Fibrin formation

The formation of an insoluble network of fibrin is the final endpoint of both coagulation pathways. Fibrin is converted from fibrinogen by the proteolytic activity of thrombin, cleaving off two different peptides from the fibrinogen backbone. The peptides are named fibrinopeptide A and B (FPA and FPB) and are present in two copies on each fibrinogen molecule. FPA is initially cleaved off at a considerably faster rate than FPB, and it has been determined that the polymerization reaction is only dependent on the FPA cleavage. The fibrin molecules assemble to form protofibrils, which are then stabilized by the secondary cleavage of FPB. The protofibrils will join in parallel to form fibrin fibers that are slightly twisted. The lateral growth is limited to a width of about 100 nm, due to stretching of the fibrin molecule along the outer surface of the fiber [47]. The fibrin formation process is sensitive to environmental factors and changes in chemical or physiological conditions can affect the final network structure. There are a several known factors that influence the fibrin network structure. The fibrin polymer fibers can be gathered in thicker or thinner bundles during formation, thus affecting the porosity of the final network [48]. Thrombin, fibrinogen and ion concentrations are some factors that have previously been reported to influence fibrin network structure. Another factor that plays a part in determining the network structure is the concentration of plasma proteins. It is believed that a high concentrations of plasma proteins will spatially restrict the fibrin fiber extension [47]. Thinner fibrin fibers do not interact with visible light to the same extent as thicker fibers and therefore fibrin networks comprised of thin fibers generate less light scattering. This makes the fine network seem almost transparent whereas the coarse network, built up by thicker fibrin bundles, is opaque [49]. In the final stage of the coagulation process the fibrin network is stabilized by the crosslinking action of the thrombin-activated factor XIII (reviewed in [50]). Factor XIII is a transglutaminase that introduce ε-(γ-glutamyl)lysin crosslinks between fibrin molecules [51]. The physiological function of factor XIII is important, and patients that are deficient in factor XIII suffer from bleeding tendencies [52]. Factor XIII also mediates the incorporation of fibronectin into the fibrin network, a process that will increase both size and density of the fibrin fibers [53].