BACKGROUND: Giant platelets and thrombocytopenia are invariable defects in the Bernard-Soulier syndrome caused by deficiency of the GPIb-V-IX complex, a receptor for von Willebrand factor supporting platelet adhesion to the damaged arterial wall. Various properties of this receptor may be considered potential determinants of the macrothrombocytopenia. DESIGN AND METHODS: To explore the underlying mechanisms of the disease, megakaryopoiesis was studied in a mouse model deficient in GPIbbeta. Megakaryocytes were initially characterized in situ in the bone marrow of adult mice, after which their capacity to differentiate into proplatelet-bearing cells was evaluated in cultured fetal liver cells. RESULTS: The number of megakaryocyte progenitors, their differentiation and progressive maturation into distinct classes and their level of endoreplication were normal in GPIbbeta(-/-) bone marrow. However, the more mature cells exhibited ultrastructural anomalies with a thicker peripheral zone and a less well developed demarcation membrane system. GPIbbeta(-/-) megakaryocytes could be differentiated in culture from Lin(-) fetal liver cells in normal amounts but the proportion of cells able to extend proplatelets was decreased by 41%. Moreover, the GPIbbeta(-/-) cells extending proplatelets displayed an abnormal morphology characterized by fewer pseudopodial extensions with thicker shaft sections and an increased diameter of the terminal coiled elements. GPIbbeta(-/-) released platelets were larger but retained a typical discoid shape. Proplatelet formation was similarly affected in bone marrow explants from adult mice examined by videomicroscopy. The marginal microtubular ring contained twice as many tubulin fibers in GPIbbeta(-/-) proplatelet buds in cultured and circulating platelets. CONCLUSIONS: Altogether, these findings point to a role of the GPIb-V-IX complex intrinsic to megakaryocytes at the stage of proplatelet formation and suggest a functional link with the underlying microtubular cytoskeleton in platelet biogenesis.
BACKGROUND: Giant platelets and thrombocytopenia are invariable defects in the Bernard-Soulier syndrome caused by deficiency of the GPIb-V-IX complex, a receptor for von Willebrand factor supporting platelet adhesion to the damaged arterial wall. Various properties of this receptor may be considered potential determinants of the macrothrombocytopenia. DESIGN AND METHODS: To explore the underlying mechanisms of the disease, megakaryopoiesis was studied in a mouse model deficient in GPIbbeta. Megakaryocytes were initially characterized in situ in the bone marrow of adult mice, after which their capacity to differentiate into proplatelet-bearing cells was evaluated in cultured fetal liver cells. RESULTS: The number of megakaryocyte progenitors, their differentiation and progressive maturation into distinct classes and their level of endoreplication were normal in GPIbbeta(-/-) bone marrow. However, the more mature cells exhibited ultrastructural anomalies with a thicker peripheral zone and a less well developed demarcation membrane system. GPIbbeta(-/-) megakaryocytes could be differentiated in culture from Lin(-) fetal liver cells in normal amounts but the proportion of cells able to extend proplatelets was decreased by 41%. Moreover, the GPIbbeta(-/-) cells extending proplatelets displayed an abnormal morphology characterized by fewer pseudopodial extensions with thicker shaft sections and an increased diameter of the terminal coiled elements. GPIbbeta(-/-) released platelets were larger but retained a typical discoid shape. Proplatelet formation was similarly affected in bone marrow explants from adult mice examined by videomicroscopy. The marginal microtubular ring contained twice as many tubulin fibers in GPIbbeta(-/-) proplatelet buds in cultured and circulating platelets. CONCLUSIONS: Altogether, these findings point to a role of the GPIb-V-IX complex intrinsic to megakaryocytes at the stage of proplatelet formation and suggest a functional link with the underlying microtubular cytoskeleton in platelet biogenesis.
Authors: Harald Schulze; Manav Korpal; Jonathan Hurov; Sang-We Kim; Jinghang Zhang; Lewis C Cantley; Thomas Graf; Ramesh A Shivdasani Journal: Blood Date: 2006-01-24 Impact factor: 22.113
Authors: N Debili; N Kieffer; M Nakazawa; J Guichard; M Titeux; E Cramer; J Breton-Gorius; W Vainchenker Journal: Blood Date: 1990-07-15 Impact factor: 22.113
Authors: David Williamson; Inna Pikovski; Susan L Cranmer; Pierre Mangin; Nayna Mistry; Teresa Domagala; Sam Chehab; Francois Lanza; Hatem H Salem; Shaun P Jackson Journal: J Biol Chem Date: 2001-11-07 Impact factor: 5.157
Authors: A Balduini; A Malara; A Pecci; S Badalucco; V Bozzi; I Pallotta; P Noris; M Torti; C L Balduini Journal: J Thromb Haemost Date: 2008-12-04 Impact factor: 5.824
Authors: Karyn E O'Connell; Amy M Mikkola; Aaron M Stepanek; Andyna Vernet; Christopher D Hall; Chia C Sun; Eda Yildirim; John F Staropoli; Jeannie T Lee; Diane E Brown Journal: Comp Med Date: 2015-04 Impact factor: 0.982