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Blood, 15 October 2006, Vol. 108, No. 8, pp. 2587-2595.
Prepublished online as a Blood First Edition Paper on May 23, 2006; DOI 10.1182/blood-2006-03-009449.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Impaired megakaryocytopoiesis in type 2B von Willebrand disease with severe thrombocytopenia
Paquita Nurden,
Najet Debili,
William Vainchenker,
Regis Bobe,
Raymonde Bredoux,
Elisabeth Corvazier,
Robert Combrie,
Edith Fressinaud,
Dominique Meyer,
Alan T. Nurden, and
Jocelyne Enouf
From the Centre de Référence des Pathologies Plaquettaires and Institut Fédératif de Recherche No. 4, Hôpital Cardiologique, Pessac; Institut National de la Santé et de la Recherche Médicale (INSERM) U.790, Villejuif; INSERM U.689, Hôpital Lariboisière, Paris; and INSERM U.710, Le Kremlin-Bicêtre, France.
In type 2B von Willebrand disease, there is spontaneous binding of mutated von Willebrand factor (VWF) multimers to platelets. Here we report a family in which severe thrombocytopenia may also be linked to abnormal megakaryocytopoiesis. A heterozygous mutation in the VWF A1 domain gave a R1308P substitution in an interactive site for glycoprotein Ib (GPIb). Electron microscopy showed clusters of platelets in close contact. Binding of antibodies to the GPIb N-terminal domain was decreased, whereas GPIX and GPV were normally detected. In Western blotting (WB), GPIb, IIb, and  3 were normally present. Proteins involved in Ca2+ homeostasis were analyzed by quantitating platelet mRNA or by WB. Plasma membrane Ca2+ ATPase (PMCA)-4b and type III inositol trisphosphate receptor (InsP3-R3) were selectively increased. The presence of degradation products of polyadenosine diphosphate (ADP)-ribose polymerase protein (PARP) suggested ongoing caspase-3 activity. These were findings typical of immature normal megakaryocytes cultured from peripheral blood CD34+ cells with TPO. Significantly, megakaryocytes from the patients in culture produced self-associated and interwoven proplatelets. Immunolocalization showed VWF not only associated with platelets, but already on the megakaryocyte surface and within internal channels. In this family, type 2B VWD is clearly associated with abnormal platelet production.
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