Factor XII Regulates the Pathological Process of Thrombus Formation on Ruptured Plaques

Abstract

A therothrombosis, characterized by atherosclerotic lesion disruption with superimposed thrombus formation, is the major cause of acute coronary syndromes and cardiovascular death. Predominantly, platelet-rich (white) thrombi are formed at the ruptured area, because platelet recruitment preferentially occurs at regions of high shear rate and disturbed flow, whereas maximal fibrin generation occurs in regions of low flow.1 Activated platelets support the tissue factor (TF) pathway of blood coagulation by binding various (anti)coagulation factors.2 There is emerging evidence that platelets also support the intrinsic coagulation pathway mediated by factors XII (FXII) and XI (FXI), for example, by releasing polyphosphates, although the exact mechanism is still unclear.3-5 Better understanding of these multifaceted roles of platelets in coagulation stimulation can lead to new approaches to selectively inhibit the pathways most relevant in atherothrombosis. See accompanying editorial on page 1607Collagen type I is not only the most potent platelet activating component in atherosclerotic plaques by binding and activating the glycoprotein VI receptor, 6-8 but has also has been shown to bind to and activate FXII. 9 Several mouse studies using nonatherosclerotic vessels point to a consolidating role of the FXII pathway in arterial thrombus formation and thrombus stabilization, as concluded from experiments with genetic ablation or pharmacological inhibition of FXII.4,10-13 Interestingly, deficiency in FXII in man or mouse is not accompanied by abnormal bleeding.3,14 On the contrary, individuals with partly reduced FXII levels have an increased risk of cardiovascular disease (reviewed in Renné et al 15 and Woodruff et al 16 ), which indicates that the clinical consequences of (partial) FXII deficiency are more complex than the reported antithrombotic effects of FXII ablation in mice.To date, no experimental data exist on a role of the intrinsic coagulation pathway in pathological thrombus formation after atherosclerotic plaque rupture. A recent report studying plaque-induced thrombin generation in vitro suggested that the intrinsic FXII pathway may not play a key role in this process, such in contrast to a predominant role for plaque-derived TF triggering the extrinsic pathway. 8 In the present article, we therefore compared the roles of both the extrinsic and intrinsic coagulation pathways in thrombus formation on atherosclerotic plaques in vivo and ex vivo. Objective-Atherothrombosis is the main cause of myocardial infarction and ischemic stroke. Although the extrinsic (tissue factor-factor VIIa [FVIIa]) pathway is considered as a major trigger of coagulation in atherothrombosis, the role of the intrinsic coagulation pathway via coagulation FXII herein is unknown. Here, we studied the roles of the extrinsic and intrinsic coagulation pathways in thrombus formation on atherosclerotic plaques both in vivo and ex vivo. Approach and Results-Plaque rupture after ultrasound treatment evoked immediate formation of subocclu...

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

“…This compound prevented thrombosis in mice using ferric chloride-induced arterial thrombosis 34 and it protected mice from lethal pulmonary embolism. 35 Furthermore, it prevented thrombus formation on acutely ruptured atherosclerotic plaques in mice, 36 suggesting that factor XII-induced coagulation plays a role in atherothrombosis in a similar fashion as factor XI. These results might pave the way for new and safer drugs for patients with stroke or coronary artery disease.…”

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).…”

Rate-limiting roles of the tenase complex of factors VIII and IX in platelet procoagulant activity and formation of platelet-fibrin thrombi under flow

“…[1][2][3] In vivo mouse models have shown that fibrin formation occurs hand-in-hand with platelet activation in the arterial and venous parts of the circulation. [4][5][6] Furthermore, in vivo and in vitro flow studies have indicated that both the extrinsic coagulation pathway -triggered via tissue factor and factor (F) VIIa - [7][8][9] and the intrinsic pathway -triggered via FXII and resulting in FXI and FIX activation - 10,11 contribute to the formation of a stable thrombus. Tissue factor becomes exposed after vascular damage, 12 but can also be recruited to a growing thrombus via leukocytes.…”