scholarly journals Activated αIIbβ3 on platelets mediates flow-dependent NETosis via SLC44A2

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Adela Constantinescu-Bercu ◽  
Luigi Grassi ◽  
Mattia Frontini ◽  
Isabelle I Salles-Crawley ◽  
Kevin Woollard ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Extracellular Loop ◽  
Cell Binding ◽  
Vein Thrombosis ◽  
Extracellular Traps ◽  
Von Willebrand ◽  
Deep Vein ◽  
Willebrand Factor ◽  
Insight Into ◽  
Impaired Binding

Platelet-neutrophil interactions are important for innate immunity, but also contribute to the pathogenesis of deep vein thrombosis, myocardial infarction and stroke. Here we report that, under flow, von Willebrand factor/glycoprotein Ibα-dependent platelet ‘priming’ induces integrin αIIbβ3 activation that, in turn, mediates neutrophil and T-cell binding. Binding of platelet αIIbβ3 to SLC44A2 on neutrophils leads to mechanosensitive-dependent production of highly prothrombotic neutrophil extracellular traps. A polymorphism in SLC44A2 (rs2288904-A) present in 22% of the population causes an R154Q substitution in an extracellular loop of SLC44A2 that is protective against venous thrombosis results in severely impaired binding to both activated αIIbβ3 and VWF-primed platelets. This was confirmed using neutrophils homozygous for the SLC44A2 R154Q polymorphism. Taken together, these data reveal a previously unreported mode of platelet-neutrophil crosstalk, mechanosensitive NET production, and provide mechanistic insight into the protective effect of the SLC44A2 rs2288904-A polymorphism in venous thrombosis.

scholarly journals Activated αIIbβ3 on platelets mediates flow-dependent NETosis via SLC44A2

2018 ◽  
Author(s):  
Adela Constantinescu-Bercu ◽  
Luigi Grassi ◽  
Mattia Frontini ◽  
Isabelle I. Salles-Crawley ◽  
Kevin J Woollard ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Von Willebrand Factor ◽  
Neutrophil Extracellular Trap ◽  
Cell Binding ◽  
Vein Thrombosis ◽  
Von Willebrand ◽  
Deep Vein ◽  
Willebrand Factor ◽  
Insight Into ◽  
Impaired Binding

AbstractPlatelet-neutrophil interactions are important for innate immunity, but also contribute to the pathogenesis of deep vein thrombosis, myocardial infarction and stroke. Here we report that, under flow, von Willebrand factor/glycoprotein Ibα-dependent platelet ‘priming’ induces integrin αIIbβ3 activation that, in turn, mediates neutrophil and T-cell binding. Binding of platelet αIIbβ3 to SLC44A2 on neutrophils leads to mechanosensitive-dependent production of highly prothrombotic neutrophil extracellular traps. A polymorphism in SLC44A2 (rs2288904-A) present in 22% of the population causes an R154Q substitution in an extracellular loop of SLC44A2 that is protective against venous thrombosis results in severely impaired binding to both activated αIIbβ3 and VWF-primed platelets. This was confirmed using neutrophils homozygous for the SLC44A2 R154Q polymorphism. Taken together, these data reveal a previously unreported mode of platelet-neutrophil cross-talk, mechanosensitive NET production, and provide mechanistic insight into the protective effect of the SLC44A2 rs2288904-A polymorphism in venous thrombosis.SummaryPlatelets that are primed following interaction with von Willebrand factor under flow mediated direct interactions with neutrophils via activated platelet integrin, αIIbβ3, and SLC44A2 on neutrophils. This interaction initiates signaling in a mechanosensitive manner that promotes neutrophil extracellular trap formation.

von Willebrand Factor and Venous Thromboembolism: Pathogenic Link and Therapeutic Implications

2017 ◽  
Vol 44 (03) ◽  
pp. 249-260 ◽  
Author(s):  
Paolo Calabrò ◽  
Felice Gragnano ◽  
Enrica Golia ◽  
Erik Grove
Keyword(s):  
Venous Thromboembolism ◽  
Venous Thrombosis ◽  
Von Willebrand Factor ◽  
Gene Mutations ◽  
Selective Inhibition ◽  
Therapeutic Implications ◽  
Vein Thrombosis ◽  
A Disintegrin And Metalloproteinase ◽  
Von Willebrand ◽  
Willebrand Factor

AbstractVenous thromboembolism (VTE) is a frequent cause of disability and mortality worldwide. Von Willebrand factor (VWF) is a major determinant of hemostasis and clot formation, in both arteries and veins. Although VWF is mainly known for its role in arterial thrombosis, several studies suggest a pathogenic role for VWF and its regulator ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) in venous thrombosis. Nongenetic and genetic factors, including gene mutations and polymorphisms, aging, hormone status, ABO blood groups, and systemic inflammation, have been involved in the modulation of both VTE predisposition and plasma levels of VWF. In several clinical settings, including inflammatory disease and cancer, VWF and ADAMTS-13 are currently investigated as possible determinants of vein thrombosis. These data indicate VWF as a potential therapeutic target in the management of VTE. Several studies report unselective antagonism of VWF for drugs used in daily clinical practice, including heparin and statins. Selective inhibition of VWF pathway has recently been tested in animal models of arterial and venous thrombosis as a novel therapeutic strategy to prevent platelet aggregation and thrombosis, promote vein lumen recanalization, and improve vein valve competency with excellent safety profile. In this review, we summarize the role of VWF in VTE, focusing on clinical and potential therapeutic implications.

Synergic effect of GPIBA and von Willebrand factor in pathogenesis of deep vein thrombosis

Vascular ◽  
2020 ◽  
Vol 28 (3) ◽  
pp. 309-313
Author(s):  
Da Li ◽  
Xiaosong Zhang ◽  
Honggang Zhang ◽  
Xiaoqiang Li
Keyword(s):  
Cardiovascular Disease ◽  
Deep Vein Thrombosis ◽  
Membrane Protein ◽  
Von Willebrand Factor ◽  
Integrin Subunit ◽  
Dynamic Changes ◽  
Vein Thrombosis ◽  
Von Willebrand ◽  
Deep Vein ◽  
Willebrand Factor

Objectives In cardiovascular disease, deep vein thrombosis is one of the vital symptoms causing pulmonary thromboembolism. However, the pathogenesis of deep vein thrombosis is still not clear. One of the critical factors leading to deep vein thrombosis is the platelet aggregation that is mediated by a set of key genes including platelet membrane protein coded by platelet glycoprotein Ib alpha chain (GPIBA). Methods Deep vein thrombosis model was established according to the previous protocol, and venous blood and thrombi were collected for further analysis. Results The dynamic changes of GPIBA and coagulation factor, von Willebrand factor, were observed in deep vein thrombosis models. Meanwhile, critical proteins participating in adhesion and binding of platelets such as epithelial membrane protein 2 (EMP2), vascular cell adhesion protein 1 (VCAM1), immunoreceptor tyrosine-based activation motif 1 (ITAM1), integrin subunit alpha M (ITGAM), or fibronectin were also differentially expressed in deep vein thrombosis models. Conclusions Application of heparin could reverse these dynamic changes in deep vein thrombosis models. Thus, we explained the potential synergic role of GPIBA and von Willebrand factor in regulating the occurrence of deep vein thrombosis and provide therapeutic target against cardiovascular disease.

Abstract 522: Activated FXI Regulates the Catalytic Activity of Adamts13 by Removing the CUB Domains

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Cristina Puy ◽  
Kathleen S Garland ◽  
Toshiaki Shirai ◽  
Stephanie E. Reitsma ◽  
Jevgenia Zilberman-Rudenko ◽  
...  
Keyword(s):  
Thrombus Formation ◽  
Adamts13 Activity ◽  
Binding Interaction ◽  
Vein Thrombosis ◽  
Cub Domain ◽  
A Cell ◽  
Von Willebrand ◽  
Deep Vein ◽  
Willebrand Factor

Background: ADAMTS13 cleaves and inactivates von Willebrand factor (VWF), which binds collagen, facilitating platelet adhesion under vascular injury. But is still uncertain how ADAMTS13 activity is regulated. Thrombin and plasmin have been shown to cleave ADAMTS13. Based on the fact that elevated levels of FXI is an independent risk factor for deep vein thrombosis and ischemic stroke, we hypothesize that FXIa inactivates ADAMTS13 leading to platelet aggregation and thrombus formation. Aim: To determine the functional role of inactivation of ADAMTS13 by FXIa. Methods and Results: Recombinant ADAMTS13 (250 nM) was incubated with FXIa (50 nM) for increasing times (0-3 hours) at 37 o C before being analyzed by western blot using an anti-ADAMTS13 antibody against the two CUB domains (C-terminal) or against the metalloproteinase (MET) domain (N-terminal). Our results show that FXIa caused the disappearance of the ADAMTS13 band (~200 kDa) and the appearance of a band at ~150 kDa when the samples were analyzed with the anti-MET antibody and a ~50 kDa band when the samples were analyzed with the anti-CUB antibody. The presence of aprotinin, which inhibits FXIa activity, blocked the degradation of ADAMTS13. Kallikrein or FXIIa were unable to cleave ADAMTS13. Using a cell surface immunoassay we observed that after incubation with FXIa, the detection of the CUB domain from ADAMTS13 was lost from endothelial cells surface. The incubation of ADAMTS13 with FXIa caused an increase in ADAMTS13 activity as measured by a fluorogenic substrate (FRETS). Conclusion: ADAMTS13 circulates in a closed conformation, which is maintained by a CUB-spacer domain binding interaction. ADAMTS13 becomes conformationally activated through interaction of its CUBs domains with VWF. Here we show that FXIa-mediated deletion of ADAMTS13-CUB domains enhances its capacity to cleave FRETS and blocks the interaction with VWF. Our results suggest that FXIa may limit ADAMTS13-mediated VWF inactivation.

Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis

The Lancet ◽  
1995 ◽  
Vol 345 (8943) ◽  
pp. 152-155 ◽  
Author(s):  
T. Koster ◽  
J.P. Vandenbroucke ◽  
F.R. Rosendaal ◽  
E. Briët ◽  
F.R. Rosendaal ◽  
...  
Keyword(s):  
Deep Vein Thrombosis ◽  
Factor Viii ◽  
Von Willebrand Factor ◽  
Clotting Factor ◽  
Vein Thrombosis ◽  
Von Willebrand ◽  
Deep Vein ◽  
Willebrand Factor

scholarly journals von Willebrand factor–mediated platelet adhesion is critical for deep vein thrombosis in mouse models

Blood ◽  
2011 ◽  
Vol 117 (4) ◽  
pp. 1400-1407 ◽  
Author(s):  
Alexander Brill ◽  
Tobias A. Fuchs ◽  
Anil K. Chauhan ◽  
Janie J. Yang ◽  
Simon F. De Meyer ◽  
...  
Keyword(s):  
Deep Vein Thrombosis ◽  
Von Willebrand Factor ◽  
Platelet Adhesion ◽  
Wild Type ◽  
Flow Disturbance ◽  
Vein Thrombosis ◽  
Flow Restriction ◽  
Von Willebrand ◽  
Deep Vein ◽  
Willebrand Factor

Abstract Deep vein thrombosis (DVT) and its complication, pulmonary embolism, are frequent causes of disability and mortality. Although blood flow disturbance is considered an important triggering factor, the mechanism of DVT initiation remains elusive. Here we show that 48-hour flow restriction in the inferior vena cava (IVC) results in the development of thrombi structurally similar to human deep vein thrombi. von Willebrand factor (VWF)–deficient mice were protected from thrombosis induced by complete (stasis) or partial (stenosis) flow restriction in the IVC. Mice with half normal VWF levels were also protected in the stenosis model. Besides promoting platelet adhesion, VWF carries Factor VIII. Repeated infusions of recombinant Factor VIII did not rescue thrombosis in VWF−/− mice, indicating that impaired coagulation was not the primary reason for the absence of DVT in VWF−/− mice. Infusion of GPG-290, a mutant glycoprotein Ibα-immunoglobulin chimera that specifically inhibits interaction of the VWF A1 domain with platelets, prevented thrombosis in wild-type mice. Intravital microscopy showed that platelet and leukocyte recruitment in the early stages of DVT was dramatically higher in wild-type than in VWF−/− IVC. Our results demonstrate a pathogenetic role for VWF-platelet interaction in flow disturbance-induced venous thrombosis.

scholarly journals Von Willebrand Factor: Antigen and Adamts-13 Level, but not Soluble P-Selectin, are Risk Factors for the First Asymptomatic Deep Vein Thrombosis in Cancer Patients Undergoing Chemotherapy

2020 ◽  
Author(s):  
Budi Setiawan ◽  
Cecilia Oktaria Permatadewi ◽  
Baringin de Samakto ◽  
Ashar Bugis ◽  
Ridho M. Naibaho ◽  
...  
Keyword(s):  
Risk Factors ◽  
Logistic Regression ◽  
Deep Vein Thrombosis ◽  
Cancer Patients ◽  
Von Willebrand Factor ◽  
Plasma Levels ◽  
Vein Thrombosis ◽  
Von Willebrand ◽  
Deep Vein ◽  
Willebrand Factor

Abstract Background There is a high incidence of deep vein thrombosis (DVT) among cancer patients undergoing chemotherapy. Chemotherapy-induced vascular endothelial cell activation (VECA) is characterized by increased plasma levels of von Willebrand factor (vWF) and soluble P-selectin (sP-selectin), leading to the activation of endothelial cells and signaling cascades. The biological role of a disintegrin-like and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS-13) is to control the activity of vWF and consequently the risk of thrombosis. The objective of this study was to investigate the roles of sP-selectin, vWF, and ADAMTS-13 as risk factors for the first episode of DVT in cancer patients undergoing chemotherapy.Methods This prospective cohort study was conducted at Dr. Kariadi Hospital, Indonesia, on 40 cancer patients. Prechemotherapy (baseline) and postchemotherapy sP-selectin, vWF antigen (vWF:Ag), and ADAMTS-13 plasma levels were determined with ELISAs before and 3 months after chemotherapy. The clinical characteristics of the patients, cancer type, cancer stage, chemotherapy regimen, ABO blood type, D-dimer level and Khorana risk score were also analyzed using logistic regression. Patients were observed for the possibility of developing DVT during chemotherapy.Results DVT was confirmed in 5 patients (12.5%) after a period of 3 months. In patients with DVT, sP-selectin and vWF were significantly higher while ADAMTS-13 was lower than in their counterparts. The levels of baseline vWF:Ag and ADAMTS-13, with cut-off points ≥ 2.35 IU/mL and ≤ 1.03 IU/mL, respectively, were found to independently predict the incidence of DVT. In the multivariate logistic regression analysis, the relative risk (RR) for DVT in patients with high vWF:Ag was 3.80 (95% CI 1.15-12.48, p=0.028), and that for patients with low ADAMTS-13 was 2.67 (95% CI 1.22-23.82, p=0.005). The vWF:Ag/ADAMTS-13 ratio and both vWF:Ag and ADAMTS-13 dynamics during treatment were also able to differentiate those with prospective DVT. However, sP-selectin and other covariates showed no statistical significance.Conclusion We found that prechemotherapy plasma levels of vWF:Ag ≥ 2.35 IU/mL and ADAMTS-13 ≤ 1.03 IU/mL are independent risk factors for DVT incidence among cancer patients.

scholarly journals von Willebrand Factor Is a Critical Mediator of Deep Vein Thrombosis in a Mouse Model of Diet-Induced Obesity

2020 ◽  
Vol 40 (12) ◽  
pp. 2860-2874 ◽  
Author(s):  
Alison Michels ◽  
Courtney N. Dwyer ◽  
Jeffrey Mewburn ◽  
Kate Nesbitt ◽  
Charlotte Kawecki ◽  
...  
Keyword(s):  
Inferior Vena ◽  
Vena Cava ◽  
Obese Mice ◽  
Vein Thrombosis ◽  
Diet Induced Obesity ◽  
Von Willebrand ◽  
Deep Vein ◽  
Willebrand Factor ◽  
Vena Cava Stenosis

Objective: Obesity is characterized by chronic low-grade inflammation and consequentially a hypercoagulable state, associating with an increased incidence of venous thromboembolism. Increased VWF (von Willebrand factor) plasma concentration and procoagulant function are independent risk factors for venous thromboembolism and are elevated in obese patients. Here, we explore the pathobiological role of VWF in obesity-associated venous thrombosis using murine models. Approach and Results: We first showed that diet-induced obese mice have increased VWF plasma levels and FVIII (factor VIII) activity compared with littermate controls. Elevated VWF levels appeared to be because of both increased synthesis and impaired clearance. Diet-induced obesity-associated venous thrombosis was assessed using the inferior vena cava-stenosis model of deep vein thrombosis. Diet-induced obese mice developed larger venous thrombi that were rich in VWF, erythrocytes, and leukocytes. Administering a polyclonal anti-VWF antibody or an anti-VWF A1 domain nanobody was protective against obesity-mediated thrombogenicity. Delayed administration (3 hours post–inferior vena cava stenosis) similarly reduced thrombus weight in diet-induced obese mice. Conclusions: This study demonstrates the critical role of VWF in the complex, thrombo-inflammatory state of obesity. It adds to the growing rationale for targeting VWF-specific interactions in thrombotic disease.

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