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

-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 gene at positions 702, 1424, or 18...

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Published in:Science advances 2022-05, Vol.8 (20), p.eabn2627-eabn2627
Main Authors: Baumann, Juliane, Sachs, Laura, Otto, Oliver, Schoen, Ingmar, Nestler, Peter, Zaninetti, Carlo, Kenny, Martin, Kranz, Ruth, von Eysmondt, Hendrik, Rodriguez, Johanna, Schäffer, Tilman E, Nagy, Zoltan, Greinacher, Andreas, Palankar, Raghavendra, Bender, Markus
Format: Article
Language:English
Subjects:
Biomedicine and Life Sciences
Biophysics
Cell Biology
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Summary:-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 gene at positions 702, 1424, or 1841, to investigate mechanisms underlying the increased bleeding risk. Agonist-induced activation of 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 -related disease, and treatment with tranexamic acid can improve the hemostatic function.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abn2627