{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:04:15Z","timestamp":1791295455182,"version":"4.1.0"},"reference-count":50,"publisher":"American Society for Clinical Investigation","issue":"16","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,10,6]]},"abstract":"<jats:p>\n                    von Willebrand disease type 2B (VWD-type 2B) is characterized by gain-of-function mutations of von Willebrand factor (vWF) that enhance its binding to platelet glycoprotein Ib\u03b1 and alter the protein\u2019s multimeric structure. Patients with VWD-type 2B display variable extents of bleeding associated with macrothrombocytopenia and sometimes with thrombopathy. Here, we addressed the molecular mechanism underlying the severe macrothrombocytopenia both in a knockin murine model for VWD-type 2B by introducing the p.V1316M mutation in the murine\n                    <jats:italic>Vwf<\/jats:italic>\n                    gene and in a patient bearing this mutation. We provide evidence of a profound defect in megakaryocyte (MK) function since: (a) the extent of proplatelet formation was drastically decreased in 2B MKs, with thick proplatelet extensions and large swellings; and (b) 2B MKs presented actin disorganization that was controlled by upregulation of the RhoA\/LIM kinase (LIMK)\/cofilin pathway. In vitro and in vivo inhibition of the LIMK\/cofilin signaling pathway rescued actin turnover and restored normal proplatelet formation, platelet count, and platelet size. These data indicate, to our knowledge for the first time, that the severe macrothrombocytopenia in VWD-type 2B p.V1316M is due to an MK dysfunction that originates from a constitutive activation of the RhoA\/LIMK\/cofilin pathway and actin disorganization. This suggests a potentially new function of vWF during platelet formation that involves regulation of actin dynamics.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.88643","type":"journal-article","created":{"date-parts":[[2016,10,5]],"date-time":"2016-10-05T11:06:06Z","timestamp":1475665566000},"source":"Crossref","is-referenced-by-count":26,"title":["LIM kinase\/cofilin dysregulation promotes macrothrombocytopenia in severe von Willebrand disease-type 2B"],"prefix":"10.1172","volume":"1","author":[{"given":"Alexandre","family":"Kauskot","sequence":"first","affiliation":[{"name":"INSERM UMR-S 1176, Univ Paris-Sud, Universit\u00e9 Paris-Saclay, 94276 Le Kremlin-Bic\u00eatre, France."},{"name":"INSERM UMR-S 1140, Univ Paris Descartes, Sorbonne Paris Cit\u00e9, Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Poirault-Chassac","sequence":"additional","affiliation":[{"name":"INSERM UMR-S 1140, Univ Paris Descartes, Sorbonne Paris 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Univ Paris-Sud, Universit\u00e9 Paris-Saclay, 94276 Le Kremlin-Bic\u00eatre, France."},{"name":"Department of Biological Hematology, CHU Bic\u00eatre, H\u00f4pitaux Universitaires Paris Sud, AP-HP, Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Pietrzyk-Nivau","sequence":"additional","affiliation":[{"name":"INSERM UMR-S 1140, Univ Paris Descartes, Sorbonne Paris Cit\u00e9, Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliane","family":"Berrou","sequence":"additional","affiliation":[{"name":"INSERM UMR-S 1176, Univ Paris-Sud, Universit\u00e9 Paris-Saclay, 94276 Le Kremlin-Bic\u00eatre, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier D.","family":"Christophe","sequence":"additional","affiliation":[{"name":"INSERM UMR-S 1176, Univ Paris-Sud, Universit\u00e9 Paris-Saclay, 94276 Le Kremlin-Bic\u00eatre, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Philippe","family":"Rosa","sequence":"additional","affiliation":[{"name":"INSERM UMR-S 1176, Univ Paris-Sud, Universit\u00e9 Paris-Saclay, 94276 Le Kremlin-Bic\u00eatre, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Lenting","sequence":"additional","affiliation":[{"name":"INSERM UMR-S 1176, Univ Paris-Sud, Universit\u00e9 Paris-Saclay, 94276 Le Kremlin-Bic\u00eatre, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marijke","family":"Bryckaert","sequence":"additional","affiliation":[{"name":"INSERM UMR-S 1176, Univ Paris-Sud, Universit\u00e9 Paris-Saclay, 94276 Le Kremlin-Bic\u00eatre, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5152-9156","authenticated-orcid":true,"given":"C\u00e9cile V.","family":"Denis","sequence":"additional","affiliation":[{"name":"INSERM UMR-S 1176, Univ 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