General haemostatic agents--fact or fiction?
Haemophilia is the most serious bleeding model that nature has provided us with, indicating the importance of factor FVIII and FIX in haemostasis. According to current knowledge, haemostasis is initiated by the formation of a complex between tissue factor (TF), exposed as a result of a vessel wall injury, and activated FVII (FVIIa) that is normally present in circulating blood. The TF-FVIIa complexes convert FX into FXa on the TF-bearing cell. FXa then activates prothrombin into thrombin. This limited amount of thrombin activates FVIII, FV, FXI and platelets. Thrombin-activated platelets change shape, resulting in exposure of negatively-charged phospholipids, which form the perfect template for full thrombin generation involving FVIII and FIX. In patients with haemophilia FVIII or FIX is missing. These individuals generate only initial limited amounts of thrombin as its generation is dependent on the presence of FVIII and FIX. Full thrombin generation is necessary for complete activation of FXIII and thrombin activatable fibrinolytic inhibitor to occur. Furthermore, full thrombin generation is important for the fibrin structure of the haemostatic plug. In the case of impaired thrombin generation, fibrin plugs will be loose and highly permeable. Such fibrin plugs are easily dissolved by normal fibrinolytic activity and thus prevent full and maintained haemostasis from occurring. The addition of rFVIIa to FVIII- or FIX-deficient plasma has been shown to increase thrombin generation in a cell-based in vitro model. Furthermore, extra rFVIIa was found to normalise fibrin clot permeability in vitro and to tighten the fibrin structure as studied by three-dimensional confocal microscopy. These findings indicate that administration of rFVIIa is capable of compensating for the lack of FVIII and FIX. Accordingly, the administration of exogenous rFVIIa has been found to stop bleedings in haemophilia patients and, provided it is given in doses high enough, to allow major surgery to be performed in severe haemophiliacs with inhibitors. As rFVIIa enhances thrombin generation on already activated platelets, it has been suggested that rFVIIa may also help to improve haemostasis in other situations involving impaired thrombin generation, such as platelet disorders (thrombocytopenia and functional platelet defects). Preliminary clinical data appear to support this. Patients with profuse bleeding due to extensive surgery or trauma often develop a complex coagulation pattern which includes reduced plasma levels of fibrinogen, FVIII and FV, and decreased platelet counts. These patients may well have an impaired capacity to generate thrombin. Consequently, they may benefit from one or two doses of rFVIIa in order to assist in the generation of a thrombin peak sufficient to form a firm, stable fibrin haemostatic plug and thereby reduce bleeding. This would facilitate any mechanical repair necessary for full haemostasis. Preliminary results in a few patients may support such an effect for rFVIIa. As thrombin has such a crucial role in providing haemostasis, any agent that enhances the thrombin generation in situations with an impaired thrombin formation may be characterised as a 'general haemostatic agent'. Let us look forward to more 'facts' through the 'evidence-based route'.
Hedner
Ulla
U
Novo Nordisk A/S, Copenhagen, Denmark. uhe@novonordisk.com
D005167:Factor VII / Q000494:pharmacology / Q000627:therapeutic use; D015942:Factor VIIa; D005337:Fibrin / Q000187:drug effects / Q000378:metabolism; D006467:Hemophilia A / Q000188:drug therapy*; D006487:Hemostasis / Q000187:drug effects / Q000502:physiology; D006490:Hemostatics / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013917:Thrombin / Q000096:biosynthesis / Q000187:drug effects
D006490:Hemostatics; D011994:Recombinant Proteins; D005167:Factor VII; D005337:Fibrin; C103587:recombinant FVIIa; D015942:Factor VIIa; D013917:Thrombin