The catch bond mechanism between von Willebrand factor and platelet surface receptors investigated by molecular dynamics simulations

AbstractRecently, the platelet-binding function of the blood protein von Willebrand factor (VWF) has been shown to be activated by oxidizing conditions such as created by inflammation. This observation has been linked to the oxidation of methionine residues in three tandem A domains of VWF. Here, we used a dynamic flow assay to investigate which auto-inhibitory mechanisms of VWF are shut down leading to the observed activation. The results show that oxidizing agents do not directly activate the A1 domain, which is the domain in VWF that contains the binding site to platelet surface receptors, but are likely to remove the inhibitory function of neighboring domains of A1.

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Arteriovenous Fistula Obstruction and Expression of Platelet Receptors for Von Willebrand Factor and for Fibrinogen (Glycoproteins GPIb and GPIIb/llla) in Hemodialysis Patients

The International Journal of Artificial Organs ◽

10.1177/039139889601900805 ◽

1996 ◽

Vol 19 (8) ◽

pp. 451-454 ◽

Cited By ~ 13

Author(s):

M. Liani ◽

F. Salvati ◽

E. Tresca ◽

G. Dl Paolo ◽

L. Vitacolonna ◽

...

Keyword(s):

Renal Failure ◽

Chronic Renal Failure ◽

Von Willebrand Factor ◽

Hemodialysis Patients ◽

Platelet Surface ◽

Surface Receptors ◽

Platelet Receptors ◽

Stage Renal Disease ◽

Von Willebrand ◽

Willebrand Factor

Platelet surface receptors for von Willebrand factor and for fibrinogen (glycoproteins GPIb and GPIIb/llla) were studied with monoclonal antibodies CD42 and CD41 and cytofluorometry in 31 healthy subjects, 10 hemodialysis patients with no A-V fistula obstruction (patent original fistula), 10 hemodialysis patients with frequent A-V fistula obstruction (more than twice), 12 patients with mild chronic renal failure (creatinine 1.75±0.40 mg/100ml), 11 patients with advanced chronic renal failure (creatinine 5.62±1.22 mg/100ml), and 10 patients with end-stage renal disease (ESRD) treated with peritoneal dialysis. There was a significant increase of platelet surface glycoproteins GPIb and GPIIb/llla in the population of hemodialysis patients with frequent A-V fistula obstruction. The expression of these platelet receptors might be related to the prothrombotic tendency of a group of patients with ESRD, who suffer more occlusive and thrombotic events of the A-V fistula. This group of patients may also have a higher frequency of systemic thrombotic and atherosclerotic complications.

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Effect of aspirin on platelet-von Willebrand factor surface expression on thrombin and ADP-stimulated platelets

Blood ◽

10.1182/blood.v74.6.2016.2016 ◽

1989 ◽

Vol 74 (6) ◽

pp. 2016-2021 ◽

Cited By ~ 12

Author(s):

RI Parker ◽

HR Gralnick

Keyword(s):

Von Willebrand Factor ◽

Shape Change ◽

Adenosine Diphosphate ◽

Surface Expression ◽

Platelet Surface ◽

Granule Secretion ◽

Von Willebrand ◽

Willebrand Factor ◽

Platelet Shape ◽

Stimulation Of

Abstract Platelets contain a pool of endogenous platelet-von Willebrand factor (vWF) that becomes expressed on the platelet surface when platelets are stimulated by a variety of agonists. Maximal platelet-vWF expression occurs in concert with platelet alpha-granule secretion. Aspirin (ASA) is known to impair platelet activation and alpha-granule secretion by irreversible inhibition of platelet cyclo-oxygenase. We studied native and ASA-treated platelets for their ability to mobilize and to express platelet-vWF in response to adenosine diphosphate (ADP) or thrombin. We found that each agonist was effective in promoting increased platelet- vWF surface expression on native and ASA-treated platelets. ASA-treated platelets responded identically to native platelets to low (0.01 U/mL) and high (1.0 U/mL) concentrations of thrombin, while the ADP-induced increase in ASA-treated platelets was only 50% to 60% of that for control platelets. Measurement of secreted platelet-vWF and beta- thromboglobulin indicated that the increase seen with ADP was largely independent of alpha-granule secretion. Using monoclonal antibodies (MoAbs) against the platelet glycoproteins (GP) IIb/IIIa and Ib (MoAbs 10E5 and 6D1, respectively), we demonstrated that the ADP-induced increase in platelet-vWF expression on control platelets primarily involved the binding of secreted platelet-vWF to the platelet GPIIb/IIIa. In contrast, the increase in platelet-vWF that occurred following ADP stimulation of ASA-treated platelets was largely insensitive to GPIIb/IIIa blockade. No effect of GPIb blockade in platelet-vWf expression was noted for either control or ASA-treated platelets. When platelet shape change was prevented by the addition of cytochalasin D, ADP-induced platelet-vWf surface expression on ASA- treated platelets was reduced by more than 80%. Our data indicate that platelets in which the cyclooxygenase pathway is blocked by the action of aspirin can increase surface expression of platelet-vWf as a consequence of platelet shape change. We speculate that this process exposes platelet-vWf bound to GPIIb/IIIa, or possibly GPIb, within the surface connected canalicular system.

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Molecular Dynamics Simulated Unfolding of von Willebrand Factor A Domains by Force

Cellular and Molecular Bioengineering ◽

10.1007/s12195-009-0051-0 ◽

2009 ◽

Vol 2 (1) ◽

pp. 75-86 ◽

Cited By ~ 14

Author(s):

Wei Chen ◽

Jizhong Lou ◽

Cheng Zhu

Keyword(s):

Molecular Dynamics ◽

Von Willebrand Factor ◽

A Domains ◽

Von Willebrand ◽

Willebrand Factor

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Adenovirus-induced thrombocytopenia: the role of von Willebrand factor and P-selectin in mediating accelerated platelet clearance

Blood ◽

10.1182/blood-2006-06-032524 ◽

2006 ◽

Vol 109 (7) ◽

pp. 2832-2839 ◽

Cited By ~ 71

Author(s):

Maha Othman ◽

Andrea Labelle ◽

Ian Mazzetti ◽

Hisham S. Elbatarny ◽

David Lillicrap

Keyword(s):

Von Willebrand Factor ◽

Cell Activation ◽

Endothelial Cell Activation ◽

Platelet Surface ◽

Adenoviral Gene Transfer ◽

Coxsackie Adenovirus Receptor ◽

Transfer Vectors ◽

Adenovirus Receptor ◽

Von Willebrand ◽

Willebrand Factor

AbstractThrombocytopenia has been consistently reported following the administration of adenoviral gene transfer vectors. The mechanism underlying this phenomenon is currently unknown. In this study, we have assessed the influence of von Willebrand Factor (VWF) and P-selectin on the clearance of platelets following adenovirus administration. In mice, thrombocytopenia occurs between 5 and 24 hours after adenovirus delivery. The virus activates platelets and induces platelet-leukocyte aggregate formation. There is an associated increase in platelet and leukocyte-derived microparticles. Adenovirus-induced endothelial cell activation was shown by VCAM-1 expression on virus-treated, cultured endothelial cells and by the release of ultra-large molecular weight multimers of VWF within 1 to 2 hours of virus administration with an accompanying elevation of endothelial microparticles. In contrast, VWF knockout (KO) mice did not show significant thrombocytopenia after adenovirus administration. We have also shown that adenovirus interferes with adhesion of platelets to a fibronectin-coated surface and flow cytometry revealed the presence of the Coxsackie adenovirus receptor on the platelet surface. We conclude that VWF and P-selectin are critically involved in a complex platelet-leukocyte-endothelial interplay, resulting in platelet activation and accelerated platelet clearance following adenovirus administration.

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