Impaired megakaryocytopoiesis in type 2B von Willebrand disease with severe thrombocytopenia

Nurden, Paquita; Debili, Najet; Vainchenker, William; Bobe, Régis; Bredoux, Raymonde; Corvazier, Elisabeth; Combrié, Robert; Fressinaud, Édith; Meyer, Dominique; Nurden, Alan T.; Enouf, Jocelyne

doi:10.1182/blood-2006-03-009449

Cited by 83 publications

(84 citation statements)

References 53 publications

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“…It has been previously reported that VWF exists on the surface of cultured megakaryocytes in a 2B-VWD patient. 24 Unlike the findings with this 2B-VWD patient, we observed a VWF distribution in megakaryocytes of hTg G233V animals that is granular and intracellular with no detectable surface VWF antigen. This still does not address whether the VWF adhering to the surface of hTg G233V platelets is a consequence of platelet release or plasmaderived.…”

contrasting

confidence: 55%

Visualizing the von Willebrand factor/glycoprotein Ib-IX axis with a platelet-type von Willebrand disease mutation

Guerrero

Kyei

Russell

et al. 2009

Blood

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Platelet-type von Willebrand disease (PT-VWD IntroductionAs an initiating step in hemostasis, surface-bound von Willebrand factor (VWF) tethers platelets to a damaged vascular surface via the platelet membrane receptor, glycoprotein (GP) Ib-IX. 1 Before the hemostatic or thrombotic response, soluble von Willebrand factor and platelets coexist without a detectable interaction. Indeed, the regulation of binding between VWF and GP Ib-IX is one of key steps controlling hemostasis and thrombosis. 2 Much of our understanding of these processes has been aided by human bleeding disorders representing "experiments of nature" that identify the key proteins. To this end, platelet-type von Willebrand disease (PT-VWD) is a hereditary bleeding disorder caused by point mutations within the extracellular ␣-subunit domain of the GP Ib-IX receptor. [3][4][5][6] A documented result of PT-VWD mutations is an increased affinity between mutant GP Ib-IX and soluble VWF. 7 A mechanistically similar situation exists with type 2B VWD where single mutations in VWF have an increased affinity for a normal platelet GP Ib-IX receptor. 8 Whether the mutation exists in the receptor, PT-VWD, or the ligand, type 2B VWD, the net result in both cases is a bleeding disorder.The bleeding phenotype in PT-VWD and type 2B VWD has been explained as a consequence of circulating platelet microaggregates composed of bridged platelets and VWF. 7,9 The aggregates are removed from the circulation resulting in a thrombocytopenia, albeit borderline in PT-VWD, and this can partially explain bleeding. 3 In addition, there is an absence of the largest circulating plasma VWF multimeric species in both PT-VWD and type 2B VWD. 3,10 The largest VWF multimer species are the most hemostatically efficient, and removal from the circulation would further add to the impairment of normal hemostasis. 11 However, the removal of the largest multimers by binding to platelets is somewhat counterintuitive because these multimers would presumably be bound to platelets and might be expected to preload a platelet for a hemostatic or thrombotic event. Nevertheless, PT-VWD and type 2B VWD remain 2 of the more interesting bleeding phenotypes providing mechanistic clues on the regulation of hemostasis and thrombosis.We have recently reported the development of a mouse expressing a mutant human subunit associated with PT-VWD. 12 The mouse expresses a human ␣-subunit of GP Ib-IX in which Gly 233 is replaced by Val 233 (G233V), the first reported genetic basis for human PT-VWD. 13 The mice display several diagnostic attributes of human PT-VWD, including the ability of platelets to agglutinate in the presence of low doses of ristocetin and a bleeding phenotype as judged by a simple assessment of hemostasis, the tail bleeding time. 12 Similar to human PT-VWD, the mice do not display significant thrombocytopenia, suggesting that the defect observed in the tail bleeding time is not solely explained by a reduced platelet count. In the present manuscript, we have used state-of-the-art imaging anal...

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contrasting

confidence: 55%

Visualizing the von Willebrand factor/glycoprotein Ib-IX axis with a platelet-type von Willebrand disease mutation

Guerrero

Kyei

Russell

et al. 2009

Blood

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“…Indeed, it has been recently reported that type 2B vWF impairs human bone marrow megakaryocytopoiesis as determined by ultrastructural changes in bone marrow megakaryocytes. 45 If a similar situation occurs in Pt-vWD, perhaps the mouse spleen is compensating for a defect in the bone marrow.…”

Section: Discussionmentioning

confidence: 99%

Platelet Dysfunction and a High Bone Mass Phenotype in a Murine Model of Platelet-Type von Willebrand Disease

Suva

Hartman

Dilley

et al. 2008

The American Journal of Pathology

110

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The platelet glycoprotein Ib-IX receptor binds surfacebound von Willebrand factor and supports platelet adhesion to damaged vascular surfaces. A limited number of mutations within the glycoprotein Ib-IX complex have been described that permit a structurally altered receptor to interact with soluble von Willebrand factor, and this is the molecular basis of platelet-type von Willebrand disease. We have developed and characterized a mouse model of platelet-type von Willebrand disease (G233V) and have confirmed a platelet phenotype mimicking the human disorder. The mice have a dramatic increase in splenic megakaryocytes and splenomegaly. Recent studies have demonstrated that hematopoetic cells can influence the differentiation of osteogenic cells. Thus, we examined the skeletal phenotype of mice expressing the G233V variant complex. At 6 months of age, G233V mice exhibit a high bone mass phenotype with an approximate doubling of trabecular bone volume in both the tibia and femur. Serum measures of bone resorption were significantly decreased in G233V animals. With decreased bone resorption, cortical thickness was increased, medullary area decreased, and consequently, the mechanical strength of the femur was significantly increased. Using ex vivo bone marrow cultures, osteoclast-specific staining in the G233V mutant marrow was diminished, whereas osteoblastogenesis was unaffected. These studies provide new insights into the relationship between the regulation of megakaryocytopoiesis and bone mass. (Am J

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“…12 Macrothrombocytopenia has not been reported in patients or mice deficient in three known GPIb-V-IX ligands, von Willebrand factor, P-selectin and integrin αMβ2, which would argue against the involvement of the extracellular binding domain. 13,14 On the other hand, impaired megakaryopoiesis has been observed in a thrombocytopenic patient with a mutation in the GPIbα interacting site of von Willebrand factor, 15 while decreased megakaryocyte differentiation has been observed in CD34 + cells cultured in the presence of antibodies against the extracellular portion of GPIbα. 16 The intracellular properties of the receptor have also been incriminated in defective platelet biogenesis in relation to the linkage of GPIb-V-IX to the submembranous actin cytoskeleton, which is mediated by filamin.…”

Section: Introductionmentioning

confidence: 99%

Intrinsic impaired proplatelet formation and microtubule coil assembly of megakaryocytes in a mouse model of Bernard-Soulier syndrome

Strassel¹,

Eckly²,

Léon³

et al. 2009

Haematologica

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The online version of this article contains a supplementary appendix. BackgroundGiant 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 MethodsTo explore the underlying mechanisms of the disease, megakaryopoiesis was studied in a mouse model deficient in GPIbβ. Megakaryocytes were initially characterized in situ in the bone marrow of adult mice, after which their capacity to differentiate into proplateletbearing cells was evaluated in cultured fetal liver cells. ResultsThe number of megakaryocyte progenitors, their differentiation and progressive maturation into distinct classes and their level of endoreplication were normal in GPIbβ -/-bone marrow. However, the more mature cells exhibited ultrastructural anomalies with a thicker peripheral zone and a less well developed demarcation membrane system. GPIbβ -/-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 GPIbβ -/-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. GPIbβ -/-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 GPIbβ -/-proplatelet buds in cultured and circulating platelets. ConclusionsAltogether, 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.Key words: megakaryocyte, platelet, Bernar-Soulier, microtubules, GPIb-V-IX.Citation: Strassel C, Eckly A, Léon C, Petitjean C, Freund M, Cazenave J-P, Gachet C, and Lanza F. Intrinsic impaired proplatelet formation and microtubule coil assembly of megakaryocytes in a mouse model of Bernard-Soulier syndrome. Haematologica 2009; 94:800-810. doi:10.3324/haematol.2008 This is an open-access paper.

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Impaired megakaryocytopoiesis in type 2B von Willebrand disease with severe thrombocytopenia

Cited by 83 publications

References 53 publications

Visualizing the von Willebrand factor/glycoprotein Ib-IX axis with a platelet-type von Willebrand disease mutation

Visualizing the von Willebrand factor/glycoprotein Ib-IX axis with a platelet-type von Willebrand disease mutation

Platelet Dysfunction and a High Bone Mass Phenotype in a Murine Model of Platelet-Type von Willebrand Disease

Intrinsic impaired proplatelet formation and microtubule coil assembly of megakaryocytes in a mouse model of Bernard-Soulier syndrome

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