What are the different types of hemophilia and their treatments?

Hemophilia Types and Treatment

Hemophilia has two main types: Hemophilia A (factor VIII deficiency) and Hemophilia B (factor IX deficiency), both X-linked recessive bleeding disorders classified by severity based on clotting factor levels, with prophylactic factor replacement being the cornerstone of treatment for severe disease. 1

Types of Hemophilia

Hemophilia A (Factor VIII Deficiency)

• Most common form of hemophilia, caused by deficiency or dysfunction of coagulation factor VIII due to mutations in the F8 gene 2, 3
• Diagnosed by prolonged aPTT with decreased factor VIII levels in patients with bleeding symptoms 4

Hemophilia B (Factor IX Deficiency)

• Less common than hemophilia A, caused by deficiency or dysfunction of coagulation factor IX due to mutations in the F9 gene 2, 3
• May have less severe bleeding tendency compared to hemophilia A with similar factor levels, potentially resulting in better long-term outcomes 5

Severity Classification (Both Types)

• Severe: Factor levels <1 IU/dL, characterized by spontaneous bleeding into joints and muscles 1
• Moderate: Factor levels 1-5 IU/dL
• Mild: Factor levels >5-40 IU/dL 2

Treatment Approach

Hemophilia A Without Inhibitors

Prophylaxis is strongly recommended over episodic (on-demand) treatment for severe hemophilia A to prevent joint damage and reduce bleeding frequency 1

Factor VIII Replacement Options:

• Standard half-life recombinant factor VIII: Requires dosing 3 times weekly (typically 25 IU/kg every other day or 20-40 IU/kg three times weekly) to maintain trough levels above 1 IU/dL 1, 6
• Extended half-life (EHL) factor VIII products: Allow reduction to potentially once weekly dosing while maintaining consistent trough levels and reducing treatment burden 6
• Plasma-derived factor VIII concentrates: Alternative option with similar efficacy 1

Emicizumab (Non-Factor Therapy):

• Approved for prophylaxis in hemophilia A patients with or without inhibitors, representing a paradigm shift as the first non-replacement therapy 4, 7
• Administered subcutaneously, eliminating need for frequent intravenous access, particularly valuable in pediatric patients 4
• Critical safety warning: Avoid concurrent use with activated prothrombin complex concentrate (aPCC) due to high risk of thrombotic microangiopathy and thromboembolic events 4
• For breakthrough bleeding on emicizumab, use recombinant factor VIIa rather than aPCC 4

Hemophilia A With Inhibitors

Bypassing agents or emicizumab are first-line options when neutralizing antibodies develop 7

• Recombinant activated factor VII (rFVIIa): Dose 90 μg/kg every 2-3 hours until hemostasis achieved 7
• Activated prothrombin complex concentrates (aPCC): Dose 50-100 IU/kg every 8-12 hours, maximum 200 IU/kg/day 7
• Emicizumab: Effective regardless of inhibitor status, particularly valuable for inhibitor patients 4
• Immune tolerance induction: Recommended to eradicate inhibitors, though optimal protocols remain under investigation 1

Hemophilia B Without Inhibitors

Prophylaxis is strongly recommended over episodic treatment for severe hemophilia B 1

Factor IX Replacement Options:

• Extended half-life factor IX products: Enable once weekly or every 1-2 week dosing; all three major prophylaxis studies in hemophilia B used EHL products 1, 6
• Standard half-life factor IX concentrates: Require more frequent dosing 1
• Prophylaxis regimens vary but typically involve dosing every 1-2 weeks with EHL products 1

Hemophilia B With Inhibitors

• Bypassing agents (rFVIIa or aPCC) for acute bleeding 1
• Immune tolerance induction/desensitization protocols, though evidence remains limited 1

Key Clinical Considerations

Dosing Principles:

• Measure baseline factor level and determine target based on bleeding severity, then calculate initial dose using product-specific recovery values 6
• In resource-limited settings, low-dose prophylaxis with 10 IU/kg factor VIII 2-3 times weekly effectively prevents joint bleeds when standard doses unavailable 6

Common Pitfalls to Avoid:

• Never combine rFVIIa and aPCC except in life- or limb-threatening bleeds due to increased thrombotic risk 7
• Bypassing agents carry thrombotic risk, particularly in elderly patients with cardiovascular comorbidities 7
• Inhibitor development is more common in severe hemophilia A than hemophilia B 7

Monitoring:

• Joint bleeding after minor trauma is characteristic of severe hemophilia and indicates need for prophylaxis 4
• Normal platelet count and bleeding time help rule out platelet disorders in diagnostic workup 4

Emerging Therapies

• Gene therapy shows promise for both hemophilia A and B, with particularly encouraging results in hemophilia B, potentially offering durable cure 2, 8, 3
• Novel non-factor therapies (fitusiran, concizumab) are under investigation but require further study 1