Factor XI contributes to thrombus propagation on injured neointima of the rabbit iliac artery

Abstract

Summary. Background: Thrombus formation through the activation of tissue factor (TF) and factor (F) XI is a critical event in the onset of cardiovascular disease. TF expressed in atherosclerotic plaques and circulating blood is an important determinant of thrombogenicity that contributes to fibrin‐rich thrombus formation after plaque disruption. However, the contribution of FXI to thrombus formation on disrupted plaques remains unclear. Methods: A mouse monoclonal antibody against FXI and activated FXI (FXIa) (XI‐5108) was generated by immunization with activated human FXI. Prothrombin time (PT), activated partial thromboplastin time (APTT), bleeding time, and ex vivo platelet aggregation in rabbits were measured before and after an intravenous bolus injection of XI‐5108. We investigated the role of FXI upon arterial thrombus growth in the rabbit iliac artery in the presence of repeated balloon injury. Results: The XI‐5108 antibody reacted to the light chain of human and rabbit FXI/FXIa, and inhibited FXIa‐initiated FXa and FXIa generation. Fibrin‐rich thrombi developed on the injured neointima that was obviously immunopositive for glycoprotein IIb‐IIIa, fibrin, TF, and FXI. Intravenous administration of XI‐5108 (3.0 mg kg−1) remarkably reduced thrombus growth, and the APTT was significantly prolonged. However, PT, bleeding time and platelet aggregation were not affected. Conclusions: These results indicate that plasma FXI plays a potent role in thrombus growth on the injured neointima. Inhibition of plasma FXI activity might help to reduce thrombus growth on ruptured plaques without prolonging bleeding time.

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).…”

Inhibition of Factor XIa as a New Approach to Anticoagulation

“…A monoclonal antibody against FXI or FXIa reduced thrombus formation in balloon-injured iliac arteries. 41 There was no effect on PT or platelet aggregation, whereas the aPTT was prolonged 2.4-fold. In another in vivo study, 42 TF-activated clots containing radiolabeled fibrin, and either a control or a polyclonal FXI antibody, were injected into jugular vein segments.…”

Intrinsic Pathway of Coagulation and Arterial Thrombosis

“…The consequences of severe factor XI deficiency (activity Ͻ0.15 U/mL) on myocardial infarction were studied in 96 Israeli patients over the age of 35 years. 53 Sixteen had histories of myocardial infarction, an incidence not statistically different from what was expected in the general population. In contrast, a recent evaluation of 125 patients with severe factor XI deficiency from a similar study population identified a significantly lower risk for ischemic stroke compared with age and sex-matched controls.…”