Prevention of bleeding in hemophilia patients with high-titer inhibitors

Abstract

Inhibitor development is the most serious adverse event linked to the treatment of hemophilia, as it renders standard hemostatic therapy ineffective. Consequently, inhibitor patients are at increased risk for difficult-to-control bleeding and complications, particularly arthropathy and physical disability. Three randomized clinical trials in patients with inhibitors have demonstrated that compared with on-demand bypassing therapy, prophylaxis with a bypassing agent reduces joint and other types of bleeding and improves health-related quality of life. In hemophilia patients without inhibitors, the initiation of prophylaxis with factor (F) VIII or IX prior to the onset of recurrent hemarthroses can prevent the development of joint disease. Whether this is also true for bypassing agent prophylaxis remains to be determined.

Keywords:

• activated prothrombin complex concentrate
• bypassing agents
• factor IX
• factor VIII
• hemophilia A
• hemophilia B
• inhibitors
• prophylaxis
• recombinant activated factor VII

Financial & competing interest disclosures

CA Leissinger has received research funding from Baxter, Bayer, CSL Behring and Novo Nordisk and served as a consultant to Baxter, Bayer, Biogen Idec, CSL Behring, Kedrion, Novo Nordisk and Pfizer. BA Konkle has received research funding from and served as a consultant to Baxter and Novo Nordisk. SV Antunes has received research funding from Baxter and Novo Nordisk and served as consultant to Baxter, Novo Nordisk and Pfizer. None of the authors received payment for participating in the preparation of this manuscript. M Grygotis, an independent consultant, provided medical writing services that were funded by Baxter Healthcare Corp.

Key issues

• Inhibitor development is the most serious complication associated with the treatment of hemophilia:

  • – Bleeding in patients with high-titer, high-responding inhibitors cannot be treated with standard hemostatic therapy.

  • – Bypassing therapy in inhibitor patients is not as predictably effective as factor VIII or IX replacement is in patients with hemophilia A or B.

  • – Consequently, inhibitor patients are at increased risk for uncontrolled bleeding, early onset joint disease and physical disability.

• Bypassing agent prophylaxis (BAP) may extend to inhibitor patients the bleed-protective benefits of routine factor VIII or IX prophylaxis enjoyed by hemophilia patients without inhibitors

  • – Three prospective clinical trials have confirmed the findings from anecdotal reports and case studies that prophylaxis with recombinant activated factor VII or activated prothrombin complex concentrate reduced joint and other types of bleeding compared with on-demand bypassing therapy.

  • – BAP may be particularly appropriate for patients with high-titer, high-responding inhibitors who bleed frequently.

• The need for central venous access, cost and concomitant immune tolerance induction are considerations in implementing BAP and in bypassing agent selection.