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...

Thrombus Aspiration Therapy and Coronary Thrombus Components in Patients with Acute ST-Elevation Myocardial Infarction

“…Under conditions of a rapid flow in atherosclerotic arteries, von Willebrand factor has been shown to play an important role in platelet aggregation/adhesion and fibrin-rich thrombus formation 17,87,88) . Moreover, abundant tissue factor expressed in plaque and the vascular wall may also play a crucial role in the activation of the coagulation cascade and the formation of platelet-fibrin thrombi at the time of plaque disruption 16-22, 27, 28) .…”

Pathology and Pathophysiology of Atherothrombosis: Virchow's Triad Revisited

“…Recent studies in vitro and in vivo showed that platelet recruitment on thrombus surface was primary mediated by VWF and GPIb on flowing platelets (Bergmeier et al 2006, Kulkuni et al 2000. We demonstrated that a large amount of VWF was localized in coronary thrombi in patients with AMI , and that monoclonal antibody against VWF A1 domain, which interacts platelet GPIb , significantly suppressed formation of platelet-fibrin thrombi and completely inhibited occlusive thrombus formation in rabbit atherosclerotic lesions (Yamashita et al, 2003(Yamashita et al, , 2004. These findings indicated a crucial role of VWF in thrombus growth via platelet recruitment.…”

“…Blood flow reduction (>75%) promoted the growth of thrombus, a mixture of platelets and fibrin, on atherosclerotic lesion, which grew to occlusive one. The flow reduction also induced thrombus formation on normal arteries, but the thrombi were very small and composed only of platelets (Yamashita et al 2004). Therefore, blood flow reduction associated with increased vascular wall thrombogenecity is considered to contribute thrombus growth.…”

Ultrasound Accelerates Thrombolysis of Acutely Induced Platelet-Rich Thrombi Similar to Those in Acute Myocardial Infarction

“…On 2 occasions separated by a 4-week interval, the rabbits were anesthetized with pentobarbital sodium (25 mg/kg body weight, iv) and balloon injury of the right femoral artery was performed as previously described, with minor modification. 25,26 Briefly, the first injury was induced by fluoroscopically inserting a PTCA balloon catheter (3.0 mm-diameter, 8.0 mmlength) via the left carotid artery to a distal site in the right femoral artery where it was inflated to 8 atm. The inflated balloon was then pulled back a distance of 3 cm 3 times.…”

“…22,24 Therefore, to confirm the utility of US for lysis of platelet-rich thrombi, in vivo, we recently established a rabbit model of femoral artery occlusion in which platelet-rich arterial thrombi are acutely induced by repeated balloon injury. 25,26 We can then test whether US can enhance the pharmacological lysis of platelet-rich thrombi. Background Although sonothrombolysis has been studied for development of recanalization that is safer and more efficacious than the methods currently used, there have been no studies of the efficacy of sonothrombolysis for the platelet-rich thrombi that typically cause acute myocardial infarction (AMI).…”