Emicizumab‐mediated haemostatic function in patients with haemophilia A is down‐regulated by activated protein C through inactivation of activated factor V

Abstract

Activated protein C (APC) inactivates activated factor V (FVa) and moderates FVIIIa by restricting FV cofactor function. Emicizumab is a humanized anti-FIXa/FX bispecific monoclonal antibody that mimicks FVIIIa cofactor function. In recent clinical trials in haemophilia A patients, once-weekly subcutaneous administration of emicizumab was remarkably effective in preventing bleeding events, but the mechanisms controlling the regulation of emicizumab-mediated haemostasis remain to be explored. We investigated the role of APC-mediated reactions in these circumstances. APC dose-dependently depressed thrombin generation (TG) initiated by emicizumab in FVIII-deficient plasmas, and in normal plasmas preincubated with an anti-FVIII antibody (FVIII-depleted). FVIIIa-independent FXa generation with emicizumab was not affected by the presence of APC, protein S and FV. The results suggested that APC-induced down-regulation of emicizumab-dependent TG was accomplished by direct inactivation of FVa. The addition of APC to emicizumab mixed with FVIII-depleted FV-deficient plasma in the presence of various concentrations of exogenous FV demonstrated similar attenuation of TG, irrespective of specific FV concentrations. Emicizumab-related TG in FVIII-depleted FV plasma was decreased by APC more than that observed with native FV plasma. The findings indicated that emicizumab-driven haemostasis was down regulated by APC-mediated FVa inactivation in plasma from haemophilia A patients without or with FV defects.

Emicizumab should be prescribed independent of immune tolerance induction

“…It has recently been shown that emicizumab-mediated FXa generation is downregulated by direct inactivation of FVa through the activated protein C pathway. 42 Supporting these assumptions, no thrombotic events were identified in HA patients without FVIII inhibitors receiving emicizumab prophylaxis in combination with repetitive FVIII infusions for the treatment of breakthrough bleeds or during surgery. 15 This may bring another argument for continuing emicizumab prophylaxis irrespective of the level of FVIII recovery detected in patients undergoing ITI.…”

Bispecific Antibodies and Advances in Non–Gene Therapy Options in Hemophilia

“…15 Emicizumab does not inhibit the regulatory effect of TFPI and antithrombin. 16 Furthermore, emicizumab-driven thrombin generation is downregulated by activated protein C through inactivation of activated factor V. 17 These in vitro data indicated that emicizumab procoagulant activity can be regulated by the natural anticoagulation system.…”

A Molecular Revolution in the Treatment of Hemophilia

“…40 Despite emicizumab's insusceptibility to activated protein C, inhibition of FVa therewith as well as inhibitory activities of tissue factor pathway inhibitor (TFPI) and antithrombin seem to regulate the procoagulant activity of emicizumab well enough. 41,42 In clinical trials, emicizumab was administered prophylactically once a week, every other week or every four weeks, and these three regimens have been used post-licensure. 33,34,[43][44][45] In HAVEN 1 and 3 studies, the drug reduced bleeding rates in persons with hemophilia A with and without FVIII inhibitors by 79 and 68% compared to pre-emicizumab prophylaxis with standard bypassing agents (aPCC and rFVIIa) and FVIII, respectively.…”