Hemophilia A/B/C

Summary

Hemophilia is an inherited bleeding disorder caused by a deficiency of clotting factors in the intrinsic pathway. The three classic types are:

• Hemophilia A – Factor VIII deficiency (most common, ~80%).
• Hemophilia B – Factor IX deficiency (also called Christmas disease).
• Hemophilia C – Factor XI deficiency (rare, milder).

A and B are X-linked recessive (males affected, females carriers); C is autosomal recessive and common in Ashkenazi Jews. Patients present with deep tissue bleeding — hemarthrosis, intramuscular hematomas, and prolonged bleeding after trauma or surgery. The hallmark lab finding is a prolonged aPTT with a normal PT and normal platelet count. Treatment is factor replacement.

Definition and Types

Hemophilia is a group of inherited disorders in which the body cannot form a stable fibrin clot due to deficiency of a specific clotting factor. All three types affect the intrinsic pathway, so they share the same lab pattern (prolonged aPTT) but differ in the missing factor and inheritance.

Comparison of Hemophilia A, B, and C

Genetics and Epidemiology

• Hemophilia A and B are X-linked recessive → almost all patients are males. Mothers are usually carriers.
• About 30% of cases of hemophilia A arise from a spontaneous (de novo) mutation — so a negative family history does not exclude the diagnosis.
• Female carriers may have mildly low factor levels and bleed after surgery or childbirth (due to skewed X-inactivation).
• Hemophilia C is autosomal recessive → affects males and females equally; classically seen in Ashkenazi Jews.

Pathophysiology

Factors VIII, IX, and XI are essential parts of the intrinsic coagulation pathway. Their deficiency impairs activation of factor X → reduced thrombin generation → unstable fibrin clot.

• Primary hemostasis (platelet plug) is intact → no petechiae or mucosal bleeding.
• Secondary hemostasis (fibrin clot) is defective → delayed, deep tissue bleeding (joints, muscles, brain).

Severity correlates with residual factor activity:

• Severe: <1% activity → spontaneous bleeding.
• Moderate: 1–5% → bleeding with minor trauma.
• Mild: 5–40% → bleeding only after surgery or major trauma.

Clinical Features

Hemophilia causes deep tissue bleeding, not surface (mucocutaneous) bleeding. Onset is usually in infancy or early childhood, when the child starts to crawl or walk.

• Hemarthrosis (joint bleed) — the hallmark. Warm, swollen, painful joint (knee, ankle, elbow). Recurrent bleeds → chronic hemophilic arthropathy and joint destruction.
• Intramuscular hematomas — especially iliopsoas (mimics appendicitis).
• Prolonged bleeding after circumcision, dental work, surgery, or minor trauma.
• Easy bruising with deep hematomas.
• Intracranial hemorrhage — leading cause of death in severe disease.
• Hematuria, GI bleeding.

Diagnosis

Diagnosis is based on the bleeding pattern + lab findings:

• aPTT: prolonged ↑
• PT, INR: normal
• Platelet count: normal
• Bleeding time / PFA-100: normal (platelets and vWF are intact)
• Mixing study: aPTT corrects after mixing with normal plasma → confirms factor deficiency (not an inhibitor).
• Specific factor assay (VIII, IX, or XI) — confirms the diagnosis and grades severity.

Differential Diagnosis

Key conditions to differentiate from hemophilia:

• von Willebrand disease (vWD) — most common inherited bleeding disorder; mucosal bleeding, ↑ aPTT (because vWF carries factor VIII), but ↑ bleeding time and abnormal ristocetin test.
• ITP / thrombocytopenia — petechiae, mucosal bleeding, low platelets.
• Vitamin K deficiency / warfarin — ↑ PT (and later ↑ aPTT).
• DIC — ↑ PT, ↑ aPTT, ↓ platelets, ↑ D-dimer.
• Acquired hemophilia — autoantibodies vs factor VIII in elderly or postpartum patients; mixing study does not correct.

Management

The mainstay is replacement of the missing factor. Avoid IM injections, aspirin, and NSAIDs.

• Hemophilia A:
  • Recombinant Factor VIII concentrate — first line for moderate/severe bleeds or surgery.
  • DDAVP (desmopressin) — used in mild hemophilia A only; releases stored factor VIII and vWF from endothelium.
  • Emicizumab — bispecific antibody mimicking factor VIII; used for prophylaxis (especially with inhibitors).
• Hemophilia B: Recombinant Factor IX concentrate. DDAVP does not work.
• Hemophilia C: usually Fresh Frozen Plasma (FFP) for bleeding episodes (no factor XI concentrate widely available).
• Adjuncts: antifibrinolytics (tranexamic acid, aminocaproic acid) — especially for mucosal/oral bleeding.
• Prophylaxis: regular factor infusions in severe disease to prevent hemarthrosis.

Complications

• Chronic hemophilic arthropathy — repeated hemarthrosis → cartilage damage, joint deformity, disability.
• Intracranial hemorrhage — leading cause of death.
• Compartment syndrome — from deep muscle bleeds.
• Development of inhibitors (alloantibodies against the infused factor) — occurs in ~30% of severe hemophilia A patients; makes bleeds harder to treat.
• Transfusion-related infections — historically HIV and hepatitis C; now rare with recombinant products.
• Pseudotumor — encapsulated chronic hematoma in bone or soft tissue.