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Prothrombotic Gain-of-Function Variants of von Willebrand Factor

1University Medical Center Hamburg-Eppendorf, Department of Dermatology and Venerology, Hamburg, Germany, 2Mayo Clinic Rochester, Division of Hematology, Rochester, United States, 3University Medical Center Hamburg-Eppendorf, Department of Pediatric Hematology and Oncology, Hamburg, Germany, 4INSERM, Univ. Paris-Sud, HITh, UMR_S1176, Le Kremlin-Bicêtre Cedex, France

Abstract Number: PB1584

Meeting: ISTH 2020 Congress

Theme: Platelet Disorders and von Willebrand Disease » VWF and von Willebrand Factor Disorders - Clinical Conditions

Background: Von Willebrand factor (VWF) is essential to primary hemostasis by mediating platelet recruitment to sites of vascular injury. A wide range of genetic VWF variants were identified leading to the bleeding disorder von Willebrand Disease (VWD). In contrast, high levels of plasmatic wildtype VWF have been shown to be associated with prothrombotic events and we recently identified the frequent polymorphism p.Phe2561Tyr as a VWF gain-of-function variant, which can increase the risk of myocardial infarction.

Aims: We identified a second VWF variant that directly enhances VWF’s hemostatic activity and strived to characterize the underlying gain-of-function effect.

Methods: The variant with a missense mutation in the C4 domain (harboring the platelet GPIIb/IIIa binding site) was functionally and structurally analyzed. GPIIb/IIIa binding was investigated in the full-length multimeric protein by static assays as well as under flow conditions. To assess the impact of the mutation on the secondary and tertiary structure of the monomeric single C4-domain and the dimeric domain construct C1-CTCK, far and near UV circular dichroism (CD) spectra were recorded.

Results: The rare mutation p.Pro2555Arg showed normal GPIIb/IIIa binding under static conditions and CD spectra revealed that the mutation has no detectable effect on secondary and tertiary structure within the isolated C4 domain. In the context of a dimeric construct, however, enhanced local disorder was found. In cone and plate assays, p.Pro2555Arg showed increased aggregate size. Importantly, microfluidic assays revealed that, while p.Phe2561Tyr lowers the critical shear rate for VWF-platelet complex formation, p.Pro255Arg forms aggregates at the same shear rate as wtVWF but results in dramatically increased aggregate sizes.

Conclusions: Missense mutations can induce a gain-of-function in VWF, which results in increased platelet aggregation via different mechanisms. The GOF properties of these variants further underline the prothrombotic character of VWF as a potential target for anti-thrombotic therapy.

To cite this abstract in AMA style:

Huck V, Tischer A, Mess C, Obser T, König G, Denis CV, Auton M, Schneider SW, Schneppenheim R, Brehm MA. Prothrombotic Gain-of-Function Variants of von Willebrand Factor [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/prothrombotic-gain-of-function-variants-of-von-willebrand-factor/. Accessed October 1, 2023.

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