Genetic disorders of blood coagulation: hemophilia A, hemophilia B, von
Genetic disorders of blood coagulation are inherited conditions caused by defects in plasma clotting factors or their regulation, leading to impaired hemostasis and a tendency to prolonged or spontaneous bleeding. They primarily affect the intrinsic pathway of coagulation or platelet adhesion and aggregation.
The most important hereditary coagulation disorders are:
- Hemophilia A (Factor VIII deficiency)
- Hemophilia B (Factor IX deficiency)
- von Willebrand disease (vWD) (defect of von Willebrand factor)
Normal Hemostasis
Hemostasis occurs in two coordinated phases:
- 1. Primary hemostasis – platelet adhesion and aggregation (requires von Willebrand factor).
- 2. Secondary hemostasis – activation of coagulation cascade forming fibrin clot (requires clotting factors VIII, IX, etc.).
Defects in these steps lead to characteristic bleeding patterns.
I. HEMOPHILIA A
Hemophilia A is an X-linked recessive bleeding disorder caused by deficiency or dysfunction of coagulation factor VIII, resulting in impaired formation of the intrinsic coagulation pathway. It is the most common inherited coagulation disorder.
Genetic and Molecular Basis
- Gene: F8 gene located on X chromosome (Xq28).
- Inheritance: X-linked recessive (affects males; females usually carriers).
- Mutation types:
- Inversions (especially intron 22 inversion – most common).
- Deletions, insertions, nonsense or missense mutations.
- Factor VIII function: Cofactor for factor IXa → activates factor X → thrombin generation.
Pathophysiology
- 1. Factor VIII deficiency disrupts the intrinsic pathway.
- 2. Reduced activation of factor X → ↓ thrombin formation.
- 3. Inadequate fibrin clot formation.
- 4. Clots form slowly and are unstable → delayed and prolonged bleeding.
Clinical Features
- Severity correlates with factor VIII activity level:
- Severe: <1% activity
- Moderate: 1–5%
- Mild: 5–40%
- Typical bleeding pattern:
- Deep tissue bleeding (not superficial).
- Hemarthroses (bleeding into joints – knees, ankles, elbows).
- Muscle hematomas.
- Prolonged bleeding after trauma or surgery.
- Spontaneous bleeding common in severe cases.
Diagnosis
- Prolonged activated partial thromboplastin time (aPTT).
- Normal prothrombin time (PT) and platelet count.
- Low factor VIII activity level.
- Genetic testing confirms F8 mutation.
Management
- Replacement therapy: recombinant or plasma-derived factor VIII.
- Prophylactic infusions in severe disease.
- Desmopressin (DDAVP): useful in mild hemophilia A (stimulates FVIII release).
- Management of inhibitors: bypassing agents (activated prothrombin complex, recombinant factor VIIa).
- Gene therapy: promising results in clinical trials.