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🩸 Hematology — Complete Pathology Chapter

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📋 CHAPTER OUTLINE

1. Red Cell Disorders (Anemias + Polycythemia)
2. White Cell Disorders (Nonneoplastic + Neoplastic)
3. Bleeding Disorders (Platelets, Coagulation, DIC)

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PART 1: RED CELL DISORDERS

1. Anemia — Overview

• Pathophysiology: Blood loss, hemolysis, or diminished erythropoiesis
• Morphology: MCV (microcytic, normocytic, macrocytic)

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2. Hemolytic Anemias

A. Hereditary Spherocytosis (HS)

• Defect: Mutations in spectrin, ankyrin, band 4.2, or band 3 → loss of membrane lipid → spherocytes
• Inheritance: Mostly autosomal dominant
• Pathogenesis: Spherocytes are rigid, get trapped and destroyed in splenic sinusoids
• Morphology: Spherocytes on smear, splenomegaly, ↑ MCHC
• Diagnosis: Osmotic fragility test (spherocytes lyse in hypotonic solutions)
• Treatment: Splenectomy (curative — removes site of destruction)
• Complications: Aplastic crises (parvovirus B19), hemolytic crises

B. Sickle Cell Anemia

• Defect: Point mutation in β-globin gene — glutamate → valine at position 6 → HbS
• HbSS = sickle cell disease; HbAS = sickle trait (usually asymptomatic)
• Pathogenesis: Deoxygenated HbS polymerizes → elongated, rigid, crescent-shaped cells → vascular occlusion + hemolysis
• Sickling promoted by: hypoxia, acidosis, dehydration, infection
• Morphology: Sickled RBCs, Howell-Jolly bodies (from functional asplenia), target cells
• Key consequences:
  • Vaso-occlusive crises: pain in bones, joints, abdomen; stroke (in children)
  • Acute chest syndrome: fever, chest pain, pulmonary infiltrates (can be fatal)
  • Splenic sequestration crises: rapid splenomegaly with pooling of blood
  • Aplastic crisis: parvovirus B19
  • Functional asplenia → susceptibility to encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae, Salmonella osteomyelitis)
  • Autosplenectomy in adults
  • Avascular necrosis of femoral head
  • Renal papillary necrosis
• Lab: ↑ reticulocytes, ↑ bilirubin, ↑ LDH, ↓ haptoglobin; HbS on electrophoresis
• Treatment: Hydroxyurea (↑ HbF production), exchange transfusion, bone marrow transplant

C. Thalassemias

• Defect: Reduced/absent synthesis of α or β globin chains → imbalanced chains → ineffective erythropoiesis + hemolysis

β-Thalassemia

• Pathogenesis: Excess unpaired α-chains → precipitate → RBC membrane damage → hemolysis + ineffective erythropoiesis
• Morphology: Severe microcytic/hypochromic anemia, target cells, nucleated RBCs, splenomegaly, expansion of erythroid marrow (crew-cut skull on X-ray, chipmunk facies)
• Treatment: Regular transfusions + iron chelation (deferoxamine/deferasirox), BMT

α-Thalassemia

• Caused by deletions in α-globin genes (chromosome 16)

D. G6PD Deficiency

• X-linked recessive; most common RBC enzyme defect
• Pathogenesis: ↓ NADPH → ↓ glutathione → RBCs vulnerable to oxidative stress
• Triggers: Infections, drugs (primaquine, dapsone, sulfonamides), fava beans
• Morphology: Heinz bodies (precipitated Hb), bite cells (macrophages bite out Heinz bodies)
• Course: Self-limited hemolytic episodes; protective against P. falciparum malaria

E. Paroxysmal Nocturnal Hemoglobinuria (PNH)

• Defect: Somatic mutation in PIG-A gene → deficiency of GPI-anchored proteins (CD55, CD59) → uncontrolled complement activation → intravascular hemolysis
• Features: Hemolytic anemia, thrombosis (especially hepatic/mesenteric veins), cytopenias
• Diagnosis: Flow cytometry (↓ CD55/CD59 on RBCs)
• Treatment: Eculizumab (anti-C5 monoclonal antibody)

F. Immunohemolytic Anemia

• Warm antibody type (IgG): Most common; occurs in SLE, CLL, drugs; extravascular hemolysis; Coombs test positive
• Cold antibody type (IgM/complement): Triggered by cold; intravascular hemolysis; seen with Mycoplasma pneumoniae, EBV (mononucleosis)

G. Malaria

• Plasmodium falciparum causes most severe hemolysis → blackwater fever (hemoglobinuria)
• Hemolysis from direct RBC invasion and immune mechanisms

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3. Anemia of Diminished Erythropoiesis

A. Iron Deficiency Anemia (IDA)

• Most common anemia worldwide
• Causes: Blood loss (GI, menstruation), malabsorption, increased demand (pregnancy)
• Pathogenesis: ↓ iron → ↓ heme synthesis → microcytic hypochromic anemia
• Lab:
  • ↓ serum iron, ↓ ferritin (most sensitive marker)
  • ↑ TIBC, ↑ transferrin
  • Microcytic hypochromic RBCs, poikilocytosis (pencil cells)
• Clinical: Koilonychia (spoon nails), glossitis, angular stomatitis, Plummer-Vinson syndrome (dysphagia + esophageal web)
• Treatment: Oral ferrous sulfate; treat underlying cause

B. Anemia of Chronic Inflammation (ACD)

• Associated with: Chronic infections, autoimmune diseases, malignancies
• Pathogenesis: ↑ hepcidin (acute-phase reactant) → ↓ ferroportin → iron sequestered in macrophages (↑ ferritin, ↓ serum iron) + ↓ EPO response
• Lab: Normocytic/normochromic (can be microcytic); ↓ serum iron, ↓ TIBC, ↑ ferritin (key distinction from IDA)

C. Megaloblastic Anemias

• Defect: Impaired DNA synthesis → large RBC precursors (megaloblasts) → hypersegmented neutrophils + macro-ovalocytes
• Two main causes:

Folate Deficiency

• Poor diet (alcoholics, elderly), malabsorption, ↑ demand (pregnancy), drugs (methotrexate, trimethoprim)
• No neurological involvement
• Dx: ↓ serum folate, ↓ RBC folate (more reliable)

Vitamin B12 (Cobalamin) Deficiency

• Causes: Pernicious anemia (autoimmune, ↓ intrinsic factor), gastrectomy, ileal resection, strict veganism
• Pernicious anemia: Autoantibodies against parietal cells (anti-intrinsic factor antibody → specific)
• Key feature: Subacute combined degeneration of spinal cord — demyelination of posterior and lateral columns → loss of vibration sense, ataxia, spasticity, weakness
• Dx: ↓ serum B12, ↑ homocysteine + ↑ methylmalonic acid (specific for B12 deficiency)
• Treatment: IM B12 injections

D. Aplastic Anemia

• Pancytopenia from bone marrow failure (destruction or suppression of stem cells)
• Causes: Idiopathic (most, ~70%) → autoimmune T-cell mediated destruction; also radiation, drugs (chloramphenicol, benzene), viral infections (EBV, hepatitis)
• Morphology: Hypocellular marrow with fatty replacement; peripheral pancytopenia
• Treatment: BMT (young patients), immunosuppression (ATG + cyclosporine), EPO/G-CSF

E. Myelophthisic Anemia

• Space-occupying lesions replace normal marrow → leukoerythroblastic picture (nucleated RBCs + immature granulocytes in blood), teardrop cells
• Causes: Metastatic cancer (breast, prostate, lung), granulomas, myelofibrosis

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4. Polycythemia

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PART 2: WHITE CELL DISORDERS

A. Nonneoplastic Disorders

Leukopenia

• Neutropenia/Agranulocytosis: ↓ neutrophils → ↑ bacterial/fungal infection risk
  • Causes: Drugs (chemotherapy, chlorpromazine, propylthiouracil), autoimmune, viral infections
  • Agranulocytosis: Severe neutropenia (<500/μL) — life-threatening

Reactive Leukocytosis

• Neutrophilia: Bacterial infections, tissue necrosis, steroids
• Lymphocytosis: Viral infections (EBV, CMV)
• Eosinophilia: Allergies, parasitic infections, drugs
• Monocytosis: Tuberculosis, SBE, SLE

Infectious Mononucleosis (IM)

• Caused by EBV (infects B cells via CD21/CR2 receptor)
• Triad: Fever + pharyngitis + lymphadenopathy
• Classic feature: Atypical lymphocytes on smear = activated CD8+ T cells (not B cells)
• Heterophile antibodies = Monospot test (positive in ~90%)
• Splenomegaly in ~50% → risk of splenic rupture (avoid contact sports)
• Complications: Hepatitis, hemolytic anemia, Guillain-Barré syndrome, lymphoma (in immunocompromised)

Reactive Lymphadenitis

• Acute: Reactive follicular hyperplasia; tender, enlarged nodes
• Chronic: Follicular, paracortical, or sinus histiocytosis depending on cause
• Cat-scratch disease: Bartonella henselae; stellate granulomas with central necrosis; Warthin-Starry silver stain

Hemophagocytic Lymphohistiocytosis (HLH)

• Uncontrolled macrophage and T-cell activation
• Familial (mutations in perforin/granzyme pathways) or secondary (viral triggers — EBV, CMV)
• Features: Fever, hepatosplenomegaly, cytopenias, ↑ ferritin (often markedly), ↑ triglycerides
• Diagnosis: Hemophagocytosis in marrow biopsy (macrophages engulfing blood cells)

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B. Neoplastic Proliferations of White Cells

1. Acute Leukemias

Classification (WHO):

• ALL (Acute Lymphoblastic Leukemia): Lymphoid precursors; most common childhood malignancy
• AML (Acute Myeloid Leukemia): Myeloid precursors; more common in adults

• Key genetics:
  • ALL: t(12;21) — best prognosis; t(9;22) Philadelphia chromosome — worst prognosis; t(1;19); hyperdiploidy (>50 chromosomes) — good prognosis
  • AML: t(15;17) — APL (AML-M3) → treated with ATRA (all-trans retinoic acid) + arsenic trioxide; t(8;21); inv(16)
• Clinical: Bone marrow failure symptoms — anemia, infections, bleeding; bone pain (especially ALL in children)
• DIC: Characteristic of APL (M3) due to release of tissue factor from granules
• CNS involvement: More common in ALL → prophylactic intrathecal chemotherapy

2. Myelodysplastic Syndromes (MDS)

• Clonal stem cell disorder → ineffective hematopoiesis + dysplasia in ≥1 cell lineage
• Pancytopenia despite hypercellular marrow (paradox!)
• Risk of transformation to AML (~30%)
• Ringed sideroblasts (iron in mitochondria around nucleus) — seen in MDS with ring sideroblasts
• Causes: Idiopathic (elderly), prior chemotherapy/radiation (therapy-related MDS)

3. Myeloproliferative Neoplasms (MPN)

Chronic Myeloid Leukemia (CML)

• t(9;22) → Philadelphia chromosome → BCR-ABL fusion → constitutively active tyrosine kinase
• Features: Massive splenomegaly, ↑ WBC (all stages of myeloid maturation in blood), basophilia
• Lab: ↓ LAP (leukocyte alkaline phosphatase) score — distinguishes from leukemoid reaction
• Blast crisis: Transformation to AML or ALL (marks terminal phase)
• Treatment: Imatinib (Gleevec) — BCR-ABL tyrosine kinase inhibitor → revolutionary therapy

Polycythemia Vera (PV)

• JAK2 V617F mutation in virtually all cases
• ↑ RBCs, WBCs, and platelets
• Features: Ruddy cyanosis, headache, pruritus after hot bath (histamine release from basophils), splenomegaly, thrombosis (Budd-Chiari, stroke, MI)
• Complication: May transform to myelofibrosis or AML
• Treatment: Phlebotomy, hydroxyurea, aspirin

Primary Myelofibrosis (PMF)

• JAK2 mutation in ~50%; also CALR, MPL mutations
• Pathogenesis: Megakaryocyte-derived TGF-β, PDGF → marrow fibrosis
• Key finding: Teardrop cells (dacrocytes) — classic on smear
• Leukoerythroblastic picture (nucleated RBCs + myelocytes in blood)
• Massive splenomegaly (extramedullary hematopoiesis)
• Dry tap on bone marrow aspiration
• Treatment: Ruxolitinib (JAK1/2 inhibitor); BMT

Essential Thrombocythemia (ET)

• JAK2 V617F in ~50%; also CALR mutations
• Markedly ↑ platelets → thrombosis + hemorrhage
• Low risk of transformation

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4. Non-Hodgkin Lymphomas (NHL) & Chronic Lymphoid Leukemias

CLL/SLL (Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma)

• Same disease — leukemic vs nodal presentation
• Most common adult leukemia in Western countries
• CD5+, CD23+, CD19+ B cells (CD5 co-expression is key)
• Smudge cells on peripheral blood smear
• Features: Lymphadenopathy, splenomegaly, ↑ absolute lymphocyte count
• Richter transformation: Transformation to DLBCL (aggressive)
• Autoimmune hemolytic anemia common (warm antibody type)
• Indolent course; many patients watch-and-wait

Follicular Lymphoma

• Second most common NHL in adults (Western world)
• t(14;18) → overexpression of BCL-2 → inhibits apoptosis
• Indolent, incurable but not immediately life-threatening
• Morphology: Back-to-back nodular follicles; centrocytes + centroblasts
• CD10+, BCL-2+, CD20+; BCL-6+
• May transform to DLBCL (~30%)

Mantle Cell Lymphoma

• t(11;14) → overexpression of Cyclin D1 → ↑ cell cycle progression
• CD5+, CD23− (distinguishes from CLL)
• Blastoid variant = aggressive
• Poor prognosis; often diagnosed at advanced stage

MALT Lymphoma (Extranodal Marginal Zone)

• Arises at sites of chronic inflammation/infection
• Classic example: Gastric MALT lymphoma → driven by H. pylori
• Treatment: H. pylori eradication can induce remission!
• t(11;18) associated with H. pylori-independent cases

Diffuse Large B-Cell Lymphoma (DLBCL)

• Most common aggressive NHL
• BCL-6 rearrangements most common; may have BCL-2, MYC
• "Double-hit" lymphoma: Both MYC and BCL-2/BCL-6 rearrangements — very aggressive
• CD20+ → treated with R-CHOP (Rituximab + CHOP chemotherapy)
• Potentially curable with chemotherapy

Burkitt Lymphoma

• t(8;14) (or t(2;8) or t(8;22)) → c-MYC overexpression → massive proliferation
• "Starry sky" pattern on histology (macrophages with apoptotic debris amid sheets of tumor cells)
• Three variants:
  • Endemic (African): EBV-associated; jaw lesion in children
  • Sporadic: Ileocecal (abdominal) mass in children; EBV in ~25%
  • Immunodeficiency-associated: HIV patients
• Extremely high mitotic rate (Ki-67 ~100%)
• Rapidly fatal if untreated; curable with intensive chemotherapy

Hodgkin Lymphoma (HL)

• Defined by Reed-Sternberg (RS) cells — derived from germinal center B cells
• RS cell morphology: Large binucleated or multilobated cell with prominent "owl-eye" nucleoli
• Immunophenotype: CD15+, CD30+, CD20−, CD45−
• Lacunar cells — in nodular sclerosis subtype (formalin artifact)

• Staging (Ann Arbor):
  • I: Single node region
  • II: ≥2 node regions, same side of diaphragm
  • III: Both sides of diaphragm
  • IV: Disseminated (extranodal)
• B symptoms: Fever, night sweats, weight loss (>10%) = worse prognosis
• Treatment: ABVD chemotherapy ± radiotherapy; highly curable (>80% 5-year survival in early stages)

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Plasma Cell Neoplasms

Multiple Myeloma

• Malignant proliferation of plasma cells in bone marrow → monoclonal immunoglobulin (M protein)
• Most common: IgG (55%), then IgA; Bence Jones proteins (free light chains in urine)
• Features (CRAB):
  • Calcium ↑ (hypercalcemia — from osteoclast activation via RANK-L)
  • Renal failure (light chain deposition, hypercalcemia, amyloid, recurrent infection)
  • Anemia (marrow replacement by plasma cells)
  • Bone lesions — lytic "punched-out" lesions on X-ray (especially skull, vertebrae, ribs)
• Pathologic fractures + bone pain (back pain classic)
• Rouleaux formation on smear (↑ serum proteins coat RBCs)
• Hyperviscosity syndrome: Headache, visual changes, bleeding
• Diagnosis: ≥10% plasma cells on BM biopsy + M protein on serum/urine electrophoresis; serum free light chain assay
• Immunosuppression → recurrent infections (especially encapsulated bacteria)
• Treatment: Bortezomib (proteasome inhibitor) + lenalidomide + dexamethasone (VRd); autologous stem cell transplant

Waldenström Macroglobulinemia

• IgM M protein (high molecular weight → hyperviscosity syndrome)
• Lymphoplasmacytic lymphoma; MYD88 L265P mutation in >90%
• No bone lesions (differs from myeloma)
• Treatment: Plasmapheresis for hyperviscosity; ibrutinib

Amyloidosis (AL amyloid)

• Light chains deposit as amyloid in organs → organ dysfunction
• Congo red stain → apple-green birefringence under polarized light

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PART 3: BLEEDING DISORDERS

Laboratory Tests for Coagulation

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Thrombocytopenia

Immune Thrombocytopenia (ITP)

• Primary ITP: Autoantibodies (IgG) against GPIIb/IIIa or GPIb/IX → splenic macrophage destruction of platelets
• Secondary ITP: SLE, HIV, HCV, drugs (heparin — HIT is separate)
• Lab: Isolated ↓ platelets, ↑ megakaryocytes in marrow (compensatory)
• Acute ITP: Children, after viral infection, self-limited
• Chronic ITP: Adults, women; persists > 3 months
• Treatment: Prednisone (first line), IVIG, rituximab, splenectomy

Heparin-Induced Thrombocytopenia (HIT)

• Antibodies against heparin-PF4 complex → platelet activation → thrombosis (paradox — thrombocytopenia + thrombosis!)
• 4T score for diagnosis
• Stop heparin immediately → switch to argatroban/bivalirudin (direct thrombin inhibitors)

Thrombotic Microangiopathies

• TTP: Deficiency of ADAMTS13 (cleaves vWF multimers) → ultralarge vWF → platelet thrombi
  • Classic pentad: MAHA + thrombocytopenia + fever + neurological symptoms + renal failure
  • Treatment: Plasma exchange (FFP) ± caplacizumab; steroids
• HUS: Usually from Shiga toxin (E. coli O157:H7 or Shigella) → endothelial damage → microangiopathy
  • Triad: MAHA + thrombocytopenia + acute renal failure (more prominent than in TTP)
  • Antibiotics contraindicated (may worsen Shiga toxin release)

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Coagulation Factor Disorders

Hemophilia A

• Deficiency of Factor VIII (X-linked recessive)
• PTT prolonged; PT, platelet count normal
• Features: Hemarthroses (bleeding into joints), deep tissue hematomas, intracranial hemorrhage
• Severity: <1% severe; 1–5% moderate; 5–30% mild
• Treatment: Factor VIII concentrate or recombinant FVIII; DDAVP (mild cases — releases stored vWF and FVIII)

Hemophilia B (Christmas Disease)

• Deficiency of Factor IX (X-linked recessive)
• Clinically identical to hemophilia A
• Treatment: Factor IX concentrate

Von Willebrand Disease (vWD)

• Most common inherited bleeding disorder
• vWF functions: 1) Bridge between subendothelial collagen and platelet GPIb → platelet adhesion; 2) Carrier for factor VIII (protects from degradation)
• Types:
  • Type 1 (most common, 70%): Quantitative ↓ in vWF; autosomal dominant; mild
  • Type 2: Qualitative defects in vWF
  • Type 3 (rare): Virtually absent vWF; severe; autosomal recessive
• Lab: ↑ PTT (due to ↓ FVIII), prolonged bleeding time, ↓ ristocetin agglutination test
• Treatment: DDAVP (releases endothelial vWF stores) for mild; vWF/FVIII concentrate for severe

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Disseminated Intravascular Coagulation (DIC)

• Systemic activation of coagulation → widespread microvascular thrombi → consumption of platelets + clotting factors → paradoxical bleeding
• Causes:
  • Obstetric complications (placental abruption, amniotic fluid embolism, eclampsia)
  • Sepsis (especially gram-negative — LPS activates coagulation)
  • APL (M3 leukemia — granule contents activate coagulation)
  • Massive tissue injury (trauma, burns)
  • Metastatic carcinoma
• Lab:
  • ↓ Platelets, ↓ Fibrinogen, ↓ Factors V & VIII
  • ↑ PT, ↑ PTT
  • ↑ D-dimers (fibrin split products — most sensitive marker)
  • Microangiopathic hemolytic anemia (schistocytes/helmet cells)
• Treatment: Treat underlying cause; FFP + cryoprecipitate + platelets for bleeding; heparin in chronic DIC (e.g., malignancy)

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Summary Table

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