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.

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.

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: 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 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.

scholarly journals Soluble P-Selectin, Von Willebrand Factor, And Adamts13 Levels As Risk Factors Of Deep Vein Thrombosis In Cancer Patients Undergoing Chemotherapy

2020 ◽  
Author(s):  
Budi Setiawan ◽  
Cecilia Oktaria Permatadewi ◽  
Baringin de Samakto ◽  
Ashar Bugis ◽  
Eko Adhi Pangarsa ◽  
...  
Keyword(s):  
Risk Factors ◽  
Deep Vein Thrombosis ◽  
Cancer Patients ◽  
Plasma Levels ◽  
Vein Thrombosis ◽  
Soluble P ◽  
Von Willebrand ◽  
Deep Vein ◽  
Willebrand Factor

Abstract Background There is a high number of deep vein thrombosis (DVT) incidence among cancer patients undergoing chemotherapy. Chemotherapy-induced vascular endothelial cell activation (VECA) is marked with increasing plasma levels of von Willebrand Factor (VWF) and soluble P-selectin (sP-selectin) leading to activation of endothelial cells and coagulation cascade. The biological role of a disintegrin-like and metalloproteinase with thrombospondin type 1, motif 13 (ADAMTS13) is to control the activity of VWF. The objectives of this study is to investigate the role of sP-selectin, VWF, and ADAMTS13 as risk factors for the incidence of DVT in cancer patients undergoing chemotherapy. Methods This prospective cohort study was conducted in Dr. Kariadi hospital, Semarang Indonesia, on 40 cancer patients. Soluble P-selectin, VWF, and ADAMS13 plasma levels were determined with enzyme-linked immunosorbent assay (ELISA) method, examined before and after chemotherapy. These patients were observed for the possibility of developing DVT during three months. Results Deep vein thrombosis was confirmed in 5 patients (12.5%) after a median period of 8 weeks. In patients with DVT, sP-selectin and VWF were significantly higher, while ADAMTS13 were significantly lower compared in cancer patients without DVT. Pre- and post-chemotherapy concentration of sP selectin, VWF, and ADAMTS13 could effectively predict the incidence of DVT in cancer patients undergoing chemotherapy. The levels of sP-selectin, VWF and ADAMTS13 pre-chemotherapy with cut-off point >106.7 ng/mL, >2.99 U/mL and <0,80 U/mL, respectively, had relative risk (RR) for DVT incidence being 16 (95% CI 2,06-124,25, p=0,001); 36 (95% CI 5,21-248,65, p=0,000) and 10,5 (95% CI 1,31-84,28, p=0,015), respectively, whereas the levels of sP-selectin, VWF and ADAMTS13 post-chemotherapy with cut-off point >111.7 ng/mL, >3,06 U/mL and <0,49 U/mL, respectively, had RR for DVT incidence being 8.7 (95% CI 1,01-74,39, p=0,045); 20,4 (95% CI 2,60-159,94, p=0,004) and 26,25 (95% CI 3,50-196,48, p=0,002), respectively. Pre-chemotherapy vWF levels (cut-off value >2.99 U/mL) was found to be independently predict DVT incidence with RR 11.1 (95% CI, 1.95-62.74, p=0.007). Conclusions Plasma levels of VWF more than 2.99 U/mL pre-chemotherapy was an independent risk factor for DVT incidence, which could be performed early and helpful for thromboprophylaxis therapy.

Asialo von Willebrand Factor Enhances Platelet Adhesion to Vessel Subendothelium

1988 ◽  
Vol 60 (01) ◽  
pp. 030-034 ◽  
Author(s):  
Eva Bastida ◽  
Juan Monteagudo ◽  
Antonio Ordinas ◽  
Luigi De Marco ◽  
Ricardo Castillo
Keyword(s):  
Von Willebrand Factor ◽  
Platelet Adhesion ◽  
Human Albumin ◽  
Membrane Receptors ◽  
Shear Rates ◽  
High Shear Rates ◽  
Platelet Deposition ◽  
Platelet Spreading ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryNative von Willebrand factor (N-vWF) binds to platelets activated by thrombin, ADP or ristocetin. Asialo vWF (As-vWF) induces platelet aggregation in absence of platelet activators. N-vWF mediates platelet adhesion to vessel subendothelium at high shear rates. We have investigated the role of As-vWF in supporting platelet deposition to rabbit vessel subendothelium at a shear rate of 2,000 sec-1, using the Baumgartner perfusion system. We have studied the effects of the addition of As-vWF (from 2 to 12 μg/ml) to perfusates consisting of washed red blood cells, 4% human albumin and washed platelets. Our results show a significant increase in platelet deposition on subendothelium (p <0.01) in perfusions to which As-vWF had been added. Blockage of the platelet glycoproteins Ib and IIb/IIIa (GPIb and GPIIb/IIIa) by specific monoclonal antibodies (LJIb1 and LJCP8, respectively) resulted in a decrease of platelet deposition in both types of perfusates prepared with N-vWF and As-vWF. Our results indicate that As-vWF enhances platelet deposition to vessel subendothelium under flow conditions. Furthermore, they suggest that this effect is mediated by the binding of As-vWF to platelet membrane receptors, which in turn, promote platelet spreading and adhesion to the subendothelium.

Interventional Thermal Injury of the Arterial Wall: Unfolding of von Willebrand Factor and Its Increased Binding to Collagen after 55° C Heating

1996 ◽  
Vol 75 (03) ◽  
pp. 515-519 ◽  
Author(s):  
Mark J Post ◽  
Anke N de Graaf-Bos ◽  
George Posthuma ◽  
Philip G de Groot ◽  
Jan J Sixma ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Conformational Changes ◽  
Arterial Wall ◽  
Platelet Adhesion ◽  
Type I ◽  
Temperature Dependent ◽  
Collagen Types ◽  
Electron Microscopic ◽  
Von Willebrand ◽  
Willebrand Factor

Summary Purpose. Thermal angioplasty alters the thrombogenicity of the arterial wall. In previous studies, platelet adhesion was found to increase after heating human subendothelium to 55° C and decrease after heating to 90° C. In the present electron microscopic study, the mechanism of this temperature-dependent platelet adhesion to the heated arterial wall is elucidated by investigating temperature-dependent conformational changes of von Willebrand factor (vWF) and collagen types I and III and the binding of vWF to heated collagen. Methods. Purified vWF and/or collagen was applied to electron microscopic grids and heated by floating on a salt-solution of 37° C, 55° C or 90° C for 15 s. After incubation with a polyclonal antibody against vWF and incubation with protein A/gold, the grids were examined by electron microscopy. Results. At 37° C, vWF was coiled. At 55° C, vWF unfolded, whereas heating at 90° C caused a reduction in antigenicity. Collagen fibers heated to 37° C were 60.3 ± 3.1 nm wide. Heating to 55° C resulted in the unwinding of the fibers, increasing the width to 87.5 ± 8.2 nm (p < 0.01). Heating to 90° C resulted in denatured fibers with an enlarged width of 85.1 ± 6.1 nm (p < 0.05). Heating of collagen to 55° C resulted in an increased vWF binding as compared to collagen heated to 37° C or to 90° C. Incubation of collagen with vWF, prior to heating, resulted in a vWF binding after heating to 55° C that was similar to the 37° C binding and a decreased binding after 90° C. Conclusions. After 55° C heating, the von Willebrand factor molecule unfolds and collagen types I and III exhibit an increased adhesiveness for von Willebrand factor. Heating to 90° C denatures von Willebrand factor and collagen. The conformation changes of von Willebrand factor and its altered binding to collagen type I and III may explain the increased and decreased platelet adhesion to subendothelium after 55° C and 90° C heating, respectively.

Levels of von Willebrand factor and ADAMTS13 determine clinical outcome after cardioversion for atrial fibrillation

2011 ◽  
Vol 105 (03) ◽  
pp. 435-443 ◽  
Author(s):  
Veronika Bruno ◽  
Rudolf Jarai ◽  
Susanne Gruber ◽  
Thomas Höchtl ◽  
Ivan Brozovic ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Von Willebrand Factor ◽  
Platelet Adhesion ◽  
Independent Predictor ◽  
Thrombus Formation ◽  
Critical Role ◽  
Inverse Correlation ◽  
Von Willebrand ◽  
Rhythm Stability ◽  
Willebrand Factor

SummaryVon Willebrand factor (vWF) plays an essential role in platelet adhesion and thrombus formation. Patients with atrial fibrillation (AF) exhibit higher plasma vWF and lower ADAMTS13 antigen levels compared to controls. Little is known about vWF and ADAMTS13 in AF patients treated with cardioversion (CV). Thus we investigated the alterations of plasma vWF and ADAMTS13 after CV and evaluated the predictive value of these parameters for recurrence of AF. In this observational study we determined plasma levels of vWF and ADAMTS13 in 77 patients before and immediately after CV, as well as 24 hours (h) and six weeks thereafter, by means of commercially available assays. The vWF/ ADAMTS13-ratio was significantly elevated immediately after CV (p=0.02) and 24 h after CV (p=0.002) as compared to baseline levels. ADAMTS13, 24 h after CV, exhibited a significant association with recurrence of AF (HR: 0.97; p=0.037). Accordingly, tertiles of ADAMTS13 showed a stepwise inverse correlation with the risk of recurrent AF (HR: 0.50; p=0.009). After adjustment for confounders, ADAMTS13 remained significant as an independent predictor of recurrent AF (HR: 0.61; p=0.047). Similarly, the vWF/ADAMTS13-ratio, 24 h after CV, was associated with rhythm stability and remained an independent predictor of recurrent AF (HR: 1.88; p=0.028). The regulation of vWF and its cleaving protease ADAMTS13 after CV might play a critical role in producing a pro-thrombotic milieu immediately after CV for AF. Since ADAMTS13 plasma concentration and the vWF/ADAMTS13-ratio are independently associated with rhythm stability, these indexes might be used for prediction of recurrence of AF.

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