia (CML).  Most patients seek medical attention in the chronic, stable phase (eg, nonspecific symptoms, abdominal fullness, leukocytosis), in which mature and immature myeloid forms are seen.  Auer rods are not typically present in CML. (Choice C)  Mantle cell lymphoma, a mature B-cell malignancy characterized by lymphoid cells with irregular nuclei, is associated with t(11;14).  This translocation results in overexpression of cyclin D1. (Choice D)  t(14;18) is associated with follicular lymphoma.  This abnormality places the BCL2 protooncogene from chromosome 18 near the immunoglobulin heavy-chain promoter region on chromosome 14.  Circulating follicular lymphoma cells are typically small lymphoid cells with cleaved nuclei. Educational objective: Acute promyelocytic leukemia (APL) can present with persistent infection and coagulopathy, causing hemorrhagic signs and symptoms.  Bone marrow examination classically reveals abnormal promyelocytes with intracytoplasmic Auer rods.  APL is associated with a t(15;17) chromosomal translocation that fuses the retinoic acid receptor-alpha and promyelocytic leukemia genes.

A 57-year-old male presents to your office complaining of fatigue and low energy.  He also notes experiencing intermittent back pain that responds to ibuprofen.  He has no significant past medical history.  His family history is significant for his father dying of a heart attack at age 60.  Fecal occult blood testing is negative.  Laboratory studies reveal: Hematocrit 36% MCV 86 fl WBC 7,000/mm3 Platelets 170,000/mm3 Sodium 136 mEq/L Potassium 4.5 mEq/L AST 34 U/L ALT 18 U/L Bilirubin 0.8 mg/dL Creatinine 2.0 mg/dL Plasma protein electrophoresis reveals a high peak corresponding to gamma-globulins.  The most likely diagnosis is: multiple myeloma, neoplastic B-lymphocytes mature into plasma cells that synthesize abnormal (typically large) amounts of monoclonal immunoglobulin or immunoglobulin fragments (e.g. light chains).  Clinical manifestations of multiple myeloma include impaired hematopoiesis leading to a normochromic, normocytic anemia and weakness; lytic bone lesions classically affecting the vertebral column and causing back pain and pathologic fractures; and hypercalcemia and AL amyloidosis, which contribute to renal dysfunction.  Severe amyloidosis can also cause cardiac and cutaneous findings. The classic laboratory abnormalities in multiple myeloma include erythrocyte rouleaux formation on peripheral blood smear and Bence-Jones proteins in the urine.  Serum protein electrophoresis (SPEP) is a more specific laboratory test used to determine if excessive monoclonal immunoglobulins are present in the serum.  An "M peak" on SPEP indicates the presence of such an immunoglobulin.  (An M peak may also be found in Waldenstrom macroglobulinemia and some lymphomas.) (Choices A and B) Iron deficiency can cause weakness due to a hypochromic, microcytic anemia and vitamin B12 (cobalamin) deficiency can cause weakness due to a macrocytic anemia.  Vitamin B12 deficiency can also cause neurologic signs. (Choice C) CLL is a lymphocytic malignancy that may cause a normochromic, normocytic anemia, but immunoglobulin production is classically depressed, not increased, in CLL. (Choice D) Aplastic anemia would cause a uniform depression of all hematologic cell lines, including leukocytes and platelets. (Choice F) Hodgkin lymphoma is a B-cell malignancy characterized by the presence of Reed-Sternberg cells on lymph node histology.  There may be anemia of chronic disease in patients with this condition, but a monoclonal gammopathy would not be expected. (Choice G) Patients with hypothyroidism may be anemic due to associated iron deficiency or pernicious anemia.  However, monoclonal gammopathy would not be expected. Educational Objective: The finding of a high peak in the gamma-globulin region on serum protein electrophoresis (SPEP) usually represents an M protein consisting of an overproduced monoclonal immunoglobulin.  Multiple myeloma causes an M protein peak on SPEP as well as anemia (weakness), lytic bone lesions (back pain, pathologic fractures), and renal insufficiency (related to amyloid deposition and hypercalcemia).

A 66-year-old woman comes to the office due to 2 months of worsening fatigue and dyspnea with moderate exertion.  The patient has a history of breast cancer treated with surgery and combination chemotherapy 6 years ago.  She has no other medical conditions.  Vital signs are within normal limits.  Physical examination reveals normal jugular venous pressure, clear lungs, and normal heart sounds; there is no hepatosplenomegaly, lymphadenopathy, or extremity edema.  Laboratory results are as follows: Hemoglobin 7.2 g/dL Mean corpuscular volume 108 µm3 Reticulocytes 1% Platelets 90,000/mm3 Leukocytes 3,800/mm3 Peripheral blood smear shows oval macrocytic red cells and hyposegmented neutrophils.  Bone marrow biopsy of this patient is most likely to reveal which of the following? Explanation Myelodysplastic syndrome Epidemiology Clonal hematopoietic malignancy Seen primarily with advanced age or previous chemotherapy or radiation treatment Can transform to acute myelogenous leukemia Manifestations ≥1 types of cytopenia: Anemia: weakness, fatigue Leukopenia: infections Thrombocytopenia: bruising, bleeding Hepatosplenomegaly & lymphadenopathy are uncommon Evaluation Peripheral blood smear: dysplastic erythrocytes (eg, oval macrocytosis) & neutrophils (eg, hyposegmentation, hypogranulation) Bone marrow biopsy: single or multilineage dysplasia with hypercellularity This patient's previous chemotherapy, pancytopenia, and cellular dysplasia (eg, hyposegmented neutrophils, oval macrocytic erythrocytes) indicate likely myelodysplastic syndrome (MDS).  MDS is a clonal hematologic malignancy associated with the development of driver mutations due to advanced age, previous chemo-/radiotherapy, or exposure to environmental toxins. MDS is marked by the following: ≥1 cytopenias:  normal hematopoiesis is impaired due to neoplastic cell replication in the bone marrow; therefore, patients usually present with symptoms of ≥1 cytopenia such as fatigue/dyspnea on exertion (anemia), bleeding/bruising (thrombocytopenia), or infections (leukopenia).  Because erythrocyte production is impaired, reticulocyte count will be low despite significant anemia.  However, significant extramedullary hematopoiesis does not occur, so hepatosplenomegaly is rare. Dysplasia of erythrocytes and neutrophils:  peripheral blood smear usually shows normocytic or macrocytic erythrocytes with a variety of abnormalities (eg, oval macrocytes).  Neutrophils are typically hypolobulated and hypogranular. Bone marrow biopsy typically reveals a hypercellular marrow with dysplasia of ≥1 cell lines.  Myeloblasts are increased (but <20% of total cells), and granulocytes show evidence of impaired maturation such as abnormalities in size, granulation, or lobulation.  Erythrocytes also show signs of abnormal development, including large size and nuclear lobation/budding. (Choice A)  Metastatic adenocarcinoma (atypical gland-forming cells) can infiltrate the bone marrow, leading to pancytopenia.  Although reticulocytes would be diminished, peripheral blood smear would not show signs of abnormal granulocyte development (eg, hyposegmentation). (Choice C)  Hypercellular marrow with sheets of plasma cells is seen in multiple myeloma.  Although it occasionally causes pancytopenia (anemia alone is more common), peripheral smear shows rouleaux formation due to increased monoclonal proteins; dysmorphic granulocytes would not be seen.  In addition, multiple myeloma is not strongly associated with chemotherapy exposure. (Choice D)  Anemia of chronic disease is associated with increased retention of iron in reticuloendothelial macrophages.  Although low reticulocyte count is common, patients usually have normocytic anemia and relatively normal peripheral smear findings (eg, no dysplasia).  In contrast, MDS can be associated with ringed sideroblasts (iron-laden erythrocyte precursors) in the bone marrow. (Choice E)  Collagen deposition in the bone marrow is associated with myelofibrosis, a chronic myeloproliferative disorder that causes anemia and variable platelet/leukocyte counts.  However, patients typically have marked splenomegaly due to extramedullary hematopoiesis. Educational objective: Myelodysplastic syndrome is a clonal hematologic neoplasm marked by ≥1 cytopenias and cellular dysplasia (eg, oval macrocytic erythrocytes, hyposegmented granulocytes).  Bone marrow evaluation usually reveals a hypercellular marrow, a mild or moderate increase in myeloblasts (<20% of total cells), and dysplastic erythrocytes/granulocytes.

A 66-year-old woman comes to the emergency department due to abdominal cramps and watery diarrhea for the past day.  The patient was hospitalized 2 weeks ago due to acute pyelonephritis and was treated with broad-spectrum antibiotics.  She has a remote history of Hodgkin disease treated with chemotherapy and radiation treatment but no other chronic medical conditions.  The patient's only home medication is a multivitamin supplement.  Temperature is 38.3 C (100.9 F), blood pressure is 124/72 mm Hg, and pulse is 92/min.  There is mild generalized abdominal tenderness with no guarding or rebound.  The remainder of the physical examination shows no abnormalities.  Laboratory results are as follows: Hemoglobin 12.8 g/dL Platelets 380,000/mm3 Leukocytes 32,000/mm3 Neutrophils 80% Bands 8% Metamyelocytes 2% Lymphocytes 10% Prior blood cell count at the time of hospital discharge was normal.  Stool testing for Clostridioides difficile is positive.  Which of the following is the most likely underlying cause of this patient's leukocytosis? his patient with Clostridioides difficile colitis has profound leukocytosis due to increased circulating mature and juvenile (eg, bands) neutrophils.  Although neutrophils are normally the most prevalent leukocyte in the blood, the vast majority of mature neutrophils are held in reserve in the bone marrow or are reversibly attached to the endothelial wall (marginated pool). However, infection, inflammation, and certain medications (eg, glucocorticoids, androgens) can rapidly mobilize bone marrow and marginated neutrophils, leading to leukocytosis.  This process is mediated by endotoxin, certain complement components (eg, C3a, C5a), and cytokines such as TNF-alpha and granulocyte-macrophage colony-stimulating factor (GM-CSF); these compounds trigger neutrophils, bands, and immature granulocyte cells (eg, metamyelocytes, late myelocytes) to undergo transcellular migration out of the bone marrow sinusoids into the circulation.  Primed neutrophils then rapidly localize to areas of inflammation by using L-selectin to bind E-selectin on the endothelial surface of nearby blood vessels. (Choice A)  In myeloid leukemia, myeloid precursor cells undergo clonal proliferation unlinked to cytokine stimulation or growth signals.  This patient is unlikely to have developed myeloid leukemia in the 2 weeks since her last admission. (Choice C)  Leukocytes leave the circulation by transmigrating through the endothelial wall near areas of infection or inflammation.  Defective leukocyte transmigration can cause leukocytosis in patients with leukocyte adhesion deficits, but is not a component of leukocytosis in those with acute infection (eg, C difficile colitis). (Choice D)  Stress hormones (eg, epinephrine) cause leukocytosis due to "demarginalization," or liberation of marginated neutrophils from the endothelial wall (ie, shift from marginated to circulating pool, rather than from circulating to marginated pool). (Choice E)  Hematologic stem cells and their immediate progenitors can differentiate into either myeloid or lymphoid cells.  Once a cell is committed to a myeloid or lymphoid lineage, it cannot generally revert. Educational objective: Infection triggers increased circulating neutrophils by stimulating the release of neutrophils, bands, and late granulocyte precursors from the bone marrow.  This is mediated by increased cytokines (eg, TNF-alpha) and complement activation.  Demarginalization of neutrophils from endothelial attachment also contributes to leukocytosis.

A 67-year-old woman is evaluated for worsening fatigue and exertional dyspnea.  She has no prior medical conditions and takes no medications.  The patient does not use tobacco, alcohol, or illicit drugs and consumes a balanced diet.  Vital signs are within normal limits.  Physical examination is notable for mucosal pallor.  Stool testing for occult blood is negative.  Laboratory studies reveal that hemoglobin is 6.7 g/dL, white blood cell count is 35,000/mm3, and platelets are 45,000/mm3.  Peripheral blood flow cytometry of the white blood cell population is shown below. his patient's symptomatic anemia (eg, fatigue, weakness), thrombocytopenia, and leukocytosis are associated with a predominance of CD20-positive cells (a B-cell surface marker), raising strong suspicion for chronic lymphocytic leukemia (CLL).  In CLL, mature B cells progressively accumulate in the bone marrow and peripheral blood due to oncogenic mutations that inhibit apoptosis.  Although most patients are asymptomatic for years, accumulation of B cells in the bone marrow eventually chokes out normal hematopoiesis, leading to symptomatic anemia, thrombocytopenia, and infections (due to neutropenia). Patients with CLL usually have dramatic elevations in peripheral leukocyte count (often >100,000/mm3) and characteristic findings on peripheral blood smear (eg, numerous small lymphocytes, smudge cells).  The diagnosis is supported by flow cytometry of peripheral blood revealing a clonal population of leukocytes with expression of B-cell surface markers such as CD19, CD20, and CD23. (Choice A)  T-cell leukemia is marked by the clonal expansion of a leukocyte population with T-cell surface markers such as CD2, CD3, and CD4.  However, this patient's flow cytometry shows very few CD3-positive cells. (Choice B)  Aplastic anemia is characterized by bone marrow failure and is usually triggered by an infection, medication, radiation, toxic substance, or autoimmune disease.  Patients have pancytopenia (not leukocytosis) and bone marrow biopsy shows a hypocellular marrow with morphologically normal hematopoietic cells; a clonal population of B cells would not be seen. (Choice D)  Chronic myeloid leukemia is a myeloproliferative neoplasm characterized by peripheral leukocytosis due to numerous circulating granulocytes (eg, neutrophils in different stages of maturation).  Diagnosis is generally made when cytogenetic studies reveal the BCR-ABL fusion gene.  A predominant population of CD20-positive cells (B cells) would not be seen. (Choice E)  Classic Hodgkin lymphoma usually causes localized peripheral lymphadenopathy and B-symptoms (eg, fever, night sweats).  The diagnosis is made by lymph node excision, which usually reveals Reed-Sternberg cells that are characteristically positive for CD15 and CD30 immunohistochemical stains.  Anemia, thrombocytopenia, and leukocytosis would be atypical. Educational objective: Chronic lymphocytic leukemia is a lymphoproliferative disorder marked by the progressive accumulation of mature B cells.  Most patients are asymptomatic for years but eventually develop anemia, thrombocytopenia, and/or neutropenia.  The diagnosis is generally made when complete blood count reveals dramatic leukocytosis, and flow cytometry subsequently shows a clonal population of leukocytes with B-cell markers such as CD19, CD20, and CD23.

A 68-year-old man comes to the office due to severe fatigue for the last few months.  He has also had 6.8-kg (15-lb) of unintentional weight loss over the same period.  The patient has no significant medical history and has not seen a physician in many years.  He takes no medications and does not use tobacco, alcohol, or illicit drugs.  Physical examination shows mucosal pallor with no scleral icterus.  The lungs are clear on auscultation, and heart sounds are normal.  Abdominal examination shows mild hepatomegaly and a markedly enlarged spleen.  Stool guaiac testing is negative.  Laboratory results show pancytopenia, and peripheral blood smear is shown below. his patient with pancytopenia, hepatosplenomegaly, and teardrop cells on peripheral blood smear likely has primary myelofibrosis, a hematopoietic stem cell malignancy associated with the clonal expansion of megakaryocytes.  Neoplastic megakaryocytes secrete the cytokine transforming growth factor-beta, which stimulates bone marrow fibroblasts to fill the medullary space with collagen.  Subsequent bone marrow fibrosis usually leads to the following: Extramedullary hematopoiesis – Because the bone marrow is destroyed by fibrotic tissue, hematopoiesis occurs in secondary hematopoietic tissue such as the spleen and liver.  This typically results in marked splenomegaly and a palpable liver edge on examination. Cytopenias – Extramedullary hematopoiesis is much less efficient than medullary hematopoiesis.  Therefore, patients often have deficits in 1 or more cell lines (eg, anemia, pancytopenia). Dacrocytes on peripheral blood smear – The red cell membrane is damaged when squeezing out of the fibrotic bone marrow or passing through the enlarged spleen, which leads to the formation of teardrop-shaped red cells. The diagnosis of primary myelofibrosis requires bone marrow examination.  Bone marrow aspiration frequently results in a dry tap (no marrow) due to significant bone marrow fibrosis.  Therefore, bone marrow biopsy is usually required; the presence of a diffusely fibrotic marrow with occasional clusters of atypical megakaryocytes confirms the diagnosis. (Choice B)  Multiple myeloma, a clonal disorder of plasma cells, is marked by a monoclonal spike (M-spike) on protein electrophoresis.  Patients typically have anemia, hypercalcemia, bone pain (osteolytic lesions), and renal insufficiency.  Bone marrow biopsy usually shows a clusters of monoclonal plasma cells. (Choice C)  Anemia of chronic disease is associated with hepcidin-induced changes in iron metabolism that cause iron trapping within macrophages.  Bone marrow biopsy with Prussian blue stain demonstrates increased iron within macrophages.  Hepatosplenomegaly and teardrop cells would be unexpected. (Choice D)  Myelodysplastic syndrome is a malignant stem cell cancer associated with the production of dysplastic, atypical blood cells.  Although most patients with myelodysplasia have cytopenias, the bone marrow is usually hypercellular with multi-lineage dysplasia. (Choice E)  Aplastic anemia results from injury (eg, drugs, radiation, viruses) to multipotent hematologic stem cells.  It is usually associated with pancytopenia and a profoundly hypocellular bone marrow predominantly composed of adipose tissue.  Extramedullary hematopoiesis is minimal and hepatosplenomegaly and dacrocytes are not typically present. Educational objective: Primary myelofibrosis is a myeloproliferative disorder associated with the clonal expansion of megakaryocytes.  Bone marrow fibrosis accounts for most of the major manifestations, including hepatosplenomegaly, cytopenias, and blood smear evidence of dacrocytes.  Bone marrow aspiration is usually dry, but bone marrow biopsy will show marked fibrosis with occasional clusters of atypical megakaryocytes.

A 67-year-old man comes to the office due to severe fatigue for the past several months.  The patient cannot eat as much as he used to and has lost nearly 10 kg (22 lb) in the past 6 months.  Physical examination shows mucosal pallor, hepatomegaly, and massive splenomegaly.  Further evaluation reveals a gain-of-function mutation of a non-receptor tyrosine kinase protein in hematopoietic cells, leading to persistent activation of signal transducers and activators of transcription (STAT) proteins.  This patient is most likely suffering from which of the following disorders? Explanation Chronic myeloproliferative disorders Disorder Diagnostic features Mutation Chronic myelogenous leukemia Constitutional symptoms (eg, fatigue, weight loss, excessive sweating), splenomegaly & leukocytosis with marked left shift (eg, myelocytes, metamyelocytes, band forms) Philadelphia chromosome t(9:22) BCR-ABL fusion protein Essential thrombocytosis Hemorrhagic & thrombotic symptoms (eg, easy bruising, microangiopathic occlusion), thrombocytosis & megakaryocytic hyperplasia JAK2 Polycythemia vera Pruritus, erythromelalgia, splenomegaly, thrombotic complications, erythrocytosis & thrombocytosis Primary myelofibrosis Severe fatigue, splenomegaly (often causing early satiety/abdominal discomfort), hepatomegaly, anemia & bone marrow fibrosis The chronic myeloproliferative disorders are bone marrow diseases characterized by overproduction of myeloid cells.  Primary myelofibrosis is caused by atypical megakaryocytic hyperplasia, which stimulates fibroblast proliferation, resulting in progressive replacement of the marrow space by extensive collagen deposition.  In the early stages, there is marrow hypercellularity with minimal fibrosis, but as the disease progresses, pancytopenia can result.  Hepatomegaly and massive splenomegaly develop because the loss of bone marrow hematopoiesis is compensated for by extramedullary hematopoiesis.  The peripheral smear characteristically shows teardrop-shaped red blood cells (dacrocytes) and nucleated red blood cells. With the exception of chronic myelogenous leukemia, the chronic myeloproliferative disorders (especially polycythemia vera) frequently harbor a mutation in the nonreceptor cytoplasmic tyrosine kinase, Janus kinase 2 (JAK2).  This mutation results in constitutive tyrosine phosphorylation activity, and consequently, in the cytokine-independent activation of the signal transducers and activators of transcription (STAT) pathway.  Once they are activated, STAT proteins translocate to the nucleus and promote transcription.  A JAK2 inhibitor (ruxolitinib) has been approved for treatment of primary myelofibrosis. (Choice A)  In acute promyelocytic leukemia, t(15;17) leads to the formation of a fusion gene between the promyelocytic leukemia (PML) and the retinoic acid receptor alpha (RARA) genes.  The abnormal PML/RARα fusion protein blocks differentiation of myeloid precursors. (Choice B)  Chronic lymphocytic leukemia is a lymphoproliferative disorder involving B lymphocytes.  The most significant laboratory finding is marked lymphocytosis, with "smudge cells" seen on peripheral blood smear.  The majority of cases exhibit increased expression of the proto-oncogene BCL2; a similar finding occurs in follicular lymphomas. (Choices C and D)  Several high-grade non-Hodgkin lymphomas (NHLs) are associated with cytogenetic abnormalities.  The t(8;14) translocation involves the c-Myc oncogene and is common in Burkitt lymphoma, which is associated with Epstein-Barr virus infection and classically has a "starry sky" histological appearance.  Mantle cell lymphoma is a low grade NHL characterized by t(11;14), leading to cyclin D1 overexpression. Educational objective: The chronic myeloproliferative disorders (polycythemia vera, essential thrombocytosis, and primary myelofibrosis) often have a mutation in Janus kinase 2 (JAK2), a cytoplasmic tyrosine kinase.  This results in constitutive tyrosine kinase activity, and consequently, in the cytokine-independent activation of signal transducers and activators of transcription (STAT) proteins (JAK-STAT signaling pathway).

A 9-year-old girl is brought to the emergency department due to prolonged epistaxis.  The girl says that she picked her nose immediately before the bleeding started.  Her parents decided to bring her to the emergency department after the epistaxis persisted for 20 minutes despite constant compression of the nasal alae.  The patient has had frequent nosebleeds that often last >10 minutes.  Her family history is significant for a grandfather who had an unspecified bleeding disorder.  Given the history of prolonged, recurrent nosebleeds, laboratory tests are ordered, and results are as follows: Hematocrit 43% Bleeding time prolonged Partial thromboplastin time (PTT) prolonged Prothrombin time (PT) normal Thrombin time (TT) normal D-dimer normal Which of the following is the most likely diagnosis? his patient has a normal prothrombin time (PT) and thrombin time (TT) and a prolonged partial thromboplastin time (PTT), indicating a defect in the intrinsic pathway (coagulation factors VIII, IX, XI, or XII).  Bleeding time is a test of platelet function and is prolonged by qualitative and quantitative platelet defects.  The term "bleeding time" refers to this particular test and not the duration of bleeding, which can be prolonged from other coagulopathies. von Willebrand disease (vWD) will cause both a prolonged PTT and bleeding time.  von Willebrand factor (vWF) is produced by endothelial cells and megakaryocytes and functions as a carrier protein for factor VIII and as a mediator of platelet adhesion to the endothelium.  Absence of vWF leads to impaired platelet function and coagulation pathway abnormalities.  vWD is inherited in an autosomal dominant fashion with variable penetrance and is the most common heritable bleeding disorder. (Choice A)  Disseminated intravascular coagulopathy (DIC) is a consumptive coagulopathy most commonly seen in septic shock.  PT, PTT, and bleeding time are prolonged, and the D-dimer, a degradation product of cross-linked fibrin, is elevated. (Choice B)  Dysfibrinogenemias are inherited abnormalities in the fibrinogen molecule that can cause excessive bleeding or thrombophilia.  TT, PT, and PTT are abnormal in this condition, but bleeding time is unaffected. (Choice C)  Factor XIII is a transglutaminase that cross-links fibrin polymers, thereby stabilizing clots.  Factor XIII deficiency causes spontaneous or excessive bleeding, but it would not prolong the bleeding time, PT, or PTT. (Choice D)  Hemophilia A is an X-linked hereditary deficiency of factor VIII that causes coagulopathy with a prolonged PTT but shows normal bleeding time. (Choice E)  Hemophilia B is an X-linked hereditary deficiency of factor IX that causes coagulopathy with a prolonged PTT but shows normal bleeding time. (Choice F)  Vitamin K is required for activation of clotting factors II, VII, IX, and X.  Vitamin K deficiency causes a coagulopathy that primarily prolongs PT, with PTT prolongation occurring in severe cases.  Bleeding time is not affected. Educational objective: von Willebrand disease is the most common inherited bleeding disorder.  It has an autosomal dominant pattern of inheritance and variable penetrance.  Absence of von Willebrand factor leads to impaired platelet function (prolonged bleeding time) and coagulation pathway abnormalities due to decreased factor VIII activity (prolonged partial thromboplastin time).

A 29-year-old woman comes to the emergency department due to fever and headache for the last week.  The patient has a generalized tonic-clonic seizure while being evaluated.  Laboratory results are as follows: Hemoglobin 6.1 g/dL Platelets 16,000/mm3 Creatinine 2.2 mg/dL Total bilirubin 4.3 mg/dL Serum haptoglobin undetectable PT 11 sec (INR 1.1) Activated PTT 30 sec Peripheral blood smear is shown in the exhibit.  Which of the following is the most likely underlying cause of this patient's current condition? Explanation Thrombotic thrombocytopenic purpura Pathophysiology ↓ ADAMTS13 level → uncleaved vWF multimers → platelet trapping & activation Acquired (autoantibody) or hereditary Clinical features Hemolytic anemia (↑ LDH, ↓ haptoglobin) with schistocytes on peripheral smear Thrombocytopenia (↑ bleeding time, normal PT/PTT) Sometimes with: Renal failure Neurologic manifestations Fever LDH = lactate dehydrogenase; vWF = von Willebrand factor. This patient has the classic pentad of manifestations for acquired thrombotic thrombocytopenic purpura (TTP): Severe thrombocytopenia:  Platelet-rich clots form in the microvasculature, leading to rapid platelet consumption. Microangiopathic hemolytic anemia (MAHA):  Erythrocytes are mechanically sheared by the microvascular thrombi, leading to intravascular hemolytic anemia.  This typically causes an elevated indirect bilirubin level and an undetectable haptoglobin level (haptoglobin binds free hemoglobin in the circulation), but confirmation of MAHA requires identification of schistocytes (eg, triangle cells, helmet cells) on peripheral blood smear. Neurologic manifestations (eg, headache, seizure), renal insufficiency, and fever (the remainder of the pentad) occur in a minority of patients Unlike patients who have disseminated intravascular coagulation (a consumptive coagulopathy also associated with MAHA and thrombocytopenia), those with TTP have normal coagulation studies because coagulation factors are not significantly consumed by the formation of platelet-rich clots (Choice A). TTP is triggered by the formation of autoantibody inhibitors against ADAMTS-13, a protease that cleaves ultralarge von Willebrand factor (VWF) multimers in the circulation, reducing their prothrombotic activity.  Patients with TTP have very low levels of ADAMTS-13, which increases the proportion of ultralarge VWF multimers and leads to the aggregation and activation of platelets.  Plasma exchange, which removes the autoantibody inhibitors against ADAMTS-13, is generally curative. (Choice C)  Expansion of neoplastic myeloid precursors in the bone marrow is seen in acute myeloid leukemia, which can cause anemia and thrombocytopenia due to bone marrow infiltration.  However, peripheral blood smear would show leukemic blast cells, not schistocytes. (Choice D)  Inherited deficiency of glucose-6-phosphate dehydrogenase typically causes hemolytic anemia during times of oxidative stress (eg, infection, medication exposure, certain foods).  High bilirubin and low haptoglobin are often present due to hemolytic anemia; however, thrombocytopenia is not seen, and peripheral smear would show bite cells and Heinz bodies, not schistocytes. (Choice E)  A missense mutation at the sixth position of the hemoglobin beta chain is seen in sickle cell anemia, which is marked by periods of acute on chronic hemolytic anemia (eg, elevated bilirubin, low haptoglobin).  However, peripheral smear would show sickled erythrocytes, not schistocytes; in addition, thrombocytopenia is not generally seen. Educational objective: Thrombotic thrombocytopenic purpura classically presents with the pentad of severe thrombocytopenia, microangiopathic hemolytic anemia (eg, schistocytes on peripheral smear), renal insufficiency, neurologic symptoms, and fever.  However, all these signs and symptoms are rarely present.  Diagnosis is often made by identifying severe deficiency of ADAMTS-13, a protease that cleaves large von Willebrand factor multimers off the endothelium.

A 26-year-old woman, gravida 2 para 1, at 8 weeks gestation comes to the office due to pain and swelling of her left leg for the past day.  The patient had a pulmonary embolism during her previous pregnancy, and prophylactic low-molecular-weight heparin therapy was initiated 6 days ago.  She has no other medical conditions and takes prenatal vitamins.  Physical examination shows left lower extremity edema and calf tenderness but no other abnormalities.  Venous duplex ultrasonography reveals acute left femoral vein thrombosis.  Platelet count, which was normal prior to anticoagulant therapy initiation, is 84,000/mm3.  Other blood cell counts and renal and liver function studies are within normal limits.  Which of the following most likely predisposed this patient to her current condition? his patient with a significant drop in platelet count and acute venous thromboembolism following recent exposure to low molecular weight heparin likely has heparin-induced thrombocytopenia and thrombosis (HITT), also known as heparin-induced thrombocytopenia type 2.  HITT typically occurs 5-10 days following exposure to heparin products and is characterized by a large drop in platelet count.  It is more common following exposure to unfractionated heparin but can occur following exposure to low-molecular weight heparin as well. Platelet factor 4 (PF4) is a protein released from the alpha granules of platelets that plays a role in platelet aggregation.  It also binds heparin and helps inactivate the molecule.  The mechanism of HITT involves the generation of IgG antibodies to these complexes of heparin and PF4.  The Fc component of the activated IgG antibodies then binds to additional platelets, resulting in further PF4 release and widespread platelet activation.  This leads to a prothrombotic state that places patients at high risk for both arterial and venous thrombosis. (Choice A)  Acquired protein C deficiency occurs early in the course of warfarin therapy, as the inhibition of protein C by warfarin occurs more rapidly than the inhibition of other factors (ie, factors II, VII, IX, X).  If not bridged with heparin when starting therapy, patients may develop warfarin-induced skin necrosis due to localized cutaneous thrombus formation. (Choice C)  Idiopathic thrombocytopenic purpura (ITP) results from splenic destruction of platelets labeled by IgG antibodies to glycoprotein IIb/IIIa receptors.  ITP often causes very low platelet levels and is associated with bleeding complications rather than thrombosis. (Choice D)  Cryoglobulinemia can occur in the setting of autoimmune disease (eg, systemic lupus erythematosus) or viral infection (eg, hepatitis C) and causes systemic vasculitis characterized by fatigue, arthralgia, and purpuric rash.  Marked thrombocytopenia is not typical. (Choice E)  Thrombotic thrombocytopenic purpura (TTP) results from decreased levels of the von Willebrand factor-cleaving protease ADAMTS13.  The classic presentation of TTP is the pentad of fever, thrombocytopenia, microangiopathic hemolytic anemia, renal insufficiency, and neurologic dysfunction. Educational objective: Heparin-induced thrombocytopenia and thrombosis results from the production of IgG antibodies against complexes of heparin and platelet factor 4.  The Fc component of these antibodies binds to platelets, resulting in widespread platelet activation and a prothrombotic state.

A 35-year-old woman comes to the hospital due to sudden-onset numbness in her left arm and face.  The patient has had generalized headache, dyspnea on exertion, and easy fatigability for several days but no weakness.  She has a history of well-controlled asthma.  Temperature is 37.7 C (99.9 F), blood pressure is 110/60 mm Hg, and pulse is 80/min.  Light touch sensation is decreased in the left upper extremity and the lower left side of the face.  Strength and reflexes are normal.  Cardiopulmonary and abdominal examinations are unremarkable.  There is no skin rash.  Laboratory results are as follows: Hemoglobin 8.6 g/dL Platelets 24,000/mm3 Blood urea nitrogen 32 mg/dL Creatinine 1.9 mg/dL PT and PTT are normal.  Peripheral blood smear shows numerous schistocytes.  Urinalysis is positive for mild proteinuria.  Which of the following is the most likely underlying cause of this patient's current condition? xplanation Thrombotic thrombocytopenic purpura Pathophysiology ↓ ADAMTS13 level → uncleaved vWF multimers → platelet trapping & activation Acquired (autoantibody) or hereditary Clinical features Hemolytic anemia (↑ LDH, ↓ haptoglobin) with schistocytes on peripheral smear Thrombocytopenia (↑ bleeding time, normal PT/PTT) Sometimes with: Renal failure Neurologic manifestations Fever LDH = lactate dehydrogenase; vWF = von Willebrand factor. This patient's severe thrombocytopenia and schistocytes on peripheral blood smear indicate microangiopathic hemolytic anemia (MAHA).  The presence of normal coagulation studies indicate that there is no systemic activation of the coagulation cascade, which makes disseminated intravascular coagulation unlikely (Choice E).  Therefore, a platelet-activated thrombotic microangiopathy such as thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome is most likely. In this case, the patient has 4 of the 5 classic findings of acquired TTP: Severe thrombocytopenia, which may cause bruising or bleeding MAHA, which may cause symptomatic anemia (eg, fatigue, dyspnea on exertion) Renal damage, which may cause renal insufficiency (eg, elevated creatinine) and mild proteinuria Neurologic damage, which may cause confusion, headache, and transient focal findings (eg, numbness, weakness) Fever (not present) Although this pentad of findings is classic, all 5 manifestations are rarely seen.  In addition, a purpuric rash (due to subcutaneous bleeding) is sometimes, but not always, present. Acquired TTP occurs due to the formation of an autoantibody inhibitor against ADAMTS-13, a von Willebrand factor (vWF)–cleaving protease.  Circulating vWF (produced by megakaryocytes and endothelial cells) normally is released as large vWF multimers that are cleaved to their regular size by ADAMTS-13.  These vWF multimers support hemostasis by bridging platelets and subendothelial components to sites of vascular injury.  In TTP, the large uncleaved vWF multimers are significantly more prothrombotic and result in diffuse microvascular thrombosis. (Choice A)  Henoch-Schönlein purpura (IgA vasculitis) is characterized by IgA immune complex deposition.  Typical manifestations include palpable purpura, renal disease, and arthritis/arthralgias.  Platelet counts are usually normal. (Choice C)  Some features of this patient's presentation could be explained by plasma cell dyscrasias such as multiple myeloma (renal failure, anemia due to bone marrow replacement) and Waldenström macroglobulinemia (neurologic symptoms due to hyperviscosity, autoimmune hemolytic anemia).  However, microangiopathic hemolytic anemia would be atypical. (Choice D)  A cerebrovascular accident caused by plaque rupture could cause neurologic deficits but would not account for the patient's hematologic and renal abnormalities. Educational objective: Thrombotic thrombocytopenic purpura frequently results from impaired function of the von Willebrand factor (vWF)–cleaving protease ADAMTS-13, which causes the accumulation of uncleaved vWF multimers that are significantly more prothrombotic.  Patients develop diffuse microvascular thrombosis, which leads to thrombocytopenia and microangiopathic hemolytic anemia.