Genetic determinants of von Willebrand factor plasma levels and the risk of stroke: the Rotterdam Study

Schie, Marianne C. van; Wieberdink, Renske G.; Koudstaal, Peter J.; Hofman, Albert; Ikram, M. Arfan; Witteman, Jacqueline C. M.; Breteler, Monique M.B.; Leebeek, Frank W.G.; Maat, Moniek P.M. de

doi:10.1111/j.1538-7836.2012.04634.x

Cited by 19 publications

(20 citation statements)

References 35 publications

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“…Table shows the MAFs of the SNPs in VWD patients. Among type 1 VWD patients, the MAF of rs687621 ( ABO ) was 19%, which is lower than that previously reported (34%) in white Caucasian subjects (CHARGE consortium) and in the Dutch population ( P < 0.001). This reflects the higher prevalence of blood group O in our study population, as this SNP reflects the O allele.…”

Section: Resultscontrasting

confidence: 72%

CLEC4M and STXBP5 gene variations contribute to von Willebrand factor level variation in von Willebrand disease

Sanders

Bom

Isaacs

et al. 2015

Journal of Thrombosis and Haemostasis

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To cite this article: Sanders YV, van der Bom JG, Isaacs A, Cnossen MH, de Maat MPM, Laros-van Gorkom BAP, Fijnvandraat K, Meijer K, 95% CI À7.9 to À0.6) and lower VWF:Act (À5.7 IU dL À1 per allele; 95% CI À10.9 to À0.5). In type 2 patients, none of the SNPs was associated with VWF levels. None of the genetic variants was associated with bleeding score. Conclusions: Genetic variations in STXBP5 and CLEC4M are associated with VWF level variation in type 1 VWD, but not in type 2 VWD. This study increases our understanding of the pathophysiology of VWD, and provides a further indication of the involvement of STXBP5 and CLEC4M in determining VWF levels in VWD.

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Section: Resultscontrasting

confidence: 72%

CLEC4M and STXBP5 gene variations contribute to von Willebrand factor level variation in von Willebrand disease

Sanders

Bom

Isaacs

et al. 2015

Journal of Thrombosis and Haemostasis

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“…The increase in VWF observed in our assay may mirror the in vivo effects seen in some of APS patients as they tend to have elevated levels of total and active VWF . Elevations of VWF in turn can lead to thrombotic events . Interestingly, the variation of VWF release induced by anti‐β2GPI antibodies from different patients suggests that elevations of VWF are not the sole driver of the prothrombotic state of APS and is consistent with the “multi‐factorial” activation hypothesis of APS.…”

Section: Discussionsupporting

confidence: 73%

Effects of anti‐β2GPI antibodies on VWF release from human umbilical vein endothelial cells and ADAMTS13 activity

McCrae

Ashworth

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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Essentials The antiphospholipid syndrome predisposes to thrombosis due to activation of endothelium and blood components.The role of anti‐β2GPI antibodies in VWF release and ADAMTS13 function is not well understood.Some anti‐β2GPI antibodies induce endothelial release of soluble VWF but not VWF strings.An anti‐β2GPI antibody can decrease ADAMTS13 activity in vitro similar to ex vivo results. BackgroundAntiphospholipid syndrome (APS) is characterized by recurrent thromboembolic events in the setting of pathologic autoantibodies, some of which are directed to β2‐Glycoprotein 1 (β2GPI). The mechanisms of thrombosis in APS appear to be multifactorial and likely include a component of endothelial activation. Among other things, activated endothelium secretes von Willebrand factor, a hemostatic protein that in excess can increase the risk of thrombosis.ObjectiveWe hypothesized that anti‐β2GPI antibodies could regulate the release and modulation of VWF from endothelial cells.Patients/MethodsIsolated anti‐β2GPI antibodies from patients with APS were assayed for their ability to induced VWF release from HUVECs and modulate the effects of ADAMTS13 in a shear‐dependent assay.ResultsWe observed that anti‐β2GPI antibodies from some patients with APS induced VWF release from human endothelial cells but did not induce formation of cell‐anchored VWF‐platelet strings. Finally, we also determined that one of the Anti‐β2GPI antibodies tested can inhibit the function of ADAMTS13, the main modulator of extracellular VWF.ConclusionsThese results suggest that VWF and ADAMTS13 may play a role in the prothrombotic phenotype of APS.

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“…In addition, basic biophysical principles indicate that the higher the molecular size of the VWF, the higher is the sensitivity to shear stress [33]. Several studies have provided compelling evidence of the relevance of VWF levels in the pathogenesis of macrovascular thrombosis, especially in the brain circulation [34]–[36]. The findings of the present study emphasize also the relevance of the multimeric structure and especially of the oxidation status of VWF multimers for their pro-thrombotic effects.…”

Section: Discussionsupporting

confidence: 63%

The Oxidative Modification of Von Willebrand Factor Is Associated with Thrombotic Angiopathies in Diabetes Mellitus

et al. 2013

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The thrombogenic activity of Von Willebrand factor (VWF) is proportional to its molecular size and inversely related to its proteolysis by ADAMTS-13. Oxidation of VWF severely impairs its proteolysis by the metalloprotease. This study was aimed at assessing in patients with type 1 and type 2 diabetes whether protein carbonyls, marker of oxidative stress, are associated with both the level and oxidation status of VWF as well as with micro- and macroangiopathic complications. Eighty-three diabetic patients (41 type 1 and 42 type 2 diabetic subjects) and their respective eighty-three healthy controls were studied after verifying the availability, through institutional databases, of clinical biochemistry records spanning at least 3 years. VWF and protein carbonyls were measured by immunoassays, whereas VWF multimers were studied by SDS-agarose gel electrophoresis. Type 2 diabetic subjects had higher levels of VWF antigen (VWF:ag), VWF activity (VWF:act) and plasma proteins’ carbonyls compared to both their controls and type 1 diabetic subjects. Moreover, high molecular weight VWF multimers and specific VWF-bound carbonyls were significantly increased in subjects with micro- and macro-angiopathic complications. In both type 1 and type 2 diabetic subjects, ADAMTS-13 activity was in the normal range. In a multivariable analysis, only VWF-bound carbonyls were significantly associated with any form of thrombotic angiopathy in the entire group of T1- and T2 diabetic patients. These data provide first evidence that not only high VWF levels but also its oxidation status and the presence of high molecular weight VWF multimers that are not observed in SDS-agarose gel electrophoresis of normal subjects are associated with thrombotic angiopathies in diabetes mellitus. These findings may help identify diabetic patients particularly at risk for these complications and elucidate a new pathophysiological mechanism of thrombotic angiopathies in this clinical setting.

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Genetic determinants of von Willebrand factor plasma levels and the risk of stroke: the Rotterdam Study

Cited by 19 publications

References 35 publications

CLEC4M and STXBP5 gene variations contribute to von Willebrand factor level variation in von Willebrand disease

CLEC4M and STXBP5 gene variations contribute to von Willebrand factor level variation in von Willebrand disease

Effects of anti‐β2GPI antibodies on VWF release from human umbilical vein endothelial cells and ADAMTS13 activity

The Oxidative Modification of Von Willebrand Factor Is Associated with Thrombotic Angiopathies in Diabetes Mellitus

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