Coagulation potential of concomitant factor VIII administration in people with hemophilia A receiving emicizumab prophylaxis (CAGUYAMA study): a multicenter, open-label, nonrandomized clinical trial.

BACKGROUND

Emicizumab prophylaxis reduces bleeding in people with hemophilia A. However, factor (F)VIII is still required to manage breakthrough bleeding and for surgical procedures. The optimal additional FVIII dose during such events remains unclear because of emicizumab's baseline hemostatic activity.

OBJECTIVES

To assess FVIII-induced changes in global coagulation potential in people with hemophilia A without inhibitors treated with emicizumab and to inform FVIII dosing during prophylaxis.

METHODS

The multicenter "Coagulation potential of concomitant factor VIII administration in people with hemophilia A receiving emicizumab prophylaxis" study enrolled 100 people with hemophilia A (aged ≥4 years) receiving emicizumab at 13 centers in Japan. For eligible bleeding or surgical events, FVIII (standard or extended half-life) was administered at a target dose of 30 IU/kg (allowable range, 25-35 IU/kg). Paired blood samples were obtained pre- and post-FVIII administration. The primary endpoint was the change in clot waveform analysis-adjusted maximum coagulation rate, expressed as IMCR% relative to pooled normal plasma and untreated severe hemophilia A plasma. Secondary endpoints included peak thrombin in the thrombin generation assay, rotational thromboelastometry, clinical hemostasis, and safety. Anti-emicizumab antibodies were used in vitro to isolate the effects of FVIII.

RESULTS

Thirty-two FVIII-treated events in 24 people with hemophilia A (15 bleeding events and 17 surgical events) were analyzed. The clot waveform analysis-adjusted maximum coagulation rate increased from 39.4% to 92.1% post-FVIII and from 3.2% to 78.6% under anti-emicizumab conditions. Peak thrombin in the thrombin generation assay increased from 249 to 348 nM (IMCR%: from 55.4% to 88.0%) and from 6.4% to 74.6% under anti-emicizumab conditions. All events achieved effective hemostasis. No thromboembolic events, thrombotic microangiopathy, or hypersensitivity reactions were reported.

CONCLUSION

FVIII administered at a target dose of 30 IU/kg (allowable range, 25-35 IU/kg) improved global coagulation parameters and achieved effective hemostasis without thrombotic complications, warranting evaluation as part of emicizumab prophylaxis.