Stored Platelets Release Nucleotides as Inhibitors of Platelet Function

Fijnheer, Rob; Boomgaard, M. N.; Eertwegh, J. M. Van Den; Homburg, Christa; Gouwerok, C. W. N.; Veldman, H. A.; Roos, Dirk; Korte, D. De

doi:10.1055/s-0038-1646323

Cited by 30 publications

(36 citation statements)

References 16 publications

(25 reference statements)

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“…Thus, adenine nucleotides may also directly limit ADPmediated reactivity of platelets (33,36,54,55). Like other members of the G protein coupled receptor family, some P2Y receptors readily undergo agonist-induced desensitization (56).…”

Section: Purinergic Receptorsmentioning

confidence: 99%

“…ATP and ADP appear to regulate hemostasis through the activation of platelet P2 receptors. ADP is a major platelet recruiting factor originating from platelet dense granules, released upon activation whereas ATP derived from the same sources is considered a competitive antagonist of ADP for platelet P2Y1 receptors (17,36,37). Platelet P2Y12 is perhaps the best known purinergic receptor and several drugs (thienopyridine agents e.g.…”

Section: Purinergic Receptorsmentioning

confidence: 99%

“…In a model of total hepatic ischemia and reperfusion injury we have shown a significantly decreased survival associated with increased biochemical and structural liver injury in Cd39-null animals as compared to wildtype controls (163). Furthermore, ADP is a major platelet recruiting factor originating from platelet dense granules during activation (17,36,37). ATP also stimulates endothelial cell production of prostacyclin (PGI2) and NO; two vasodilators and inhibitors of platelet aggregation (39,40).…”

Section: Liver Diseasementioning

confidence: 99%

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The role of purinergic signaling in the liver and in transplantation: effects of extracellular nucleotides on hepatic graft vascular injury, rejection and metabolism

Beldi

Enjyoji²,

Wu³

et al. 2008

Front Biosci

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Extracellular nucleotides (e.g. ATP, UTP, ADP) are released by activated endothelium, leukocytes and platelets within the injured vasculature and bind specific cell-surface type-2 purinergic (P2) receptors. This process drives vascular inflammation and thrombosis within grafted organs. Importantly, there are also vascular ectonucleotidases i.e. ectoenzymes that hydrolyze extracellular nucleotides in the blood to generate nucleosides (viz. adenosine). Endothelial cell NTPDase1/ CD39 has been shown to critically modulate levels of circulating nucleotides. This process tends to limit the activation of platelet and leukocyte expressed P2 receptors and also generates adenosine to reverse inflammatory events. This vascular protective CD39 activity is rapidly inhibited by oxidative reactions, such as is observed with liver ischemia reperfusion injury. In this review, we chiefly address the impact of these signaling cascades following liver transplantation. Interestingly, the hepatic vasculature, hepatocytes and all non-parenchymal cell types express several components co-ordinating the purinergic signaling response. With hepatic and vascular dysfunction, we note heightened P2-expression and alterations in ectonucleotidase expression and function that may predispose to progression of disease. In addition to documented impacts upon the vasculature during engraftment, extracellular nucleotides also have direct influences upon liver function and bile flow (both under physiological and pathological states). We have recently shown that alterations in purinergic signaling mediated by altered CD39 expression have major impacts NIH Public Access Author ManuscriptFront Biosci. Author manuscript; available in PMC 2010 June 25. Published in final edited form as:Front Biosci. ; 13: 2588-2603. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript upon hepatic metabolism, repair mechanisms, regeneration and associated immune responses. Future clinical applications in transplantation might involve new therapeutic modalities using soluble recombinant forms of CD39, altering expression of this ectonucleotidase by drugs and/or using small molecules to inhibit deleterious P2-mediated signaling while augmenting beneficial adenosine-mediated effects within the transplanted liver. KeywordsTransplantation; Liver; Purinergic Receptors; Bile; CD39; ecto-ATPase; Endothelium; Immunology; Metabolism; NTPDase; Platelet; Vasculature; Review INTRODUCTIONPurinergic signaling comprises release of extracellular nucleotides, stimulation of purinergic receptors and the modulation of nucleotide levels by ectoenzymes. Over the past decade, many advances have been made in the study of purinergic receptors and the regulation of extracellular nucleotide concentrations (1). It is now generally accepted that extracellular nucleotides (e.g. ATP, UTP, ADP), and the derivative nucleosides (e.g. adenosine from ATP), are released in a regulated manner by cells to provide the primary components for purinergic responses (2). Specific nucleo...

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Section: Purinergic Receptorsmentioning

confidence: 99%

Section: Purinergic Receptorsmentioning

confidence: 99%

Section: Liver Diseasementioning

confidence: 99%

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The role of purinergic signaling in the liver and in transplantation: effects of extracellular nucleotides on hepatic graft vascular injury, rejection and metabolism

Beldi

Enjyoji²,

Wu³

et al. 2008

Front Biosci

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“…It has been known for a long time that platelets can become refractory to activation by ADP in vitro (O'Brien, 1965;Spaet and Lejnieks, 1966) or after major surgical operations (O'Brien et al, 1971), which could represent a postsurgical bleeding risk. ADP accumulates extracellularly in suspensions of washed platelets and is sufficient to desensitize the aggregation response to ADP (Ardlie et al, 1971;Holme and Holmsen, 1975;Fijnheer et al, 1992). Addition of apyrase (ATP-diphosphohydrolase; EC 3.6.1.5), an ATP/ADP degrading enzyme extracted from potatoes, protects the cells from desensitization and enhances their aggregability (Ardlie et al, 1971;Holme and Holmsen, 1975;Fijnheer et al, 1992).…”

mentioning

confidence: 99%

Differential Regulation and Relocalization of the Platelet P2Y Receptors after Activation: A Way to Avoid Loss of Hemostatic Properties?

Baurand¹,

Eckly²,

Hechler³

et al. 2004

Mol Pharmacol

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In the present study, we investigated the desensitization and trafficking of the P2Y 1 and P2Y 12 receptors after agonist-induced stimulation of platelets or astrocytoma cells transfected with the P2Y 1 or P2Y 12 receptors fused to green fluorescent protein. In platelets and in transfected cells, exposure to 10 M ADP caused desensitization of the P2Y 1 receptor-driven calcium signal, whereas the P2Y 12 receptor-mediated inhibition of cAMP formation was not affected. Plasma membranes from ADP-stimulated platelets also retained P2Y 12 activity. Agonistinduced P2Y 1 receptor desensitization was accompanied by its internalization in platelets and transfected cells. In contrast, although a substantial fraction of P2Y 12 receptors was rapidly and transiently internalized, most of the P2Y 12 receptors remained at the plasma membrane. Activated P2Y 1 receptors were internalized through a clathrin-dependent pathway in cells and platelets, whereas the P2Y 12 receptors seemed to use a distinct, clathrin-independent pathway. Together, these data indicate that the P2Y 1 and P2Y 12 receptors are differentially regulated upon activation. The absence of desensitization of the Gi protein-coupled P2Y 12 receptor-dependent responses could represent a mechanism to preserve the hemostatic properties of otherwise unresponsive platelets.

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“…Concerning p-Nacetylglucosaminidase activity, no lysosome content secretion in the storage container could account for a decrease in the supernatant activity since the total suspension activity remained constant. Investigations on secretory mechanisms showed that dense granule [20] and alpha granule [21] releases occurred during storage. It has also been reported [22, 231 that lysosome content secretion is the ultimate response of platelets when activated by strong agonists such as thrombin or A23187.…”

Section: Discussionmentioning

confidence: 99%

Loss of phospholipid asymmetry in human platelet plasma membrane after 1–12 days of storage

Gaffet¹,

Bassé²,

Bienvenüe³

1994

European Journal of Biochemistry

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We used paramagnetic analogs of endogenous phospholipids to study modification of phospholipid distribution in platelet plasma membranes during aging. Asymmetrical distributions and translocation kinetics were very different for spin-labeled phosphatidylserine and spin-labeled phosphatidylcholine in fresh platelet plasma membranes. In freshly prepared platelets and up to day 7, spin-labeled phosphatidylserine very rapidly penetrated to the inner leaflet of the platelet plasma membrane. However, spin-labeled phosphatidylcholine was mainly retained on the external leaflet. From day 7 to day 9, the two translocation kinetics became identical with symmetrical distribution of both spin-labeled phospholipids at equilibrium. Inhibition of translocase activity and modification of membrane stability accounted for these transformations. The rapid re-exposition of spin-labeled phosphatidylserine after stimulation by the calcium ionophore A231 87, measured in fresh platelet concentrates, persisted up to day 9 but disappeared between day 10 and day 12. From day 7 to day 9, a strong cytoskeleton proteolysis and marked decrease in intracellular ATP were observed. Moreover, complete suppression of P-N-acetyl glucosaminidase secretion and vesicle formation after A23187 stimulation of aged platelets indicated that platelets could no longer be activated beyond day 9. Taken together, these results showed that during in vitro aging there are metabolic and membrane modifications in platelet similar to those described for platelet activation. In addition, all of the observed events occurred simultaneously between day 7 and day 9. These results highlight the importance of maintaining plasma membrane asymmetry to increase the hemostatic effectiveness of transfused platelet concentrates.The coagulation cascade begins after vascular injury to maintain hemostasis in the circulatory blood system. Briefly, the coagulation process starts when blood platelets interact with the tissue factor released by subendothelium cells, inducing platelet activation close to the lesion [l]. These activated platelets undergo several transformations such as skeleton proteolysis, granule secretion, vesicle shedding, shape change and lose their transmembrane phospholipid asymmetry to acquire a surface rich in phosphatidylserine (PtdSer) and phosphatidylethanolamine (PtdEtn) [2-41. All coagulation events then occur and result in formation of the hemostatic plug.Storage lesion, a phenomenon very similar to platelet activation transformation, was observed during in vitro aging of blood bank platelet concentrates. In fact, skeleton proteolysis, degranulation, shape change and vesicle formation have been described during in vitro platelet aging, whereas phos- The aim of this study was to investigate modifications in PL distribution in the plasma membrane during in vitro platelet aging. The study was carried out using paramagnetic phospholipids that were previously described to be good reporters for endogenous PL movements [7, 81. Cytoskeleton proteolysis and intrace...

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Stored Platelets Release Nucleotides as Inhibitors of Platelet Function

Cited by 30 publications

References 16 publications

The role of purinergic signaling in the liver and in transplantation: effects of extracellular nucleotides on hepatic graft vascular injury, rejection and metabolism

The role of purinergic signaling in the liver and in transplantation: effects of extracellular nucleotides on hepatic graft vascular injury, rejection and metabolism

Differential Regulation and Relocalization of the Platelet P2Y Receptors after Activation: A Way to Avoid Loss of Hemostatic Properties?

Loss of phospholipid asymmetry in human platelet plasma membrane after 1–12 days of storage

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