Individual thrombin generation and spontaneous bleeding rate during personalized prophylaxis with Nuwiq® (human‐cl rhFVIII) in previously treated patients with severe haemophilia A

Abstract

For individuals with haemophilia A, prophylaxis with factor VIII (FVIII) is typically directed towards trough activity >1IU/dL; however, some patients still experience spontaneous bleeding events (sBEs). Aims were to evaluate relationships of endogenous thrombin potential (ETP) and FVIII:C with occurrence of clinical bleeding. GENA-21 was a prospective, open-label, phase IIIb study investigating the safety and efficacy of Nuwiq® (human-cl rhFVIII) in previously treated adults with severe haemophilia A. The study included a 72-hour pharmacokinetic (PK) evaluation phase and a 6-month personalized prophylaxis phase in which treatment was guided by PK parameters. This subanalysis assessed FVIII:C by one-stage assay and ETP by thrombin generation assay in blood samples. Baseline mean ETP was lower in the 7 patients who experienced sBEs during personalized prophylaxis versus 25 who did not (n=32 with data from PK phase and prophylaxis phase; P=.0002). During personalized prophylaxis (n=49), only patients with lower median trough ETP experienced sBEs (8/49 patients; ROC AUC=0.9421; P<.0001); there was no significant relationship for FVIII:C in predicting sBEs (ROC AUC=0.5838; P=.4750). Directly following infusion of human-cl rhFVIII, ETP was lower in patients who experienced sBEs versus those who did not (P=.0002), whereas FVIII:C did not differ significantly between these groups. In adults with severe haemophilia A and reduced thrombin generation, increased frequency of spontaneous bleeding was observed irrespective of trough FVIII levels. Thus, personalized prophylaxis should take into account variables other than FVIII:C. Large prospective trials are needed to verify ETP as a marker for spontaneous bleeding.