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.