Distinct antithrombotic consequences of platelet glycoprotein Ibα and VI deficiency in a mouse model of arterial thrombosis

Konstantinides, Stavros; Ware, Jerry; Marchese, Patrizia; Almus-Jacobs, Fanny; Loskutoff, David J.; Ruggeri, Zaverio M.

doi:10.1111/j.1538-7836.2006.02086.x

Cited by 90 publications

(91 citation statements)

References 49 publications

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“…These results contrast with those obtained using GPVI Ϫ/Ϫ mice, in which only 50% of the injured arteries were patent at the end of the monitoring period. 59 Therefore, the results obtained in vivo with the Btk Ϫ/Ϫ mice demonstrate that Btk is critically important for GPIb␣-mediated stable thrombus formation in this model system.…”

Section: Discussionmentioning

confidence: 75%

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Bruton tyrosine kinase is essential for botrocetin/VWF-induced signaling and GPIb-dependent thrombus formation in vivo

Liu

Fitzgerald

Berndt

et al. 2006

Blood

129

113

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Section: Discussionmentioning

confidence: 75%

“…59 As with the Btk Ϫ/Ϫ mice, all of the FeCl 3 -injured carotid arteries of mice lacking the extracellular domain of GPIb␣ were patent at the end of the monitoring period. These results contrast with those obtained using GPVI Ϫ/Ϫ mice, in which only 50% of the injured arteries were patent at the end of the monitoring period.…”

Section: Discussionmentioning

confidence: 84%

Bruton tyrosine kinase is essential for botrocetin/VWF-induced signaling and GPIb-dependent thrombus formation in vivo

Liu

Fitzgerald

Berndt

et al. 2006

Blood

129

113

View full text Add to dashboard Cite

“…When the results are plotted as a function of the LONG versus SHORT phenotype (Figure 7A), the time to occlusion for the 8 Gp6 Ϫ/Ϫ SHORT mice (4 male mice; 4 female mice) was 8.6 (Ϯ 1.2) minutes (mean Ϯ SD) and not significantly different (P Ͼ .9) from that previously recorded for wild-type mice 19 ). In contrast, the time to occlusion of 10 Gp6 Ϫ/Ϫ LONG mice (5 male mice; 5 female mice) ranged from 11.5 to at least 25 minutes, with a median at of at least 25 minutes.…”

Section: Carotid Artery Injury Modelmentioning

confidence: 67%

The Modifier of hemostasis (Mh) locus on chromosome 4 controls in vivo hemostasis of Gp6−/− mice

Chéli

Jensen

Marchese

et al. 2008

Blood

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Platelet glycoprotein VI (GPVI) is a key receptor for collagens that mediates the propagation of platelet attachment and activation. Targeted disruption of the murine gene Gp6 on a mixed 129 ؋ 1/ SvJ ؋ C57BL/6J background causes the expected defects in collagen-dependent platelet responses in vitro. The extent of this dysfunction in all Gp6 ؊/؊ mice is uniform and is not affected by genetic background. However, the same Gp6 ؊/؊ mice exhibit 2 diametrically opposed phenotypes in vivo. In some mice, tail bleeding times are extremely prolonged, and thrombus formation in an in vivo carotid artery ferric chloride-injury model is significantly impaired. In other littermates, tail bleeding times are within the range of wild-type mice, and in vivo thrombus formation is indistinguishable from that of control mice. Directed intercrosses revealed that these phenotypes are heritable, and a genome-wide singlenucleotide polymorphism scan revealed the most significant linkage to a single locus (8 megabases) on chromosome 4 (logarithm of the odds [LOD] score ‫؍‬ 6.9, P < .0001) that we designate Modifier of hemostasis (Mh) . IntroductionGlycoprotein VI (GPVI), which is restricted in expression to megakaryocytes and platelets, is an important receptor for collagens. GPVI (60-65 kDa) is noncovalently associated with the fragment crystallizable receptor ␥ (FcR␥) subunit, an immunoreceptor tyrosine-based activation motif (ITAM)-based signaling coreceptor, 1,2 and in the mouse, surface GPVI expression requires coexpression of FcR␥. 3 Upon engagement of collagens, the GPVI-FcR␥ complex transduces outside-in signals that involve spleen tyrosine kinase (Syk), linker for the activation of T cells (LAT), and Src homology 2 domain-containing leukocyte-specific phosphoprotein of 76 kDa (SLP-76), resulting in phospholipase ␥2 and phosphatidylinositol 3-kinase activation, leading to release of granule contents, prothrombinase activity, and platelet aggregation. [4][5][6][7] Targeted gene deletion in the mouse is one strategy to generate experimental models to assess the role of membrane receptors in hemostasis and thrombosis. We were the first to report the targeted disruption of murine Gp6 8 and demonstrated, using functional in vitro assays, that platelets from homozygous Gp6 Ϫ/Ϫ mice fail to aggregate upon stimulation with type I fibrillar collagen and fail to form thrombi upon perfusion over collagen-coated surfaces. However, the in vivo tail bleeding times for the same Gp6 Ϫ/Ϫ mice were more often within the range seen with wild-type littermates (45-140 seconds), and only a minority of the Gp6 Ϫ/Ϫ F2 littermates (3/13) exhibited an abnormal, extremely prolonged tail bleeding time (Ͼ 600 seconds). Similar proportions of normal and abnormal mice have been observed in studies of genetically engineered FcR␥ Ϫ/Ϫ mice, in which platelet surface GPVI expression is ablated, or wild-type mice made GPVI-deficient after 7 days by intraperitoneal injection of rat anti-mouse GPVI monoclonal antibody JAQ1. [9][10][11] On repeated examination, we dete...

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“…on May 10, 2018. by guest www.bloodjournal.org From vascular damage induced by ferric chloride. 20 Consequently, we analyzed the ability of hTg G233V mice to develop an occlusive thrombus after chemical injury. In control hTg WT mice, the flow dropped within approximately 5 minutes after the removal of ferric chloride, and the carotid remained occluded through completion of the experiment (40 minutes).…”

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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Distinct antithrombotic consequences of platelet glycoprotein Ibα and VI deficiency in a mouse model of arterial thrombosis

Cited by 90 publications

References 49 publications

Bruton tyrosine kinase is essential for botrocetin/VWF-induced signaling and GPIb-dependent thrombus formation in vivo

Bruton tyrosine kinase is essential for botrocetin/VWF-induced signaling and GPIb-dependent thrombus formation in vivo

The Modifier of hemostasis (Mh) locus on chromosome 4 controls in vivo hemostasis of Gp6−/− mice

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

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