Platelet ADP receptors contribute to the initiation of intravascular coagulation

Léon, Catherine; Alex, Meike; Klocke, Antje; Morgenstern, Eberhard; Moosbauer, Christine; Eckly, Anita; Spannagl, Michael; Gachet, Christian; Engelmann, Bernd

doi:10.1182/blood-2003-05-1385

Cited by 118 publications

(73 citation statements)

References 37 publications

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“…This is also the case in the procoagulant activity of platelets. While both receptors are indirectly involved through their role in platelet P-selectin exposure and in the formation of platelet-leukocyte conjugates leading to leukocyte tissue factor exposure [81,82], the P2Y 12 receptor is also directly implicated in the exposure of phosphatidylserine at the surface of platelets [81,83,84].…”

Section: Receptormentioning

confidence: 99%

P2 receptors and platelet function

Hechler

Gachet

2011

Purinergic Signalling

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138

127

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Following vessel wall injury, platelets adhere to the exposed subendothelium, become activated and release mediators such as TXA 2 and nucleotides stored at very high concentration in the so-called dense granules. Released nucleotides and other soluble agents act in a positive feedback mechanism to cause further platelet activation and amplify platelet responses induced by agents such as thrombin or collagen. Adenine nucleotides act on platelets through three distinct P2 receptors: two are G proteincoupled ADP receptors, namely the P2Y 1 and P2Y 12 receptor subtypes, while the P2X 1 receptor ligand-gated cation channel is activated by ATP. The P2Y 1 receptor initiates platelet aggregation but is not sufficient for a full platelet aggregation in response to ADP, while the P2Y 12 receptor is responsible for completion of the aggregation to ADP. The latter receptor, the molecular target of the antithrombotic drugs clopidogrel, prasugrel and ticagrelor, is responsible for most of the potentiating effects of ADP when platelets are stimulated by agents such as thrombin, collagen or immune complexes. The P2X 1 receptor is involved in platelet shape change and in activation by collagen under shear conditions. Each of these receptors is coupled to specific signal transduction pathways in response to ADP or ATP and is differentially involved in all the sequential events involved in platelet function and haemostasis. As such, they represent potential targets for antithrombotic drugs.

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Section: Receptormentioning

confidence: 99%

P2 receptors and platelet function

Hechler

Gachet

2011

Purinergic Signalling

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138

127

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“…Both P2Y 1 and P2Y 12 activation leads to the expression of platelet P-selectin and the formation of platelet-leukocyte complexes (Leon et al, 2003(Leon et al, , 2004. The activation of platelets via chemokines and low levels of primary agonists such as ADP have been shown to be dependent on the purinergic P2Y 1 receptor rather than the P2Y 12 receptor , which is believed to have a greater role in sustained thrombus formation (Leon et al, 2003;Nylander et al, 2003;Mazzucato et al, 2004).…”

Section: Purinergic Receptor Antagonistsmentioning

confidence: 99%

Novel uses for anti‐platelet agents as anti‐inflammatory drugs

Pitchford

2007

British J Pharmacology

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An alteration in the character and function of platelets is manifested in patients with inflammatory diseases, and these alterations have been dissociated from the well‐characterized involvement of platelets in thrombosis and haemostasis. Recent evidence reveals platelet activation is sometimes critical in the development of inflammation. The mechanisms by which platelets participate in inflammation are diverse, and offer numerous opportunities for future drug intervention. There is now acceptance that platelets act as innate inflammatory cells in immune responses, with roles as sentinel cells undergoing surveillance, responding to microbial invasion, orchestrating leukocyte recruitment, and migrating through tissue, causing damage and influencing repair processes in chronic disease. Some of these processes are targeted by drugs that are being developed to target platelet participation in atherosclerosis. The actions of platelets therefore influence the pathogenesis of diverse inflammatory diseases in various body compartments, encompassing parasitic and bacterial infection, allergic inflammation (especially asthma and rhinitis), and non‐atopic inflammatory conditions, for example, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and atherosclerosis. This review will first discuss the evidence for platelet activation in these various inflammatory diseases, and secondly discuss the mechanisms by which this pathogenesis occurs and the various anti‐platelet agents which have been developed to combat platelet activation in atherosclerosis and their potential future use for the treatment of other inflammatory diseases.British Journal of Pharmacology (2007) 152, 987–1002; doi:10.1038/sj.bjp.0707364; published online 2 July 2007

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“…Sepsis is, however, in general followed by a reduced amount of red blood cells, partly as a result of hemolysis and partly because of eryptosis (''apoptosis'' in erythrocytes) (51). It is known that pore-forming toxins activate human platelets (52), and that platelet ADP receptors contribute to the initiation of intravascular coagulation (29). Pore-forming bacterial toxins in the blood are likely to release ATP, which might in the end trigger thrombocyte aggregation.…”

Section: Hlya-induced Hemolysis Is Prevented By Pannexin1mentioning

confidence: 99%

α-Hemolysin from Escherichia coli uses endogenous amplification through P2X receptor activation to induce hemolysis

Skals

Jørgensen

Leipziger

et al. 2009

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

118

165

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Escherichia coli is the dominant facultative bacterium in the normal intestinal flora. E. coli is, however, also responsible for the majority of serious extraintestinal infections. There are distinct serotypical differences between facultative and invasive E. coli strains. Invasive strains frequently produce virulence factors such as ␣-hemolysin (HlyA), which causes hemolysis by forming pores in the erythrocyte membrane. The present study reveals that this pore formation triggers purinergic receptor activation to mediate the full hemolytic action. Non-selective ATP-receptor (P2) antagonists (PPADS, suramin) and ATP scavengers (apyrase, hexokinase) concentration dependently inhibited HlyA-induced lysis of equine, murine, and human erythrocytes. The pattern of responsiveness to more selective P2-antagonists implies that both P2X 1 and P2X7 receptors are involved in HlyA-induced hemolysis in all three species. In addition, our results also propose a role for the pore protein pannexin1 in HlyA-induced hemolysis, as non-selective inhibitors of this channel significantly reduced hemolysis in the three species. In conclusion, activation of P2X receptors and possibly also pannexins augment hemolysis induced by the bacterial toxin, HlyA. These findings potentially have clinical perspectives as P2 antagonists may ameliorate symptoms during sepsis with hemolytic bacteria.alpha-hemolysin ͉ E. coli ͉ erythrocytes ͉ hemolysis ͉ P2X

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Platelet ADP receptors contribute to the initiation of intravascular coagulation

Cited by 118 publications

References 37 publications

P2 receptors and platelet function

P2 receptors and platelet function

Novel uses for anti‐platelet agents as anti‐inflammatory drugs

α-Hemolysin from Escherichia coli uses endogenous amplification through P2X receptor activation to induce hemolysis

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