Compaction of fibrin clots reveals the antifibrinolytic effect of factor XIII

Abstract

To cite this article: Rijken DC, Abdul S, Malfliet JJMC, Leebeek FWG, Uitte de Willige S. Compaction of fibrin clots reveals the antifibrinolytic effect of factor XIII. J Thromb Haemost 2016; 14: 1453-61. Essentials• Factor XIIIa inhibits fibrinolysis by forming fibrinfibrin and fibrin-inhibitor cross-links.• Conflicting studies about magnitude and mechanisms of inhibition have been reported.• Factor XIIIa most strongly inhibits lysis of mechanically compacted or retracted plasma clots.• Cross-links of a2-antiplasmin to fibrin prevent the inhibitor from being expelled from the clot.Summary. Background: Although insights into the underlying mechanisms of the effect of factor XIII on fibrinolysis have improved considerably in the last few decades, in particular with the discovery that activated FXIII (FXIIIa) cross-links a 2 -antiplasmin to fibrin, the topic remains a matter of debate. Objective: To elucidate the mechanisms of the antifibrinolytic effect of FXIII. Methods and Results: Platelet-poor plasma clot lysis, induced by the addition of tissue-type plasminogen activator, was measured in the presence or absence of a specific FXIIIa inhibitor. Both in a turbidity assay and in a fluorescence assay, the FXIIIa inhibitor had only a small inhibitory effect: 1.6-fold less tissue-type plasminogen activator was required for 50% clot lysis in the presence of the FXIIIa inhibitor. However, when the plasma clot was compacted by centrifugation, the FXIIIa inhibitor had a strong inhibitory effect, with 7.7-fold less tissue-type plasminogen activator being required for 50% clot lysis in the presence of the FXIIIa inhibitor. In both experiments, the effects of the FXIIIa inhibitor were entirely dependent on the cross-linking of a 2 -antiplasmin to fibrin. The FXIIIa inhibitor reduced the amount of a 2 -antiplasmin present in the compacted clots from approximately 30% to < 4%. The results were confirmed with experiments in which compaction was achieved by platelet-mediated clot retraction. Conclusions: Compaction or retraction of fibrin clots reveals the strong antifibrinolytic effect of FXIII. This is explained by the cross-linking of a 2 -antiplasmin to fibrin by FXIIIa, which prevents the plasmin inhibitor from being fully expelled from the clot during compaction/retraction.

Fibrinogen splice variation and cross-linking: Effects on fibrin structure/function and role of fibrinogen γ′ as thrombomobulin II

“…Cross-linking of fibrin by FXIII has been shown to increase the clot lysis time, but this was found to be exclusively mediated by cross-linking of  2 -antiplamin within the clot [34]. It has recently been proposed by Rijken et al that cross-linking of  2 -antiplamin to fibrin by FXIII prevents it from being expelled from the clot during the process of clot contraction [35]. As such,  2 -antiplamin density within the fibrin fibres increases during the contraction process, rendering the whole clot more resistant to fibrinolysis.…”

Fibrinogen and factor XIII: newly recognized roles in venous thrombus formation and composition

“…Although some studies have suggested platelet FXIII is essential for platelet contraction(45), we and others have detected only moderate or no influence of platelet FXIII on platelet contractile events. (31, 46, 47)…”

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

“…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.…”

“…The interesting article on the antifibrinolytic effect of factor XIII by Rijken et al [1] was predicated on the assumption that fibrinolysis is mediated only by tissuetype plasminogen activator (t-PA), as that is what was studied. However, there is evidence that this common assumption should be questioned.…”