Plasma‐Derived Factor VIIa/Factor X Improves Thrombin Generation Potential in a Plasma Model of Haemophilia A Supplemented With Direct Oral Anticoagulants

BACKGROUND: Patients with haemophilia (PwH) complicated with atrial fibrillation require direct oral anticoagulants (DOACs) to prevent thrombosis, but still require haemostatic management to control bleeding. However, specific recommendations for managing bleeding in PwH with inhibitors (PwH-inh) receiving DOACs remain lacking. In Japan, plasma-derived (pd-) factor (F)VIIa/FX products are available for clinical management of PwH-inh, and may also be beneficial for haemostatic treatment in PwH-inh receiving DOACs. AIM: To assess coagulation potential of pd-FVIIa/FX or other bypassing agents (BPAs) using an in vitro plasma model of PwHA-inh receiving DOACs. METHODS: FVIII-deficient plasma was preincubated with anti-FVIII inhibitor (termed 'FVIII-depleted'). Pd-FVIIa/FX (1.5 µg/mL as FVIIa), recombinant (r)FVIIa (2.2 µg/mL), activated prothrombin complex concentrates (aPCC; 1.3 IU/mL), or FX preparation (520 nM) were added to FVIII-depleted plasmas supplemented with apixaban (100 ng/mL) or edoxaban (100 ng/mL). A similar model was prepared using plasma samples spiked with emicizumab (50 µg/mL). Coagulation potential was assessed utilizing thrombin generation assay (TGA). RESULTS: The addition of pd-FVIIa/FX to FVIII-depleted plasmas supplemented with DOACs increased TG potential to near-normal range, irrespective of the presence of emicizumab. However, the addition of rFVIIa or FX alone to the FVIII-depleted plasma with DOACs exhibited coagulation potential below the normal range. The addition of aPCC and emicizumab to FVIII-depleted plasmas with DOACs enhanced TG potential above the normal range. CONCLUSION: Pd-FVIIa/FX improved coagulation potential in the in vitro model plasma of PwHA-inh spiked with DOACs, irrespective of concomitant emicizumab. The clinical efficacy and safety of pd-FVIIa/FX require further evaluation.