Factor XI Regulates Pathological Thrombus Formation on Acutely Ruptured Atherosclerotic Plaques

Abstract

Objective-Coagulation factor XI is proposed as therapeutic target for anticoagulation. However, it is still unclear whether the antithrombotic properties of factor XI inhibitors influence atherosclerotic disease and atherothrombosis. Our aim is to investigate whether factor XI antisense oligonucleotides could prevent thrombus formation on acutely ruptured atherosclerotic plaques. Approach and Results-Atherosclerotic plaques in the carotid arteries of Apoe −/− mice were acutely ruptured using ultrasound. The subsequent thrombus formation was visualized and quantified by intravital microscopy and immunohistochemistry. Mice were pretreated with either factor XI antisense or nonsense oligonucleotides (50 mg/kg) to lower factor XI plasma levels. A tail bleeding assay was used to determine the safety. On plaque rupture, initial platelet adhesion and platelet plug formation were not impaired in animals treated with factor XI antisense oligonucleotides. However, the ensuing thrombus formation and fibrin deposition were significantly lower after 5 to 10 minutes (P<0.05) in factor XI antisense oligonucleotide-treated animals without inducing a bleeding tendency. Furthermore, thrombi from antisense-treated animals were less stable than thrombi from placebo-treated animals. Moreover, macrophage infiltration and collagen deposition were lower in the carotid arteries of factor XI antisense-treated animals. No neutrophils were present. Conclusions-Factor

Lipoprotein (a): truly a direct prothrombotic factor in cardiovascular disease?

“…Crucially, mouse models of the thrombotic complications of atherosclerosis have recently been developed, where plaque rupture in carotid arteries of fat-fed Apoe / mice is provoked by ultrasound and thrombosis monitored by intravital fluorescence microscopy (142). These studies have illuminated roles for both platelets and the intrinsic pathway of coagulation in atherothrombosis (142)(143)(144).…”

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

“…Recently, we investigated whether factor XI inhibition with antisense oligonucleotides would be successful in reducing thrombus formation in an atherosclerosis mouse model. 31 ApoE knockout mice were given a Western-type diet containing 0.25% cholesterol and, after 18 weeks, thrombus formation was induced on atherosclerotic plaques with an ultrasound-induced injury. Factor XI was not involved in platelet plug and initial thrombus formation.…”

FXIa and platelet polyphosphate as therapeutic targets during human blood clotting on collagen/tissue factor surfaces under flow

“…4 The prothrombotic function of FXII and FXI has been demonstrated in several animal vessel injury models. [5][6][7][8][9][10][11][12][13][14][15] Additionally, platelet-derived polyphosphate (polyP; ;60-70mer) has recently been identified as a weak FXII activator 16 that also promotes the feedback activation of FXI by thrombin 17 and factor V (FV) activation by FXIa, factor Xa (FXa), or thrombin 18,19 and enhances fibrin physical structure. 20,21 Cationic inhibitors of polyP also reduce venous and arterial thrombosis in animal injury models.…”