The von Willebrand factor Tyr2561 allele is a gain-of-function variant and a risk factor for early myocardial infarction

Abstract

The frequent von Willebrand factor (VWF) variant p.Phe2561Tyr is located within the C4 domain, which also harbors the platelet GPIIb/IIIa-binding RGD sequence. To investigate its potential effect on hemostasis, we genotyped 865 patients with coronary artery disease (CAD), 915 with myocardial infarction (MI), and 417 control patients (Ludwigshafen Risk and Cardiovascular Health Study) and performed functional studies of this variant. A univariate analysis of male and female carriers of the Tyr2561 allele aged 55 years or younger revealed an elevated risk for repeated MI (odds ratio, 2.53; 95% confidence interval [CI], 1.07-5.98). The odds ratio was even higher in females aged 55 years or younger, at a value of 5.93 (95% CI, 1.12-31.24). Cone and plate aggregometry showed that compared with Phe2561, Tyr2561 was associated with increased platelet aggregate size both in probands’ blood and with the recombinant variants. Microfluidic assays revealed that the critical shear rate for inducing aggregate formation was decreased to 50% by Tyr2561 compared with Phe2561. Differences in C-domain circular dichroism spectra resulting from Tyr2561 suggest an increased shear sensitivity of VWF as a result of altered association of the C domains that disrupts the normal dimer interface. In summary, our data emphasize the functional effect of the VWF C4 domain for VWF-mediated platelet aggregation in a shear-dependent manner and provide the first evidence that a functional variant of VWF plays a role in arterial thromboembolism.

DNA binds to a specific site of the adhesive blood-protein von Willebrand factor guided by electrostatic interactions

“…Nevertheless, they could be detected when aggregate motion tracking of images was implemented. This visualization approach, consisting of the superposition of several images of different times, has been proven successful in visualizing rolling vWF-based conglomerates ( 31 , 85 ).…”

Domain-specific mechanical modulation of VWF–ADAMTS13 interaction

“…Hemodynamic forces in the circulation stretch ULVWF or immobilized VWF to a more extended configuration to enhance platelet binding, which may induce thrombosis formation (Schneppenheim et al , 2019), and to expose the cryptic proteolytic site in the A2 domain for cleavage by ADAMTS13 (Furlan et al , 1996; Tsai, 1996; Zhang et al , 2009; Wu et al , 2010), which may reduce VWF activity. Here we further demonstrated that mechanical forces modulate VWF–ADAMTS13 interaction when the enzyme and the substrate come into rapid, repetitive, but brief contacts, which is likely to occur in flowing blood.…”

Impact of Von Willebrand Factor on Bacterial Pathogenesis

“…As further explanation, functional variants of VWF have been identified, which elicit differences in the protein conformation and shear sensitivity. These variants are associated with increased platelet aggregate size and the occurrence of these VWF variants correlates with a higher risk of thromboembolisms including myocardial infarction and stroke (82). In line with these observations, it can be assumed that bacterial interaction with VWF might effect the hemostatic function in various ways, i.e., by sterical hindrance of the platelet binding site, by alteration of the VWF conformation, and by inhibition of dimerization and multimerization activities, thereby increasing the risk for cardiovascular complications.…”