Definition of Hemophilia
Hemophilia is a congenital X-linked bleeding disorder caused by deficiency of functional coagulation factor VIII (hemophilia A) or factor IX (hemophilia B), resulting from pathogenic variants in the F8 or F9 genes, respectively 1.
Epidemiology and Classification
Hemophilia affects approximately 1,125,000 individuals worldwide 1. The estimated prevalence at birth is:
- Hemophilia A: 24.6 cases per 100,000 males (80-85% of all cases)
- Hemophilia B: 5.0 cases per 100,000 males (15-20% of all cases) 1
Severity Classification
Hemophilia severity is determined by baseline plasma factor levels 1, 2:
- Severe: <1 IU/dL (<1% of normal)
- Moderate: 1-5 IU/dL (1-5% of normal)
- Mild: >5-40 IU/dL (>5-40% of normal)
This classification correlates well with clinical bleeding phenotype in most cases, though clinical heterogeneity exists even within severity categories 2.
Clinical Manifestations
The bleeding risk varies according to baseline factor levels 1:
Severe hemophilia (without prophylaxis):
- Spontaneous bleeding episodes
- Recurrent joint bleeding (hemarthroses) - most characteristic feature
- Muscle bleeding
- Life-threatening intracranial and internal organ hemorrhage
- Early onset in childhood
- Progressive hemophilic arthropathy leading to painful, disabling joint disease 3
Moderate hemophilia:
- Intermediate bleeding phenotype
- May present with clinical features similar to severe hemophilia 1
Mild hemophilia:
- Bleeding primarily with surgical procedures or trauma
- May remain undiagnosed until adulthood 1
Genetic and Inheritance Pattern
- X-linked recessive inheritance: affects predominantly males
- Female carriers may have reduced factor levels (22-116% due to lyonization/random X-chromosome inactivation) and can experience bleeding symptoms 4
- Most cases result from pathogenic variants in F8 (hemophilia A) or F9 (hemophilia B) genes 1
Key Clinical Considerations
Factor VIII is produced primarily by liver sinusoidal endothelial cells 3, though therapeutic gene therapy targets hepatocytes for FVIII production, which still results in functional protein synthesis.
The hallmark bleeding pattern in severe hemophilia is musculoskeletal hemorrhage (joints, muscles, soft tissues), distinguishing it from other bleeding disorders 5. Without treatment, this leads to chronic arthropathy and significant morbidity affecting quality of life 1, 3.