title: Compaction of fibrin clots reveals the antifibrinolytic effect of factor XIII.
abstract: Essentials Factor XIIIa inhibits fibrinolysis by forming fibrin-fibrin 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 α2-antiplasmin to fibrin prevent the inhibitor from being expelled from the clot.
  
  
  
  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 α2 -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 α2 -antiplasmin to fibrin. The FXIIIa inhibitor reduced the amount of α2 -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 α2 -antiplasmin to fibrin by FXIIIa, which prevents the plasmin inhibitor from being fully expelled from the clot during compaction/retraction.
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: D C
authors.initials: DC
authors.lastname: Rijken
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Abdul
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: J J M C
authors.initials: JJ
authors.lastname: Malfliet
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: F W G
authors.initials: FW
authors.lastname: Leebeek
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Uitte de Willige
mesh_terms: D000933:Antifibrinolytic Agents / Q000737:chemistry*; D001777:Blood Coagulation; D003432:Cross-Linking Reagents / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D026122:Factor XIIIa / Q000737:chemistry*; D005337:Fibrin / Q000737:chemistry*; D005340:Fibrinogen / Q000737:chemistry*; D005342:Fibrinolysis; D006801:Humans; D009391:Nephelometry and Turbidimetry; D010949:Plasma / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000737:chemistry; D000979:alpha-2-Antiplasmin / Q000737:chemistry
chemical_list: D000933:Antifibrinolytic Agents; D003432:Cross-Linking Reagents; D000979:alpha-2-Antiplasmin; D005337:Fibrin; D005340:Fibrinogen; D026122:Factor XIIIa; C067262:PLAT protein, human; D010959:Tissue Plasminogen Activator
keywords: clot retraction; factor XIII; fibrinolysis; hemostasis; thrombosis