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🩸 HEMATOLOGY PATHOLOGY - Complete Notes

Key Concept First: Blood disorders affect 3 systems - Red cells (anemia/polycythemia), White cells (leukocyte disorders), and Coagulation system (hemorrhagic disorders). Understanding this framework makes everything easier.

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📌 TOPIC 1: MICROCYTIC ANEMIA

What is it?

The Master Mnemonic: TICS

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1. Iron Deficiency Anemia (IDA) - MOST COMMON anemia worldwide

• Inadequate intake (poor diet, vegetarians)
• Poor absorption (celiac disease, post-gastrectomy)
• Increased demand (pregnancy, growing children)
• Chronic blood loss (GI bleed, menorrhagia) ← Most common cause in adults

• Fatigue, pallor, palpitations
• Koilonychia (spoon-shaped nails) - classic sign
• Pica (craving for dirt, ice, clay)
• Glossitis (smooth, red tongue)
• Angular stomatitis (cracks at corners of mouth)
• Plummer-Vinson syndrome = IDA + dysphagia + esophageal web (triad)

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2. Thalassemia (also microcytic!)

• Due to deletion of α-globin genes (chromosome 16)
• 4 genes total - severity depends on how many are deleted:
  • 1 gene deleted = Silent carrier (normal)
  • 2 genes deleted = α-thalassemia trait (mild microcytic anemia)
  • 3 genes deleted = HbH disease (moderate hemolytic anemia; HbH = β4 tetramers)
  • 4 genes deleted = Hydrops fetalis (lethal in utero; Hb Bart = γ4 tetramers)

• Due to point mutations in β-globin gene (chromosome 11)
• Results in excess α-chains that precipitate and damage RBCs
• Types:
  • β-thalassemia minor (trait): One mutant gene, mild anemia, usually asymptomatic
  • β-thalassemia intermedia: Moderate severity
  • β-thalassemia major (Cooley's anemia): Both genes mutant, severe
    • Manifests after birth when HbF switches to HbA
    • Features: severe anemia, growth retardation, crew-cut skull X-ray (bone marrow expansion), hepatosplenomegaly, iron overload
    • Treatment: Regular blood transfusions + iron chelation (deferoxamine)

• Both are microcytic hypochromic
• IDA: Ferritin LOW, RDW HIGH
• Thalassemia: Ferritin NORMAL/HIGH, RDW less elevated, HbA2 elevated in β-thal

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📌 TOPIC 2: MACROCYTIC ANEMIA

What is it?

1. Megaloblastic (most common) - due to impaired DNA synthesis
2. Non-megaloblastic - liver disease, alcoholism, hypothyroidism

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Megaloblastic Anemia

A. Vitamin B12 (Cobalamin) Deficiency

• Pernicious anemia (most important) - autoimmune destruction of gastric parietal cells → no Intrinsic Factor (IF) → no B12 absorption
• Strict vegetarians/vegans
• Total gastrectomy
• Crohn's disease (terminal ileum absorbs B12)
• Fish tapeworm (Diphyllobothrium latum)

• Subacute combined degeneration of spinal cord - demyelination of dorsal and lateral columns
  • Dorsal column: loss of vibration sense, proprioception
  • Lateral column: upper motor neuron signs (spasticity, hyperreflexia)
• Neuropsychiatric symptoms - memory loss, dementia ("megaloblastic madness")

• Anti-parietal cell antibodies (90% sensitive)
• Anti-intrinsic factor antibodies (specific)
• Schilling test confirms diagnosis (now historical)

B. Folate Deficiency

• Poor diet (most common - alcoholics, elderly)
• Pregnancy (increased demand)
• Malabsorption (celiac disease)
• Drugs: Methotrexate, Phenytoin, Trimethoprim (all block folate metabolism)

• Macro-ovalocytes (large oval red cells)
• Hypersegmented neutrophils (≥5 lobes in neutrophil nucleus - PATHOGNOMONIC)
• Pancytopenia in severe cases

Memory tip: Methylmalonic acid is elevated ONLY in B12 deficiency - use this to differentiate!

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📌 TOPIC 3: HEMOLYTIC ANEMIA

What is it?

Key Lab Features of ALL Hemolytic Anemias:

• ↑ Indirect (unconjugated) bilirubin → jaundice
• ↑ LDH (released from lysed RBCs)
• ↓ Haptoglobin (binds free Hb, gets consumed)
• ↑ Reticulocyte count (marrow compensating)
• Hemoglobinuria/hemosiderinuria (in intravascular hemolysis)

Classification: Intravascular vs Extravascular

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INTRINSIC (Intracorpuscular) Defects

1. Hereditary Spherocytosis (HS)

• Defect: Mutations in spectrin, ankyrin, band 3, or band 4.2 (red cell membrane proteins)
• Cells lose their biconcave shape → become spheres → trapped and destroyed in spleen
• Inheritance: Autosomal dominant (most common)
• Features: Anemia, jaundice, splenomegaly, gallstones (pigmented, from excess bilirubin)
• Lab: Spherocytes on smear, positive osmotic fragility test, negative Coombs test
• Treatment: Splenectomy (removes the site of destruction) - very effective

2. G6PD Deficiency

• Defect: Glucose-6-phosphate dehydrogenase enzyme deficiency → can't make NADPH → can't protect Hb from oxidative damage
• X-linked recessive (mostly affects males)
• Triggers: Infection, drugs (primaquine, dapsone, sulfonamides), fava beans, oxidative stress
• Crisis: Hb oxidized → Heinz bodies (denatured Hb precipitates) → red cells removed by spleen
• Smear: Heinz bodies (with crystal violet stain), bite cells (spleen "bites" out the Heinz bodies)
• Self-limiting - only older cells are destroyed (younger cells have enough G6PD)

3. Sickle Cell Disease (SCD)

• Defect: Point mutation in β-globin gene: Glutamic acid → Valine at position 6
• HbS polymerizes under low O2, acidosis, dehydration → rigid sickle-shaped cells
• Inheritance: Autosomal recessive (HbSS = disease; HbAS = sickle cell trait, protective)
• Sickle cell trait protects against Plasmodium falciparum malaria

4. Paroxysmal Nocturnal Hemoglobinuria (PNH)

• Defect: PIG-A gene mutation → loss of GPI anchor proteins (CD55, CD59) → complement attacks RBCs
• Intravascular hemolysis, especially at night (CO2↑ during sleep → acidosis → complement activation)
• Features: Hemoglobinuria (dark urine in morning), thrombosis (Budd-Chiari syndrome), cytopenias
• Diagnosed by flow cytometry (loss of CD55, CD59)
• Treatment: Eculizumab (complement C5 inhibitor)

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EXTRINSIC (Extracorpuscular) Defects

1. Autoimmune Hemolytic Anemia (AIHA)

• Antibodies attack RBCs
• Warm AIHA (IgG antibodies, react at 37°C): SLE, CLL, drugs (methyldopa)
• Cold AIHA (IgM antibodies, react at cold temps): Mycoplasma pneumonia, EBV (infectious mononucleosis)
• Coombs test (DAT) = POSITIVE (key diagnostic test)
• Treatment: Steroids (warm type), cold avoidance (cold type)

2. Microangiopathic Hemolytic Anemia (MAHA)

• RBCs are mechanically fragmented as they squeeze through damaged/narrowed vessels
• Schistocytes (helmet cells, fragmented cells) on smear - PATHOGNOMONIC
• Causes: TTP, HUS, DIC, malignant hypertension, prosthetic heart valves

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📌 TOPIC 4: LEUKOCYTE DISORDERS

Reactive Leukocyte Changes

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Neoplastic Leukocyte Disorders

LEUKEMIAS (blood/bone marrow based)

• Auer rods (pink crystalline inclusions in blasts) = AML (never seen in ALL)
• Philadelphia chromosome [t(9;22)] = BCR-ABL fusion gene → constitutively active tyrosine kinase → treated with imatinib (Gleevec)
• TdT (terminal deoxynucleotidyl transferase) = positive in ALL and AML-M0/M1 (marker of lymphoid precursors)
• CLL smudge cells = fragile lymphocytes that rupture during smear preparation

LYMPHOMAS (lymph node / solid organ based)

1. Nodular Sclerosis (most common, young women, mediastinal)
2. Mixed Cellularity
3. Lymphocyte Rich (best prognosis)
4. Lymphocyte Depleted (worst prognosis, elderly, HIV)
5. Nodular Lymphocyte Predominant HL (different - RS cells are "popcorn cells")

• Follicular lymphoma: t(14;18) → BCL-2 overexpression (anti-apoptosis) → cells don't die; indolent but incurable
• Diffuse Large B-Cell Lymphoma (DLBCL): Most common NHL; aggressive but potentially curable
• Burkitt lymphoma: t(8;14) → c-MYC translocation; "starry sky" pattern; associated with EBV
• Mantle cell lymphoma: t(11;14) → Cyclin D1 overexpression; poor prognosis

PLASMA CELL DISORDERS

• Malignant proliferation of plasma cells in bone marrow
• Produces monoclonal immunoglobulin (M-protein) - usually IgG or IgA
• Bence Jones proteins (free light chains) in urine

• C = hyperCalcemia (bone destruction)
• R = Renal failure (light chain deposition)
• A = Anemia (marrow infiltration)
• B = Bone pain/lytic lesions ("punched out" on X-ray)

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📌 TOPIC 5: HEMORRHAGIC DISORDERS

1. Vascular wall (rare)
2. Platelets (thrombocytopenia or platelet dysfunction)
3. Coagulation factors (hemophilias, liver disease, DIC)

Normal Hemostasis (Quick Review)

1. Primary hemostasis → Platelet plug forms (fast)
   • Vascular injury → collagen exposed → vWF links to GPIb on platelets → platelet adhesion → ADP/TXA2 → platelet aggregation via GPIIb/IIIa
2. Secondary hemostasis → Coagulation cascade → fibrin clot (slower, stronger)
   • Intrinsic pathway (XII, XI, IX, VIII)
   • Extrinsic pathway (VII + tissue factor)
   • Common pathway (X, V, II, I)
3. Fibrinolysis → Plasmin dissolves the clot

Platelet Disorders

Thrombocytopenia (low platelets <150,000)

• Acute ITP (children): Post-viral (post-infection), self-limiting, abrupt onset
• Chronic ITP (adults, women): Autoimmune - IgG antibodies against GPIIb/IIIa on platelets → destroyed in spleen
• Features: Petechiae, purpura, mucosal bleeding; spleen is NORMAL size
• Treatment: Steroids → IVIG → Rituximab → Splenectomy

• ADAMTS-13 deficiency (enzyme that cleaves vWF multimers)
• Large vWF multimers accumulate → platelet microthrombi form everywhere
• Pentad of TTP:
  1. Thrombocytopenia
  2. Microangiopathic hemolytic anemia (MAHA)
  3. Fever
  4. Renal failure
  5. Neurological symptoms
• Treatment: Plasma exchange (replaces ADAMTS-13)

• Similar to TTP but mainly affects kidneys
• Most common in children; triggered by E. coli O157:H7 (Shiga toxin)
• Triad: MAHA + thrombocytopenia + acute renal failure
• Treatment: Supportive (no antibiotics - can worsen by releasing more toxin)

Platelet Function Disorders

• Most common inherited bleeding disorder
• Type 1 (most common): Partial quantitative deficiency of vWF
• Lab: ↑ bleeding time, ↑ PTT, normal PT
• Treatment: DDAVP (desmopressin) - releases stored vWF from endothelium

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Coagulation Factor Disorders

Hemophilias

• Both cause hemarthroses (bleeding into joints), deep tissue hematomas, after trauma bleeding
• PT is normal because extrinsic pathway is intact
• PTT is elevated because intrinsic pathway is affected

DIC (Disseminated Intravascular Coagulation)

• ↑ PT and ↑ PTT
• ↓ Platelets
• ↓ Fibrinogen (consumed)
• ↑ D-dimer (fibrin degradation products - KEY marker)
• ↑ FDP (fibrin degradation products)
• Schistocytes on smear

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📌 TOPIC 6: BLOOD TRANSFUSION

Blood Products and Their Uses

Blood Compatibility

• Type A: Has A antigens, anti-B antibodies
• Type B: Has B antigens, anti-A antibodies
• Type AB: Has both antigens, NO antibodies → Universal recipient
• Type O: No antigens, both anti-A and anti-B → Universal donor (for RBCs)
• Type O negative = Universal donor for all blood products

• Rh positive or negative (based on D antigen)
• Critical in pregnancy: Rh- mother with Rh+ fetus → hemolytic disease of newborn (HDN)
• Prevention: Anti-D immunoglobulin (RhoGAM)

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Transfusion Reactions

1. Acute Hemolytic Transfusion Reaction (AHTR)

• Timing: During or within 24 hours of transfusion
• Cause: ABO incompatibility (clerical error - wrong blood given!)
• Mechanism: Pre-formed recipient IgM antibodies attack donor RBCs → massive intravascular hemolysis
• Features: Fever, chills, flank/back pain, hemoglobinuria (red/brown urine), hypotension, DIC
• Can be fatal - MEDICAL EMERGENCY
• Management: STOP transfusion immediately, IV fluids, treat DIC

2. Delayed Hemolytic Transfusion Reaction

• Timing: 3-10 days after transfusion
• Cause: Anamnestic (memory) response to minor blood group antigens (Kidd, Duffy, Kell)
• Milder than acute; often just unexplained drop in Hb
• Coombs test (DAT) turns positive

3. Febrile Non-Hemolytic Reaction (FNHTR)

• Most common transfusion reaction
• Cause: Recipient antibodies against donor WBCs (HLA antigens)
• Mild fever and chills during transfusion
• Prevention: Leukoreduction (filter out WBCs from blood product)
• Stop transfusion, rule out hemolysis, then can restart with pre-medication (antipyretics)

4. Allergic/Anaphylactic Reactions

• Mild: Urticaria (hives) - common
• Severe anaphylaxis: IgA-deficient patients receiving IgA-containing plasma
• Treatment: Stop transfusion, antihistamines (mild), epinephrine (severe)

5. Transfusion-Related Acute Lung Injury (TRALI)

• Life-threatening!
• Timing: Within 6 hours
• Cause: Donor antibodies against recipient HLA antigens → neutrophil activation → capillary leak in lungs
• Features: Fever, hypoxia, bilateral pulmonary infiltrates (non-cardiogenic pulmonary edema)
• Treatment: Supportive, often needs ICU/mechanical ventilation

6. Transfusion-Associated Circulatory Overload (TACO)

• Too much fluid too fast → pulmonary edema (cardiogenic)
• Seen in elderly, patients with cardiac/renal problems
• Treatment: Slow infusion rate, diuretics

7. Graft-vs-Host Disease (TA-GvHD)

• Donor lymphocytes attack immunocompromised recipient
• Occurs in immunocompromised patients
• Prevention: Irradiation of blood products (kills donor lymphocytes)

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Summary Table: Transfusion Reactions at a Glance

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🧠 MASTER SUMMARY FOR QUICK REVISION

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