Abstract
The inhibitory effect of coagulation factor XIII (FXIII) on fibrinolysis has been studied for at least 50 years. Our insight into the underlying mechanisms has improved considerably, aided in particular by the discovery that activated FXIII cross-links α2-antiplasmin (α2AP) to fibrin. In this review, the most important effects of different cross-linking reactions on fibrinolysis are summarized. A distinction is made between fibrin-fibrin cross-links studied in purified systems and fibrin-α2AP cross-links studied in plasma or whole blood systems. While the formation of γ chain dimers in fibrin does not affect clot lysis, the formation of α chain polymers has a weak inhibitory effect. Only strong cross-linking of fibrin, associated with high molecular weight α chain polymers and/or γ chain multimers, results in a moderate inhibition fibrinolysis. The formation of fibrin-α2AP cross-links has only a weak effect on clot lysis, but this effect becomes strong when clot retraction occurs. Under these conditions, FXIII prevents α2AP being expelled from the clot and makes the clot relatively resistant to degradation by plasmin.
Highlights
Coagulation factor XIII (FXIII) is activated by thrombin into activated FXIII (FXIIIa)
Jansen et al [42] studied the lysis rate of fresh whole blood clots containing t-PA that was added before clotting in vitro. They reported that fibrin-α2AP cross-linking explains the FXIIIa-induced resistance of blood clots to fibrinolysis, whereas fibrin-fibrin cross-linking has only a small, if any, influence. This was later confirmed by Fraser et al [43], who showed that the antifibrinolytic function of FXIII in plasma clots prepared in a Chandler loop and incubated in a buffer containing t-PA is independent of fibrin-fibrin cross-linking and is expressed exclusively through α2AP
We recently studied the effect of clot retraction on the antifibrinolytic effect of FXIII [47], stimulated by preliminary clot must show in order to reveal FXIII-dependent clot resist
Summary
Coagulation factor XIII (FXIII) is activated by thrombin into activated FXIII (FXIIIa). Umbilical bleeding a few days after birth is a characteristic feature and occurs in about 80% of the cases, while intracranial hemorrhage at birth constitutes a main threat to life [4]. It is not fully established which mechanisms are primarily responsible for the bleeding tendency. These mechanisms may involve the lack of physical stabilization of fibrin, the enhanced sensitivity to fibrinolysis, and/or even other mechanisms. We will review the effect of FXIII on fibrinolysis, in particular on the extent of inhibition of lysis and the biochemical mechanisms that are involved. Excellent reviews about FXIII, including its effect on fibrinolysis, have been published earlier [1, 5]
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