Hemophilia: An Inherited Bleeding Disorder
Hemophilia is an inherited X-linked recessive bleeding disorder characterized by deficiency of clotting factors, primarily affecting males, with hemophilia A (factor VIII deficiency) being more common than hemophilia B (factor IX deficiency). 1, 2
Classification and Pathophysiology
Hemophilia is classified based on factor activity levels:
| Severity | Factor Level (IU/dL) |
|---|---|
| Severe | <1 |
| Moderate | 1-5 |
| Mild | >5-40 |
- Prevalence: Hemophilia A affects approximately 1 in 4,000 male births, while hemophilia B affects about 1 in 10,000 male births 1
- Genetics: X-linked recessive inheritance pattern with the F8 gene (hemophilia A) or F9 gene (hemophilia B) located on the X chromosome 2
- Pathophysiology: Deficiency of functional coagulation factor VIII or IX disrupts the coagulation cascade, preventing proper blood clot formation
Clinical Manifestations
The severity of bleeding correlates with factor activity levels:
- Severe hemophilia (<1% factor activity): Spontaneous bleeding into joints and muscles, potential life-threatening bleeding in brain and internal organs
- Moderate hemophilia (1-5% factor activity): Bleeding with minor trauma, occasional spontaneous bleeds
- Mild hemophilia (>5-40% factor activity): Bleeding typically only with significant trauma or surgery
Common bleeding manifestations include:
- Joint bleeds (hemarthrosis) - most common in ankles, knees, and elbows
- Muscle hematomas
- Soft tissue bleeding
- Intracranial hemorrhage (life-threatening complication)
Treatment Approaches
Prophylactic Therapy
Prophylactic therapy with factor concentrates is strongly recommended over episodic treatment for severe hemophilia A and B to prevent joint damage and improve quality of life. 1, 2
- Factor VIII replacement (Hemophilia A): Regular infusions of recombinant or plasma-derived factor VIII 3
- Factor IX replacement (Hemophilia B): Regular infusions of recombinant or plasma-derived factor IX
- Emicizumab (Hemophilia A): Subcutaneous FVIII-mimetic bispecific antibody for prophylaxis, especially valuable for patients with inhibitors 4
Episodic Treatment
For breakthrough bleeding episodes:
- Hemophilia A: Factor VIII concentrates dosed according to bleed severity
- Hemophilia B: Factor IX concentrates dosed according to bleed severity
- Mild Hemophilia A: Desmopressin (DDAVP) may be effective for minor bleeding episodes (0.3 μg/kg IV) 2
Management of Patients with Inhibitors
Approximately 20-35% of patients with severe hemophilia A develop neutralizing antibodies (inhibitors) against factor VIII:
- Bypassing agents:
- Emicizumab: Preferred prophylactic agent for hemophilia A patients with inhibitors 4
Emerging Therapies
- Gene therapy: Using recombinant adeno-associated virus (AAV) vectors to transfer functional F8 or F9 genetic information into hepatocytes, showing promising results especially for hemophilia B 1, 2
- Anti-TFPI therapies: Novel monoclonal antibodies (concizumab and marstacimab) that enhance thrombin generation by blocking tissue factor pathway inhibitor 5
- Extended half-life products: Reduce frequency of infusions and improve quality of life 6
Complications and Monitoring
- Inhibitor development: Regular monitoring using Bethesda assay is essential 2
- Hemophilic arthropathy: Progressive joint damage from recurrent bleeds
- Thromboembolic risk: Higher in older patients, especially with bypassing agents 2
Key Considerations for Management
- Regular assessment of factor levels and inhibitor screening
- Joint health evaluation to monitor for arthropathy
- Avoidance of high-risk activities and appropriate precautions
- Early treatment of bleeds is crucial to prevent long-term complications
- Multidisciplinary care involving hematologists, physical therapists, orthopedic specialists, and psychosocial support
With modern treatment approaches, particularly prophylactic therapy, patients with hemophilia can now expect a near-normal life expectancy and quality of life, though access to factor concentrates remains a global challenge 7.