Reduced platelet forces underlie impaired hemostasis in mouse models.....pdf (7.9 MB)
Download file

Reduced platelet forces underlie impaired hemostasis in mouse models of MYH9-related disease.

Download (7.9 MB)
journal contribution
posted on 03.06.2022, 15:16 by Juliane Baumann, Laura Sachs, Oliver Otto, Ingmar SchoenIngmar Schoen, Peter Nestler, Carlo Zaninetti, Martin KennyMartin Kenny, Ruth Kranz, Hendrik von Eysmondt, Johanna Rodriguez, Tilman E Schäffer, Zoltan Nagy, Andreas Greinacher, Raghavendra Palankar, Markus Bender
MYH9-related disease patients with mutations in the contractile protein nonmuscle myosin heavy chain IIA display, among others, macrothrombocytopenia and a mild-to-moderate bleeding tendency. In this study, we used three mouse lines, each with one point mutation in the Myh9 gene at positions 702, 1424, or 1841, to investigate mechanisms underlying the increased bleeding risk. Agonist-induced activation of Myh9 mutant platelets was comparable to controls. However, myosin light chain phosphorylation after activation was reduced in mutant platelets, which displayed altered biophysical characteristics and generated lower adhesion, interaction, and traction forces. Treatment with tranexamic acid restored clot retraction in the presence of tPA and reduced bleeding. We verified our findings from the mutant mice with platelets from patients with the respective mutation. These data suggest that reduced platelet forces lead to an increased bleeding tendency in patients with MYH9-related disease, and treatment with tranexamic acid can improve the hemostatic function.

Funding

TR240 grant with project number 374031971 of the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation)

Deutsches Zentrum für Herz-Kreislauf-Forschung (Postdoc Start-up Grant under grant agreement 81X3400107)

Bundesministerium für Bildung und Forschung (ZIK grant under grant agreement 03Z22CN11)

DFG project number 335549539/GRK2381

Royal College of Surgeons in Ireland

History

Comments

The original article is available at https://www.science.org/ Pre-print is available on bioRxiv https://doi.org/10.1101/2021.11.10.468045 and RCSI repository https://hdl.handle.net/10779/rcsi.19950443.v1

Published Citation

Baumann J. et al. Reduced platelet forces underlie impaired hemostasis in mouse models of MYH9-related disease. Sci Adv. 2022;8(20):eabn2627.

Publication Date

18 May 2022

PubMed ID

35584211

Department/Unit

  • School of Pharmacy and Biomolecular Sciences

Research Area

  • Vascular Biology
  • Biomaterials and Regenerative Medicine

Publisher

American Association for the Advancement of Science (AAAS)

Version

  • Published Version (Version of Record)