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Hematology Propaedeutics - Complete Exam Guide (Grade 9-10)

Sources: Harrison's Principles of Internal Medicine 22E, Robbins & Kumar Pathology, Goldman-Cecil Medicine, Robbins Basic Pathology

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PART 1: HEMATOLOGICAL HISTORY TAKING

Chief Complaints in Hematology

• Fatigue/weakness - cardinal symptom of anemia
• Pallor - reduced hemoglobin
• Dyspnea on exertion - reduced O2 carrying capacity
• Palpitations - compensatory tachycardia in anemia
• Bleeding - petechiae, purpura, ecchymosis, mucosal bleeding, hemarthrosis
• Lymph node swelling - lymphadenopathy
• Bone pain - marrow infiltration (leukemia, myeloma)
• Fever/night sweats/weight loss ("B symptoms") - lymphoma, leukemia
• Pruritus - polycythemia vera, Hodgkin lymphoma (especially after hot bath)
• Jaundice - hemolytic anemia

Key History Points

• Duration and progression of symptoms
• Family history (hemophilia, sickle cell, thalassemia, hereditary spherocytosis)
• Medications (NSAIDs, anticoagulants, chemotherapy agents causing cytopenias)
• Dietary habits (vegetarian diet -> B12/iron deficiency)
• Alcohol use (macrocytosis, thrombocytopenia)
• Previous blood transfusions
• Occupational exposure (benzene -> aplastic anemia/leukemia)
• Geographic origin (malaria, G6PD deficiency, thalassemia endemic areas)
• Menstrual history in women (blood loss)

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PART 2: PHYSICAL EXAMINATION IN HEMATOLOGY

Vital Signs

• Tachycardia and tachypnea in anemia
• Fever in leukemia/lymphoma/hemolysis
• Blood pressure drop in acute hemorrhage

General Appearance

• Pallor: best assessed at conjunctivae, palmar creases, nail beds, mucous membranes
• Jaundice: scleral icterus in hemolytic anemia
• Plethora (ruddy face): polycythemia vera

Skin and Mucous Membranes

• Petechiae - pinpoint non-blanching spots (<3 mm); indicates thrombocytopenia or capillary fragility
• Purpura (3 mm - 1 cm) and ecchymoses (>1 cm) - thrombocytopenia, coagulation disorders
• Koilonychia (spoon nails) - iron deficiency anemia
• Angular cheilitis - iron or B12 deficiency
• Glossitis (smooth beefy red tongue) - B12 or folate deficiency
• Jaundice - hemolytic anemia

Lymph Node Examination

• Size (normal <1 cm; axillary <1.5 cm)
• Consistency: soft/rubbery (reactive) vs. hard/firm (metastatic cancer) vs. matted/fixed (tuberculosis, lymphoma)
• Tenderness: tender = reactive/inflammatory; non-tender = lymphoma/metastasis
• Mobility: mobile = benign; fixed = malignancy or TB

1. Occipital - scalp infections, rubella
2. Pre-auricular - eye/scalp infections
3. Post-auricular - scalp infections
4. Submandibular - mouth, lip infections
5. Submental - floor of mouth
6. Anterior cervical - upper respiratory infections
7. Posterior cervical - mononucleosis, scalp infections
8. Supraclavicular - LEFT (Virchow's node = gastric/abdominal malignancy); RIGHT = pulmonary/mediastinal pathology
9. Axillary - breast, arm, chest wall
10. Epitrochlear - hand/forearm infections, secondary syphilis, lymphoma
11. Inguinal - lower extremity, genitalia, perineum

• Generalized lymphadenopathy (>2 non-contiguous regions) = systemic disease (HIV, EBV/mono, leukemia, lymphoma, SLE)
• Localized lymphadenopathy = regional infection or malignancy

Splenomegaly

1. Patient supine, examiner on right side
2. Start palpation from right iliac fossa moving toward left hypochondrium
3. Ask patient to breathe deeply (descends on inspiration)
4. Spleen has notch on medial border (differentiates from enlarged kidney - kidney is bimanually ballotable, retroperitoneal)
5. Percussion: dullness in Traube's space (left 6th rib, anterior axillary line to left costal margin) indicates splenomegaly

• Grade I: palpable only on deep inspiration
• Grade II: palpable on normal inspiration, <3 fingerbreadths below costal margin
• Grade III: extends to umbilicus
• Grade IV (massive): extends beyond umbilicus to pelvis

Hepatomegaly

• Can accompany splenomegaly in lymphoma, leukemia, infiltrative diseases
• Hepatosplenomegaly = key finding in chronic leukemias

Sternal Tenderness

• Press on sternum; pain suggests marrow infiltration (leukemia, myeloma)

Fundoscopic Examination

• In severe anemia: flame hemorrhages, cotton wool spots, Roth spots
• Hyperviscosity (myeloma, polycythemia): engorged tortuous veins

Neurological

• Subacute combined degeneration of spinal cord in B12 deficiency: posterior column (loss of vibration, proprioception) + lateral column (UMN signs)
• Peripheral neuropathy: B12 deficiency, amyloid neuropathy

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PART 3: CBC INTERPRETATION

Normal Values

MCV-Based Anemia Classification

• Iron deficiency (most common worldwide)
• Thalassemia
• Anemia of chronic disease (usually normocytic)
• Sideroblastic anemia
• Lead poisoning

• Megaloblastic: B12 deficiency, folate deficiency, hydroxyurea, methotrexate, myelodysplasia
• Non-megaloblastic: alcoholism, liver disease, hypothyroidism, reticulocytosis

• Hemolytic anemias (early)
• Aplastic anemia
• Anemia of chronic disease
• Renal disease (EPO deficiency)
• Acute blood loss

Reticulocyte Count

• High reticulocytes = bone marrow responding = blood loss or hemolysis
• Low reticulocytes = bone marrow not responding = decreased production (iron deficiency, B12, aplastic anemia, bone marrow infiltration)
• Reticulocyte Production Index (RPI) = (reticulocyte % × patient Hct / normal Hct) / maturation factor
• RPI >2 = adequate response; RPI <2 = hypoproliferative

WBC Differential

Platelet Disorders

• Thrombocytopenia (<150 × 10⁹/L): ITP, TTP, HUS, DIC, hypersplenism, marrow failure, heparin
• Thrombocytosis (>400 × 10⁹/L): reactive (infection, iron deficiency, post-splenectomy) vs. essential thrombocythemia

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PART 4: PERIPHERAL BLOOD SMEAR

Red Cell Morphology

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PART 5: MAJOR HEMATOLOGIC DISEASES

A. ANEMIAS

1. Iron Deficiency Anemia

• Total body iron: 2.5 g (women), 3.5 g (men)
• 80% in hemoglobin, myoglobin, iron enzymes; 15-20% in storage pool (ferritin, hemosiderin)
• Transported by transferrin; normally 33% saturated
• Normal serum iron: 120 µg/dL (men), 100 µg/dL (women)
• Normal TIBC: 300-350 µg/dL
• Regulated by hepcidin (liver peptide): upregulated by iron + inflammation (IL-6), downregulated by erythroferrone

1. Pre-latent: depleted stores (low ferritin), no anemia
2. Latent: low ferritin + low serum iron + high TIBC, no anemia
3. Iron deficiency anemia: low Hb, microcytic hypochromic RBCs

• Low serum iron, high TIBC, low transferrin saturation (<16%)
• Low serum ferritin (<12 µg/L - most specific test)
• Microcytic hypochromic RBCs, anisocytosis, poikilocytosis
• High RDW (early, before MCV drops)
• Low reticulocyte count

• Increased demand: infancy, pregnancy, growth spurts
• Decreased intake: malnutrition, malabsorption (celiac disease)
• Chronic blood loss: GI (peptic ulcer, colon cancer, hookworm), gynecological (menorrhagia)

• Fatigue, pallor, dyspnea
• Koilonychia (spoon nails)
• Angular cheilitis, glossitis
• Pica (eating ice, dirt, chalk)
• Plummer-Vinson syndrome (iron deficiency + dysphagia from esophageal webs)

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2. B12 and Folate Deficiency (Megaloblastic Anemia)

• Pernicious anemia (autoimmune destruction of gastric parietal cells -> no intrinsic factor -> no B12 absorption in terminal ileum) - most common in adults
• Gastrectomy
• Terminal ileum disease (Crohn's)
• Strict veganism
• Fish tapeworm (Diphyllobothrium latum)

• Poor dietary intake (alcoholism, elderly)
• Malabsorption
• Increased demand (pregnancy, hemolysis, rapid cell turnover)
• Drugs: methotrexate, trimethoprim, phenytoin

• Macrocytic anemia (oval macrocytes)
• Hypersegmented neutrophils (>5 lobes in neutrophil = pathognomonic)
• Low B12 or folate levels
• High homocysteine (both B12 and folate deficiency)
• High methylmalonic acid (only B12 deficiency - useful to distinguish)
• Megaloblastic changes on bone marrow: large erythroblasts with fine nuclear chromatin

• Subacute combined degeneration of spinal cord: posterior column (vibration, proprioception loss) + lateral column (UMN signs, spasticity, Babinski)
• Peripheral neuropathy
• Glossitis
• Neuropsychiatric symptoms (dementia, psychosis)

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3. Hemolytic Anemias

• Intravascular hemolysis: hemoglobinemia, hemoglobinuria, hemosiderinuria; causes: G6PD deficiency, PNH, mismatched transfusion, microangiopathic
• Extravascular hemolysis: splenomegaly, jaundice, no hemoglobinuria; causes: hereditary spherocytosis, AIHA (warm type), sickle cell

• Increased LDH, indirect bilirubin
• Decreased haptoglobin (binds free hemoglobin; low in hemolysis)
• High reticulocytes
• Peripheral smear: schistocytes (microangiopathic), spherocytes (AIHA, hereditary spherocytosis)

• Autosomal dominant; spectrin or ankyrin defect -> loss of membrane surface area -> spherocytes
• Splenomegaly, jaundice, anemia; gallstones (pigment stones) from chronic hemolysis
• Osmotic fragility test positive
• Treatment: splenectomy (curative)

• X-linked; affects males predominantly
• Episodic hemolysis triggered by: oxidative stress (infections, fava beans, primaquine, dapsone)
• During crisis: Heinz bodies (denatured Hb), bite cells on smear
• Screen with G6PD enzyme assay (do NOT test during acute crisis - reticulocytes have normal levels)

• Warm AIHA: IgG antibodies active at 37°C; extravascular hemolysis; associated with SLE, CLL, drugs (methyldopa, penicillin); treat with steroids
• Cold AIHA: IgM antibodies, active at cold temps; complement activation; associated with Mycoplasma pneumoniae, EBV; acrocyanosis in cold

• Autosomal recessive; HbS (glutamate->valine substitution at position 6 of beta-globin)
• Sickling triggered by: hypoxia, dehydration, infection, cold, acidosis
• Complications: vaso-occlusive crisis (pain), acute chest syndrome, stroke, splenic sequestration, aplastic crisis (parvovirus B19), priapism, avascular necrosis
• Spleen: "autosplenectomy" by repeated infarctions in adults -> functional asplenia -> susceptible to encapsulated bacteria (Strep pneumoniae, H. influenzae, Neisseria meningitidis)
• Howell-Jolly bodies = marker of asplenia

• Alpha-thalassemia: deletion of alpha globin genes (chromosome 16)
• Beta-thalassemia: mutations in beta globin genes (chromosome 11)
• Beta-thalassemia major: transfusion-dependent; extramedullary hematopoiesis -> skull "hair-on-end" X-ray, hepatosplenomegaly; iron overload from transfusions
• Lab: microcytic hypochromic anemia, target cells, high HbA2 (>3.5%) and HbF in beta-thalassemia trait

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4. Aplastic Anemia

• Idiopathic (most common, immune-mediated T-cell destruction of stem cells)
• Drugs: chloramphenicol, benzene, chemotherapy agents
• Infections: parvovirus B19, hepatitis viruses, EBV
• Inherited: Fanconi anemia (congenital anomalies + progressive marrow failure)

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5. Anemia of Chronic Disease (ACD)

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B. POLYCYTHEMIA (ERYTHROCYTOSIS)

• Relative (spurious): dehydration, fluid loss; plasma volume decreased
• Absolute Primary: Polycythemia Vera (JAK2 V617F mutation in >95%); panmyelosis; low EPO
• Absolute Secondary: high EPO; physiologic (high altitude, COPD, sleep apnea) or pathologic (EPO-secreting renal cell carcinoma, hepatocellular carcinoma, hemangioblastoma)

• Panmyelosis (red cells + WBC + platelets all increased)
• Splenomegaly
• Pruritus after hot bath (histamine release)
• Thrombosis risk (stroke, MI, Budd-Chiari)
• JAK2 V617F mutation
• Low EPO level (distinguishes from secondary)
• Treatment: phlebotomy, hydroxyurea, aspirin

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C. LEUKEMIAS

Key Distinction: Acute vs. Chronic

Acute Myeloid Leukemia (AML)

• Most common acute leukemia in adults
• Auer rods = pathognomonic (pink needle-like cytoplasmic inclusions in blast cells)
• Presents with: anemia, infections (neutropenia), bleeding (thrombocytopenia)
• Gum infiltration (leukemic infiltrates) - characteristic of monocytic AML
• Special: Acute Promyelocytic Leukemia (APL/AML M3) - t(15;17) translocation -> PML-RARA fusion; high risk DIC; treat with ATRA (all-trans retinoic acid)
• Treatment: Induction chemotherapy (cytarabine + daunorubicin "7+3")

Acute Lymphoblastic Leukemia (ALL)

• Most common malignancy in children (peak age 2-5 years)
• Philadelphia chromosome t(9;22) BCR-ABL = poor prognosis
• CNS involvement common -> prophylactic intrathecal chemotherapy
• Testicular involvement in boys
• Lymphoblasts: TdT positive (terminal deoxynucleotidyl transferase)
• Treatment: multiagent chemotherapy; high cure rate in children (~85%)

Chronic Myeloid Leukemia (CML)

• Philadelphia chromosome t(9;22) BCR-ABL - present in nearly 100%
• Massive splenomegaly (often extending to pelvis)
• High WBC with full maturation spectrum (blasts to mature neutrophils; "left shift")
• Low leukocyte alkaline phosphatase (LAP) score - distinguishes from leukemoid reaction (high LAP)
• Basophilia characteristic
• Natural history: chronic phase -> accelerated phase -> blast crisis
• Treatment: Imatinib (tyrosine kinase inhibitor targeting BCR-ABL) - revolutionary; highly effective

Chronic Lymphocytic Leukemia (CLL)

• Most common leukemia in adults in Western countries (>50 years, male predominance)
• Neoplastic mature B cells (CD5+, CD19+, CD23+)
• Smudge cells (Basket cells) on peripheral smear - pathognomonic
• Lymphocytosis (usually the presenting finding)
• Lymphadenopathy, splenomegaly, hepatomegaly
• Autoimmune hemolytic anemia (warm AIHA), autoimmune thrombocytopenia
• Hypogammaglobulinemia -> recurrent infections
• Richter transformation (conversion to aggressive DLBCL)
• Treatment: watch and wait (early); ibrutinib (BTK inhibitor), venetoclax, chemoimmunotherapy

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D. LYMPHOMAS

Hodgkin Lymphoma (HL)

• Reed-Sternberg cells (RS cells) = pathognomonic: large binucleated cells with prominent "owl-eye" nucleoli; CD15+, CD30+
• Bimodal age distribution: young adults (15-34) and older adults (>55)
• EBV association (especially mixed cellularity type)
• Presents: painless cervical lymphadenopathy, then contiguous spread
• B symptoms: fever >38°C, drenching night sweats, unintended weight loss >10% in 6 months -> worse prognosis
• Alcohol-induced lymph node pain - characteristic of HL
• Mediastinal mass common
• Ann Arbor staging: I (1 region) -> II (2+ regions same side of diaphragm) -> III (both sides) -> IV (disseminated/organ involvement); +A (no B symptoms) or +B (with B symptoms)
• Highly curable (ABVD chemotherapy ± radiation)

Non-Hodgkin Lymphoma (NHL)

• Diffuse Large B Cell Lymphoma (DLBCL): most common NHL in adults; aggressive; cure possible with R-CHOP
• Follicular Lymphoma: indolent; t(14;18) BCL-2 overexpression; incurable but treatable; "waxing and waning" nodes
• Burkitt Lymphoma: t(8;14) c-MYC translocation; "starry sky" pattern on biopsy; associated with EBV; jaw mass in endemic form; very aggressive but curable
• Mantle Cell Lymphoma: t(11;14) cyclin D1; poor prognosis; CD5+, CD20+, cyclin D1+
• Peripheral T-cell lymphomas: less common, generally poor prognosis

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E. MULTIPLE MYELOMA

• C = hyperCalcemia (>11 mg/dL) - osteoclast activation
• R = Renal insufficiency (creatinine >2 mg/dL) - light chain nephrotoxicity, cast nephropathy
• A = Anemia (Hb <10 g/dL) - marrow infiltration
• B = Bone lesions (lytic "punched-out" lesions on X-ray) - skull, vertebrae, ribs, pelvis
  • Note: bone scan often NEGATIVE in myeloma (pure lytic, no osteoblastic activity)

• Monoclonal spike on serum protein electrophoresis (SPEP)
• IgG most common (50%), IgA second; rarely IgM, IgD, light chain only
• Bence-Jones protein in urine (free light chains)
• Rouleaux formation on peripheral smear
• Elevated ESR
• Hypercalcemia
• Beta-2 microglobulin elevated (prognostic)

• Pathological fractures (especially vertebrae -> spinal cord compression = emergency)
• AL amyloidosis (light chain deposition in organs)
• Recurrent infections (suppressed normal Ig)
• Hyperviscosity syndrome (IgA/IgM; headache, visual blurring, bleeding)

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F. MYELODYSPLASTIC SYNDROME (MDS)

• Clonal stem cell disorder; ineffective hematopoiesis
• Cytopenias despite hypercellular marrow
• Dysplastic changes (abnormal morphology): hypogranular neutrophils, hypolobated neutrophils (pseudo-Pelger-Huet), megaloblastic changes
• Risk of transformation to AML
• Causes: idiopathic, prior chemo/radiation ("therapy-related MDS")
• Ringed sideroblasts (iron in mitochondria around nucleus) on iron stain = sideroblastic pattern of MDS

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G. MYELOPROLIFERATIVE NEOPLASMS (MPN)

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H. BLEEDING DISORDERS

Hemostasis Overview

1. Primary hemostasis: platelet plug formation (platelets + vWF + collagen)
2. Secondary hemostasis: coagulation cascade -> fibrin clot
3. Fibrinolysis: plasmin dissolves clot

Coagulation Cascade

• Intrinsic pathway: XII -> XI -> IX -> VIII -> X (measured by PTT/APTT)
• Extrinsic pathway: Tissue factor + VII -> X (measured by PT/INR)
• Common pathway: X -> V -> thrombin -> fibrin

Hemophilia A and B

• Hemophilia A: Factor VIII deficiency; X-linked recessive
• Hemophilia B (Christmas disease): Factor IX deficiency; X-linked recessive
• Both: prolonged APTT, normal PT, normal platelet count
• Clinical: hemarthrosis (bleeding into joints - hallmark), deep muscle hematomas, excessive bleeding after surgery/trauma
• Petechiae/purpura are NOT features (those suggest platelet/vascular problems)
• Treatment: Factor VIII/IX concentrate; DDAVP for mild Hemophilia A

Von Willebrand Disease (vWD)

• Most common inherited bleeding disorder
• vWF is carrier for factor VIII and mediates platelet adhesion to subendothelial collagen
• Autosomal dominant (mostly)
• Clinical: mucocutaneous bleeding (epistaxis, menorrhagia, gum bleeding)
• Lab: prolonged bleeding time, prolonged APTT (in severe cases), low vWF antigen and activity (ristocetin cofactor assay)
• Treatment: DDAVP (desmopressin; releases stored vWF from endothelium), vWF concentrate

ITP (Immune Thrombocytopenic Purpura)

• Autoimmune IgG antibodies against GPIIb/IIIa on platelets
• Acute form: children, after viral infection, self-limiting
• Chronic form: adults, especially young women; often idiopathic
• Lab: isolated thrombocytopenia, normal PT/APTT, megakaryocytes in marrow
• Clinical: petechiae, purpura, mucous membrane bleeding; splenomegaly is NOT typical (distinguishes from TTP)
• Treatment: corticosteroids, IVIG, anti-D (Rh+), romiplostim/eltrombopag (TPO-mimetics), splenectomy

TTP (Thrombotic Thrombocytopenic Purpura)

DIC (Disseminated Intravascular Coagulation)

• Pathological systemic activation of coagulation -> thrombosis + consumption of coagulation factors + platelets -> bleeding

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PART 6: BONE MARROW EXAMINATION

Indications

• Unexplained pancytopenia
• Staging/diagnosis of leukemia, lymphoma, myeloma
• Fever of unknown origin with suspected marrow pathology
• Monitoring response to therapy

Procedure

• Aspiration: liquid marrow drawn out for cell morphology and flow cytometry
• Biopsy (trephine): core of bone for architecture; essential for cellularity assessment and fibrosis

Sites

• Posterior iliac crest (most common)
• Sternum (aspiration only; NOT biopsy - risk of cardiac puncture)

Normal marrow cellularity

• Children: ~100% cellularity (all fat replaced by marrow)
• Adults: ~50% (50/50 fat/cells)
• Elderly: ~30% cellularity

Marrow:Erythroid (M:E) ratio

• Normal: 3:1 to 4:1
• Increased (>4:1): myeloid hyperplasia (infection, CML) or erythroid hypoplasia (pure red cell aplasia)
• Decreased (<3:1): erythroid hyperplasia (hemolysis, iron deficiency) or myeloid hypoplasia (agranulocytosis)

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PART 7: KEY LAB INVESTIGATIONS SUMMARY

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PART 8: SPECIAL TESTS TO KNOW

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PART 9: BLOOD TRANSFUSION - BASICS

Blood Groups

• ABO system: A (anti-B), B (anti-A), AB (no antibodies = universal recipient), O (anti-A and anti-B = universal donor)
• Rh system: D antigen most important; Rh+ has D antigen; Rh- does not
• Rh incompatibility in pregnancy: Rh- mother + Rh+ fetus -> maternal anti-D IgG can cross placenta in subsequent pregnancies -> hemolytic disease of the newborn (HDN)
• Prevention: Anti-D immunoglobulin (Rhogam) given to Rh- mothers

Transfusion Reactions

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PART 10: PROPAEDEUTICS PRACTICAL TIPS

Sequence for Hematology Patient Examination

1. General inspection: pallor, jaundice, plethora, petechiae, purpura, dyspnea
2. Vital signs: HR (tachycardia in anemia), temperature (fever in leukemia/lymphoma)
3. Hands: koilonychia, pallor of palmar creases, leukonychia (nail changes), Osler nodes (SBE)
4. Face/Eyes: conjunctival pallor, scleral jaundice, retinal changes
5. Mouth: glossitis, angular cheilitis, gum hypertrophy (AML monocytic), tonsillar enlargement
6. Neck/supraclavicular: lymph node examination
7. Axillary lymph nodes
8. Chest: sternal tenderness
9. Abdomen: hepatomegaly, splenomegaly (most important)
10. Inguinal lymph nodes
11. Lower limbs: edema (cardiac failure from severe anemia), skin changes
12. Neurological: vibration/proprioception (B12 deficiency), Babinski (subacute combined degeneration)

"Spot Diagnoses" Examiners Love

• Pallor + koilonychia + pica = Iron deficiency anemia
• Pallor + glossitis + neurological signs = B12 deficiency
• Massive splenomegaly = CML (most common cause of massive splenomegaly)
• Smudge cells + mature lymphocytes = CLL
• Auer rods = AML
• Owl-eye RS cells = Hodgkin lymphoma
• Reed-Sternberg cells = Hodgkin lymphoma
• Schistocytes + thrombocytopenia + normal PT/APTT = TTP
• Rouleaux + lytic bone lesions + M-spike = Multiple myeloma
• Hypersegmented neutrophils + oval macrocytes = Megaloblastic anemia
• JAK2 + elevated all three cell lines = Polycythemia vera
• BCR-ABL t(9;22) + massive spleen = CML
• t(15;17) + DIC + auer rods = AML M3 (APL)

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Sources: Harrison's Principles of Internal Medicine 22E (2025) | Robbins & Kumar Pathologic Basis of Disease | Robbins & Kumar Basic Pathology | Goldman-Cecil Medicine | Katzung's Basic and Clinical Pharmacology 16EThis is your complete hematology propaedeutics exam guide. Here is a quick orientation to how it's structured:

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What's Covered (10 Parts)

High-Priority Topics for a Practical Exam

• Physical exam technique for lymph nodes and spleen (examiner will ask you to demonstrate)
• Recognizing peripheral smear findings (spherocytes, schistocytes, blasts, hypersegmented neutrophils, smudge cells)
• Interpreting a CBC and naming the type of anemia from MCV + reticulocyte count
• The classic "spot diagnoses" in Part 10 - these are very likely to appear
• CRAB criteria for myeloma and B symptoms for lymphoma
• Distinguishing TTP from DIC (normal vs. abnormal PT/APTT)
• Iron deficiency vs. ACD lab patterns (the TIBC is the key differentiator)

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Hematology Department Disorders - Mechanisms Only

Sources: Robbins & Kumar Pathologic Basis of Disease, Robbins Basic Pathology, Harrison's Principles of Internal Medicine 22E, Goldman-Cecil Medicine

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I. ANEMIAS

1. Iron Deficiency Anemia

• Hepcidin falls -> ferroportin upregulated -> more duodenal absorption
• But when supply is insufficient (poor intake, chronic blood loss, malabsorption), stores are exhausted
• Without iron, protoporphyrin cannot bind iron to form heme, and heme cannot combine with globin -> deficient hemoglobin synthesis -> microcytic hypochromic RBCs
• Cells become smaller because each division produces less hemoglobin per cell

2. Anemia of Chronic Disease (ACD)

• IL-6 upregulates hepcidin in the liver
• Excess hepcidin degrades ferroportin on macrophages -> iron trapped inside macrophages and cannot be released to transferrin
• Simultaneously, inflammatory cytokines suppress EPO production and blunt EPO receptor sensitivity on erythroid progenitors
• Result: functional iron deficiency - iron is present in the body but unavailable for red cell production

3. Megaloblastic Anemia (B12 / Folate Deficiency)

• Folate as methylenetetrahydrofolate donates a methyl group to uracil to make thymine
• B12 is required to regenerate active THF from methyl-THF (the methyl trap hypothesis)
• Without adequate thymidylate, DNA synthesis is impaired while RNA and protein synthesis continue normally
• Nuclear maturation lags behind cytoplasmic growth -> megaloblasts (large cells with immature-looking nuclei and abundant cytoplasm)
• Ineffective hematopoiesis: many megaloblasts die in the marrow before release (intramedullary hemolysis)
• B12 also specifically required for conversion of methylmalonyl-CoA to succinyl-CoA; deficiency -> methylmalonyl-CoA accumulates -> incorporated into abnormal fatty acids -> myelin sheath damage (subacute combined degeneration)

4. Hemolytic Anemias

a. Hereditary Spherocytosis

b. G6PD Deficiency

• Oxidative stress (infections, fava beans, drugs like primaquine, dapsone) causes oxidation of hemoglobin -> denatured hemoglobin precipitates as Heinz bodies -> Heinz bodies bind to membrane -> macrophages "bite" them out (bite cells) -> membrane damage -> intravascular and extravascular hemolysis
• Older RBCs most vulnerable because G6PD activity declines with cell age

c. Autoimmune Hemolytic Anemia (AIHA) - Warm Type

d. AIHA - Cold Type (Cold Agglutinin Disease)

e. Sickle Cell Disease

1. Obstruct microvascular flow (vaso-occlusion) -> ischemia and infarction
2. Are rigid and destroyed in the spleen -> hemolysis
3. Repeated splenic infarction leads to autosplenectomy -> functional asplenia Polymerization is promoted by: low PO2, low pH, high 2,3-DPG, dehydration, and high HbS concentration. HbF inhibits polymerization (protective in newborns).

f. Thalassemias

• Beta-thalassemia: reduced or absent beta-globin -> excess unpaired alpha chains precipitate -> oxidative membrane damage -> intramedullary destruction of erythroblasts (ineffective erythropoiesis) and peripheral hemolysis. Compensatory expansion of erythroid marrow -> skeletal deformities ("chipmunk face," "hair-on-end" skull X-ray)
• Alpha-thalassemia: reduced alpha chains -> excess gamma chains form HbBart's (gamma4) or HbH (beta4) tetramers; these have very high O2 affinity and cannot deliver O2 to tissues

g. Paroxysmal Nocturnal Hemoglobinuria (PNH)

5. Aplastic Anemia

1. Immune-mediated (dominant theory): A drug, infection, or unknown environmental insult antigenically alters hematopoietic stem cells. Activated Th1 lymphocytes release IFN-gamma and TNF-alpha, which suppress and destroy HSCs. This explains why immunosuppression (anti-thymocyte globulin + cyclosporin) restores hematopoiesis in 60-70% of patients.
2. Intrinsic stem cell defect: 5-10% have mutations in telomerase (TERT/TERC genes) -> premature stem cell senescence; another 50% have abnormally short telomeres. Short telomeres may also generate neoantigens that provoke an autoimmune attack, linking both mechanisms.

6. Myelophthisic Anemia

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II. MYELOPROLIFERATIVE NEOPLASMS (MPNs)

7. Polycythemia Vera (PV)

8. Essential Thrombocythemia (ET)

9. Primary Myelofibrosis (PMF)

10. Chronic Myeloid Leukemia (CML)

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III. MYELOID MALIGNANCIES

11. Acute Myeloid Leukemia (AML)

• Class I mutations: activate proliferation/survival signaling (e.g., FLT3-ITD, RAS mutations) -> proliferative advantage
• Class II mutations: block differentiation (e.g., t(8;21) RUNX1-RUNX1T1, inv(16) CBFB-MYH11, t(15;17) PML-RARA) -> immature blasts accumulate

12. Myelodysplastic Syndrome (MDS)

• Splicing factors (SF3B1, SRSM2, U2AF1): abnormal mRNA processing
• Epigenetic regulators (TET2, DNMT3A, ASXL1, EZH2): aberrant DNA methylation and histone modification -> dysregulated gene expression
• Transcription factors (RUNX1, TP53): disrupted differentiation

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IV. LYMPHOID MALIGNANCIES

13. Acute Lymphoblastic Leukemia / Lymphoma (ALL)

• t(12;21) TEL-AML1 (most common in children, favorable prognosis)
• t(9;22) BCR-ABL1 (Ph+ ALL, poor prognosis; same fusion as CML but different breakpoint -> p190 isoform)
• t(1;19) E2A-PBX1
• Hyperdiploidy (>50 chromosomes) = favorable

14. Chronic Lymphocytic Leukemia (CLL)

• Overexpression of BCL-2 (anti-apoptotic protein) -> cells accumulate rather than dying
• Trisomy 12, deletions of 13q14 (loss of miR-15a and miR-16-1 which normally suppress BCL-2), 11q, 17p (TP53)
• CLL cells receive survival signals through the B-cell receptor (BCR) signaling pathway (targeted by ibrutinib, a BTK inhibitor)
• The CLL cells are immunologically incompetent -> hypogammaglobulinemia -> recurrent infections

15. Hodgkin Lymphoma (HL)

• EBV (in ~40-50%) infects B cells -> expresses LMP-1 (viral oncogene) which constitutively activates NF-kB -> promotes survival and inhibits apoptosis
• EBV-negative cases: often have activating mutations in NF-kB pathway genes directly
• RS cells produce cytokines (IL-5, IL-13, CCL5, CCL17) that recruit eosinophils, plasma cells, lymphocytes, and fibroblasts -> the reactive cellular background that defines each HL subtype (lymphocyte-rich, mixed cellularity, nodular sclerosis, lymphocyte-depleted)
• RS cells express CD30 and CD15 (target of brentuximab vedotin)

16. Non-Hodgkin Lymphomas (NHL)

a. Diffuse Large B Cell Lymphoma (DLBCL)

• BCL-6 translocations: BCL-6 is a transcriptional repressor that sustains germinal center reactions; its deregulation blocks exit from the GC state
• BCL-2 translocations (in some cases via t(14;18))
• MYC activation: drives proliferation
• "Double-hit" (MYC + BCL-2) or "triple-hit" (MYC + BCL-2 + BCL-6) lymphomas = very aggressive due to both proliferation drive AND apoptosis resistance

b. Follicular Lymphoma

c. Burkitt Lymphoma

d. Mantle Cell Lymphoma

17. Multiple Myeloma

• Translocations involving IgH locus (chr 14): most commonly t(11;14) - cyclin D1; t(4;14) - MMSET/FGFR3; t(14;16) - MAF -> dysregulates proliferation
• RAS and BRAF mutations: activate MAPK proliferation signaling
• TP53 deletion/mutation and del(17p): loss of tumor suppression
• Myeloma cells produce RANKL and suppress OPG -> osteoclast activation -> lytic bone lesions + hypercalcemia
• Myeloma cells rely on the bone marrow microenvironment for survival signals (IL-6 from stromal cells -> JAK-STAT3 signaling -> key survival signal)
• Monoclonal immunoglobulin (M-protein) or free light chains deposit in kidneys (cast nephropathy), nerves, and organs (AL amyloidosis)

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V. BLEEDING DISORDERS

18. Hemophilia A (Factor VIII Deficiency)

19. Hemophilia B (Factor IX Deficiency)

20. Von Willebrand Disease (vWD)

• vWF normally binds GPIb on platelets AND subendothelial collagen -> acts as a bridge anchoring platelets to damaged vessel walls (primary hemostasis)
• vWF also carries and protects Factor VIII from proteolytic degradation in circulation
• In vWD: impaired platelet adhesion -> deficient platelet plug formation -> mucocutaneous bleeding (nosebleeds, menorrhagia, GI bleeding)
• Type 1: quantitative partial reduction; Type 2: qualitative defect; Type 3: complete absence

21. Immune Thrombocytopenic Purpura (ITP)

22. Thrombotic Thrombocytopenic Purpura (TTP)

• Acquired TTP: autoantibodies against ADAMTS13
• Congenital (Upshaw-Schulman syndrome): ADAMTS13 gene mutations

23. Disseminated Intravascular Coagulation (DIC)

• Endotoxin (sepsis) and cytokines (TNF, IL-1) -> upregulate tissue factor (TF) expression on monocytes and endothelium -> massive TF-VIIa driven thrombin generation throughout the circulation
• Obstetric emergencies (amniotic fluid embolism): amniotic fluid is rich in TF and phospholipids -> direct activation
• AML M3 / malignancy: granule contents of promyelocytes contain TF-like substances; some cancers express TF constitutively
• Consequence: widespread microvascular thrombosis (ischemia) simultaneously with consumption of clotting factors and platelets -> paradoxical bleeding. Plasminogen is also activated -> fibrinolysis -> fibrin degradation products (D-dimer) accumulate, which themselves inhibit platelet function and fibrin polymerization.

24. Heparin-Induced Thrombocytopenia (HIT)

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VI. OTHER IMPORTANT DISORDERS

25. Polycythemia (Secondary)

26. Hemolytic Uremic Syndrome (HUS)

27. Myelodysplastic/Myeloproliferative Overlap Neoplasms (e.g., CMML)

28. Lymphocytosis / Reactive Changes

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Quick Reference: Core Molecular Mechanisms

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Sources: Robbins, Cotran & Kumar Pathologic Basis of Disease | Robbins & Kumar Basic Pathology | Harrison's Principles of Internal Medicine 22E | Henry's Clinical Diagnosis and Management by Laboratory Methods