Role of von Willebrand Factor—A1 Domain Variants P1266L, H1268D, C1272R, and C1272F in VWD

2016 ◽  
pp. 299-330
Author(s):  
C. George Priya Doss ◽  
Shabana Kouser Ali
Keyword(s):  
Von Willebrand Factor ◽  
A1 Domain ◽  
Von Willebrand ◽  
Willebrand Factor

Interaction between von Willebrand factor and glycoprotein Ib activates Src kinase in human platelets: role of phosphoinositide 3–kinase

Blood ◽  
2003 ◽  
Vol 101 (9) ◽  
pp. 3469-3476 ◽  
Author(s):  
Yi Wu ◽  
Naoki Asazuma ◽  
Kaneo Satoh ◽  
Yutaka Yatomi ◽  
Toshiro Takafuta ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Kinase Inhibitor ◽  
Signal Transduction Pathway ◽  
Human Platelets ◽  
Glutathione S Transferase ◽  
Phosphoinositide 3 Kinase ◽  
A1 Domain ◽  
Von Willebrand ◽  
Willebrand Factor

The binding of von Willebrand factor (VWF) to glycoprotein (GP) Ib-IX-V stimulates transmembrane signaling events that lead to platelet adhesion and aggregation. Recent studies have implied that activation of Src family kinases is involved in GPIb-mediated platelet activation, although the related signal transduction pathway remains poorly defined. This study presents evidence for an important role of Src and GPIb association. In platelet lysates containing Complete, a broad-spectrum protease inhibitor mixture, Src and Lyn dynamically associated with GPIb on VWF-botrocetin stimulation. Cytochalasin D, which inhibits translocation of Src kinases to the cytoskeleton, further increased Src and GPIb association. Similar results were obtained with botrocetin and monomeric A1 domain, instead of intact VWF, with induction of both Src activation and association between GPIb and Src. These findings suggest that ligand binding of GPIb, without receptor clustering, is sufficient to activate Src. Immunoprecipitation studies demonstrated that Src, phosphoinositide 3– kinase (PI 3–kinase), and GPIb form a complex in GPIb-stimulated platelets. When the p85 subunit of PI 3–kinase was immunodepleted, association of Src with GPIb was abrogated. However, wortmannin, a specific PI 3–kinase inhibitor, failed to block complex formation between Src and GPIb. The Src-SH3 domain as a glutathione S-transferase (GST)–fusion protein coprecipitated the p85 subunit of PI 3–kinase and GPIb. These findings taken together suggest that the p85 subunit of PI 3–kinase mediates GPIb-related activation signals and activates Src independently of the enzymatic activity of PI 3– kinase.

scholarly journals The Flow Dependent Adhesion of von Willebrand Factor (VWF)-A1 Functionalized Nanoparticles in an in Vitro Coronary Stenosis Model

Molecules ◽  
2019 ◽  
Vol 24 (15) ◽  
pp. 2679 ◽  
Author(s):  
Yathreb Asaad ◽  
Mark Epshtein ◽  
Andrew Yee ◽  
Netanel Korin
Keyword(s):  
Von Willebrand Factor ◽  
Coronary Stenosis ◽  
Nano Particles ◽  
Adhesive Properties ◽  
Polystyrene Nanoparticles ◽  
A1 Domain ◽  
Von Willebrand ◽  
Willebrand Factor

In arterial thrombosis, von Willebrand factor (VWF) bridges platelets to sites of vascular injury. The adhesive properties of VWF are controlled by its different domains, which may be engineered into ligands for targeting nanoparticles to vascular injuries. Here, we functionalized 200 nm polystyrene nanoparticles with the VWF-A1 domain and studied their spatial adhesion to collagen or collagen-VWF coated, real-sized coronary stenosis models under physiological flow. When VWF-A1 nano-particles (A1-NPs) were perfused through a 75% stenosis model coated with collagen-VWF, the particles preferentially adhered at the post stenotic region relative to the pre-stenosis region while much less adhesion was detected at the stenosis neck (~ 65-fold less). When infused through collagen-coated models or when the A1 coating density of nanoparticles was reduced by 100-fold, the enhanced adhesion at the post-stenotic site was abolished. In a 60% stenosis model, the adhesion of A1-NPs to collagen-VWF-coated models depended on the location examined within the stenosis. Altogether, our results indicate that VWF-A1 NPs exhibit a flow-structure dependent adhesion to VWF and illustrate the important role of studying cardiovascular nano-medicines in settings that closely model the size, geometry, and hemodynamics of pathological environments.

E-Beam Nanopost Arrays Reveal That Glycoprotein Ib-IV-X Complex and Von Willebrand Factor Interactions Transmit Platelet Cytoskeletal Forces

2013 ◽  
Author(s):  
Shirin Feghhi ◽  
Adam D. Munday ◽  
Wes W. Tooley ◽  
Jose A. Lopez ◽  
Nathan J. Sniadecki
Keyword(s):  
Von Willebrand Factor ◽  
Platelet Adhesion ◽  
Integrin Receptor ◽  
Spread Area ◽  
Contractile Forces ◽  
A1 Domain ◽  
Factor Interactions ◽  
Von Willebrand ◽  
Willebrand Factor

We have developed a new tool to measure the contractility of single platelets. This tool consists of an array of nano-scale polydimethylsiloxane (PDMS) posts. Von Willebrand factor (VWF) and a recombinant protein encompassing the GPIb-IX-V binding region of VWF (A1 domain) were used to study the role of GPIb-VWF interactions in platelet contractility. Platelets were treated with AK2 and 7E3 antibodies to block platelet adhesion through receptors GPIb and α IIbβ 3, respectively. Platelets treated with these antibodies showed reduced spread area and forces in comparison to untreated platelets on VWF. Furthermore, platelets were able to generate contractile forces on substrates coated with A1 domain of VWF. These results suggest that platelet contractile forces can be transmitted through a non-integrin receptor, such as GPIb.

scholarly journals Evidence for the Misfolding of the A1 Domain within Multimeric von Willebrand Factor in Type 2 von Willebrand Disease

2020 ◽  
Vol 432 (2) ◽  
pp. 305-323 ◽  
Author(s):  
Alexander Tischer ◽  
Maria A. Brehm ◽  
Venkata R. Machha ◽  
Laurie Moon-Tasson ◽  
Linda M. Benson ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
A1 Domain ◽  
Von Willebrand ◽  
Willebrand Factor

scholarly journals Quantification of von Willebrand factor and ADAMTS-13 after traumatic injury: a pilot study

2021 ◽  
Vol 6 (1) ◽  
pp. e000703
Author(s):  
Taleen A MacArthur ◽  
Julie Goswami ◽  
Laurie Moon Tasson ◽  
Alexander Tischer ◽  
Kent R Bailey ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Acute Phase ◽  
Von Willebrand Factor ◽  
Thrombin Generation ◽  
Trauma Patients ◽  
Phase Reaction ◽  
Time Points ◽  
A1 Domain ◽  
Von Willebrand ◽  
Willebrand Factor

BackgroundVon Willebrand factor (VWF) is an acute phase reactant synthesized in the megakaryocytes and endothelial cells. VWF forms ultra-large multimers (ULVWF) which are cleaved by the metalloprotease ADAMTS-13, preventing spontaneous VWF–platelet interaction. After trauma, ULVWF is released into circulation as part of the acute phase reaction. We hypothesized that trauma patients would have increased levels of VWF and decreased levels of ADAMTS-13 and that these patients would have accelerated thrombin generation.MethodsWe assessed plasma concentrations of VWF antigen and ADAMTS-13 antigen, the Rapid Enzyme Assays for Autoimmune Diseases (REAADS) activity of VWF, which measure exposure of the platelet-binding A1 domain, and thrombin generation kinetics in 50 samples from 30 trauma patients and an additional 21 samples from volunteers. Samples were analyzed at 0 to 2 hours and at 6 hours from the time of injury. Data are presented as median (IQR) and Kruskal-Wallis test was performed between trauma patients and volunteers at both time points.ResultsREAADS activity was greater in trauma patients than volunteers both at 0 to 2 hours (190.0 (132.0–264.0) vs. 92.0 (71.0–114.0), p<0.002) and at 6 hours (167.5 (108.0–312.5.0) vs. 92.0 (71.0–114.0), p<0.001). ADAMTS-13 antigen levels were also decreased in trauma patients both at 0 to 2 hours (0.84 (0.51–0.94) vs. 1.00 (0.89–1.09), p=0.010) and at 6 hours (0.653 (0.531–0.821) vs. 1.00 (0.89–1.09), p<0.001). Trauma patients had accelerated thrombin generation kinetics, with greater peak height and shorter time to peak than healthy volunteers at both time points.DiscussionTrauma patients have increased exposure of the VWF A1 domain and decreased levels of ADAMTS-13 compared with healthy volunteers. This suggests that the VWF burst after trauma may exceed the proteolytic capacity of ADAMTS-13, allowing circulating ULVWF multimers to bind platelets, potentially contributing to trauma-induced coagulopathy.Level of evidenceProspective case cohort study.

scholarly journals The role of von Willebrand factor in breast cancer metastasis

2021 ◽  
Vol 14 (4) ◽  
pp. 101033
Author(s):  
Chia Yin Goh ◽  
Sean Patmore ◽  
Albert Smolenski ◽  
Jane Howard ◽  
Shane Evans ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Von Willebrand Factor ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Von Willebrand ◽  
Willebrand Factor

Role of Platelet Membrane Glycoproteins and Von Willebrand Factor in Adhesion of Platelets to Subendothelium and Collagen

1987 ◽  
Vol 516 (1 Blood in Cont) ◽  
pp. 52-65 ◽  
Author(s):  
KJELL S. SAKARIASSEN ◽  
EDITH FRESSINAUD ◽  
JEAN-PIERRE GIRMA ◽  
DOMINIQUE MEYER ◽  
HANS R. BAUMGARTNER
Keyword(s):  
Von Willebrand Factor ◽  
Platelet Membrane ◽  
Membrane Glycoproteins ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Adhesion Of Platelets
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