Publications

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52 Publications visible to you, out of a total of 52

Abstract

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Authors: Ryosuke Hirai, Philipp Podsiadlowski, Stanley P. Owocki, Fabian R. N. Schneider, Nathan Smith

Date Published: 1st May 2021

Publication Type: Journal

Abstract

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Authors: F. R. N. Schneider, Ph. Podsiadlowski, B. Müller

Date Published: 2021

Publication Type: Journal

Abstract (Expand)

The multimeric plasma glycoprotein (GP) von Willebrand factor (VWF) is best known for recruiting platelets to sites of injury during primary hemostasis. Generally, mutations in the VWF gene lead to loss of hemostatic activity and thus the bleeding disorder von Willebrand disease. By employing cone and platelet aggregometry and microfluidic assays, we uncovered a platelet GPIIb/IIIa-dependent prothrombotic gain of function (GOF) for variant p.Pro2555Arg, located in the C4 domain, leading to an increase in platelet aggregate size. We performed complementary biophysical and structural investigations using circular dichroism spectra, small-angle X-ray scattering, nuclear magnetic resonance spectroscopy, molecular dynamics simulations on the single C4 domain, and dimeric wild-type and p.Pro2555Arg constructs. C4-p.Pro2555Arg retained the overall structural conformation with minor populations of alternative conformations exhibiting increased hinge flexibility and slow conformational exchange. The dimeric protein becomes disordered and more flexible. Our data suggest that the GOF does not affect the binding affinity of the C4 domain for GPIIb/IIIa. Instead, the increased VWF dimer flexibility enhances temporal accessibility of platelet-binding sites. Using an interdisciplinary approach, we revealed that p.Pro2555Arg is the first VWF variant, which increases platelet aggregate size and shows a shear-dependent function of the VWF stem region, which can become hyperactive through mutations. Prothrombotic GOF variants of VWF are a novel concept of a VWF-associated pathomechanism of thromboembolic events, which is of general interest to vascular health but not yet considered in diagnostics. Thus, awareness should be raised for the risk they pose. Furthermore, our data implicate the C4 domain as a novel antithrombotic drug target. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Authors: Volker Huck, Po-Chia Chen, Emma-Ruoqi Xu, Alexander Tischer, Ulrike Klemm, Camilo Aponte-Santamaría, Christian Mess, Tobias Obser, Fabian Kutzki, Gesa König, Cécile V. Denis, Frauke Gräter, Matthias Wilmanns, Matthew Auton, Stefan W Schneider, Reinhard Schneppenheim, Janosch Hennig, Maria A. Brehm

Date Published: 31st Dec 2020

Publication Type: Journal

Abstract

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Authors: Joachim M. Bestenlehner, Paul A. Crowther, Saida M. Caballero-Nieves, Fabian R. N. Schneider, Sergio Simón-Dı́az, Sarah A. Brands, Alex de Koter, Götz Gräfener, Artemio Herrero, Norbert Langer, Daniel J. Lennon, Jesus Maı́z Apellániz, Joachim Puls, Jorick S. Vink

Date Published: 1st Dec 2020

Publication Type: Journal

Abstract

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Authors: Christian Sand, Sebastian T. Ohlmann, Fabian R. N. Schneider, Rüdiger Pakmor, Friedrich K. Röpke

Date Published: 1st Dec 2020

Publication Type: Journal

Abstract

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Authors: Christian Sand, Sebastian T. Ohlmann, Fabian R. N. Schneider, Rüdiger Pakmor, Friedrich K. Röpke

Date Published: 1st Dec 2020

Publication Type: Journal

Abstract

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Authors: M. Kramer, F. R. N. Schneider, S. T. Ohlmann, S. Geier, V. Schaffenroth, R. Pakmor, F. K. Röpke

Date Published: 1st Oct 2020

Publication Type: Journal

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