What is the management of Hemophilia A?

Management of Hemophilia A

The cornerstone of hemophilia A management is prophylactic factor VIII replacement therapy, which should be initiated early in patients with severe disease to prevent joint deterioration and reduce bleeding episodes, with dosing and frequency tailored based on disease severity and bleeding phenotype. 1, 2

Primary Treatment Strategy

Prophylaxis vs On-Demand Treatment

• Prophylaxis is the standard of care for severe hemophilia A and should be prioritized over on-demand treatment, as it significantly reduces annualized bleeding rates (median 1.0-2.0 bleeds/year with prophylaxis vs 43.9 bleeds/year with on-demand treatment) 3
• Primary prophylaxis (regular infusions started after the first joint bleed and/or before age 2 years) is recognized as first-line treatment in children with severe hemophilia to prevent progressive joint deterioration and hemophilic arthropathy 4
• Prophylaxis reduces bleeding episodes so effectively that 33% of patients experience no bleeding episodes at all, compared to 0% on on-demand treatment 3

Factor VIII Replacement Products

Available options include:

• Plasma-derived FVIII concentrates 1
• Standard half-life recombinant FVIII concentrates 1, 5
• Extended half-life (EHL) recombinant FVIII concentrates, which allow less frequent dosing and improved treatment adherence 1, 6

Standard dosing regimens:

• Standard prophylaxis: 20-40 IU/kg every other day 3
• PK-tailored prophylaxis: 20-80 IU/kg every third day, adjusted to maintain FVIII trough levels ≥1% 3
• Both regimens show comparable efficacy and safety 3

Alternative Prophylactic Therapy

• Emicizumab (a subcutaneous FVIII-mimetic bispecific monoclonal antibody) is approved for prophylaxis in patients with severe hemophilia A, both with and without inhibitors 1, 2
• Administered every 1-2 weeks subcutaneously, reducing treatment burden compared to IV factor replacement 1
• Important caveat: FVIII replacement is still required for breakthrough bleeding or surgical procedures 1

Management of Acute Bleeding Episodes

Patients Without Inhibitors

• Factor VIII concentrates are first-line treatment for acute bleeding 2
• Dosing should be based on bleeding severity and location 1
• For minor hemarthroses and muscle hemorrhages: 250 IU in children, 500 IU in adults when treated promptly 7
• Continue treatment until bleeding is controlled, typically 24-72 hours depending on severity 1

Patients With Inhibitors (20-35% of severe hemophilia A patients)

First-line bypassing agents: 1, 2

• Recombinant activated factor VII (rFVIIa): 90 μg/kg every 2-3 hours until hemostasis is achieved 1, 2
• Activated prothrombin complex concentrates (aPCC): 50-100 IU/kg every 8-12 hours, maximum 200 IU/kg/day 1, 2

Critical safety warning: Combination therapy with rFVIIa and aPCC should be restricted to life- or limb-threatening bleeds due to increased thrombotic risk 1, 2

If first-line bypassing agent fails: Switch to the alternative bypassing agent 1

Inhibitor Management

Eradication Strategy

• All patients with inhibitors should receive immunosuppressive therapy immediately following diagnosis 1, 2
• First-line regimen: Corticosteroids 1 mg/kg/day PO for 4-6 weeks, either alone or in combination with cyclophosphamide 1.5-2 mg/kg/day for maximum 6 weeks 1, 2
• Second-line therapy: Rituximab if first-line immunosuppression fails or is contraindicated 1, 2
• Immune tolerance induction (ITI): Regular FVIII infusions for congenital hemophilia A with inhibitors, though unsuccessful in approximately 30% of cases 1

Monitoring After Inhibitor Eradication

• aPTT and FVIII:C monitoring monthly during first 6 months 1, 2
• Every 2-3 months up to 12 months 1, 2
• Every 6 months during second year and beyond 1, 2

Surgical Management

• Prophylactic use of bypassing agents is recommended prior to minor or major invasive procedures in patients with inhibitors 1
• For patients without inhibitors, ensure adequate FVIII levels perioperatively based on procedure type 1
• Delay invasive procedures until inhibitor eradication when possible 1

Emerging Therapies

• Gene therapy using AAV vectors to transfer functional F8 genetic information into hepatocytes is now available, enabling long-term endogenous FVIII production after a single IV infusion 1
• Requires careful monitoring for hepatotoxicity and immune responses 1

Critical Pitfalls to Avoid

• Never use high-dose intravenous immunoglobulin for inhibitor eradication in hemophilia A—it is ineffective 1, 2
• Avoid combination bypassing therapy (rFVIIa + aPCC) except in life- or limb-threatening situations due to thrombotic risk 1, 2
• Tranexamic acid is contraindicated with aPCC administration 1
• Do not delay treatment for acute bleeding—early administration prevents chronic joint damage 7
• Monitor for inhibitor development with blood tests, as inhibitors can render FVIII replacement ineffective 5
• Beware of thrombotic complications with bypassing agents, particularly in elderly patients with comorbidities (atherosclerosis, previous cardiovascular events, hypertension, diabetes) 1, 2

Treatment Goals

• Maintain FVIII trough levels ≥1% with prophylaxis 3
• Achieve zero or near-zero bleeding rates 6
• Preserve joint health and prevent hemophilic arthropathy 4
• Optimize quality of life while minimizing treatment burden 8, 6