scholarly journals Oxidation shuts down an auto-inhibitory mechanism of von Willebrand factor

2019 ◽  
Author(s):  
Rachel Tsai ◽  
Gianluca Interlandi
Keyword(s):  
Von Willebrand Factor ◽  
Blood Protein ◽  
Platelet Surface ◽  
Surface Receptors ◽  
Inhibitory Function ◽  
Methionine Residues ◽  
A Domains ◽  
Oxidation Of Methionine ◽  
Von Willebrand ◽  
Willebrand Factor

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.

scholarly journals Comparative analysis of type 2b von Willebrand disease mutations: implications for the mechanism of von Willebrand factor binding to platelets

Blood ◽  
1996 ◽  
Vol 87 (6) ◽  
pp. 2322-2328 ◽  
Author(s):  
KA Cooney ◽  
D Ginsburg
Keyword(s):  
Von Willebrand Factor ◽  
Binding Domain ◽  
Von Willebrand Disease ◽  
Surface Glycoprotein ◽  
Platelet Surface ◽  
Disease Mutations ◽  
A Domains ◽  
Adhesive Proteins ◽  
Von Willebrand ◽  
Willebrand Factor

von Willebrand factor (vWF) is a multimeric glycoprotein that forms an adhesive link following vascular injury between the vessel wall and its primary ligand on the platelet surface, glycoprotein Ib (GpIb). Type 2b von Willebrand disease (vWD) is a qualitative form of vWD resulting from enhanced binding of vWF to platelets. Molecular characterization of the vWF gene in patients with type 2b vWD has resulted in identification of a panel of mutations associated with this disorder, all clustered within the GpIb binding domain in exon 28 of the vWF gene. We have expressed six of the most common type 2b vWD mutations in recombinant vWF and show that each mutation produces a similar increase in vWF binding to platelets in the absence or presence of ristocetin. Furthermore, expression of more than one type 2b vWD mutation in the same molecule (cis) or in different molecules within the same multimer (trans) failed to produce an increase in vWF platelet binding compared with any of the individually expressed mutations. Taken together, these data support the hypothesis that the vWF GpIb binding domain can adopt either a discrete “on” or “off” conformation, with most type 2b vWD mutations resulting in vWF locked in the on conformation. This model may have relevance to other adhesive proteins containing type A domains.

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

1996 ◽  
Vol 19 (8) ◽  
pp. 451-454 ◽  
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.

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

Blood ◽  
1989 ◽  
Vol 74 (6) ◽  
pp. 2016-2021 ◽  
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.

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

Blood ◽  
2006 ◽  
Vol 109 (7) ◽  
pp. 2832-2839 ◽  
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.

Abstract 2641: Plasma Von Willebrand Factor and ADAMTS13 Concentrations in Atrial Fibrillation

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Takashi Uemura ◽  
Koichi Kaikita ◽  
Hiroshige Yamabe ◽  
Masakazu Matsukawa ◽  
Kenji Soejima ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Von Willebrand Factor ◽  
Left Atrial ◽  
Thrombus Formation ◽  
Significant Negative Correlation ◽  
Platelet Surface ◽  
Control Subjects ◽  
Number Of Patients ◽  
Von Willebrand ◽  
Willebrand Factor

Background : Von Willebrand factor (VWF) is released from damaged endothelium, and has a role in platelet aggregation through a receptor on the platelet surface. A metalloprotease that cleaves VWF multimers has been identified, namely, ADAMTS13. We recently reported that the serial changes in plasma VWF and ADAMTS13 antigen levels in patients with acute myocardial infarction (AMI), and that the VWF/ADAMTS13 ratio was a useful prognostic indicator of long-term thrombotic events after AMI. Although previous studies have shown raised plasma VWF in patients with atrial fibrillation (AF), little is known about the role of ADAMTS13 in the pathogenesis of AF. In the present study, we examined the relation between VWF and ADAMTS13 in AF patients. Methods and Results : We measured the plasma VWF and ADAMTS13 antigen levels by ELISA in 45 AF patients and 49 control subjects, and also performed echocardiography to examine the relations between these markers and left atrial or ventricular functions. The plasma VWF antigen levels were significantly higher in AF patients compared with controls (2017±749 vs. 1504±497 mU/ml, P=0.0002). In contrast, the plasma ADAMTS13 antigen levels were significantly lower in AF patients compared with controls (825±181 vs. 911±193 mU/ml, P=0.03). The VWF/ADAMTS13 ratio was significantly higher in AF patients compared with controls (2.59±1.20 vs. 1.75±0.76, P<0.0001). The number of patients who received aspirin and warfarin was significantly higher in AF group than control subjects, however, those medical therapy did not affect the VWF and ADAMTS13 antigen levels. There was significant positive correlation between VWF antigen levels and the left atrial dimension (n=128, r=0.228, P=0.0095). Furthermore, there was significant negative correlation between VWF antigen levels and the left atrial appendage peak flow velocity measured by transesophageal echocardiography (n=23, r=-0.611, p=0.0015). Conclusions : These findings suggest that the balance between VWF and ADAMTS13 levels may play an important role in the intra-atrial thrombus formation in AF patients. The present results would open a new therapeutic target for prevention of thromboembolic complications in AF.

scholarly journals von Willebrand factor bound to glycoprotein Ib is cleared from the platelet surface after platelet activation by thrombin

Blood ◽  
1992 ◽  
Vol 79 (8) ◽  
pp. 2011-2021 ◽  
Author(s):  
P Hourdille ◽  
HR Gralnick ◽  
E Heilmann ◽  
A Derlon ◽  
AM Ferrer ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Platelet Activation ◽  
Von Willebrand Factor ◽  
Platelet Rich Plasma ◽  
Surface Expression ◽  
Von Willebrand Disease ◽  
Platelet Surface ◽  
Immunogold Staining ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract We recently reported that after activation of human platelets by thrombin, glycoprotein (GP) Ib-IX complexes are translocated to the surface-connected canalicular system (SCCS) (Blood 76:1503, 1990). As GPIb is a major receptor for von Willebrand factor (vWF) in platelet adhesion, we have now examined the consequences of thrombin activation on the organization of vWF bound to GPIb on the platelet surface. Studies were performed using monoclonal or polyclonal antibodies in either immunogold staining and electron microscopy (Au-EM) or in flow cytometry. When unstirred platelet-rich plasma was incubated with ristocetin, bound vWF was located by Au-EM as discrete masses regularly distributed over the cell surface. Platelets from a patient with Glanzmann's thrombasthenia, lacking GPIIb-IIIa complexes, gave a similar pattern, confirming that this represented binding to GPIb. That ristocetin was not precipitating vWF before their binding to the platelets was shown by the detection of similar masses on the surface of platelets of a patient with type IIB von Willebrand disease. Experiments were continued using washed normal platelets incubated in Tyrode-EDTA, the purpose of the EDTA being to limit the surface expression of endogenous vWF after platelet stimulation. Under these conditions, platelets were treated with ristocetin for 5 minutes at 37 degrees C in the presence of increasing amounts of purified vWF. This was followed by incubation with thrombin (0.5 U/mL) for periods of up to 10 minutes. Flow cytometry showed a time-dependent loss in the surface expression of vWF bound to GPIb and these changes were confirmed by Au-EM. In particular, immunogold staining performed on ultrathin sections showed that the bulk of the vWF was being cleared to internal membrane systems. Surface clearance of vWF during thrombin- induced platelet activation is a potential mechanism for regulating platelet adhesivity.

scholarly journals Neutrophil cathepsin G modulates the platelet surface expression of the glycoprotein (GP) Ib-IX complex by proteolysis of the von Willebrand factor binding site on GPIb alpha and by a cytoskeletal-mediated redistribution of the remainder of the complex

Blood ◽  
1994 ◽  
Vol 84 (1) ◽  
pp. 158-168 ◽  
Author(s):  
CA LaRosa ◽  
MJ Rohrer ◽  
SE Benoit ◽  
MR Barnard ◽  
AD Michelson
Keyword(s):  
Binding Site ◽  
Von Willebrand Factor ◽  
Cytochalasin B ◽  
Surface Expression ◽  
Cathepsin G ◽  
Prostaglandin I2 ◽  
Platelet Surface ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Platelet Content

Abstract The effects of neutrophil cathepsin G on the glycoprotein (GP) Ib-IX complex of washed platelets were examined. Cathepsin G resulted in a concentration- and time-dependent decrease in the platelet surface GPIb- IX complex, as determined by flow cytometry, binding of exogenous von Willebrand factor (vWF) in the presence of ristocetin, and ristocetin- induced platelet agglutination. Cathepsin G resulted in proteolysis of the vWF binding site on GPIb alpha (defined by monoclonal antibody [MoAb] 6D1), as determined by increased supernatant glycocalicin fragment (a proteolytic product of GPIb alpha); decreased total platelet content of GPIb; and lack of effect of either cytochalasin B (an inhibitor of actin polymerization), prostaglandin I2 (an inhibitor of platelet activation), or prior fixation of the platelets. However, cathepsin G resulted in minimal decreases in the binding to fixed platelets of MoAbs TM60 (directed against the thrombin binding site on GPIb alpha) and WM23 (directed against the macroglycopeptide portion of GPIb alpha). In contrast to its proteolytic effect on GPIb alpha, the cathepsin G-induced decrease in platelet surface GPIX and the remnant of the GPIb-IX complex (defined by MoAbs FMC25 and AK1) was via a cytoskeletal-mediated redistribution, as determined by lack of change in the total platelet content of GPIX and the GPIb-IX complex; complete inhibition by cytochalasin B, prostaglandin I2, and prior fixation of platelets. Experiments with Serratia protease-treated and Bernard- Soulier platelets showed that neither platelet surface GPIb nor cathepsin G-induced proteolysis of GPIb were required for the cathepsin G-induced redistribution of the remnant of the GPIb-IX complex or the cathepsin G-induced increase in platelet surface P-selectin. In summary, neutrophil cathepsin G modulates the platelet surface expression of the GPIb-IX complex both by proteolysis of the vWF binding site on GPIb alpha and by a cytoskeletal-mediated redistribution of the remainder of the complex. Prior studies show that, although thrombospondin 1, antiserine proteases, and plasma are all inhibitors of cathepsin G, the effects of cathepsin G on platelets, including an increase in surface GPIIb-IIIa, occur during close contact between neutrophils and platelets in a protective microenvironment (eg, thrombosis and local inflammation).(ABSTRACT TRUNCATED AT 400 WORDS).

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