Myosin-II repression favors pre/proplatelets but shear activation generates platelets and fails in macrothrombocytopenia

Blood. 2015 Jan 15;125(3):525-33. doi: 10.1182/blood-2014-05-576462. Epub 2014 Nov 13.


Megakaryocyte ploidy and the generation of pre/proplatelets are both increased in culture by pharmacologic inhibition of myosin-II, but nonmuscle myosin-IIA (MIIA) mutations paradoxically cause MYH9-related diseases (MYH9-RD) that adversely affect platelets. In marrow, megakaryocytes extend projections into the microcirculation, where shear facilitates fragmentation to large pre/proplatelets, suggesting that fluid stresses and myosin-II activity somehow couple in platelet biogenesis. Here, in bulk shear, plateletlike particles generated from megakaryocytes are maximized at a shear stress typical of that in the microcirculation and after treatment with a myosin-II inhibitor. MIIA activity in static cells is naturally repressed through phosphorylation at Serine-1943, but shear decreases phosphorylation, consistent with MIIA activation and localization to platelet cortex. Micropipette aspiration of cells shows myosin-II accumulates at stressed sites, but its inhibition prevents such mechanoactivation and facilitates generation of CD41(+) fragments similar in size to pre/proplatelets. MYH9-RD mutants phenocopy inhibition, revealing a dominant negative effect. MIIA is diffuse in the large platelets of a MYH9-RD patient with macrothrombocytopenia and is also diffuse in normal pre/proplatelets treated with inhibitor that blocks in vitro division to small platelets. The findings explain the large platelets in MYH9-RD and the near-normal thrombocrit of patients. Myosin-II regulation thus controls platelet size and number.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Blood Platelets / metabolism
  • Blood Platelets / pathology*
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Genes, Dominant
  • Humans
  • Megakaryocytes / metabolism
  • Megakaryocytes / pathology*
  • Molecular Motor Proteins / genetics
  • Molecular Motor Proteins / metabolism*
  • Mutation / genetics
  • Myosin Heavy Chains / genetics
  • Myosin Heavy Chains / metabolism*
  • Phosphorylation
  • Shear Strength
  • Stress, Mechanical*
  • Thrombocytopenia / genetics
  • Thrombocytopenia / metabolism
  • Thrombocytopenia / pathology*


  • MYH9 protein, human
  • Molecular Motor Proteins
  • Myosin Heavy Chains