Increased Vascular Wall Thrombogenicity Combined With Reduced Blood Flow Promotes Occlusive Thrombus Formation in Rabbit Femoral Artery

Abstract

Objective-Plaque disruption does not always result in complete thrombotic occlusion. The mechanism of arterial thrombus propagation remains unclear. Methods and Results-We studied how vascular wall thrombogenicity and blood flow reduction affect thrombus propagation using a rabbit model of single and repeated balloon injury. After balloon injury of the normal femoral artery, the blood flow was reduced to 50%, 25%, or 10% (nϭ5). Small mural thrombi composed of aggregated platelets were produced, but no occlusive thrombi developed in any flow reduction. Three weeks after the first balloon injury, neointima with tissue factor expression and increased procoagulant activity was developed. Balloon injury of the neointima with the same blood flow reduction (nϭ5) induced fibrin-rich thrombus formation. Additionally, injury with flow reduced to 25% and 10% promoted thrombus propagation resulting in vessel occlusion within 160Ϯ18 and 71Ϯ17 seconds, respectively. An injection of anti-von Willebrand factor (vWF) monoclonal antibody (AJW200; 1.0 mg/kg) prevented occlusive thrombus formation. Conclusions-Increased vascular wall thrombogenicity together with a substantial blood flow reduction is crucial for occlusive thrombus formation, and vWF plays an important role in thrombus propagation. Reduced blood flow at plaque disruption sites might contribute to thrombus propagation leading to acute coronary syndromes. Key Words: thrombus propagation Ⅲ blood flow Ⅲ von Willebrand factor Ⅲ tissue factor T he rapid closure of coronary arteries caused by occlusive thrombi is the major cause of acute myocardial infarction. Disruption of coronary atherosclerotic plaques is recognized as one trigger of coronary thrombosis. 1,2 However, this process does not always result in complete thrombotic occlusion with subsequent acute myocardial infarction. Because microscopic coronary thrombi are frequently detected during autopsies of noncardiac death, 3,4 plaque disruption is considered a common complication and a high proportion of such events would be clinically silent. 5 Therefore, whether thrombus on plaque disruption is occlusive or nonocclusive is critical to the onset of clinical events. Although the mechanisms of plaque rupture and thrombus formation in lesions have been intensively investigated, how arterial thrombi are propagated remains unclear. See page 2207The thrombotic response to plaque disruption is probably regulated by the thrombogenicity of exposed plaque constituents, local hemorheology, systemic thrombogenicity, and fibrinolytic activity. 5 Many thrombotic factors are involved in acute thrombus formation. In particular, von Willebrand factor (vWF) binding to glycoprotein (platelet glycoprotein [GP]) Ib␣ and GP IIb-IIIa that plays an important role in platelet aggregation under conditions of rapid flow, might arise in atherosclerotic stenotic arteries. 6 -8 Tissue factor (TF) is a trigger of the extrinsic coagulation cascade. When simultaneously released from atheromatous plaques, TF potently activates the coagulation casc...

Pathophysiology of Atherothrombosis — Thrombus Growth, Vascular Thrombogenicity, and Plaque Metabolism

“…Studies in vitro and in vivo have shown that platelet recruitment to the thrombus surface is primarily mediated by VWF and GPIbα on flowing platelets [45,46]. We found a large amount of VWF localized to coronary thrombi in patients with AMI [11], and that a monoclonal antibody against the VWF A1 domain that interacts with platelet GPIbα, significantly suppresses the formation of platelet-fibrin thrombi and completely inhibits the occlusive thrombus formation in rabbit atherosclerotic lesions [25,47]. These findings indicate that VWF plays a crucial role in thrombus growth via platelet recruitment.…”

Pathophysiology of atherothrombosis: Mechanisms of thrombus formation on disrupted atherosclerotic plaques

“…7). These results indicate that hemodynamic forces, particularly that of disturbed blood flow induced by stenosis, could be a significant factor in the generation of plaque erosion and thrombosis, and suggest that altered blood flow combined with increased thrombogenicity in plaques is crucial for thrombus propagation and thrombotic occlusion 85 …”

“…Furthermore, plaque disruption and coronary intervention can induce distal microembolisms and microvascular constriction that reduce or disrupt coronary blood flow at sites of plaque disruption 83,84 . Reduced blood flow facilitated thrombus propagation and thrombotic occlusion at plaque disruption sites in our animal models 85 …”

Neurological deficits associated with the elastase-induced aneurysm model in rabbits

“…In our study, 70% of the ND group experienced a total occlusion time of more than 20 minutes while in 70% of the NDF group, the occlusion time was less than 20 minutes. Nevertheless, it has been previously reported13 that increased vascular wall thrombogenicity together with substantial blood flow reduction is crucial for occlusive thrombus formation in a very short period of time. Small mural thrombi composed of aggregated platelets were produced after balloon injury and flow reduction.…”