Hemophilia A: Definition and Management
Hemophilia A is an inherited X-linked recessive bleeding disorder characterized by a deficiency of functional coagulation factor VIII (FVIII), affecting approximately 1 in 4000 male newborns and accounting for 80-85% of all hemophilia cases. 1
Disease Characteristics
Hemophilia A results from mutations in the F8 gene located on the X chromosome. The gene is primarily expressed in liver sinusoidal endothelial cells, producing factor VIII which is essential for normal blood clotting 1, 2.
Classification by Severity
Severity is classified based on plasma levels of factor VIII activity 1:
| Severity | Factor VIII Level (IU/dL) |
|---|---|
| Severe | <1% |
| Moderate | 1-5% |
| Mild | >5-40% |
Clinical Presentation
- Patients experience spontaneous and trauma-induced bleeding
- Severe cases: frequent joint and muscle bleeding (hemarthroses)
- Potential life-threatening bleeding in brain and other internal organs
- Clinical heterogeneity exists even among patients with similar factor VIII levels 1
Genetic Basis
X-linked recessive inheritance pattern
Approximately one-third of cases result from spontaneous mutations 3
Various mutation types have been identified:
- Intron 22 inversion (52.5% of severe cases)
- Intron 1 inversion (3% of severe cases)
- Missense mutations
- Frameshift mutations
- Other genetic alterations 4
Research suggests that about half of mutations causing severe hemophilia A may be outside the coding regions and splice junctions of the factor VIII gene 5
Diagnosis
Diagnosis is based on:
- Isolated prolonged activated partial thromboplastin time (aPTT)
- Decreased factor VIII activity levels
- Family history (though not always present)
- Genetic testing to identify specific mutations 1, 6
Treatment Approaches
Factor Replacement Therapy
- Prophylactic therapy with FVIII concentrates is strongly recommended over episodic treatment for severe and moderately severe hemophilia A to prevent joint damage and improve quality of life 1, 2
- Standard prophylaxis involves regular FVIII infusions (at least once per week)
- Dosing: 20-50 IU/kg every 6-8 hours or 3-4 IU/kg/hour via continuous infusion 1
Alternative Treatments
For mild hemophilia A (FVIII >5%): Desmopressin (DDAVP) at 0.3 μg/kg intravenously 30 minutes prior to procedures 1, 7
- Not effective for severe hemophilia A
- Can cause tachyphylaxis with repeated dosing
- Risk of hyponatremia, especially in elderly patients
For patients with inhibitors:
Emerging therapy: Gene therapy using recombinant adeno-associated virus (AAV) vectors 1, 2
Complications
Inhibitor Development
- Occurs in 20-35% of hemophilia A patients
- Requires regular monitoring
- Cumulative inhibitor incidence reported at 22% 4
- Management may include immune tolerance induction 2, 1
Other Complications
- Hemophilic arthropathy from recurrent joint bleeding
- Risk of viral transmission (historically)
- Central venous access complications
- Thromboembolic risk (higher in older patients, especially with bypassing agents) 1
Monitoring
- Regular assessment of factor VIII levels
- Inhibitor screening (Bethesda assay)
- Joint health evaluation
- Quality of life assessment 1
Special Cases: Acquired Hemophilia A
Though rare, hemophilia A can also be acquired (not inherited) due to autoantibodies against factor VIII. This requires different management strategies including immunosuppression therapy with corticosteroids, cyclophosphamide, rituximab, or combinations 3, 6.
Female Hemophilia A
While extremely rare, females can develop hemophilia A due to:
- Heterozygous mutations in both X chromosomes
- Skewed X-chromosome inactivation
- Turner syndrome (single X chromosome)
- De novo mutations 8