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HEMOPHILIA — PATHOLOGY SUMMARY FOR NEET PG 2026

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OVERVIEW

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HEMOPHILIA A (FACTOR VIII DEFICIENCY)

Genetics & Epidemiology

• Inheritance: X-linked recessive
• Affects males primarily; homozygous females rarely affected
• Heterozygous females (carriers) occasionally bleed due to unfavorable lyonization (random inactivation of the X chromosome carrying the normal allele in most cells)
• ~30% of cases have NO family history — caused by new (de novo) mutations
• Most common hereditary disease associated with life-threatening bleeding

Molecular Pathology

• Caused by mutations in the gene encoding Factor VIII on the X chromosome
• Most severe cases: inversion of the X chromosome that completely abolishes Factor VIII synthesis
• Less commonly: point mutations that impair function (Factor VIII protein may be present on immunoassay but non-functional)
• Milder disease: mutations permitting some active Factor VIII to be synthesized

Severity Classification (by Factor VIII activity level)

• Spontaneous bleeding occurs when factor activity is < 5–10% of normal

Pathophysiology

• Factor VIII is an essential cofactor for Factor IX in activating Factor X (intrinsic/contact pathway)
• Factor VIII is synthesized by endothelial cells (and also the liver)
• In the plasma, Factor VIII is bound to and stabilized by vWF — this interaction increases Factor VIII half-life from ~2.4 hours to ~12 hours
• Loss of Factor VIIIa/Factor IXa complex → failure to activate Factor X → failure of secondary hemostasis (fibrin clot formation)

Clinical Features

• Easy bruising and massive hemorrhage after trauma or surgery
• Hemarthroses (bleeding into joints) — most characteristic; recurrent hemarthroses cause progressive joint deformity (hemophilic arthropathy)
• Hemorrhage into deep soft tissues, muscles, and CNS
• Petechiae are characteristically ABSENT (primary hemostasis/platelets are normal)
• Delayed bleeding after trauma (unlike platelet disorders which bleed immediately)
• Hematuria is frequent even without genitourinary pathology
• Iliopsoas bleed — can mimic appendicitis

Laboratory Findings

• Definitive diagnosis: Factor VIII–specific assay
• Mixing study (adding normal plasma to patient plasma): corrects the prolonged aPTT (confirms factor deficiency, not inhibitor — unless inhibitor is present)

Complications

• Inhibitor development: ~15% of patients with severe Hemophilia A develop antibodies (IgG inhibitors) against Factor VIII after treatment with recombinant Factor VIII — most serious complication of treatment
• Hemophilic arthropathy from recurrent hemarthroses
• Compartment syndrome, nerve compression from bleeds
• CNS hemorrhage (life-threatening)

Treatment (Pathology-Relevant)

• Recombinant Factor VIII concentrate infusion — mainstay
• DDAVP (Desmopressin): Works in mild Hemophilia A only — triggers release of preformed Factor VIII and vWF stores from endothelial cells; NOT effective in Hemophilia B
• Emicizumab (bispecific antibody): Links Factor IXa and Factor Xa, bypassing the need for Factor VIII; also effective in patients with inhibitors
• Cryoprecipitate: Contains Factor VIII, vWF, fibrinogen, Factor XIII — used when concentrate unavailable (Hemophilia A only)
• Gene therapy (emerging): Now available for both Hemophilia A and B
• Antifibrinolytics (tranexamic acid, aminocaproic acid) for minor mucosal bleeds

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HEMOPHILIA B (CHRISTMAS DISEASE — FACTOR IX DEFICIENCY)

Key Facts

• Inheritance: X-linked recessive (same as Hemophilia A)
• Caused by mutations in the gene encoding Factor IX
• Named after Stephen Christmas — the first identified patient (not the holiday)
• Clinically indistinguishable from Hemophilia A
• Hemophilia A accounts for ~85% of all hemophilia cases; Hemophilia B accounts for most of the remainder

Molecular/Functional Difference

• Wide spectrum of mutations in Factor IX gene
• In ~15% of patients, Factor IX protein is present but non-functional (CRM-positive)
• Factor IX functions together with Factor VIII to activate Factor X — hence identical clinical presentation

Lab Findings

• PTT: Prolonged | PT: Normal (same pattern as Hemophilia A)
• Definitive diagnosis: Factor IX assay
• Mixing study corrects aPTT

Treatment

• Recombinant Factor IX concentrate
• DDAVP is NOT effective (Factor IX does not respond to desmopressin)
• Even mild Hemophilia B requires factor replacement for surgery
• Gene therapy: Approved — one-time infusion of recombinant virus delivering Factor IX coding sequence to hepatocytes

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HEMOPHILIA A vs. HEMOPHILIA B — COMPARISON TABLE

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HEMOPHILIA vs. VON WILLEBRAND DISEASE — KEY DISTINCTIONS (NEET FAVORITE)

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ACQUIRED HEMOPHILIA

• Development of autoantibodies (inhibitors) against Factor VIII (occasionally Factor IX) in previously non-hemophilic individuals
• Associated with: autoimmune disease, malignancy, postpartum, idiopathic
• Treatment: Bypassing agents (recombinant Factor VIIa, emicizumab), immunosuppression

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HIGH-YIELD PATHOLOGY POINTS FOR NEET PG

1. Most common hereditary life-threatening bleeding disorder = Hemophilia A
2. Most common inherited bleeding disorder overall = von Willebrand Disease
3. Hemophilia = defect in secondary hemostasis → no petechiae, no prolonged bleeding time
4. Hallmark of hemophilia: hemarthrosis → recurrent joint deformity
5. Inversion of X chromosome = most common mutation causing severe Hemophilia A
6. Factor VIII half-life without vWF = ~2.4 hours; with vWF = ~12 hours
7. Factor VIII synthesized by: endothelial cells (also liver); vWF made by endothelial cells and megakaryocytes
8. DDAVP works only in Hemophilia A (mild) — not in Hemophilia B
9. Cryoprecipitate contains: Factor VIII, vWF, fibrinogen, Factor XIII, fibronectin
10. ~15% of severe Hemophilia A patients develop Factor VIII inhibitors after treatment
11. Hemophilia B gene therapy target = hepatocytes
12. Emicizumab — bispecific antibody (Factor IXa × Factor Xa) — works even with inhibitors
13. Spontaneous bleeding occurs at Factor activity < 1% (severe); spontaneous bleeding threshold < 5–10%
14. Hemophilia A is associated with higher frequency of bleeding and more hospitalizations than Hemophilia B despite identical clinical presentation
15. New mutations account for 30% of Hemophilia A cases (no family history)

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ANKI CARD

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• Hemophilia A = Factor VIII deficiency (85% of cases)
• Hemophilia B = Factor IX deficiency (Christmas disease, 15%)

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• X-linked recessive → mainly males affected
• Carriers (females) may bleed: unfavorable lyonization
• 30% are new (de novo) mutations
• Most common severe mutation in Hem A: Inversion of X chromosome
• Hem B (15%): Factor IX present but non-functional (CRM+)

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• Factor VIII is cofactor for Factor IX → activates Factor X (intrinsic pathway)
• Factor VIII made by endothelial cells; stabilized by vWF (half-life: 2.4h → 12h)
• Failure of Factor VIIIa/IXa complex → no Factor X activation → no fibrin clot

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• Severe: < 1% → spontaneous bleeds
• Moderate: 2–5% → minor trauma bleeds
• Mild: 6–50% → major trauma/surgical bleeds
• Spontaneous bleeding threshold: < 5–10%

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• Hemarthrosis (most characteristic) → recurrent = joint deformity
• Deep soft tissue/muscle bleeds, CNS bleeds
• Petechiae ABSENT (platelets normal)
• Delayed bleeding after trauma
• Hematuria (without GU pathology)
• Iliopsoas bleed mimics appendicitis

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• Hem A: Recombinant Factor VIII; DDAVP (mild only); Emicizumab (inhibitor cases)
• Hem B: Recombinant Factor IX; NO DDAVP; Gene therapy (hepatocyte delivery)
• Cryoprecipitate (Hem A only): contains Factor VIII, vWF, fibrinogen, Factor XIII
• Antifibrinolytics (tranexamic acid) for mucosal bleeds

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• Most common hereditary LIFE-THREATENING bleeding disorder = Hemophilia A
• Most common inherited bleeding disorder OVERALL = von Willebrand Disease
• Emicizumab = bispecific antibody (IXa × Xa), works with inhibitors
• ~15% severe Hem A → develop Factor VIII inhibitors after recombinant Factor VIII therapy
• Factor VIII half-life without vWF = 2.4 h; with vWF = 12 h
• 30% Hemophilia A = new mutations (no family history)

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