Contribution of von Willebrand Factor to Thrombus Formation on Neointima of Rabbit Stenotic Iliac Artery Under High Blood-Flow Velocity

Abstract

Objective-It has become clear that von Willebrand factor (vWF) plays important roles in platelet adhesion and aggregation under high blood-flow velocity conditions observed in stenotic atherosclerotic arteries. However, its roles in thrombus formation in vivo on diseased arteries have not been fully understood. We examined the contribution of vWF to thrombus formation and subsequent intimal growth by using a repeated balloon-injury model in rabbits. Methods and Results-Rabbit iliac arteries 4 weeks after a first balloon injury showed 37% luminal stenosis by neointimal growth, and blood velocity increased by 2.1 times compared with that of uninjured arteries. The second balloon injury induced fibrin-rich thrombus formation on the injured neointima. Intravenous administration of a monoclonal antibody against vWF (AJW200, 1.0 mg/kg body weight) remarkably prevented botrocetin-induced platelet aggregation ex vivo for 2 days; moreover, thrombus formation, cell proliferation, and subsequent neointimal growth were significantly reduced at 30 minutes, 5 days, and 4 weeks, respectively, after the second balloon injury. Conclusions-These results indicate that vWF plays a potent role in fibrin-rich thrombus formation on the neointima under high blood-flow velocity conditions. Inhibition of plasma vWF activity might be effective for the reduction of thrombus formation and/or subsequent neointimal development after coronary interventions. T hrombus formation on a disrupted atherosclerotic plaque is a threatening event that leads to acute coronary syndromes. 1,2 Because platelet adhesion and aggregation are essential steps in hemostatic and thrombotic processes, the development of platelet-rich thrombi has been regarded as a trigger of acute coronary syndromes. 2,3 On the other hand, autopsy studies have revealed that thrombi that have caused myocardial infarction contain not only platelets but also a large amount of fibrin, suggesting increased activation of the coagulation cascade at the time of the event. 4,5 We and other investigators have demonstrated that tissue factor (TF) is expressed in atherosclerotic lesions, 6 -9 is an important determinant of thrombogenicity, and contributes to fibrin-rich thrombus formation after plaque disruption. 7,10 Recent angiographic studies have revealed that coronary occlusions that induce myocardial infarction most frequently evolve in segments with stenoses that are Ͻ80%. 11 On the basis of this evidence, fluid-dynamic forces (elevated shear rates) would be expected to have certain effects on thrombus formation in the stenotic arteries. Current ex vivo experiments have indicated a crucial role for von Willebrand factor (vWF) in platelet aggregation under rapid-flow conditions. 12,13 In addition, inhibition of vWF activity prevents in vivo arterial platelet thrombus formation in the normal arteries of some species. 14 -16 However, the actual role of vWF in thrombus formation in stenotic, atherosclerotic arteries has not been elucidated.We therefore examined whether or not vWF contribute...

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

“…6,7,8 We and others have also demonstrated the contribution of vWF to the interaction between platelets and fibrin 29,30 and also fibrin-rich thrombus formation. 10 The occlusive thrombi in this study were composed of a large amount of fibrin and platelets and were rich in vWF. The presence of vWF in the occlusive thrombi suggests that vWF plays an important role in this process.…”

“…Our previous studies also demonstrated that the repeated balloon injuries of rabbit aortas and femoral arteries induce fibrin-rich mural thrombi, but do not become occlusive. 10,17 These results suggest that not only increased vascular thrombogenicity but also other factors are required to propagate arterial occlusive thrombi.Blood flow is one of the most important modulators of thrombus formation and propagation. Plaque disruption initiates thrombus formation at the disrupted site and frequently causes a reduction in coronary blood flow.…”

“…We demonstrated that thrombi on injured neointima are fibrin-rich in a model of repeated balloon injury even when blood flow is high. 10 However, these thrombi remained exclusively mural and did not become occlusive.Blood flow is a key modulator of thrombus propagation. After plaque disruption, coronary blood flow is frequently However, the effect of reduced blood flow on thrombus propagation in diseased arteries remains obscure.…”

“…The arteries were subsequently injured in the same areas with a 2-French balloon catheter using the same procedure as used for the SI group. 10 Immediately after the second injury, the blood flow rate of the injured artery was reduced to the same levels as those of the SI group (nϭ5 each). The role of vWF in arterial thrombus formation was evaluated by injecting an intravenous bolus of human anti-vWF monoclonal antibody (AJW200; at doses of 1.0 mg/kg) or saline (as control) via the ear vein 30 minutes before the second balloon injury.…”

T1 measurement of flowing blood and arterial input function determination for quantitative 3D T1‐weighted DCE‐MRI

“…This strategy circumvents signal correction for the transient response to steady-state magnetization, which depends on flow velocity, FA, TR, and T 1 (19). All ROIs were placed at least 9 cm distal from entry into the image slab, which satisfies the required 7 cm under our experimental settings using an assumed maximum velocity of 16 cm/second in the rabbit iliac artery (20). Time to acquire the center of k-space can be adjusted using alternative sampling schemes, such as elliptical-centric.…”