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🩸 Haematology Exam Study Guide — From Robbins & Kumar Basic Pathology

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1. ANEMIA

Classification (Robbins):

Causes:

• Blood loss (hemorrhage)
• Increased destruction (hemolysis)
• Decreased production (marrow failure)

Hemolytic Anemias — Key Distinction:

• Hyperbilirubinemia + jaundice
• Splenomegaly
• Pigment gallstones (if long-standing)

• Hemoglobinemia, hemoglobinuria, hemosiderinuria
• Iron deficiency (iron lost in urine)
• Decreased haptoglobin (seen in both types)

Clinical Features:

• Acute (large bleed): dyspnea, organ failure, shock
• Chronic: pallor, fatigue, lassitude
• Severe congenital: growth retardation, bone deformities from marrow hyperplasia (especially thalassemia)

Robbins & Kumar Basic Pathology, p.433

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2. SICKLE CELL ANEMIA

Pathogenesis:

• Deoxygenated HbS self-associates into polymers → distorts RBC into elongated crescentic/sickle shape
• Initially reversible on reoxygenation; repeated episodes cause membrane damage (Ca²⁺ influx, loss of K⁺/water) → irreversibly sickled cells prone to hemolysis

Factors determining clinical severity:

1. Level of other haemoglobins (HbA, HbF): HbA retards sickling → heterozygotes (HbAS, "sickle cell trait") rarely sickle in vivo. HbF also inhibits sickling - newborns asymptomatic until HbF falls at ~5-6 months
2. Degree of deoxygenation: low O₂ triggers sickling
3. Intracellular Hb concentration: dehydration worsens sickling

Consequences:

• Hemolytic anemia (moderate to severe) - extravascular + intravascular
• Vaso-occlusion: sickled cells block microvessels → pain crises, tissue infarction (bones, spleen, lungs, brain)
• Splenic sequestration → functional asplenia by adulthood (autosplenectomy)
• Susceptibility to encapsulated bacteria (Streptococcus pneumoniae, H. influenzae) due to asplenia
• Stroke risk
• Aplastic crisis triggered by parvovirus B19

Robbins & Kumar Basic Pathology, p.384–386

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3. THALASSEMIA

• β-globin gene: chromosome 11 (single gene - mainly point mutations)
• α-globin genes: chromosome 16 (two tandem genes - mainly deletions)

Classification Table (Robbins):

Key Pathology:

• Excess unpaired α-chains precipitate → damage RBC membranes → extravascular hemolysis
• Ineffective erythropoiesis → marked marrow erythroid hyperplasia → bone deformities ("chipmunk face," "hair-on-end" skull X-ray in β-thal major)
• Iron overload (from transfusions + increased GI absorption) → heart and endocrine failure

Robbins & Kumar Basic Pathology, p.386–388

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4. LEUKAEMIA

A. Acute Lymphoblastic Leukaemia/Lymphoma (ALL)

• Most common cancer in children. ~85% are B-ALL; T-ALL more common in adolescent males as thymic masses
• B-ALL peaks at age ~3 years; T-ALL peaks in adolescence
• Composed of immature B or T lymphoblasts

• Mutations in transcription factors (B-ALL: PAX5, EBF1, TCF3, RUNX1, BCR-ABL1; T-ALL: NOTCH1)
• ~90% have chromosomal changes: most common is hyperploidy (>50 chromosomes) → good prognosis
• Philadelphia chromosome (BCR-ABL1) in ~5% of childhood ALL - poorer prognosis; treated with tyrosine kinase inhibitors

B. Chronic Myeloid Leukaemia (CML)

• Adults aged 25-60; peak incidence 4th-5th decade
• t(9;22) Philadelphia chromosome in ~95% → BCR-ABL fusion gene → constitutively active tyrosine kinase → growth factor-independent proliferation
• Affects granulocytic, erythroid, megakaryocytic, B-cell precursors (transformed haematopoietic stem cell)

• WBC often >100,000/μL with neutrophils, immature granulocytes, basophils, eosinophils
• Bone marrow hypercellular; massive splenomegaly (extramedullary haematopoiesis + splenic infarcts)

• Insidious onset: fatigue, weakness, weight loss, dragging sensation in abdomen
• ~50% undergo blast crisis (transformation to AML or ALL) - median survival untreated = 3 years
• Treatment: Imatinib (BCR-ABL tyrosine kinase inhibitor) has transformed prognosis

C. Chronic Lymphocytic Leukaemia / Small Lymphocytic Lymphoma (CLL/SLL)

• Most common leukemia of adults in the Western world
• CLL: peripheral blood lymphocytes >5,000/μL; SLL: predominantly lymph node involvement (4% of NHLs)
• Pathogenesis: BCL2 overexpression (inhibits apoptosis; via deletion 13q) + BCR signaling via Bruton tyrosine kinase (BTK)
• Causes immune dysregulation → hypogammaglobulinemia + 15% develop warm autoantibodies (against own RBCs or platelets)

Robbins & Kumar Basic Pathology, p.411–412

Acute Myeloid Leukaemia (AML) — Brief:

• Aggressive tumor of immature myeloid blasts replacing marrow
• Mutations in transcription factors (interfere with myeloid differentiation) + growth factor receptor signaling or epigenome regulators

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5. HODGKIN LYMPHOMA

1. Distinctive Reed-Sternberg (RS) giant cells (neoplastic cells)
2. Robust but ineffective host immune response - RS cells are minority of tumor mass
3. Arises in single lymph node or chain - spreads in stepwise, contiguous fashion (unlike NHL)

Classification - 5 Subtypes:

Pathogenesis:

• RS cells arise from germinal center B cells (proven by microdissection showing same immunoglobulin gene rearrangements with somatic hypermutation in every RS cell)
• EBV present in RS cells in up to 70% of mixed cellularity; identical EBV integration in all RS cells → infection precedes transformation
• RS cells secrete cytokines: IL-5 (eosinophil chemoattractant), TGF-β (fibrogenic), IL-13 (autocrine RS growth)
• RS cells escape immunity: loss of β₂-microglobulin (no MHC class I expression) + overexpression of PD-L1 (inhibits T-cell responses) - chromosome 9p amplification

Reed-Sternberg Cell Morphology:

• Giant binucleated/multilobed cell
• "Owl-eye" prominent eosinophilic nucleoli
• Immunophenotype: CD15+, CD30+, PAX5 dim, negative for most B-cell markers (CD20-)

Robbins & Kumar Basic Pathology, p.417–420

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6. PURPURA / THROMBOCYTOPENIA

• Risk of post-traumatic bleeding: 20,000-50,000/μL
• Risk of spontaneous bleeding: <5,000/μL
• Bleeding is superficial: petechiae, ecchymoses, epistaxis, gum bleeding, mucosal hemorrhage

Causes (Robbins Table):

• Aplastic anemia, marrow infiltration (leukemia), drug-induced (alcohol, thiazides, cytotoxic drugs), infections (measles, HIV), megaloblastic anemia

• Immunologic: ITP, SLE, drug-associated (quinidine, heparin), infections
• Non-immunologic: DIC, TTP, HUS, microangiopathic hemolytic anemias

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Immune Thrombocytopenic Purpura (ITP)

• Chronic ITP: Women aged 20-40; autoimmune
• Acute ITP: Children after viral infections; self-limited

• Antibodies against platelet membrane glycoproteins IIb/IIIa or Ib/IX complexes detected in ~80%
• Spleen = major site of antiplatelet antibody production + IgG-coated platelet destruction
• Bone marrow: increased megakaryocytes (compensatory)

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Heparin-Induced Thrombocytopenia (HIT)

• 3-5% of patients on unfractionated heparin after 1-2 weeks
• IgG antibodies bind platelet factor 4 in heparin-dependent fashion → immune complexes → platelet Fc receptor binding → platelet activation → paradoxical THROMBOSIS (not just bleeding)
• Both venous and arterial thromboses occur
• Treatment: Stop heparin immediately

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Thrombotic Thrombocytopenic Purpura (TTP)

Robbins & Kumar Basic Pathology, p.428-430

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7. DIC (Disseminated Intravascular Coagulation)

Pathogenesis:

1. Release of tissue factor / procoagulants into circulation (e.g., placenta in obstetric complications, cancer cells from acute promyelocytic leukemia or adenocarcinoma)
2. Widespread endothelial cell damage (bacterial sepsis: endotoxins stimulate tissue factor on monocytes; monocytes release IL-1 and TNF → stimulate tissue factor on endothelium + downregulate thrombomodulin → more thrombin + less protein C activation)

Important causes of DIC:

• Obstetric complications (amniotic fluid embolism, abruptio placentae, retained dead fetus)
• Bacterial sepsis (most common infectious cause)
• Malignancy (acute promyelocytic leukemia, adenocarcinomas)
• Massive tissue injury (trauma, burns, heat stroke)
• Antigen-antibody complex deposition (SLE)
• Infections (meningococci, rickettsiae)

Two Consequences:

1. Microvascular thrombi → tissue ischemia → microinfarcts + microangiopathic hemolytic anemia
2. Bleeding tendency from consumption of platelets + clotting factors + secondary fibrinolysis (plasmin cleaves fibrin, factor V, factor VIII; fibrin degradation products inhibit platelet aggregation + thrombin activity)

Morphology:

• Microthrombi in kidneys (most severely affected - bilateral cortical necrosis), adrenals (Waterhouse-Friderichsen syndrome), brain, heart
• Diffuse petechiae and ecchymoses on skin, serosal linings, epicardium, endocardium, lungs, urinary mucosa

Clinical:

• Acute DIC: fulminant, dominated by bleeding (e.g., obstetric complications)
• Chronic DIC: dominated by thrombosis (e.g., adenocarcinoma)
• Manifestations: petechiae/ecchymoses, shock, acute renal failure, dyspnea, cyanosis, convulsions, coma

Lab findings:

• Thrombocytopenia
• Prolonged PT and PTT
• Low fibrinogen
• Elevated fibrin degradation products (D-dimer)

Robbins & Kumar Basic Pathology, p.427-428

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8. BLOOD GROUPING (ABO System)

Basis of ABO antigens:

• O allele: enzymatically inactive → only H antigen expressed
• A allele: adds N-acetylgalactosamine to H antigen → A antigen
• B allele: adds galactose to H antigen → B antigen

ABO Blood Group Table:

Why do we have natural antibodies?

Bombay Blood Group (Oh):

• Rare mutation in fucosyltransferase gene → cannot produce H antigen
• Cannot produce A, B, or H antigens
• Makes anti-H, anti-A, anti-B antibodies - can only receive blood from other Bombay donors!

Rh System (brief):

• Rh-positive individuals express RhD antigen
• Rh-negative individuals develop anti-D antibodies only after exposure (transfusion or pregnancy)
• Clinically important in haemolytic disease of the newborn (Rh-negative mother + Rh-positive fetus)

Cellular and Molecular Immunology, Robbins, p.1157-1159

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