Thrombin generation in haemophilia A patients with factor VIII inhibitors after infusion of recombinant factor VIIa

Abstract

Development of factor VIII inhibitors is a serious complication in haemophilia A patients. Recombinant factor VIIa (rVIIa) is clinically effective, but its effects on haemostatic system need still to be fully elucidated. In an open controlled study, we measured thrombin generation (peak thrombin) in venous blood and prothrombin fragment F1 + 2 (F1 + 2) and D-dimer in venous and in shed blood in five haemophilia A patients with inhibitors before and after rVIIa infusion. A total of five healthy individuals who did not receive rVIIa served as controls. At baseline, patients had lower mean (min-max) peak thrombin levels than controls [0.12 (0.0-0.6) vs. 186.9 (116.0-254.4) nM, P = 0.001]. After infusion, peak thrombin levels increased in average to 40.7 (28.3-51.6) nM, which translates into 80.2% (95% CI 65.4-88.6%) lower levels compared to that of controls. Mean (min-max) F1 + 2 levels in venous blood did not differ significantly between patients and controls [160.7 (89.8-331.3) vs. 160.8 (104.4-242.3) pmol L(-1)], but increased in average (min-max) by 39.4% (14.1-58.5%) after infusion. In blood emerging from incisions made to determine the bleeding (shed blood), F1 + 2 levels were lower in patients than controls [1383.3 (906.4-2044.6) vs. 2981.7 (1610.0-4539.6) pmol L(-1); P = 0.04], but were not affected by rVIIa; D-dimer levels were significantly higher in haemophiliacs than in controls and remained unchanged after infusion. Haemophilia A patients with factor VIII inhibitors have low thrombin generation. After rVIIa, the extent of coagulation activation as measured by levels of F1 + 2 is increased, but thrombin generation is restored to only 20%. Peak thrombin levels could reflect the effects of rVIIa on coagulation mechanisms, and their relevance with regard to the clinical coagulation defect of haemophilia A patients with factor VIII inhibitors might be evaluated.