Factor V ^Leiden Inhibits Fibrinolysis In Vivo

Abstract

Background— Factor V Leiden (fV Leiden ) predisposes to thrombosis by enhancing thrombin formation. This study tested the hypothesis that fV Leiden inhibits fibrinolysis in vivo. Methods and Results— Radiolabeled clots were injected into the jugular veins of wild-type mice and mice heterozygous ( fV +/Q ) or homozygous ( fV Q/Q ) for fV Leiden . Mean percent clot lysis 5 hours later was significantly reduced in fV Q/Q mice (14.3±3.6%, n=13) compared with wild-type mice (40.2±7.0%, n=17; P <0.01) and intermediate in fV +/Q mice (29.4±8.7%, n=9; P <0.03 versus fV Q/Q , P =0.36 versus wild type). The rate of in vitro lysis of plasma clots prepared from fV +/Q or fV Q/Q mice was significantly slower than that of wild-type plasma clots, whereas in vitro clot lysis did not differ significantly between groups after inhibiting thrombin-activatable fibrinolysis inhibitor. Conclusions— fV Leiden inhibits fibrinolysis in vivo, suggesting an additional pathway by which this mutation promotes thrombosis.

Deep venous thrombosis or pulmonary embolism and factor V Leiden: enigma or paradox

“…Their results suggested an impaired TAFIdependent profibrinolytic response to activated protein C in FVL-carriers. 22 These results were confirmed by Parker and co-workers, 23 who also injected radiolabeled clots into the jugular veins of wild-type and FVL heterozygous or homozygous mice. Pulmonary clot lysis was significantly reduced in homozygous FVL mice compared with wildtype supporting the hypothesis that factor V Leiden might inhibit fibrinolysis in vivo, although the relevance of TAFI is controversial.…”

“…Pulmonary clot lysis was significantly reduced in homozygous FVL mice compared with wildtype supporting the hypothesis that factor V Leiden might inhibit fibrinolysis in vivo, although the relevance of TAFI is controversial. 23 Against this hypothesis, FVL-carriers did not show an increased risk of post-thrombotic syndrome, which would be attributable to an increased clot resistance to fibrinolysis. Therefore, further pathophysiological studies are required to establish the mechanism(s) involved in the inhibition of fibrinolysis by factor V Leiden in vivo, including evaluation of plasma fibrin degradation products.…”

Broadening the factor V Leiden paradox: pulmonary embolism and deep-vein thrombosis as 2 sides of the spectrum

“…This preferential effect of APC resistance on DVT has been explained for FVL through an impaired thrombin-activable fibrinolysis inhibitor-dependent profibrinolytic response to APC, hence decreased fibrinolysis and thereby decreased embolization. 73,74 Possibly this also applies to persons who are APC-resistant for other reasons.…”

Vascular Functions of the Plasminogen Activation System

“…14 Not only does TAFI allow thrombin to modulate fibrinolysis but also it provides a mechanism by which deficient or excessive thrombin generation, resulting from, for example, hemophilia, protein C deficiency, or factor V Leiden , may contribute to pathologic bleeding or thrombosis, ie, by upregulating or downregulating TAFI activation and fibrinolysis. 15,16 …”