Low normal factor V enhances thrombin generation in hemophilia A by a substrate competition mechanism with factor Xa

Abstract

Bleeding patterns in people with hemophilia A cannot be predicted solely by factor VIII (FVIII) levels. Some of the variance in bleeding may be attributed to differences in plasma protein composition, and specifically other coagulation factors where the normal ranges span 50-150% of the population mean. We recently used a mathematical model of thrombus formation that identified factor V (FV) levels as a strong modifier of thrombin generation in FVIII deficiencies. Counterintuitively, the model predicted low normal FV levels enhanced thrombin generation. Here, we tested this prediction and investigated its mechanism. Thrombin generation in plasma from people with FVIII deficiencies (<5%) were negatively correlated with FV levels. A substrate competition mechanism wherein FV and FVIII compete for activation by FXa during the initiation of coagulation was tested in three models: In a purified system containing only FV, FVIII, and FXa, reducing FV enhanced FVIII activation