Mechanism of fibrin coagulation based on selective, cation-driven, protofibril association.

Abstract

AbstractThe cation sensitivity of linear and lateral assembly processes of thrombin‐ and reptilase‐activated fibrinogen was examined. Analytic ultracentrifugation shows that the linear assembly of fibrin oligomers (protofibrils) is neither cation dependent nor sensitive to chelating agents. Protofibrils generated with thrombin–hirudin gelate with either 1–2 mM Ca(II) or 15–100 μM Zn(II). By contrast, protofibril B, generated with reptilase–diisopropylfluorophosphonate, gelates only with Ca(II) but is insensitive to Zn(II). These results indicate that the release of fibrinopeptides A and B (FPA and FPB) expose two types of lateral binding sites that are sensitive to Ca(II) and Zn(II) respectively. Transmission electron (TEM) micrographs of negatively stained gels indicate that the linear packing of the monomers within the fibrin‐ and cation‐induced protofibrin fibers is essentially identical. Scanning electron (SEM) micrographs show that the Ca(II)‐induced protofibrin B gel is similar to fibrin. In all, it seems that branching and gelation derive from two types of cation‐sensitive, lateral associative processes. Based on these findings, a new paradigm for fibrin coagulation is proposed.