The Evaluation of Clot Waveform Analyses for Assessing Hypercoagulability in Patients Treated with Factor VIII Concentrate

Background: Regular prophylactic therapy has become an increasingly common treatment for severe hemophilia. Therefore, hypercoagulability—a potential risk factor of thrombosis—is a cause for concern in hemophilic patients treated with a high dose of FVIII concentrate. In clot waveform analysis (CWA)-thrombin time (TT), a small amount of thrombin activates clotting factor VIII (FVIII) instead of fibrinogen, resulting in FVIII measurements using CWA-TT with a small amount of thrombin. Methods: The coagulation ability of patients treated with FVIII concentrate or emicizumab was evaluated using activated partial thromboplastin time (APTT), TT and a small amount of tissue factor-induced FIX activation assay (sTF/FIXa) using CWA. Results: The FVIII activity based on CWA-TT was significantly greater than that based on the CWA-APTT or chromogenic assay. FVIII or FVIII-like activities based on the three assays in plasma without emicizumab were closely correlated; those in plasma with emicizumab based on CWA-TT and chromogenic assays were also closely correlated. CWA-APTT and CWA-TT showed different patterns in patients treated with FVIII concentrates compared to those treated with emicizumab. In particular, CWA-TT in patients treated with FVIII concentrate showed markedly higher peaks in platelet-rich plasma than in platelet-poor plasma. CWA-APTT showed lower coagulability in hemophilic patients treated with FVIII concentrate than in healthy volunteers, whereas CWA-sTF/FIXa did not. In contrast, CWA-TT showed hypercoagulability in hemophilic patients treated with FVIII concentrate. Conclusions: CWA-TT can be used to evaluate the thrombin bursts that cause hypercoagulability in patients treated with emicizumab. Although routine APTT evaluations demonstrated low coagulation ability in patients treated with FVIII concentrate, CWA-TT showed hypercoagulability in these patients, suggesting that the evaluation of coagulation ability may be useful when using multiple assays.