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Blood, 1 November 2007, Vol. 110, No. 9, pp. 3183-3191.
Prepublished online as a Blood First Edition Paper on July 30, 2007; DOI 10.1182/blood-2007-03-080184.


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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY

Megakaryocyte-restricted MYH9 inactivation dramatically affects hemostasis while preserving platelet aggregation and secretion

Catherine Léon1,3, Anita Eckly1,3, Béatrice Hechler1,3, Boris Aleil1,3, Monique Freund1,3, Catherine Ravanat1,3, Marie Jourdain1,3, Christelle Nonne1,3, Josiane Weber1,3, Ralph Tiedt4, Marie-Pierre Gratacap5,6, Sonia Severin5,6, Jean-Pierre Cazenave1,3, François Lanza1,3, Radek Skoda4, and Christian Gachet1,3

1 INSERM, U311 Strasbourg, France; 2 Établissement Français du Sang–Alsace, Strasbourg, UMR-S311 France; 3 Université Louis Pasteur, Strasbourg, UMR-S311 France; 4 Department of Research, Experimental Hematology, University Hospital Basel, Basel, Switzerland; 5 Institut National de la Santé et de la Recherche Médicale, U563 Centre de Physiopathologie de Toulouse, Département d'Oncogenèse et Signalisation dans les Cellules Hématopoïétiques, Toulouse, France; 6 Université Toulouse III Paul Sabatier, Faculté de médecine Toulouse-Purpan, UMR-S563, Toulouse, France

Mutations in the MYH9 gene encoding the nonmuscle myosin heavy chain IIA result in bleeding disorders characterized by a macrothrombocytopenia. To understand the role of myosin in normal platelet functions and in pathology, we generated mice with disruption of MYH9 in megakaryocytes. MYH9{Delta} mice displayed macrothrombocytopenia with a strong increase in bleeding time and absence of clot retraction. However, platelet aggregation and secretion in response to any agonist were near normal despite absence of initial platelet contraction. By contrast, integrin outside-in signaling was impaired, as observed by a decrease in integrin ß3 phosphorylation and PtdIns(3,4)P2 accumulation following stimulation. Upon adhesion on a fibrinogen-coated surface, MYH9{Delta} platelets were still able to extend lamellipodia but without stress fiber–like formation. As a consequence, thrombus growth and organization, investigated under flow by perfusing whole blood over collagen, were strongly impaired. Thrombus stability was also decreased in vivo in a model of FeCl3-induced injury of carotid arteries. Overall, these results demonstrate that while myosin seems dispensable for aggregation and secretion in suspension, it plays a key role in platelet contractile phenomena and outside-in signaling. These roles of myosin in platelet functions, in addition to thrombocytopenia, account for the strong hemostatic defects observed in MYH9{Delta} mice.


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