Regulating thrombus growth and stability to achieve an optimal response to injury

Brass, Lawrence F.; Wannemacher, Kenneth M.; Ma, Peisong; Stalker, Timothy J.

doi:10.1111/j.1538-7836.2011.04364.x

Cited by 68 publications

(68 citation statements)

References 88 publications

(116 reference statements)

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“…The hemostatic process after a mild injury in vivo only leads to limited local activation of platelets and the coagulation system, without jeopardizing downstream blood supply (27,43). Based on our results demonstrating the dual role of pFn, we propose a novel model to explain the fine balance between maintenance of hemostasis and prevention of vessel occlusion.…”

Section: Methodsmentioning

confidence: 77%

Plasma fibronectin supports hemostasis and regulates thrombosis

Wang¹,

Adili²,

Spring³

et al. 2014

J. Clin. Invest.

160

161

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Section: Methodsmentioning

confidence: 77%

Plasma fibronectin supports hemostasis and regulates thrombosis

Wang¹,

Adili²,

Spring³

et al. 2014

J. Clin. Invest.

160

161

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“…Thrombus formation and its stabilization is complex and tightly coordinated by cells and components of the vessel wall, platelets, and other blood cells in conjunction with plasma proteins. 43,44 Many factors can influence thrombus stability including platelet-ligand interactions, outside-in signaling events via a IIb b 3 , presence of soluble molecules such as Gas6, or secondary wave mediators ADP and thromboxane A2. Both nitric oxide and prostacyclin (PGI2) released from the endothelium as well as adenosine triphosphate (ATP) diphosphohydrolase (CD39) and ectonucleotidase (CD73) can influence thrombus formation, as recently shown for Kindlin 1/2 mice.…”

Section: Discussionmentioning

confidence: 99%

Vessel wall BAMBI contributes to hemostasis and thrombus stability

Salles‐Crawley

Monkman

Ahnström

et al. 2014

Blood

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Key Points• This is the first report to describe the influence of BAMBI on both hemostasis and thrombus stability.• BAMBI present in the blood vessel wall (most likely the endothelium) rather than platelet BAMBI is required for thrombus stability.Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) is a transmembrane protein related to the transforming growth factor-b superfamily, and is highly expressed in platelets and endothelial cells. We previously demonstrated its positive role in thrombus formation using a zebrafish thrombosis model. In the present study, we used Bambi-deficient mice and radiation chimeras to evaluate the function of this receptor in the regulation of both hemostasis and thrombosis. We show that Bambi 2/2 and Bambi 1/2 mice exhibit mildly prolonged bleeding times compared with Bambi 1/1 littermates. In addition, using 2 in vivo thrombosis models in mesenterium or cremaster muscle arterioles, we demonstrate that Bambi-deficient mice form unstable thrombi compared with Bambi 1/1 mice. No defects in thrombin generation in Bambi 2/2 mouse plasma could be detected ex vivo. Moreover, the absence of BAMBI had no effect on platelet counts, platelet activation, aggregation, or platelet procoagulant function. Similar to Bambi 2/2 mice, Bambitransplanted with Bambi 1/1 bone marrow formed unstable thrombi in the laser-induced thrombosis model that receded more rapidly than thrombi that formed in Bambi 1/1 mice receiving Bambi 2/2 bone marrow transplants.Taken together, these results provide strong evidence for an important role of endothelium rather than platelet BAMBI as a positive regulator of both thrombus formation and stability. (Blood. 2014;123(18):2873-2881

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“…Yet, these and other regulators of platelet activation affect the hemostatic response as well. 34 The studies presented here, along with those of Gegenbauer et al 26,27 and Delesque-Touchard et al 25 build a picture in which the activity of the platelet signaling network is modulated at an early step that is common to most platelet agonists: that is, the duration of G-protein signaling. Human and mouse platelets express multiple members of the RGS family, 2 of which, RGS10 and RGS18, appear to be the most abundant.…”

Section: Discussionmentioning

confidence: 99%

Modulating platelet reactivity through control of RGS18 availability

Sinnamon

et al. 2015

Blood

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Key Points• RGS18 acts as a brake on persistent or inappropriate platelet activation after it is released from binding sites in resting platelets.• Control of free RGS18 levels provides a mechanism for coordinating signaling networks in platelets.Most platelet agonists activate platelets by binding to G-protein-coupled receptors. We have shown previously that a critical node in the G-protein signaling network in platelets is formed by a scaffold protein, spinophilin (SPL), the tyrosine phosphatase, Src homology region 2 domain-containing phosphatase-1 (SHP-1), and the regulator of G-protein signaling family member, RGS18. Here, we asked whether SPL and other RGS18 binding proteins such as 14-3-3g regulate platelet reactivity by sequestering RGS18 and, if so, how this is accomplished. The results show that, in resting platelets, free RGS18 levels are relatively low, increasing when platelets are activated by thrombin. Free RGS18 levels also rise when platelets are rendered resistant to activation by exposure to prostaglandin I 2 (PGI 2 ) or forskolin, both of which increase platelet cyclic adenosine monophosphate (cAMP) levels. However, the mechanism for raising free RGS18 is different in these 2 settings. Whereas thrombin activates SHP-1 and causes dephosphorylation of SPL tyrosine residues, PGI 2 and forskolin cause phosphorylation of SPL Ser94 without reducing tyrosine phosphorylation. Substituting alanine for Ser94 blocks cAMP-induced dissociation of the SPL/RGS/SHP-1 complex. Replacing Ser94 with aspartate prevents formation of the complex and produces a loss-of-function phenotype when expressed in mouse platelets. Together with the defect in platelet function we previously observed in SPL 2/2 mice, these data show that (1) regulated sequestration and release of RGS18 by intracellular binding proteins provides a mechanism for coordinating activating and inhibitory signaling networks in platelets, and (2) differential phosphorylation of SPL tyrosine and serine residues provides a key to understanding both. (Blood. 2015;126(24):2611-2620

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Regulating thrombus growth and stability to achieve an optimal response to injury

Cited by 68 publications

References 88 publications

Plasma fibronectin supports hemostasis and regulates thrombosis

Plasma fibronectin supports hemostasis and regulates thrombosis

Vessel wall BAMBI contributes to hemostasis and thrombus stability

Modulating platelet reactivity through control of RGS18 availability

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