HEMOPHILIA — PATHOLOGY SUMMARY (NEET PG 2026)

OVERVIEW

PATHOGENESIS

• Factor VIII is a critical cofactor in the intrinsic (contact activation) coagulation pathway
• It circulates bound to von Willebrand Factor (vWF) — vWF acts as a carrier protein that protects Factor VIII from proteolytic degradation
• When activated (Factor VIIIa), it amplifies Factor IXa activity → activates Factor X → ultimately generates thrombin → fibrin clot

• Deficiency of Factor VIII (or IX) impairs the intrinsic pathway → inadequate thrombin generation → unstable fibrin clot → bleeding tendency
• The extrinsic pathway (PT) is unaffected → PT is normal

GENETICS

• X-linked recessive: gene on X chromosome → males affected, females are carriers
• Females (carriers): usually asymptomatic; rarely symptomatic due to unfavorable lyonization (preferential inactivation of the X chromosome carrying the normal Factor VIII gene)
• ~30% of cases arise from new mutations (no family history)
• Multiple causative mutations: deletions, inversions (large inversion of intron 22 of F8 gene is the most common cause of severe hemophilia A — ~45% of severe cases), splice junction mutations, missense mutations

CLASSIFICATION BY SEVERITY

CLINICAL FEATURES (PATHOLOGY FOCUS)

• Hemarthroses (bleeding into joints) — most characteristic; knees, elbows, ankles most commonly affected
• Repeated hemarthroses → synovial hypertrophy → cartilage destruction → joint deformity (hemophilic arthropathy) — most crippling complication
• Deep soft tissue hematomas — muscles (especially iliopsoas)
• Spontaneous hemorrhage in severe cases
• Bleeding after trauma, surgery, dental procedures

• Petechiae are ABSENT — platelet plug formation is normal (primary hemostasis intact)
• Mucosal bleeding (epistaxis, gum bleeding) is less prominent — platelet function is intact
• Bleeding time is NORMAL — platelet function normal
• PT is NORMAL — extrinsic pathway intact

LABORATORY FINDINGS

1. Prolonged aPTT + normal PT → intrinsic pathway defect → suspect hemophilia
2. Mixing study: patient plasma + normal plasma → aPTT corrects → factor deficiency confirmed
3. Specific factor assays → identify Factor VIII vs Factor IX deficiency

HEMOPHILIA A vs von WILLEBRAND DISEASE (High-yield Comparison)

HEMOPHILIA A vs HEMOPHILIA B (Distinction)

Key NEET point: Clinically indistinguishable — only distinguished by specific factor assays

COMPLICATIONS

• ~15% of severe Hemophilia A patients develop neutralizing antibodies (inhibitors) against infused Factor VIII
• Mechanism: Immune system recognizes infused Factor VIII as "foreign antigen"
• Effect: aPTT does NOT correct on mixing study (distinguishes inhibitor from simple deficiency)
• Treatment: Bypassing agents (recombinant Factor VIIa, FEIBA — Factor Eight Inhibitor Bypassing Activity); Emicizumab (bispecific antibody mimicking Factor VIII activity)

• Repeated hemarthroses → iron deposition in synovium (hemosiderin) → synovitis → cartilage destruction → ankylosis
• Most common in knees, ankles, elbows

• Prior to 1985 screening: HIV, Hepatitis C transmission through factor concentrates
• Now largely eliminated with recombinant products and viral inactivation

TREATMENT (PATHOLOGY-RELEVANT ASPECTS)

HEMOPHILIA C (Factor XI Deficiency)

• Autosomal recessive (not X-linked)
• "Very mild hemophilia"
• Common in Ashkenazi Jewish population
• Mild bleeding tendency; often only after surgery/trauma
• aPTT prolonged; specific Factor XI assay confirms

KEY HIGH-YIELD FACTS FOR NEET PG

1. Most common hereditary cause of serious bleeding = Hemophilia A (Factor VIII deficiency)
2. Hemophilia B = Christmas disease = Factor IX deficiency
3. Characteristic lesion = Hemarthrosis (joint bleeding)
4. Petechiae ABSENT (platelet function normal)
5. PT normal, aPTT prolonged = intrinsic pathway defect
6. Mixing study corrects aPTT = factor deficiency (not inhibitor)
7. 15% develop inhibitors to Factor VIII → aPTT fails to correct
8. DDAVP useful only in MILD Hemophilia A
9. Emicizumab = bispecific antibody for inhibitor patients (Factor IXa + Factor X bridge)
10. Cryoprecipitate = contains Factor VIII (used historically)
11. New mutation in 30% of hemophilia A cases
12. Severe = <1% factor activity = spontaneous bleeding
13. Unfavorable lyonization = why some female carriers bleed
14. Most common inversion = intron 22 inversion = ~45% of severe Hemophilia A

MNEMONIC AIDS

ANKI CARD

HEMOPHILIA — Pathology (NEET PG)

HEMOPHILIA — Complete Pathology Summary

• Hemophilia A = Factor VIII deficiency | Hemophilia B (Christmas disease) = Factor IX deficiency
• Both: X-linked recessive → males affected; females are carriers
• ~30% de novo mutations (no family history)
• Severe HA: Intron 22 inversion in F8 gene (~45% of severe cases)
• Symptomatic females: unfavorable lyonization

• Factor VIII circulates bound to vWF (carrier/protects from degradation)
• FVIII deficiency → impaired intrinsic pathway → ↓ thrombin → unstable fibrin clot
• Primary hemostasis (platelets) = INTACT → petechiae ABSENT

• Severe: <1% activity → spontaneous bleeding
• Moderate: 1–5% → bleeding with minor trauma
• Mild: 5–40% → bleeding with significant trauma/surgery only

• Hemarthroses (hallmark) → hemophilic arthropathy (knees, elbows, ankles)
• Deep soft tissue/muscle hematomas (especially iliopsoas)
• Prolonged post-surgical/dental bleeding
• NO petechiae, NO mucosal bleeding (platelet function intact)

• aPTT: PROLONGED
• PT: NORMAL
• Bleeding time: NORMAL
• Platelet count: NORMAL
• Mixing study: aPTT CORRECTS (factor deficiency) vs. does NOT correct (inhibitor)
• Specific factor assay: LOW Factor VIII (HA) or LOW Factor IX (HB)

• Clinically IDENTICAL — distinguished ONLY by specific factor assays
• HA more common (80%) | HB less common (20%)

• HA: X-linked, males, deep bleeding, BT normal, ristocetin normal
• vWD: AD/AR, both sexes, mucosal bleeding, BT prolonged, ristocetin abnormal

• Factor VIII inhibitors in ~15% severe HA → aPTT does NOT correct on mixing study
• Treatment of inhibitors: Emicizumab (bispecific Ab: bridges FIXa + FX, bypasses FVIII)
• Hemophilic arthropathy: synovial hemosiderin → inflammation → cartilage destruction → ankylosis

• HA: Recombinant Factor VIII; DDAVP (mild HA only — releases FVIII + vWF from Weibel-Palade bodies); Cryoprecipitate (FVIII + vWF + fibrinogen + FXIII)
• HB: Recombinant Factor IX; FFP
• Inhibitors: Emicizumab / Bypassing agents (rFVIIa, FEIBA)

1. Most common hereditary cause of SERIOUS bleeding = Hemophilia A
2. Hemarthrosis = hallmark; Petechiae = ABSENT
3. PTT prolonged + PT normal = intrinsic pathway defect
4. Mixing study corrects = deficiency; doesn't correct = inhibitor
5. DDAVP only for MILD HA (releases stored FVIII)

1. Save the line above (between the triple dashes) into a .txt file — name it something like hemophilia_anki.txt
2. Open AnkiDroid → tap the menu → Import
3. Select your file → field separator = Tab → fields mapped as: Field 1 = Front, Field 2 = Back
4. Import → done. You will get one card with the full summary on the back.

1. Paste the single line above into a .txt file
2. AnkiDroid → menu → Import
3. Field separator = Tab
4. Field 1 = Front, Field 2 = Back → Import

1. Paste all lines into a .txt file
2. AnkiDroid → menu → Import
3. Field separator = Tab → Field 1 = Front, Field 2 = Back → Import
4. All 20 cards will be created in one step