Antagonism of vWF Inhibits both Injury Induced Arterial and Venous Thrombosis in the Hamster

Yamamoto, Hiroshi; Vreys, Ingrid; Stassen, Jean Marie; Yoshimoto, Ryota; Vermylen, Jos; Hoylaerts, Marc

doi:10.1055/s-0037-1614240

Cited by 63 publications

(47 citation statements)

References 32 publications

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“…In general, in flow chambers a more effective inhibition with vWF-GPIb inhibitors is obtained at higher shear rates, 11,12,36 which we also demonstrated here by finding a more pronounced effect of 6B4 on platelet adhesion to collagen when a higher shear was applied in a flow chamber; also, in vivo an arterial thrombus was more readily prevented than a venous one. 11 This implies that inhibition of GPIb would result especially in arterial effects, which in addition could result in less bleeding risk.…”

Section: Discussionsupporting

confidence: 82%

“…This finding supports data obtained with other GPIb-vWF-blocking agents (VCL, anti-vWF MoAb AJvW-2) that lengthened the bleeding time only moderately. 11,12,17,18 This finding is important and might provide a major advantage in the development of antithrombotic agents compared with GPIIb-IIIa antagonists, like ReoPro. 37 On the other hand, the GPIb-vWF interaction in contrast to the GPIIb-IIIa-fibrinogen interaction is the ultimate first step in platelet adhesion under fast blood flow.…”

Section: Discussionmentioning

confidence: 97%

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Antithrombotic Effect of Platelet Glycoprotein Ib–Blocking Monoclonal Antibody Fab Fragments in Nonhuman Primates

Cauwenberghs

Meiring

Vauterin

et al. 2000

ATVB

118

107

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Abstract-Platelet adhesion in arterial blood flow is mainly supported by the platelet receptor glycoprotein (GP) Ib, which interacts with von Willebrand factor (vWF) that is bound to collagen at the site of vessel wall injury. Antibody 6B4 is a monoclonal antibody (MoAb) raised against purified human GPIb. MoAb 6B4 inhibits both ristocetin-and botrocetin-induced, vWF-dependent human platelet agglutination. MoAb 6B4 furthermore blocks shear-induced adhesion of human platelets to collagen I. We studied the antithrombotic effect of this inhibitory murine MoAb 6B4 in a baboon model of arterial thrombosis. When injected into baboons, intact IgG and its F(abЈ) 2 fragments caused almost immediate thrombocytopenia, whereas injection of the Fab fragments alone did not. Fab fragments were subsequently used to investigate their in vivo effect on platelet deposition onto a thrombogenic device, consisting of collagen-rich, glutaraldehyde-fixed bovine pericardium (0.6 cm 2 ), at a wall shear rate ranging from 700 to 1000 s Ϫ1 . Baboons were either pretreated with Fabs to study the effect of inhibition on platelet adhesion or treated 6 minutes after placement of the thrombogenic device to investigate the effect on interplatelet cohesion. Pretreatment of the animals with bolus doses ranging from 80 to 640 g/kg Fab fragments significantly reduced 111 In-labeled platelet deposition onto the collagen surface by Ϸ43% to 65%. Only the highest dose caused a significant prolongation (doubling) of the bleeding time. Ex vivo ristocetin-induced platelet agglutination was equally reduced. Treatment with a bolus of 110 g/kg Fab fragments after a thrombus was allowed to form for 6 minutes had no effect on further platelet deposition. We therefore conclude that Fab fragments or derivatives of inhibitory anti-GPIb antibodies may be useful compounds to prevent thrombosis.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 97%

Antithrombotic Effect of Platelet Glycoprotein Ib–Blocking Monoclonal Antibody Fab Fragments in Nonhuman Primates

Cauwenberghs

Meiring

Vauterin

et al. 2000

ATVB

118

107

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“…Our finding is consistent with another in vivo study where, in a crushed femoral vein model (hamster), it was shown that the presence of an antagonist to the VWF A1 domain decreased thrombus size. 29 The key finding in our study is the essential role for VWF in forming an occlusive thrombus under venous flow conditions. The importance of VWF in occlusive thrombus formation at arterial shear conditions has been shown in vivo.…”

Section: Role Of Vwf In Venous Thrombosis 2427mentioning

confidence: 59%

von Willebrand factor and factor VIII are independently required to form stable occlusive thrombi in injured veins

Chauhan

Kisucka

Lamb

et al. 2006

Blood

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von Willebrand factor (VWF) protects factor VIII (FVIII) from proteolysis and mediates the initial contact of platelets with the injured vessel wall, thus playing an important role in hemostasis and thrombosis. VWF is crucial for the formation of occlusive thrombi at arterial shear rates. However, with only a few conflicting studies published, the role of VWF in venous thrombosis is still unclear. Using genetargeted mice, we show that in ferric chloride-injured veins platelet adhesion to subendothelium is decreased and thrombus growth is impaired in VWF ؊/؊ mice when compared with wild type (WT). We also observed increased embolization in the VWF ؊/؊ mice, which was due to lower FVIII levels in these mice as recombinant factor VIII (r-FVIII) restored thrombus stability. Despite normalization of blood clotting time and thrombus stability after r-FVIII infusion, the VWF ؊/؊ venules did not occlude. Introductionvon Willebrand factor (VWF) is a large adhesive glycoprotein synthesized in megakaryocytes and endothelial cells and stored in platelet ␣-granules and Weibel-Palade bodies, respectively. VWF circulates in plasma as a series of multimers ranging from 500 to 20 000 kDa. The size of the multimers is regulated through proteolysis 1,2 by a specific protease ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type I repeats-13). [3][4][5] There are 3 pools of VWF: (1) soluble plasma VWF, (2) subendothelial (ECM) VWF, and (3) cellular VWF in storage granules. 6 VWF is a carrier for factor VIII (FVIII) and protects it from inactivation. 7 The formation of a thrombus on an injured vessel wall is a complex process that involves multiple adhesion molecules (VWF, collagen, fibrinogen, and fibronectin) and their respective receptors on the platelet surface (GPIb␣, GPVI, ␤1 and ␤3 integrins). VWF has 2 main receptors, GPIb␣ in the GPIb-IX-V complex and the integrin ␣IIb␤3. 8 Pathological thrombosis can occur in arteries and veins. Arterial thrombosis is often linked to inappropriate platelet activation and can result in myocardial infarction and ischemic stroke, while venous thrombosis (eg, deep vein thrombosis) is commonly linked to high procoagulant activity, which produces fibrin-rich thrombi. In the clinical setting, elevated levels of FVIII and VWF are associated with an increased risk of venous thrombosis. The Leiden Thrombophilia Study suggested that the effect of elevated VWF on the risk of venous thrombosis was due to increased FVIII levels. 9 In contrast, the Longitudinal Investigation of Thromboembolism Etiology (LITE) Study showed FVIII and VWF were independently associated with venous thromboembolism. 10 Under high shear, the VWF-GPIb␣ interaction is necessary for initial platelet contact with the subendothelium, while irreversible platelet aggregation also requires interaction between the VWF and integrin ␣IIb␤3. 8,[11][12][13] Although an important role for VWF in platelet-platelet cohesion and thrombus formation at arterial shear rates was demonstrated both in vitro 13,14 and in vivo, 15,...

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“…AJvW-2 is a murine MoAb that recognizes a conformational epitope of the A1 domain of vWF involved in its binding to platelet GPIb. 12,33 AJvW-2 has been shown to specifically inhibit platelet adhesion and aggregation under conditions of high shear stress by blocking the interaction between vWF and GPIb. 12,33 Our finding that AJvW-2 completely inhibits the high shear-induced platelet aggregation in the blood from patients with a very acute phase of ACSs, as well as recent demonstrations that the vWF-GPIb interaction is essential during coronary occlusion and that inhibition of vWF binding to GPIb can prevent coronary thrombosis 7,[33][34][35][36] and further restenosis after vascular injury, 36,37 suggests that AJvW-2, if administered after coronary interventions (eg, angioplasty, stenting, or atherectomy), may prevent new events in the coronary arteries and inhibit restenosis.…”

Section: Discussionmentioning

confidence: 99%

AJvW-2, an Anti-vWF Monoclonal Antibody, Inhibits Enhanced Platelet Aggregation Induced by High Shear Stress in Platelet-Rich Plasma From Patients With Acute Coronary Syndromes

Eto

Isshiki²,

Yamamoto³

et al. 1999

ATVB

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Abstract-The platelet aggregation that is dependent on von Willebrand factor (vWF) is important in the thrombogenesisthat occurs under conditions of high shear stress, eg, during acute coronary syndromes (ACSs). A monoclonal antibody, AJvW-2, directed against the A1 domain of human vWF specifically blocks the interaction between plasma vWF and platelet glycoprotein (GP) Ib. To evaluate the association between the vWF-GPIb interaction and the enhanced shear-induced platelet aggregation (SIPA) observed in ACSs, we tested the effect of this antibody on platelet aggregation. Platelet-rich plasma was prepared from the citrated blood of 12 patients with unstable angina (UAP) and 20 patients with acute myocardial infarction (AMI) who were admitted within 3 hours of the onset of cardiac symptoms and from 18 controls. We observed the following: (1) 1.7-fold higher plasma levels of vWF and ristocetin cofactor activity in UAP patients and (2) 2.8-fold higher levels in the AMI group than in controls. Using a cone-and-plate viscometer, we measured the mean value of SIPA under high-shear conditions (108 dyne/cm 2 ) and found them to be 1.3-fold higher in the UAP group and 2.0-fold higher in the AMI group than in controls. The high SIPA in all groups was completely inhibited by 10 g/mL AJvW-2. Under low-shear conditions (12 dyne/cm 2 ), platelet aggregation was increased only in the AMI group, but this was unaffected by AJvW-2. We observed a significant correlation in both ACS groups between high SIPA and the plasma vWF level or vWF larger multimers. These findings suggest that the vWF-GPIb interaction is important in coronary occlusion and that inhibition of this interaction (with the use of AJvW-2) may prevent further events in the coronary arteries. A ctivation of platelets induced by physical shear stress or by physiological agonists is important in arterial thrombogenesis. 1,2 Increased levels of plasma von Willebrand factor (vWF) in patients with thrombotic disorders have suggested that this protein may be involved in thrombosis. For example, in survivors of acute myocardial infarction (AMI), the level of plasma vWF may be an index of the increased risk for reinfarction and mortality. 3 In addition, an enhanced plasma vWF concentration is thought to be an independent predictor of such acute coronary syndromes (ACSs) as unstable angina (UAP). 4 Most importantly, high physiological and/or pathological shear stress can induce vWF-mediated platelet aggregation in vitro 1,2,5,6 and may stimulate the interaction between plasma vWF and glycoprotein (GP) Ib on platelets in vivo, eg, in animal models with coronary artery occlusion. 7 To further clarify the molecular mechanism for arterial thrombogenesis and to seek an effective strategy for its prevention or treatment, efforts have focused on developing simple methods for monitoring vWFplatelet interactions in the blood of patients with ACSs. 2 The recent development of a cone-and-plate viscometer to monitor platelet aggregation under various shear conditions in the absence of an...

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Antagonism of vWF Inhibits both Injury Induced Arterial and Venous Thrombosis in the Hamster

Cited by 63 publications

References 32 publications

Antithrombotic Effect of Platelet Glycoprotein Ib–Blocking Monoclonal Antibody Fab Fragments in Nonhuman Primates

Antithrombotic Effect of Platelet Glycoprotein Ib–Blocking Monoclonal Antibody Fab Fragments in Nonhuman Primates

von Willebrand factor and factor VIII are independently required to form stable occlusive thrombi in injured veins

AJvW-2, an Anti-vWF Monoclonal Antibody, Inhibits Enhanced Platelet Aggregation Induced by High Shear Stress in Platelet-Rich Plasma From Patients With Acute Coronary Syndromes

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