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.

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.

Combined effects of plasma von Willebrand factor and platelet measures on the risk of incident venous thromboembolism

Blood ◽  
2021 ◽  
Author(s):  
Magnus Sandvik Edvardsen ◽  
Ellen-Sofie Hansen ◽  
Kristian Hindberg ◽  
Vânia Maris Morelli ◽  
Thor Ueland ◽  
...  
Keyword(s):  
Platelet Count ◽  
Venous Thromboembolism ◽  
Von Willebrand Factor ◽  
Platelet Reactivity ◽  
High Plasma ◽  
Combined Effects ◽  
Exposure Group ◽  
Increased Risk ◽  
Von Willebrand ◽  
Willebrand Factor

Plasma von Willebrand factor (VWF) and platelet reactivity are both risk factors for venous thromboembolism (VTE), and VWF can promote hemostasis by interaction with platelets. In this study, we explored the combined effects of plasma VWF and platelet measures on the risk of incident VTE. A population-based nested case-control study with 403 cases and 816 controls was derived from the Tromsø Study. VWF, platelet count and mean platelet volume (MPV) were measured in blood samples drawn at baseline. Odds ratios (ORs) with 95% confidence intervals (CIs) for VTE were estimated across VWF tertiles, within predefined MPV (<8.5, 8.5-9.5, ≥9.5 fL) and platelet count (<230, 230-299, ≥300·109 L-1) strata. Here, participants with VWF levels in the highest tertile and MPV ≥9.5 fL had an OR of 1.98 (95% CI 1.17-3.36) for VTE compared with those in the lowest VWF tertile and with MPV <8.5 fL in the age- and sex-adjusted model. In the joint exposure group, 48% (95% CI 15% to 96%) of VTEs were attributable to the biological interaction between VWF and MPV. Similarly, individuals with VWF in the highest tertile and platelet count ≥300·109 L-1 had an OR of 2.91 (95% CI 1.49-5.67) compared with those with VWF in the lowest tertile and platelet count <230, and 39% (95% CI -2% to 97%) of VTEs in the joint exposure group were explained by the interaction. Our results suggest that both platelet reactivity and platelet count interact biologically with high plasma VWF, resulting in an increased risk of incident VTE.

scholarly journals Insights Into Immunothrombosis: The Interplay Among Neutrophil Extracellular Trap, von Willebrand Factor, and ADAMTS13

2020 ◽  
Vol 11 ◽  
Author(s):  
Junxian Yang ◽  
Zhiwei Wu ◽  
Quan Long ◽  
Jiaqi Huang ◽  
Tiantian Hong ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Therapeutic Strategy ◽  
Endothelial Activation ◽  
Endothelial Damage ◽  
Neutrophil Extracellular Trap ◽  
Activated Neutrophils ◽  
A Disintegrin And Metalloproteinase ◽  
Von Willebrand ◽  
Willebrand Factor

Both neutrophil extracellular traps (NETs) and von Willebrand factor (VWF) are essential for thrombosis and inflammation. During these processes, a complex series of events, including endothelial activation, NET formation, VWF secretion, and blood cell adhesion, aggregation and activation, occurs in an ordered manner in the vasculature. The adhesive activity of VWF multimers is regulated by a specific metalloprotease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13). Increasing evidence indicates that the interaction between NETs and VWF contributes to arterial and venous thrombosis as well as inflammation. Furthermore, contents released from activated neutrophils or NETs induce the reduction of ADAMTS13 activity, which may occur in both thrombotic microangiopathies (TMAs) and acute ischemic stroke (AIS). Recently, NET is considered as a driver of endothelial damage and immunothrombosis in COVID-19. In addition, the levels of VWF and ADAMTS13 can predict the mortality of COVID-19. In this review, we summarize the biological characteristics and interactions of NETs, VWF, and ADAMTS13, and discuss their roles in TMAs, AIS, and COVID-19. Targeting the NET-VWF axis may be a novel therapeutic strategy for inflammation-associated TMAs, AIS, and COVID-19.

scholarly journals Cerebral Sinus and Venous Thrombosis Associated with von Willebrand Factor, Independently of Factor VIII

2008 ◽  
Vol 1 ◽  
pp. CCRep.S737
Author(s):  
Mari Terashima ◽  
Hiroshi Kataoka ◽  
Hirosei Horikawa ◽  
Hiroyuki Nakagawa ◽  
Toshiaki Taoka ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Factor Viii ◽  
Von Willebrand Factor ◽  
Transluminal Angioplasty ◽  
Right Hand ◽  
Increased Risk ◽  
Cerebral Sinus ◽  
The Right ◽  
Von Willebrand ◽  
Willebrand Factor

Background and purpose Previous studies have linked procoagulant factor VIII (F VIII) to an increased risk of venous thrombosis, whereas the relation between plasma von Willebrand factor (VWF) and venous thrombosis remains poorly understood. Elevated VWF levels are frequently found in patients with cerebral sinus and venous thrombosis (CSVT), always in association with high F VIII levels. We describe a patient with CSVT accompanied by elevated VWF levels without high F VIII levels. Case description A 23-year-old healthy man who had headache noticed difficulty in moving the right hand. On the following day, he lost consciousness and had partial seizures of the right hand. After regaining consciousness, weakness of the right extremities developed. The cranial angiogram confirmed occlusion of the superior sagittal sinus. The levels of VWF and F VIII were 238% and 101.9 IU/dl, respectively. We performed balloon percutaneous transluminal angioplasty and mechanical thrombectomy, leading to successful recanalization of the intracranial sinuses. VWF levels were decreased along with radiographic improvement, independently of F VIII. Conclusion VWF may contribute to CSVT and that inhibition of VWF activity potentially has a role in the future treatment of pathological conditions related to venous thrombosis.

The Role Of High Von Willebrand Factor and Low ADAMTS13 Levels In The Risk Of Venous Thromboembolism

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1128-1128 ◽  
Author(s):  
Christiane Pereira Gouvea ◽  
Sandra Satiko Matsuda ◽  
Rodrigo Vaez ◽  
Patrícia Nunes Bezerra Pinheiro ◽  
Maria Aparecida Eiko Noguti ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Von Willebrand Factor ◽  
Control Group ◽  
Exclusion Criteria ◽  
Reference Category ◽  
Gender And Age ◽  
History Of ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Background Venous thromboembolism (VTE) is a common multicausal disease in the general population. von Willebrand factor (VWF) has been associated with VTE in epidemiological studies and recently VWF-mediated platelet adhesion has been shown to be critical for deep vein thrombosis (DVT) in mouse models. The large VWF multimers are cleaved by ADAMTS13 into smaller, less active multimers. Because of the key role of ADAMTS13, VWF and factor VIII (FVIII) in hemostasis and their close biological relationship, we aimed at investigating in the same population the effect of these proteins on VTE risk. Materials and Methods We included consecutive patients admitted to our anticoagulation clinic with a first objectively confirmed VTE event between January 2007 and July 2011. The study included only patients with DVT of the lower limbs and/or pulmonary embolism aged between 18-70 years, and without medical history of overt malignancy, arterial thrombosis, liver cirrhosis, renal failure on hemodialysis, connective tissue disease and other conditions characterized by chronic inflammation. Blood was collected at least 1 month after stopping anticoagulation and ≥ 6 months after VTE. Controls were recruited from friends or partners of patients, had no personal history of VTE and were matched to patients by gender and age. The other exclusion criteria for controls were the same as for patients, and in both groups pregnant or postpartum women at blood collection were excluded. ADAMTS13 and VWF antigens were determined by commercial ELISA and FVIII activity was measured using FVIII deficient plasma. High VWF (>150%) and FVIII (>150%) were defined by plasma levels of these proteins exceeding the 88th and 94th percentiles of the control group, respectively. To define low ADAMTS13 levels we used the 10th percentile of the controls (≤0.64 μg/ml). Odds ratios (OR) and 95% confidence intervals (CI) were presented adjusted for gender and age and medians with interquartile variation (25th-75th percentiles). Results 358 patients with a first objectively confirmed VTE event were admitted to our clinic, of whom 282 did not participate in the study due to the exclusion criteria (n= 249) and loss of follow-up or refusal (n= 33). Therefore, we included 76 patients (53 women, 70%) with a median age of 43 years (33-55 years) and 96 controls (66 women, 69%), with a median age of 42 years (31-52 years). In controls, there was a negative albeit weak correlation between ADAMTS13 levels and VWF (rs= -0.213 by Spearman coefficient, p= 0.037) and FVIII (rs= -0.251, p= 0.014). As expected, VTE was associated with high levels of VWF (OR 2.80, 95% CI 1.20-6.54) and FVIII (OR 3.02, 95% CI 1.08-8.43). Low ADAMTS13 levels were detected in 12 patients and 9 controls (OR 1.76, 95% CI 0.70-4.46). The population was dichotomized according to the 88th percentile of VWF of the controls. Median ADAMTS13 was lower in the group with VWF >p88 compared to the group with VWF ≤p88 in controls (0.80μg/ml, 0.63-0.94μg/ml vs. 0.98μg/ml, 0.81-1.23μg/ml, p= 0.051) and in patients (0.75μg/ml, 0.53-0.95μg/ml vs. 0.95μg/ml, 0.81-1.14μg/ml, p= 0.001). Next the population was categorized into subjects with VWF ≤p88 and ADAMTS13 >p10 (reference category: 52 patients, 79 controls), VWF ≤p88 and ADAMTS13 ≤p10 (4 patients, 6 controls), VWF >p88 and ADAMTS13 >p10 (12 patients, 8 controls) and VWF >p88 and ADAMTS13 ≤p10 (8 patients, 3 controls). The combination of high VWF and low ADAMTS13 increased VTE risk when compared to the reference category (OR 4.14; 95% CI 1.03-16.71). The risk did not substantially change with adjustment for acute phase proteins and ABO group, and it was attenuated when further adjusted for high FVIII (OR 3.41, 95% CI 0.80-14.70). No correlation was found between the time since the VTE event and levels of VWF, FVIII and ADAMTS13 (p>0.05). Conclusions our data suggest a potential effect of high VWF and low ADAMTS13 on VTE risk. An unbalance between these two interconnected proteins might have a role in the pathophysiology of VTE. Results should be interpreted with caution due to the wide 95% CI and to the attenuation of VTE risk with further adjustment for FVIII. In order to better explain our results studies with larger sample size are warranted. Disclosures: No relevant conflicts of interest to declare.

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