The Contribution of Activated Factor XIII to Fibrinolytic Resistance in Experimental Pulmonary Embolism

Abstract

Background —The resistance of thrombi to fibrinolysis induced by plasminogen activators remains a major impediment to the successful treatment of thrombotic diseases. This study examines the contribution of activated factor XIII (factor XIIIa) to fibrinolytic resistance in experimental pulmonary embolism. Methods and Results —The fibrinolytic effects of specific inhibitors of factor XIIIa–mediated fibrin-fibrin cross-linking and α2-antiplasmin–fibrin cross-linking were measured in anesthetized ferrets with pulmonary emboli. Five experimental groups were treated with heparin (100 U/kg) and/or tissue plasminogen activator (TPA, 1 mg/kg) and the percent (mean±SD) lysis of emboli was determined: (1) control, normal factor XIIIa activity (14.1±4.8% lysis); (2) inhibited factor XIIIa activity (42.7±7.4%); (3) normal factor XIIIa activity+TPA (32.3±7.7%); (4) inhibited factor XIIIa activity+TPA (76.0±11.9%); and (5) inhibited α2-antiplasmin–fibrin cross-linking+TPA (54.7±3.9%). Inhibition of factor XIIIa activity increased endogenous lysis markedly (group 1 versus 2; P <0.0001), to a level comparable to that achieved with TPA (group 2 versus 3; P <0.05). Among groups receiving TPA, selective inhibition of factor XIII-mediated α2-antiplasmin–fibrin cross-linking enhanced lysis (group 3 versus 5; P <0.0005). Complete inhibition of factor XIIIa also amplified lysis (group 3 versus 4; P <0.0001) and had greater effects than inhibition of α2-antiplasmin cross-linking alone (group 4 versus 5; P <0.0005). No significant fibrinogen degradation occurred in any group. Conclusions —Factor XIIIa–mediated fibrin-fibrin and α2-antiplasmin–fibrin cross-linking both caused experimental pulmonary emboli to resist endogenous and TPA-induced fibrinolysis. This suggests that factor XIIIa may play a critical role in regulating fibrinolysis in human thrombosis.