Compaction of fibrin clots reveals the antifibrinolytic effect of factor XIII: reply

Abstract

6 Bugge TH, Flick MJ, Danton MJS, Daugherty CC, Rømer J, Danø K, Carmeliet P, Collen D, Degen JL. Urokinase-type plasminogen activator is effective in fibrin clearance in the absence of its receptor or tissue-type plasminogen activator. Proc Natl Acad Sci USA 1996; 93: 5899-904. Compaction of fibrin clots reveals the antifibrinolytic effect of factor XIII: reply We thank Dr Gurewich [1] for his critical evaluation of the impact of our recently published article on factor XIII (FXIII) [2]. This article reports that mechanical compaction or platelet-mediated retraction of plasma clots is essential to fully reveal the antifibrinolytic effect of FXIII on tissue-type plasminogen activator (t-PA)-induced plasma clot lysis. Gurewich argues that we cannot assume that these results are applicable to endogenous fibrinolysis in vivo, because endogenous fibrinolysis depends not only on t-PA, but also on urokinase-type plasminogen activator (u-PA). We fully agree that the role of u-PA in fibrin degradation is frequently underestimated or even neglected in the literature on fibrinolysis, as discussed in our review on the molecular transport of fibrinolytic components during fibrin clot lysis [3]. The relative contributions of t-PA and u-PA to fibrinolysis, however, may depend on the design of the in vitro test system or on the particular thrombosis model applied in experimental animals [4,5]. In addition, it is quite possible that the relative contributions of t-PA and u-PA to fibrinolysis in vivo vary, depending on the mechanism and site of thrombus formation, and the speed of thrombus resolution.Although we agree that the role of u-PA in fibrin degradation is frequently underestimated, we probably estimate the relative contribution of t-PA to endogenous fibrinolysis to be greater than Gurewich does. For instance, Gurewich et al.[6] observed only a limited role of t-PA in the spontaneous lysis of platelet-rich plasma clots. The source of t-PA activity in their experiments was pooled normal plasma, which contains hardly any free t-PA, owing to the rapid formation of a complex with plasminogen activator inhibitor-1 [7]. In contrast, the t-PA activity in the plasma compartment of circulating blood is much higher, because a substantial proportion of t-PA in blood is in its free form [8].In addition, it is still a matter of dispute whether endogenous fibrinolysis in a blood vessel depends on systemic levels of plasminogen activators, on local release of t-PA by injured endothelial cells, or on both [9]. If local release of t-PA is important, then the contribution of t-PA to endogenous fibrinolysis is more substantial than studies with isolated blood or plasma suggest.Finally, the antifibrinolytic effect of FXIII is explained by the cross-linking of a 2 -antiplasmin to fibrin, which prevents the plasmin inhibitor from being expelled from the clot during compaction or retraction [2]. This mechanism primarily involves a 2 -antiplasmin, which is able to inhibit plasmin that is generated either by t-PA or by u-PA [10]. It is therefore...

Fibrin(ogen) engagement of S. aureus promotes the host antimicrobial response and suppression of microbe dissemination following peritoneal infection

“…S. aureus produces a non-proteolytic activator of plasminogen called staphylokinase which allows the bacteria to escape entrapment by promoting fibrin degradation [6]. Fibrin that is not crosslinked by FXIII is more sensitive to degradation by plasmin [48], so it is possible that elimination of FXIII could allow S. aureus to more readily escape entrapment by proteolytically degrading fibrin matrices. Another possibility is that fibrin cross-linked by FXIII could function as a more efficient ligand for α M β 2 compared to non-cross-linked fibrin, thus driving a more potent macrophage-driven antimicrobial response.…”