Hemophilia and the Dynamics of Hemostasis.

The conversion of fibrinogen to fibrin and cross-linking to form a stable clot are key processes in effective hemostasis. We investigated fibrinopeptide (FP) A and FPB release, factor XIII (FXIII) activation and fibrin mass in tissue factor initiated coagulation in whole blood from individuals with hemophilia (n=8) and healthy subjects (n=35). For hemophilia whole blood, the rates and patterns of fibrin formation are altered when compared to blood from healthy individuals. The rate of FPA release is decreased from 2.3μ M/min in healthy individuals to 1.5μ M/min in hemophilia and more significantly the rate of FPB release is decreased from 1.3μ M/min to 0.19 μ M/min in hemophilia whole blood. The activated form of FXIII in hemophilia whole blood is formed at a rate of 4nM/min versus healthy individuals where the rate is accelerated to 7nM/min. Prior to clot time in hemophilia whole blood, FPB release is reduced. Whereas more FPA is released in hemophilia whole blood prior to clot time than in whole blood from healthy individuals, 67% versus 47%, respectively. FXIII activation is delayed relative to FPA release. Around clot time in hemophilia whole blood, FPB levels are only ~1μ M and FPA levels are 8 fold higher. In normal whole blood at clot time, FPA release is only 2.5 fold higher than FPB release, potentially suggesting that there is an essential correlation of time dependence between FPA, FPB and FXIII activation to form a stable clot. Whereas, this pattern of fibrin formation is altered in the hemophilia state. Clots from hemophilia whole blood are more soluble as evidenced by a 43% decrease in fibrin mass compared to clots from healthy individuals. Overall, data indicate that hemophilia clots are weaker due to decreased lateral association (FPB release) and are mostly composed of fibrin units that are only partially cross-linked. Thus, suggesting that FXIII activation and FPB release play crucial roles in the pathology of hemophilia and the fragile nature of blood clots in hemophiliacs.