What causes low factor 8 (factor VIII) activity in females?

Causes of Low Factor VIII Activity in Females

Low factor VIII activity in females can result from congenital hemophilia A (inherited or de novo mutations), acquired hemophilia A (autoantibodies against factor VIII), or other conditions affecting factor VIII levels. 1, 2

Congenital Causes

X-linked Inheritance Patterns

• Heterozygous carrier state: Females with one mutated F8 gene typically have factor VIII levels around 50% of normal, but can have lower levels due to:
  • Skewed X-chromosome inactivation (non-random lyonization)
  • Compound heterozygosity (mutations on both X chromosomes)
  • Turner syndrome (single X chromosome) 3

De Novo Mutations

• Spontaneous mutations in the F8 gene can occur without family history
• Can affect one or both X chromosomes 3
• In rare cases, females can present with two different mutations (one inherited, one de novo) 3

Severity Classification Based on Factor VIII Activity

Severity	Factor VIII Activity Level
Severe	<1% of normal
Moderate	1-5% of normal
Mild	>5% to <40% of normal
[2]

Acquired Causes

Acquired Hemophilia A

• Autoantibodies (inhibitors) against factor VIII that neutralize its activity
• Associated conditions:
  • Postpartum period (within 3 months of delivery)
  • Autoimmune disorders (systemic lupus erythematosus, rheumatoid arthritis)
  • Malignancies
  • Dermatologic disorders
  • Adverse drug reactions
  • Idiopathic (approximately 50% of cases) 1, 4

Other Conditions Affecting Factor VIII

• Von Willebrand Disease (VWD)
  • Reduced or dysfunctional von Willebrand factor leads to decreased factor VIII stability
  • Factor VIII levels are typically proportional to VWF levels
• Liver disease (reduced synthesis)
• Disseminated intravascular coagulation (DIC)
• Sepsis
• Advanced malignancies 2, 5

Diagnostic Considerations

Laboratory Testing

• Prolonged activated partial thromboplastin time (aPTT) with normal prothrombin time (PT)
• Specific factor VIII activity assay (one-stage clotting or chromogenic)
• Bethesda assay to detect and quantify inhibitors 2, 6

Potential Diagnostic Pitfalls

• Lupus anticoagulant interference: Can cause falsely low factor VIII levels in laboratory testing
  • Specific tests for lupus anticoagulant should be performed when suspected
  • Factor assays should be repeated at higher dilutions to attenuate inhibitor effects 1
• Assay discrepancies: Approximately one-third of patients with mild/moderate hemophilia may have different results between one-stage and chromogenic assays 6
• Delayed inhibitor detection: Some inhibitors may become detectable only after several days, requiring repeat testing 1

Clinical Implications

• Females with low factor VIII activity may experience:
  • Excessive bleeding after trauma or surgery
  • Menorrhagia (heavy menstrual bleeding)
  • Postpartum hemorrhage
  • Spontaneous bleeding (in severe cases) 1, 7

When evaluating a female with low factor VIII activity, it's essential to distinguish between congenital and acquired causes through comprehensive testing, including genetic analysis for congenital cases and inhibitor assays for acquired hemophilia. Treatment approaches differ significantly between these conditions, with factor replacement being appropriate for congenital deficiency and immunosuppressive therapy plus bypassing agents being necessary for acquired hemophilia with inhibitors 2, 7.