Pro‐ and anticoagulant factors facilitate thrombin generation and balance the haemostatic response to FEIBA^® in prophylactic therapy

Abstract

Introduction: FEIBA â consists of zymogens and traces of activated forms of procoagulant factors II, VII, IX, X, anticoagulants protein C and TFPI, and small amounts of cofactors FV, FVIII and protein S, in a balanced ratio. As shown previously, FII-FXa complex plays a key role in FEIBA's mode of action (MoA). Methods: Thrombin generation (TG) was measured by spiking coagulation factors, cofactors and inhibitors to high titer FVIII inhibitor plasma, and in plasma samples from patients in a phase 3 clinical study evaluating the safety and efficacy of FEIBA prophylaxis in haemophilia A patients with inhibitors. Results: Increasing the FXa/FII ratio improved TG, while adding coagulation enzyme components had a negligible effect. Adding FX, FIX, and FVII increased the peak thrombin and decreased the lag time. The presence of FV and phospholipids led to faster TG, while protein C and protein S reduced the amount of peak thrombin. TFPI appeared to have no effect. Patients on prophylaxis with FEIBA â showed higher peak thrombin and AUC with elevated FII, FX, FIX, FVIIa, and protein C levels, and experienced significantly less bleeding episodes than those receiving on-demand treatment. Conclusion: These experiments showed that although the FII-FXa complex induced immediate thrombin formation on the activated platelet surface, other procoagulant components of FEIBA were necessary to achieve an optimal thrombin burst. The presence of the pro-and anti-coagulants in FEIBA provides a haemostatic balance, and is thus expected to prevent thrombotic events. Recent clinical data verified the postulated MoA of FEIBA in prophylaxis treatment.

Successful prophylaxis using activated prothrombin complex concentrates (aPCC) in a severe haemophilia A patient with inhibitor previously unresponsive to on‐demand daily infusions of aPCC

“…In contrast with our report, Varadi et al 11 concluded that TFPI appeared unlikely to be related to a poor response to aPCC. These workers evaluated changes in thrombin generation mediated by adding each coagulation clotting factor contained in aPCC to FVIIIdeficient plasma in vitro, and in plasma samples from patients in a phase 3 clinical study of aPCC prophylaxis.…”

“…These workers evaluated changes in thrombin generation mediated by adding each coagulation clotting factor contained in aPCC to FVIIIdeficient plasma in vitro, and in plasma samples from patients in a phase 3 clinical study of aPCC prophylaxis. 11 Individual responses to aPCC appear to be highly variable, however, and no patients with a poor response to treatment were found in that study. Moreover, the half-life of TFPI in the circulation appears unknown with certainty.…”

Modified clot waveform analysis to measure plasma coagulation potential in the presence of the anti‐factor IXa/factor X bispecific antibody emicizumab

“…phases [22]. In contrast, in mixtures of aPCC and emicizumab, Ad|min1| was increased and the CT was decreased dose-dependently by the bypassing agent, although the coagulation potential at clinically used concentrations of aPCC (0.5-2.0 IU mL À1 [23]) with emicizumab (100 lg mL À1 ) remained below that of normal plasma. aPCC contains a mixture of clotting components, including FII, FVII(a), FIX(a), and FX/activated FX [23], and could be expected to amplify the potential of emicizumab following FVIIa-induced activation of the initiation phase by supplementing FIXa-mediated and FX-mediated intrinsic coagulation reactions.…”

In vitro studies show synergistic effects of a procoagulant bispecific antibody and bypassing agents

“…In order to provide a mechanistic explanation for the observed effect, selected single aPCC components – FII/activated FII (FIIa), FIX, FIXa, FX, FXa – at concentrations corresponding to 0.5 U mL −1 aPCC were investigated in combination with SIA (600 n m ) in FVIII‐inhibited plasma (Fig. S1) and FVIII inhibitor plasma (Fig.…”