Dysfunctional platelet membrane receptors: from humans to mice

Ware, Jerry

doi:10.1160/th04-05-0308

Cited by 54 publications

(51 citation statements)

References 67 publications

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“…In the case of platelets, the majority of thrombotic mechanisms are similar in mice and humans. 96 Armed with decades of important platelet-dependent insights, the future is bright for broadening an appreciation of the platelet's influence on many hematologic disorders. For personal use only.…”

Section: Discussionmentioning

confidence: 99%

Platelets at the interface of thrombosis, inflammation, and cancer

Franco

Corken

Ware

2015

Blood

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551

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Although once primarily recognized for its roles in hemostasis and thrombosis, the platelet has been increasingly recognized as a multipurpose cell. Indeed, circulating platelets have the ability to influence a wide range of seemingly unrelated pathophysiologic events. Here, we highlight some of the notable observations that link platelets to inflammation, reinforcing the platelet’s origin from a lower vertebrate cell type with both hemostatic and immunologic roles. In addition, we consider the relevance of platelets in cancer biology by focusing on the hallmarks of cancer and the ways platelets can influence multistep development of tumors. Beyond its traditional role in hemostasis and thrombosis, the platelet’s involvement in the interplay between hemostasis, thrombosis, inflammation, and cancer is likely complex, yet extremely important in each disease process. The existence of animal models of platelet dysfunction and currently used antiplatelet therapies provide a framework for understanding mechanistic insights into a wide range of pathophysiologic events. Thus, the basic scientist studying platelet function can think beyond the traditional hemostasis and thrombosis paradigms, while the practicing hematologist must appreciate platelet relevance in a wide range of disease processes.

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Section: Discussionmentioning

confidence: 99%

Platelets at the interface of thrombosis, inflammation, and cancer

Franco

Corken

Ware

2015

Blood

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551

453

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“…In addition, induction of arterial thrombosis in mouse models has helped to identify the relevant elements that play a significant role in hemostasis and thrombosis in vivo. 19 (A) Fixed platelets from hTg WT animals were allowed to adhere to glass coverslips and subjected to immunofluorescent staining. Maximum intensity projections of a deconvolved image stack were obtained using confocal microscopy.…”

Section: In Vivo Impairment Of Occlusive Thrombi In Htg G233v Micementioning

confidence: 99%

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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“…Insights into the molecular regulation of platelet function have most often come from the characterization of human bleeding disorders that are supported with corresponding animal models. 1 Two clinically similar human bleeding disorders distinct at the molecular level, are type 2B von Willebrand disease (vWD) and platelet-type von Willebrand disease (Pt-vWD), the latter also referred to as pseudo-von Willebrand disease. 2,3 In type 2B vWD, the soluble form of von Willebrand factor (vWF) has an increased affinity for platelets and, unlike normal vWF, binds to circulating platelets via the platelet glycoprotein (GP) Ib-IX receptor complex.…”

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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

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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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Dysfunctional platelet membrane receptors: from humans to mice

Cited by 54 publications

References 67 publications

Platelets at the interface of thrombosis, inflammation, and cancer

Platelets at the interface of thrombosis, inflammation, and cancer

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

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