Effect of a humanized monoclonal antibody to von Willebrand factor in a canine model of coronary arterial thrombosis

Kageyama, Shunsuke; Matsushita, Junko; Yamamoto, Hiroshi

doi:10.1016/s0014-2999(02)01590-x

Cited by 37 publications

(28 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…9,11 Moreover, antibodies against VWF reversed cyclic flow reductions after experimental femoral or coronary artery stenosis. 15,16 Although our study using VWF Ϫ/Ϫ mice cannot definitely differentiate between the contribution of VWF-GPIb␣ and VWF-collagen interactions, the present results, in context with our previous complementary findings on the central role of GPIb␣ for platelet adhesion 2 and stroke formation, 3 emphasize the functional significance of the GPIb␣-VWF pathway in the pathophysiology of ischemic stroke. In support of this notion, elevated serum levels of VWF are an independent stroke risk factor in humans, 17,18 and polymorphisms of platelet GPIb␣ exist that are associated with an increased risk of stroke due to enhanced VWF-GPIb␣ engagement.…”

Section: Resultssupporting

confidence: 53%

Deficiency of von Willebrand factor protects mice from ischemic stroke

Kleinschnitz

Meyer

Schwarz

et al. 2009

Blood

146

122

View full text Add to dashboard Cite

Section: Resultssupporting

confidence: 53%

Deficiency of von Willebrand factor protects mice from ischemic stroke

Kleinschnitz

Meyer

Schwarz

et al. 2009

Blood

146

122

View full text Add to dashboard Cite

“…We have already reported that AJW200 reduced platelet thrombus formation in animal experiments. 17,18 However, these experiments were performed with animal models of endothelial denudation of normal arteries; therefore, these experiments and results are not sufficient to mimic the pathologic setting in diseased human arteries. In this study, the flow velocity in stenotic iliac arteries was two times higher than in nonstenotic arteries.…”

Section: Discussionmentioning

confidence: 99%

“…We used two doses (1.0 and 3.0 mg/kg) of AJW200, based on our data from previous studies. 17,18 A bolus injection of AJW200 at a dose of 1.0 mg/kg significantly inhibited the botrocetininduced platelet aggregation within 2 days; moreover, the aggregation was significantly reduced until 7 days after a bolus injection of 3.0 mg/kg AJW200 (Table). In contrast, AJW200 administration did not affect collagen-induced platelet aggregation and systemic coagulation (PT and aPTT).…”

Section: Inhibition Of Botrocetin-induced Platelet Aggregation and Nomentioning

confidence: 95%

“…Immediately after that, the catheter was inserted again via the femoral artery into the iliac artery, and the second injury was performed by using the same procedure as in the first. 10 A bolus injection of the humanized anti-vWF monoclonal antibody (AJW200, 1.0 and 3.0 mg/kg IV) 17,18 or saline was administered into the ear vein 30 minutes before the second injury. This antibody reacts to the A1 domain of vWF in some species, including humans and rabbits.…”

Section: Repeated Balloon-injury Model In Rabbitsmentioning

confidence: 99%

See 1 more Smart Citation

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

Yamashita

Asada²,

Sugimura³

et al. 2003

ATVB

Self Cite

View full text Add to dashboard Cite

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...

show abstract

“…74 Analogous results have been demonstrated with the related humanized monoclonal antibody AJW200 that likewise reacts with the A1 domain of human VWF. 112,142 Recently, the pegylated anti VWF aptamer ARC1779 has completed a phase I trial program, 143 and a phase II efficacy and safety trial of ARC1779 in patients with MI has been initiated (ClinicalTrials.gov ID: NCT00507338).…”

Section: Interventions Targeting Vwfmentioning

confidence: 99%

Von Willebrand Factor in Cardiovascular Disease

2008

View full text Add to dashboard Cite

Abstract-von Willebrand factor (VWF) plays a pivotal role in platelet adhesion and aggregation at sites of high shear rates (eg, in coronary arteries that have stenotic or ruptured atherosclerotic plaque lesions). Numerous studies have investigated the relationship between VWF plasma levels and thromboembolic cardiovascular events. In contrast to the rather weak association in the general population, in patients with preexisting vascular disease, VWF is significantly predictive for adverse cardiac events, including death. Likewise, VWF typically rises during the course of acute coronary syndrome, and the extent of this VWF release is an independent predictor of adverse clinical outcome in these patients. Key Words: coronary disease Ⅲ myocardial infarction Ⅲ platelets Ⅲ thrombosis Ⅲ von Willebrand factor F or Ͼ150 years, it has been known that alterations in blood flow, vascular wall, and blood components, the so-called Virchow's triad, 1 may progressively lead to thrombus formation. Yet, a more complete understanding of the complex interactions among the vascular endothelium, platelet adhesion, activation, aggregation, and clotting factor activation involved in this process is still emerging from contemporary research.Under physiological conditions, the vascular endothelium produces many substances that contribute importantly to hemostasis, fibrinolysis, and regulation of vessel tone and permeability. One such substance is the multimeric glycoprotein von Willebrand factor (VWF), which is produced almost exclusively by endothelial cells. 2 Plasma levels of VWF are raised in different states of endothelial damage and have therefore been proposed as useful markers of endothelial dysfunction. 3 Along this line, blockade of nitric oxide enhances the stimulated release of VWF in humans. 4,5 Furthermore, VWF plays a crucial role in platelet adhesion and aggregation under high shear conditions. 6 Finally, VWF supports the third component of Virchow's triad, clotting factor activation, by acting as a carrier protein and stabilizer for factor VIII. 7 Almost all acute coronary syndromes (ACS) result from thrombus formation in preexisting coronary atherosclerosis. As a result of plaque rupture and exposure of prothrombotic subendothelial matrix, local thrombus formation occurs, which subsequently leads to coronary artery occlusion and acute myocardial infarction (AMI). The presence of VWF has been shown to play a pivotal role in platelet aggregation at sites of high shear, eg, at the sites of lesions in the coronary arteries. 8 Accordingly, VWF is a well-characterized marker of cardiovascular risk, and VWF plasma levels are increased in patients with ACS. 9 Considering the central role of VWF in thrombogenesis, therapies that specifically inhibit VWF are of particular interest as potential new antiplatelet drugs.

show abstract

Effect of a humanized monoclonal antibody to von Willebrand factor in a canine model of coronary arterial thrombosis

Cited by 37 publications

References 22 publications

Deficiency of von Willebrand factor protects mice from ischemic stroke

Deficiency of von Willebrand factor protects mice from ischemic stroke

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

Von Willebrand Factor in Cardiovascular Disease

Contact Info

Product

Resources

About