What is the primary treatment for individuals with hemophilia?

Primary Treatment for Hemophilia

For individuals with severe and moderately severe hemophilia A or B without inhibitors, prophylactic replacement therapy with clotting factor concentrates (FVIII for hemophilia A, FIX for hemophilia B) is the primary treatment and is strongly preferred over episodic (on-demand) treatment of bleeding events. 1

Treatment Framework by Hemophilia Type and Severity

Hemophilia A Without Inhibitors

Prophylaxis is the cornerstone of management and consists of regular intravenous administration of FVIII concentrates to prevent bleeding and joint damage rather than treating bleeds after they occur. 1, 2

Standard prophylaxis dosing:

• 15 to 40 IU/kg body weight of FVIII administered 2 to 3 times per week 1
• Both plasma-derived and recombinant FVIII concentrates (standard half-life or extended half-life formulations) are effective options 2
• Extended half-life products allow fewer infusions while maintaining similar bleeding prevention outcomes 1

Alternative prophylactic option:

• Emicizumab (subcutaneous FVIII-mimetic bispecific monoclonal antibody) administered every 1-2 weeks is an alternative to FVIII concentrates for prophylaxis 2, 3
• The choice between emicizumab and FVIII concentrates should be guided by availability, resources, costs, and patient preferences, as indirect comparisons show similar reductions in annual bleeding rates 1

Resource-limited settings:

• Low-dose prophylaxis with 10 IU/kg plasma-derived FVIII twice weekly is an effective alternative when standard-dose options are unavailable 1

Hemophilia B Without Inhibitors

Standard prophylaxis dosing:

• 20 to 60 IU/kg of FIX administered twice per week 1
• Extended half-life recombinant FIX products are available and reduce infusion frequency 1

Severity-Based Treatment Approach

Severe hemophilia (factor levels <1 IU/dL):

• Prophylaxis is strongly recommended as these patients experience spontaneous bleeding 1, 2
• Should be initiated early, ideally at 1-2 years of age and before the second joint bleed to prevent hemophilic arthropathy 1, 4

Moderate hemophilia (factor levels 1-5 IU/dL):

• May have bleeding phenotype similar to severe disease 2
• Prophylaxis is recommended for those with severe bleeding phenotype even when FVIII levels are ≥2 IU/dL 1

Mild hemophilia (factor levels >5-40 IU/dL):

• On-demand treatment is recommended for bleeding episodes or before procedures 2

Management of Inhibitor Development

Critical complication: Approximately 20-35% of severe hemophilia A patients develop neutralizing alloantibodies (inhibitors) against infused FVIII, defined as titer >0.6 Bethesda units. 1, 2

Treatment for bleeding in patients with inhibitors:

• Bypassing agents are first-line: recombinant activated Factor VII (rFVIIa) at 90 μg/kg every 2-3 hours or activated prothrombin complex concentrates (aPCCs) at 50-100 IU/kg every 8-12 hours (maximum 200 IU/kg/day) 1, 3
• Anti-hemorrhagic treatment should be initiated immediately for active severe bleeding regardless of inhibitor titer 1, 3

Inhibitor eradication:

• Immune tolerance induction (ITI) with regular high-dose FVIII infusions (200 IU/kg/day) or low-dose regimen (50 IU/kg 3 times per week) is the standard approach, successful in approximately 70% of patients 1, 2
• Immunosuppressive therapy should be started immediately after diagnosis: corticosteroids at 1 mg/kg/day for 4-6 weeks, either alone or combined with cyclophosphamide at 1.5-2 mg/kg/day for maximum six weeks 1, 3
• Rituximab is suggested as second-line therapy if first-line immunosuppression fails 1, 3

Inhibitor prevention in previously untreated patients:

• For the first 50 exposure days, plasma-derived FVIII is suggested over standard half-life recombinant FVIII to reduce inhibitor risk (26.7-31.1% with recombinant vs lower with plasma-derived) 1

Evidence Supporting Prophylaxis Over On-Demand Treatment

The superiority of prophylaxis is based on moderate-certainty evidence showing:

• Large benefit in reducing bleeding risk with minimal adverse events 1
• Median annualized bleeding rate of 4.9 bleeds per year with prophylaxis versus 28.0 bleeds per year with on-demand therapy in severe hemophilia A 5
• Prevention of progressive joint deterioration and hemophilic arthropathy 6, 4
• Improved quality of life and reduced missed days from work 7

Critical Implementation Considerations

Common barriers:

• Cost and access to prophylactic concentrates remain the main barriers to implementation 1
• Central venous access devices may be needed in young children with difficult venous access 1

Monitoring requirements:

• Monitor for breakthrough bleeding episodes, particularly when FVIII levels are at trough 2
• For patients with inhibitors who achieve complete response, follow aPTT and FVIII:C monthly for first 6 months, every 2-3 months up to 12 months, then every 6 months during second year 1, 3

Thrombotic risk:

• Bypassing agents carry thrombotic risk, particularly in elderly patients with cardiovascular comorbidities 3
• Avoid combination therapy with rFVIIa and aPCC except in life- or limb-threatening bleeds 3