Role of thrombin signalling in platelets in haemostasis and thrombosis

Sambrano, Gilberto R.; Weiss, Ethan J.; Zheng, Yaowu; Huang, Wei; Coughlin, Shaun R.

doi:10.1038/35092573

Cited by 483 publications

(457 citation statements)

References 28 publications

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“…Par4 Ϫ/Ϫ mice have prolonged tail bleeding times and decreased thrombosis in mesenteric arterioles after ferric chloride injury, and they are protected against pulmonary embolism after i.v. thromboplastin injection (2,3). The expression pattern of Par4 as well as data from bone marrow reconstitution experiments strongly suggest that the protection against thrombosis seen in Par4 Ϫ/Ϫ mice is due to loss of thrombin signaling in platelets rather than in other cell types (4).…”

mentioning

confidence: 94%

Par4 is required for platelet thrombus propagation but not fibrin generation in a mouse model of thrombosis

Vandendries

Hamilton

Coughlin

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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158

168

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Thrombin, a central mediator of hemostasis and thrombosis, converts fibrinogen to fibrin and is a potent platelet activator. Activated platelets provide a surface for assembly of the tenase and prothrombinase complexes required for thrombin generation. The role of thrombin-induced platelet activation in platelet accumulation and its interplay with fibrin deposition during thrombus assembly has not been fully defined. We studied these processes during laser-induced thrombus formation by using real-time digital fluorescence microscopy in mice lacking protease-activated receptor-4 (Par4), which is necessary for thrombin responsiveness in mouse platelets. Juxtamural platelet accumulation immediately after laser injury was not different in wild-type and Par4 ؊/؊ mice. However, subsequent growth of platelet thrombi was markedly diminished in Par4 ؊/؊ mice. At the time of maximal thrombus size in wild type, platelet accumulation was more than 10-fold higher in wild type than in Par4 ؊/؊ mice. P-selectin expression, a marker of platelet activation, was reduced and delayed in Par4 ؊/؊ thrombi. In contrast to platelet activation and accumulation, the rate and amount of fibrin deposition, predominantly intramural and juxtamural in this model, were indistinguishable in Par4 ؊/؊ and wild-type mice. These results suggest that platelet activation by thrombin is necessary for normal propagation of a platelet thrombus at a distance from the injured vessel wall and hence for normal thrombus growth. However, platelet activation by thrombin is unnecessary for initial and limited accumulation of platelets at or near the vessel wall, and this limited accumulation of platelets and/or platelet-independent mechanism(s) of thrombin generation are sufficient for normal fibrin deposition in this model. blood coagulation ͉ intravital microscopy ͉ P-selectin

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mentioning

confidence: 94%

Par4 is required for platelet thrombus propagation but not fibrin generation in a mouse model of thrombosis

Vandendries

Hamilton

Coughlin

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

158

168

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“…A similar developmental defect is not detectable in embryos with normal platelet numbers but disturbed platelet function [Par4 or Gq (F2rl3 or Gnaq -Mouse Genome Informatics) null mice] (Camerer et al, 2004;Palumbo et al, 2004). A developmental role for platelets is not necessarily precluded by the normal development of Par4 -/-or Gq -/-embryos, as platelets lacking Par4 or Gq can still be activated (Ohlmann et al, 2000;Sambrano et al, 2001). This raises the question of whether embryonic platelets have an as yet undefined developmental function or whether p45NF-E2 has a developmental function that is independent of platelets.…”

Section: Introductionmentioning

confidence: 99%

p45NF-E2 represses Gcm1 in trophoblast cells to regulate syncytium formation, placental vascularization and embryonic growth

et al. 2011

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SUMMARYAbsence of the leucine zipper transcription factor p45NF-E2 results in thrombocytopenia, impaired placental vascularization and intrauterine growth restriction (IUGR) in mice. The mechanism underlying the p45NF-E2-dependent placental defect and IUGR remains unknown. Here, we show that the placental defect and IUGR of p45NF-E2 (Nfe2) null mouse embryos is unrelated to thrombocytopenia, establishing that embryonic platelets and platelet-released mediators are dispensable for placentation. Rather, p45NF-E2, which was hitherto thought to be specific to hematopoietic cells, is expressed in trophoblast cells, where it is required for normal syncytiotrophoblast formation, placental vascularization and embryonic growth. Expression of p45NF-E2 in labyrinthine trophoblast cells colocalizes with that of Gcm1, a transcription factor crucial for syncytiotrophoblast formation. In the absence of p45NF-E2, the width of syncytiotrophoblast layer 2 and the expression of Gcm1 and Gcm1-dependent genes (Synb and Cebpa) are increased. In vitro, p45NF-E2 deficiency results in spontaneous syncytiotrophoblast formation, which can be reversed by Gcm1 knockdown. Increased Gcm1 expression in the absence of p45NF-E2 is dependent on enhanced protein acetylation, including post-translational modification of Gcm1. Increasing and inhibiting acetylation in the placenta of wild-type control embryos phenocopies and corrects, respectively, the changes observed in p45NF-E2-deficient embryos. These studies identify a novel function of p45NF-E2 during placental development: in trophoblast cells, p45NF-E2 represses Gcm1 and syncytiotrophoblast formation via acetylation.

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“…PARs are found on the surface of many cell types including platelets, endothelial cells, smooth muscle cells as well as effector cells of the immune system 4,5 . Thrombin activation of platelets through PARs is central to their haemostatic and prothrombotic functions 6,7 and leads to the generation and release of a broad range of proinflammatory molecules 8,9 . Thrombin activation of endothelial and immune effector cells induces the production of several growth factors, chemokines and cytokines 4,10,11 and also alters their adhesive phenotype 12,13 .…”

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confidence: 99%

Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4

et al. 2015

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Thrombin is a central regulator of leukocyte recruitment and inflammation at sites of vascular injury, a function thought to involve primarily endothelial PAR cleavage. Here we demonstrate the existence of a distinct leukocyte-trafficking mechanism regulated by components of the haemostatic system, including platelet PAR4, GPIba and fibrin. Utilizing a mouse endothelial injury model we show that thrombin cleavage of platelet PAR4 promotes leukocyte recruitment to sites of vascular injury. This process is negatively regulated by GPIba, as seen in mice with abrogated thrombin-platelet GPIba binding (hGPIba D277N ). In addition, we demonstrate that fibrin limits leukocyte trafficking by forming a physical barrier to intravascular leukocyte migration. These studies demonstrate a distinct 'checkpoint' mechanism of leukocyte trafficking involving balanced thrombin interactions with PAR4, GPIba and fibrin. Dysregulation of this checkpoint mechanism is likely to contribute to the development of thromboinflammatory disorders.

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Role of thrombin signalling in platelets in haemostasis and thrombosis

Cited by 483 publications

References 28 publications

Par4 is required for platelet thrombus propagation but not fibrin generation in a mouse model of thrombosis

Par4 is required for platelet thrombus propagation but not fibrin generation in a mouse model of thrombosis

p45NF-E2 represses Gcm1 in trophoblast cells to regulate syncytium formation, placental vascularization and embryonic growth

Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4

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