Effects of factor XI deficiency on ferric chloride‐induced vena cava thrombosis in mice

Abstract

Summary. Background: Increased plasma levels of coagulation factor (F) XI are a risk factor for venous thrombosis. Objective: To further explore the relationship between FXI and venous thrombosis, we evaluated FXI‐deficient and wild‐type mice in a ferric chloride (FeCl3)‐induced vena cava thrombosis model. Methods and Results: Thrombosis was induced by 3‐min topical application of filter papers containing increasing concentrations of FeCl3 and the thrombus was measured at 30 min. In contrast to wild‐type mice, FXI‐deficient mice failed to form a thrombus with 5% FeCl3, and were partially protected against 7.5% and 10% FeCl3, respectively. The protective effect was substantially stronger than a high dose of heparin (1000 units kg−1, i.v.), clopidogrel (30 mg kg−1, p.o.) or argatroban (30 mg kg−1, i.p.). These antithrombotic agents resulted in off‐scale bleeding in a tail bleeding time assay, whereas the bleeding time of FXI‐deficient mice was unchanged compared to wild‐type mice. In addition to its known effect on the coagulation cascade, enhanced clot lysis was demonstrated in FXI‐deficient mouse and human plasma compared to those supplemented with FXIa. Conclusion: Given the strong antithrombotic efficacy (possibly contributed by strong anticoagulant activity associated with increased fibrinolytic activity) and mild bleeding diathesis associated with FXI deficiency, therapeutic inhibition of FXI may be a reasonable therapeutic strategy to treat or prevent venous thrombosis.

Factor XI in haemostasis and thrombosis: Past, present and future

“…This antithrombotice ffect wascomparabletoheparin infusion. Similar protective effects by FXI deficiency were obtained in an iliac arteryb alloon injury model in rabbits (50),and in FeCl 3 -inducedthrombosis of the inferior vena cava in mice (51).Inanotherstudyinmice,the antithrombotic effects of FXIo rF XIId eficiency wase xaminedb y four thrombosismodels,i.e.pulmonary embolism induced by infusion of collagen andepinephrine,FeCl 3 -inducedinjuryofmesenteric arterioles, mechanical injury of the aortaand carotidartery injury accomplished by ligation with asurgical filament. Striking antithrombotic effects were discernedinFXII-deficient micethat were examinedb ya ll four models of thrombosis (52).Arecent study by the sameinvestigators demonstratedthatboth FXII-and FXI-deficientmice were similarlyprotected from transient middle cerebrala rteryo cclusion ( 53).…”

Recent insights into the role of the contact pathway in thrombo-inflammatory disorders

“…Factor XI knockout mice are protected against several forms of artificially induced thrombosis, both arterial and venous. [21][22][23][24] These developments led to the generation of various factor XI inhibitors, including small-molecule inhibitors, antibodies against factor XI, factor XI antisense oligonucleotides, and "naturally occurring" factor XI inhibitors derived from bats. Without exception, these approaches showed thromboprotective effects in rodent thrombosis models using ferric chloride or vena cava ligation.…”

“…Without exception, these approaches showed thromboprotective effects in rodent thrombosis models using ferric chloride or vena cava ligation. [22][23][24][25][26] For example, inhibitory factor XI antibodies, which prevent the activation of factor XI by factor XII, protected mice from ferric chloride-induced arterial and venous thrombosis. 27,28 Furthermore, factor XI and factor XI antisense oligonucleotides have been studied in higher species using a vascular graft occlusion model in primates, 29,30 which paved the way for human studies using factor XI antisense oligonucleotides.…”

Prevention of vascular graft occlusion and thrombus-associated thrombin generation by inhibition of factor XI

“…These findings are consistent with the antithrombotic and antiocclusive phenotype observed in FXI-deficient mice after ferric chloride-induced arterial injury and thrombosis. 17,18,40 FXI promotes clot resistance to fibrinolysis through thrombinmediated activation of the metalloproteinase TAFI, which proteolytically modifies fibrin, making it resistant to plasmin. 41,42 In addition, inhibition of thrombin generation by anticoagulants enhances clot lysis due to a slower forming, less dense fibrin network.…”