Abstract
Factor XIII zymogen activation is a complex series of events that involve fibrinogen acting in several different roles. This report focuses on the role of fibrinogen as a cofactor in factor XIII activation by thrombin. We demonstrate that fibrinogen has two distinct activities that lead to an increased rate of factor XIII activation. First, the thrombin proteolytic activity is increased by fibrin. The cleavage rates of both a small chromogenic substrate and the factor XIII activation peptide are increased in the presence of either the major fibrin isoform, gammaA/gammaA fibrin, or a minor variant form, gammaA/gamma' fibrin. This enhancement of thrombin activity by fibrin is independent of fibrin polymerization and requires only cleavage of the fibrinopeptides. Subsequently, gammaA/gamma' fibrinogen accelerates plasma factor XIII activation by a non-proteolytic mechanism. This increased rate of activation results in a slightly more rapid cross-linking of fibrin gammaA and gamma' chains and a significantly more rapid cross-linking of fibrin alpha chain multimers. Together, these results show that although both forms of fibrin increase the rate of activation peptide cleavage by thrombin, gammaA/gamma' fibrinogen also increases the rate of factor XIII activation in a non-proteolytic manner. A revised model of factor XIII activation is presented below.
Highlights
Plasma coagulation factor XIII (EC 2.3.2.13) is the zymogen precursor to the active transglutaminase factor XIIIa
In the process of investigating the mechanism responsible for the more extensive cross-linking in ␥A/␥Ј fibrin, we discovered that both forms of fibrin increase the rate of factor XIII activation peptide cleavage by thrombin and that the ␥A/␥Ј form of fibrinogen subsequently increases the rate of factor XIII activation to a much greater extent than ␥A/␥A fibrinogen
Factor XIII Is Activated by Thrombin More Rapidly in the Presence of ␥A/␥Ј Fibrinogen—To determine the mechanism behind the increased cross-linking and fibrinolytic resistance of ␥A/␥Ј fibrin clots [17], especially in light of previous reports that ␥A/␥Ј fibrinogen binds to both thrombin [18] and factor XIII [19], we tested the hypothesis that ␥A/␥Ј fibrinogen affects the rate of factor XIII activation
Summary
These findings provide a mechanistic explanation for the more extensive cross-linking observed in ␥A/␥Ј fibrin clots and necessitate a reevaluation of the current model of factor XIII activation
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