Role of Fibrinopeptide Release in Determining Fibrin Clot Structure during in situ Thrombin Generation (2006)

Undergraduate: Judson Englert

Faculty Advisor: Alisa Wolberg
Department: Chemistry

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Thrombin-mediated conversion of fibrinogen to fibrin occurs with the proteolytic release of fibrinopeptides A (FpA) and B (FpB) from the fibrinogen A? and B? chains, respectively. In vitro assays suggest that FpA release initiates end-to-end polymerization of fibrin monomers into protofibrils; while, subsequent FpB release promotes lateral aggregation of protofibrils into fibers. Thus, FpA release determines the fiber length; while, FpB release influences the fiber thickness. Since clots containing thicker fibers are more susceptible to fibrinolysis than clots containing thinner fibers, it has been suggested that clots with thick fibers are more prone to bleeding, and that this results in certain bleeding disorders. Hemophilia is a hereditary bleeding disorder due to a deficiency of clotting factors VIII (hemophilia A) or IX (hemophilia B). In hemophilia, the thrombin generation rate is reduced and clots are composed of thicker fibrin fibers than normal clots. We hypothesized that fibrinopeptide release is altered in hemophilia.
We studied FpA and FpB release under both normal and hemophilic conditions using in vitro models of coagulation (Wolberg et al. (2003) Blood 101(8):3008). Our results show that in the absence of factor IX, both FpA and FpB release are delayed. Additionally, less FpA is released prior to the release of FpB in hemophilia versus normal conditions. We conclude that the amount of FpA released at the onset of FpB release dictates the thickness of the fibrin fibers and that in hemophilia, earlier release of FpB relative to FpA leads to the formation of thicker fibrin fibers.