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

For individuals with haemophilia A, prophylaxis with factor VIII ( FVIII ) is typically directed towards trough activity >1  IU / dL ; however, some patients still experience spontaneous bleeding events ( sBE s). Aim Aims were to evaluate relationships of endogenous thrombin potential ( ETP ) and FVIII :C with occurrence of clinical bleeding. Methods GENA ‐21 was a prospective, open‐label, phase III b study investigating the safety and efficacy of Nuwiq ® (human‐cl rh FVIII ) 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. Results Baseline mean ETP was lower in the 7 patients who experienced sBE s 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 sBE s (8/49 patients; ROC AUC  = 0.9421; P  < .0001); there was no significant relationship for FVIII :C in predicting sBE s ( ROC AUC = 0.5838; P  = .4750). Directly following infusion of human‐cl rh FVIII , ETP was lower in patients who experienced sBE s versus those who did not ( P  = .0002), whereas FVIII :C did not differ significantly between these groups. Conclusions 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.