Skip to main content
SpringerLink
Log in

Platelet Prostanoids and their receptors

  • Chapter
  • First Online:
Platelets in Thrombotic and Non-Thrombotic Disorders

Abstract

The prostanoids, which include the prostaglandins (PGs) and thromboxane (Tx)A2, are a family of locally acting lipid mediators. Two isozymes, cyclooxygenase (COX)-1 and COX-2, of which only COX-1 is expressed in mature platelets, form an unstable intermediate product, PGH2, from arachidonic acid released from membrane phospholipids. At least nine PG synthases metabolize PGH2 further to five biologically active prostanoids, which each act through one or more specific G-protein coupled receptor.

These components of the arachidonic acid biosynthetic response pathway all underlie cell-specific regulation and affect platelet biology through a diverse array of signaling events. The primary prostanoid synthesized by platelets is TxA2, which via the TP receptor acts as an amplification signal to recruit further platelets to a growing blood clot. Patients with genetic defects in the TxA2 pathway have a mild bleeding disorder, and pharmacological suppression of TxA2 formation or signaling causes platelet inhibition. Suppression of TxA2 formation is also the mechanism by which aspirin reduces the incidence of myocardial infarction and stroke. Prostacyclin (PGI2) acting through the IP receptor is the most potent endogenous platelet inhibitor. It is formed by COX-1 and COX-2 in the vasculature and serves to constrain platelet clotting to the site of vascular injury. The inhibition of COX-2-dependent PGI2 formation by COX-2-selective nonsteroidal anti-inflammatory drugs (NSAIDs) explains their increased risk of myocardial infarction and stroke. The role of other prostanoids in platelet biology is less established. PGD2 is synthesized upon platelet activation in a process that involves both platelet COX-1 and plasma PGD synthase. Acting through its inhibitory DP1 receptor on platelets, it may afford a self-regulating response to thrombogenic stimuli. PGE2, which is formed in smaller amounts than PGD2 during clotting, can either enhance platelet activation, via the EP3 receptor, or inhibit platelet aggregation via the IP or possibly EP2 or EP4 receptors. Platelet EP receptor signaling has been hypothesized to play a role in modulating platelet function in fetal and neonatal circulation and in atherosclerosis. Prostaglandin F2α is also formed during platelet activation by various agonists, and higher concentrations inhibit platelets through cross-reaction with other prostanoid receptors.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 299.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 379.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 379.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Alberghina M (2010) Phospholipase A2: new lessons from endothelial cells. Microvasc Res 80(2):280–285

    Article  CAS  PubMed  Google Scholar 

  • Andersen NH, Eggerman TL, Harker LA, Wilson CH, De B (1980) On the multiplicity of platelet prostaglandin receptors. I: Evaluation of competitive antagonism by aggregometry. Prostaglandins 19(5):711–735

    Article  CAS  PubMed  Google Scholar 

  • Angiolillo DJ, Hwang C, Datto C, Desai B, Sostek M (2011) Impact of a fixed-dose combination of naproxen and esomeprazole magnesium on serum thromboxane B2 inhibition by low-dose aspirin over 5 days in healthy adults: a phase I, randomized, double-blind, placebo-controlled, noninferiority trial. Clin Ther 33(12):1883–1893

    Article  CAS  PubMed  Google Scholar 

  • Anzellotti P, Capone ML, Jeyam A, Tacconelli S, Bruno A, Tontodonati P, Di Francesco L, Grossi L, Renda G, Merciaro G, Di Gregorio P, Price TS, Garcia Rodriguez LA, Patrignani P (2011) Low-dose naproxen interferes with the antiplatelet effects of aspirin in healthy subjects: recommendations to minimize the functional consequences. Arthritis Rheum 63(3):850–859

    Article  CAS  PubMed  Google Scholar 

  • Arehart E, Stitham J, Asselbergs FW, Douville K, MacKenzie T, Fetalvero KM, Gleim S, Kasza Z, Rao Y, Martel L, Segel S, Robb J, Kaplan A, Simons M, Powell RJ, Moore JH, Rimm EB, Martin KA, Hwa J (2008) Acceleration of cardiovascular disease by a dysfunctional prostacyclin receptor mutation: potential implications for cyclooxygenase-2 inhibition. Circ Res 102(8):986–993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Armstrong RA, Jones RL, Wilson NH (1985) Mechanism of the inhibition of platelet aggregation produced by prostaglandin F2α. Prostaglandins 29(4):601–610

    Article  CAS  PubMed  Google Scholar 

  • Audoly LP, Rocca B, Fabre JE, Koller BH, Thomas D, Loeb AL, Coffman TM, FitzGerald GA (2000) Cardiovascular responses to the isoprostanes iPF2α-III and iPE2-III are mediated via the thromboxane A2 receptor in vivo. Circulation 101(24):2833–2840

    Article  CAS  PubMed  Google Scholar 

  • Boilard E, Larabee K, Shnayder R, Jacobs K, Farndale RW, Ware J, Lee DM (2011) Platelets participate in synovitis via Cox-1-dependent synthesis of prostacyclin independently of microparticle generation. J Immunol 186(7):4361–4366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bousser MG, Amarenco P, Chamorro A, Fisher M, Ford I, Fox KM, Hennerici MG, Mattle HP, Rothwell PM, de Cordoue A, Fratacci MD, Investigators PS (2011) Terutroban versus aspirin in patients with cerebral ischaemic events (PERFORM): a randomised, double-blind, parallel-group trial. Lancet 377(9782):2013–2022

    Article  CAS  PubMed  Google Scholar 

  • Brash AR, Jackson EK, Saggese CA, Lawson JA, Oates JA, FitzGerald GA (1983) Metabolic disposition of prostacyclin in humans. J Pharmacol Exp Ther 226(1):78–87

    CAS  PubMed  Google Scholar 

  • Breder CD, Dewitt D, Kraig RP (1995) Characterization of inducible cyclooxygenase in rat brain. J Comp Neurol 355(2):296–315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buerkle MA, Lehrer S, Sohn HY, Conzen P, Pohl U, Krotz F (2004) Selective inhibition of cyclooxygenase-2 enhances platelet adhesion in hamster arterioles in vivo. Circulation 110(14):2053–2059

    Article  CAS  PubMed  Google Scholar 

  • Burke JE, Dennis EA (2009) Phospholipase A2 structure/function, mechanism, and signaling. J Lipid Res 50(Suppl):S237–S242

    PubMed  PubMed Central  Google Scholar 

  • Canobbio I, Reineri S, Sinigaglia F, Balduini C, Torti M (2004) A role for p38 MAP kinase in platelet activation by von Willebrand factor. Thromb Haemost 91(1):102–110

    CAS  PubMed  Google Scholar 

  • Capone ML, Sciulli MG, Tacconelli S, Grana M, Ricciotti E, Renda G, Di Gregorio P, Merciaro G, Patrignani P (2005) Pharmacodynamic interaction of naproxen with low-dose aspirin in healthy subjects. J Am Coll Cardiol 45(8):1295–1301

    Article  CAS  PubMed  Google Scholar 

  • Catella-Lawson F, McAdam B, Morrison BW, Kapoor S, Kujubu D, Antes L, Lasseter KC, Quan H, Gertz BJ, FitzGerald GA (1999) Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and vasoactive eicosanoids. J Pharmacol Exp Ther 289(2):735–741

    CAS  PubMed  Google Scholar 

  • Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco S, Tournier B, Vyas SN, FitzGerald GA (2001) Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 345(25):1809–1817

    Article  CAS  PubMed  Google Scholar 

  • Cathcart MC, Tamosiuniene R, Chen G, Neilan TG, Bradford A, O’Byrne KJ, Fitzgerald DJ, Pidgeon GP (2008) Cyclooxygenase-2-linked attenuation of hypoxia-induced pulmonary hypertension and intravascular thrombosis. J Pharmacol Exp Ther 326(1):51–58

    Article  CAS  PubMed  Google Scholar 

  • Censarek P, Steger G, Paolini C, Hohlfeld T, Grosser T, Zimmermann N, Fleckenstein D, Schror K, Weber AA (2007) Alternative splicing of platelet cyclooxygenase-2 mRNA in patients after coronary artery bypass grafting. Thromb Haemost 98(6):1309–1315

    CAS  PubMed  Google Scholar 

  • Channon JY, Leslie CC (1990) A calcium-dependent mechanism for associating a soluble arachidonoyl-hydrolyzing phospholipase A2 with membrane in the macrophage cell line RAW 264.7. J Biol Chem 265(10):5409–5413

    CAS  PubMed  Google Scholar 

  • Chen W, Pawelek TR, Kulmacz RJ (1999) Hydroperoxide dependence and cooperative cyclooxygenase kinetics in prostaglandin H synthase-1 and -2. J Biol Chem 274(29):20301–20306

    Article  CAS  PubMed  Google Scholar 

  • Chen L, Yang G, Grosser T (2013) Prostanoids and inflammatory pain. Prostaglandins Other Lipid Mediat 104–105:58–66

    Article  PubMed  CAS  Google Scholar 

  • Cheng Y, Austin SC, Rocca B, Koller BH, Coffman TM, Grosser T, Lawson JA, FitzGerald GA (2002) Role of prostacyclin in the cardiovascular response to thromboxane A2. Science 296(5567):539–541

    Article  CAS  PubMed  Google Scholar 

  • Cheng Y, Wang M, Yu Y, Lawson J, Funk CD, Fitzgerald GA (2006) Cyclooxygenases, microsomal prostaglandin E synthase-1, and cardiovascular function. J Clin Invest 116(5):1391–1399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Coyle AT, Miggin SM, Kinsella BT (2002) Characterization of the 5′ untranslated region of alpha and beta isoforms of the human thromboxane A2 receptor (TP). Differential promoter utilization by the TP isoforms. Eur J Biochem 269(16):4058–4073

    Article  CAS  PubMed  Google Scholar 

  • Cryan LM, Pidgeon GP, Fitzgerald DJ, O’Brien CJ (2006) COX-2 protects against thrombosis of the retinal vasculature in a mouse model of proliferative retinopathy. Mol Vis 12:405–414

    CAS  PubMed  Google Scholar 

  • DeWitt DL, Smith WL (1983) Purification of prostacyclin synthase from bovine aorta by immunoaffinity chromatography. Evidence that the enzyme is a hemoprotein. J Biol Chem 258(5):3285–3293

    CAS  PubMed  Google Scholar 

  • Diczfalusy U, Falardeau P, Hammarstrom S (1977) Conversion of prostaglandin endoperoxides to C17-hydroxy acids catalyzed by human platelet thromboxane synthase. FEBS Lett 84(2):271–274

    Article  CAS  PubMed  Google Scholar 

  • Fabre JE, Nguyen M, Athirakul K, Coggins K, McNeish JD, Austin S, Parise LK, FitzGerald GA, Coffman TM, Koller BH (2001) Activation of the murine EP3 receptor for PGE2 inhibits cAMP production and promotes platelet aggregation. J Clin Invest 107(5):603–610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • FitzGerald GA (1991) Mechanisms of platelet activation: thromboxane A2 as an amplifying signal for other agonists. Am J Cardiol 68(7):11B–15B

    Article  CAS  PubMed  Google Scholar 

  • Fitzgerald DJ, FitzGerald GA (2013) Historical lessons in translational medicine: cyclooxygenase inhibition and P2Y12 antagonism. Circ Res 112(1):174–194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • FitzGerald GA, Brash AR, Falardeau P, Oates JA (1981) Estimated rate of prostacyclin secretion into the circulation of normal man. J Clin Invest 68(5):1272–1275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • FitzGerald GA, Smith B, Pedersen AK, Brash AR (1984) Increased prostacyclin biosynthesis in patients with severe atherosclerosis and platelet activation. N Engl J Med 310(17):1065–1068

    Article  CAS  PubMed  Google Scholar 

  • FitzGerald GA, Catella F, Oates JA (1987) Eicosanoid biosynthesis in human cardiovascular disease. Hum Pathol 18(3):248–252

    Article  CAS  PubMed  Google Scholar 

  • Fries S, Grosser T, Price TS, Lawson JA, Kapoor S, DeMarco S, Pletcher MT, Wiltshire T, FitzGerald GA (2006) Marked interindividual variability in the response to selective inhibitors of cyclooxygenase-2. Gastroenterology 130(1):55–64

    Article  CAS  PubMed  Google Scholar 

  • Galliard-Grigioni KS, Reinhart WH (2009) A randomized, controlled study on the influence of acetaminophen, diclofenac, or naproxen on aspirin-induced inhibition of platelet aggregation. Eur J Pharmacol 609(1–3):96–99

    Article  CAS  PubMed  Google Scholar 

  • Garcia A, Quinton TM, Dorsam RT, Kunapuli SP (2005) Src family kinase and Erk-mediated thromboxane A2 generation is essential for vWf/GPIb-induced fibrinogen receptor activation in human platelets. Blood 106(10):3410–3414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gladding PA, Webster MW, Farrell HB, Zeng IS, Park R, Ruijne N (2008) The antiplatelet effect of six non-steroidal anti-inflammatory drugs and their pharmacodynamic interaction with aspirin in healthy volunteers. Am J Cardiol 101(7):1060–1063

    Article  CAS  PubMed  Google Scholar 

  • Grosser T, Yusuff S, Cheskis E, Pack MA, FitzGerald GA (2002) Developmental expression of functional cyclooxygenases in zebrafish. Proc Natl Acad Sci U S A 99(12):8418–8423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grosser T, Fries S, FitzGerald GA (2006) Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest 116(1):4–15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grosser T, Yu Y, Fitzgerald GA (2010) Emotion recollected in tranquility: lessons learned from the COX-2 saga. Annu Rev Med 61:17–33

    Article  CAS  PubMed  Google Scholar 

  • Grosser T, Smyth E, FitzGerald G (2011) Analgesic-antipyretic agents; pharmacotherapy of gout. In: Brunton L, Chabner B, Knollman B (eds) Goodman & Gilman’s the pharmacological basis of therapeutics. McGraw-Hill, New York, pp 959–1004

    Google Scholar 

  • Grosser T, Fries S, Lawson JA, Kapoor SC, Grant GR, FitzGerald GA (2013) Drug resistance and pseudoresistance: an unintended consequence of enteric coating aspirin. Circulation 127(3):377–385

    Article  CAS  PubMed  Google Scholar 

  • Group HTC, Landray MJ, Haynes R, Hopewell JC, Parish S, Aung T, Tomson J, Wallendszus K, Craig M, Jiang L, Collins R, Armitage J (2014) Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 371(3):203–212

    Article  CAS  Google Scholar 

  • Habib A, FitzGerald GA, Maclouf J (1999) Phosphorylation of the thromboxane receptor alpha, the predominant isoform expressed in human platelets. J Biol Chem 274(5):2645–2651

    Article  CAS  PubMed  Google Scholar 

  • Harris RC, McKanna JA, Akai Y, Jacobson HR, Dubois RN, Breyer MD (1994) Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J Clin Invest 94(6):2504–2510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hirata T, Kakizuka A, Ushikubi F, Fuse I, Okuma M, Narumiya S (1994) Arg60 to Leu mutation of the human thromboxane A2 receptor in a dominantly inherited bleeding disorder. J Clin Invest 94(4):1662–1667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hohlfeld T, Zimmermann N, Weber AA, Jessen G, Weber H, Schror K, Holtje HD, Ebel R (2008) Pyrazolinone analgesics prevent the antiplatelet effect of aspirin and preserve human platelet thromboxane synthesis. J Thromb Haemost 6(1):166–173

    Article  CAS  PubMed  Google Scholar 

  • Kaufmann WE, Worley PF, Pegg J, Bremer M, Isakson P (1996) COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex. Proc Natl Acad Sci U S A 93(6):2317–2321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kohsaka S, Volcik KA, Folsom AR, Wu KK, Ballantyne CM, Willerson JT, Boerwinkle E (2008) Increased risk of incident stroke associated with the cyclooxygenase 2 (COX-2) G-765C polymorphism in African-Americans: the Atherosclerosis Risk in Communities Study. Atherosclerosis 196(2):926–930

    Article  CAS  PubMed  Google Scholar 

  • Kramer RM, Checani GC, Deykin A, Pritzker CR, Deykin D (1986) Solubilization and properties of Ca2+-dependent human platelet phospholipase A2. Biochim Biophys Acta 878(3):394–403

    Article  CAS  PubMed  Google Scholar 

  • Kramer RM, Roberts EF, Um SL, Borsch-Haubold AG, Watson SP, Fisher MJ, Jakubowski JA (1996) p38 mitogen-activated protein kinase phosphorylates cytosolic phospholipase A2 (cPLA2) in thrombin-stimulated platelets. Evidence that proline-directed phosphorylation is not required for mobilization of arachidonic acid by cPLA2. J Biol Chem 271(44):27723–27729

    Article  CAS  PubMed  Google Scholar 

  • Lands WE (2000) Stories about acyl chains. Biochim Biophys Acta 1483(1):1–14

    Article  CAS  PubMed  Google Scholar 

  • Lemaitre RN, Rice K, Marciante K, Bis JC, Lumley TS, Wiggins KL, Smith NL, Heckbert SR, Psaty BM (2009) Variation in eicosanoid genes, non-fatal myocardial infarction and ischemic stroke. Atherosclerosis 204(2):e58–e63

    Article  CAS  PubMed  Google Scholar 

  • Li X, Fries S, Li R, Lawson JA, Propert KJ, Diamond SL, Blair IA, FitzGerald GA, Grosser T (2014) Differential impairment of aspirin-dependent platelet cyclooxygenase acetylation by nonsteroidal antiinflammatory drugs. Proc Natl Acad Sci U S A 111(47):16830–16835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin LL, Wartmann M, Lin AY, Knopf JL, Seth A, Davis RJ (1993) cPLA2 is phosphorylated and activated by MAP kinase. Cell 72(2):269–278

    Article  CAS  PubMed  Google Scholar 

  • Liu M, Saeki K, Matsunobu T, Okuno T, Koga T, Sugimoto Y, Yokoyama C, Nakamizo S, Kabashima K, Narumiya S, Shimizu T, Yokomizo T (2014) 12-Hydroxyheptadecatrienoic acid promotes epidermal wound healing by accelerating keratinocyte migration via the BLT2 receptor. J Exp Med 211(6):1063–1078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma H, Hara A, Xiao CY, Okada Y, Takahata O, Nakaya K, Sugimoto Y, Ichikawa A, Narumiya S, Ushikubi F (2001) Increased bleeding tendency and decreased susceptibility to thromboembolism in mice lacking the prostaglandin E receptor subtype EP3. Circulation 104(10):1176–1180

    Article  CAS  PubMed  Google Scholar 

  • Maclouf J, Kindahl H, Granstrom E, Samuelsson B (1980) Interactions of prostaglandin H2 and thromboxane A2 with human serum albumin. Eur J Biochem 109(2):561–566

    Article  CAS  PubMed  Google Scholar 

  • Mayeux PR, Kadowitz PJ, McNamara DB (1989) Evidence for a bidirectional prostaglandin endoperoxide shunt between platelets and the bovine coronary artery. Biochim Biophys Acta 1011(1):18–24

    Article  CAS  PubMed  Google Scholar 

  • McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, FitzGerald GA (1999) Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci U S A 96(1):272–277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murata T, Ushikubi F, Matsuoka T, Hirata M, Yamasaki A, Sugimoto Y, Ichikawa A, Aze Y, Tanaka T, Yoshida N, Ueno A, Oh-ishi S, Narumiya S (1997) Altered pain perception and inflammatory response in mice lacking prostacyclin receptor. Nature 388(6643):678–682

    Article  CAS  PubMed  Google Scholar 

  • Nakahata N (2008) Thromboxane A2: physiology/pathophysiology, cellular signal transduction and pharmacology. Pharmacol Ther 118(1):18–35

    Article  CAS  PubMed  Google Scholar 

  • Narumiya S, FitzGerald GA (2001) Genetic and pharmacological analysis of prostanoid receptor function. J Clin Invest 108(1):25–30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • O’Banion MK, Winn VD, Young DA (1992) cDNA cloning and functional activity of a glucocorticoid-regulated inflammatory cyclooxygenase. Proc Natl Acad Sci U S A 89(11):4888–4892

    Article  PubMed  PubMed Central  Google Scholar 

  • Oelz O, Oelz R, Knapp HR, Sweetman BJ, Oates JA (1977) Biosynthesis of prostaglandin D2. 1. Formation of prostaglandin D2 by human platelets. Prostaglandins 13(2):225–234

    Article  CAS  PubMed  Google Scholar 

  • Oestvang J, Johansen B (2006) Phospholipase A2: a key regulator of inflammatory signalling and a connector to fibrosis development in atherosclerosis. Biochim Biophys Acta 1761(11):1309–1316

    Article  CAS  PubMed  Google Scholar 

  • Palazzini E, Galli G, Babbini M (1990) Multiple-dose pharmacokinetics of naproxen from a controlled-release tablet in healthy volunteers. Int J Clin Pharmacol Res 10(5):277–284

    CAS  PubMed  Google Scholar 

  • Parent JL, Labrecque P, Driss Rochdi M, Benovic JL (2001) Role of the differentially spliced carboxyl terminus in thromboxane A2 receptor trafficking: identification of a distinct motif for tonic internalization. J Biol Chem 276(10):7079–7085

    Article  CAS  PubMed  Google Scholar 

  • Patrignani P, Sciulli MG, Manarini S, Santini G, Cerletti C, Evangelista V (1999) COX-2 is not involved in thromboxane biosynthesis by activated human platelets. J Physiol Pharmacol 50(4):661–667

    CAS  PubMed  Google Scholar 

  • Patrignani P, Tacconelli S, Piazuelo E, Di Francesco L, Dovizio M, Sostres C, Marcantoni E, Guillem-Llobat P, Del Boccio P, Zucchelli M, Patrono C, Lanas A (2014) Reappraisal of the clinical pharmacology of low-dose aspirin by comparing novel direct and traditional indirect biomarkers of drug action. J Thromb Haemost 12(8):1320–1330

    Article  CAS  PubMed  Google Scholar 

  • Patrono C (2015) The multifaceted clinical readouts of platelet inhibition by low-dose aspirin. J Am Coll Cardiol 66(1):74–85

    Article  CAS  PubMed  Google Scholar 

  • Patrono C, Garcia Rodriguez LA, Landolfi R, Baigent C (2005) Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 353(22):2373–2383

    Article  CAS  PubMed  Google Scholar 

  • Pedersen AK, FitzGerald GA (1984) Dose-related kinetics of aspirin. Presystemic acetylation of platelet cyclooxygenase. N Engl J Med 311(19):1206–1211

    Article  CAS  PubMed  Google Scholar 

  • Pidgeon GP, Tamosiuniene R, Chen G, Leonard I, Belton O, Bradford A, Fitzgerald DJ (2004) Intravascular thrombosis after hypoxia-induced pulmonary hypertension: regulation by cyclooxygenase-2. Circulation 110(17):2701–2707

    Article  PubMed  Google Scholar 

  • Reilly IA, FitzGerald GA (1987) Inhibition of thromboxane formation in vivo and ex vivo: implications for therapy with platelet inhibitory drugs. Blood 69(1):180–186

    CAS  PubMed  Google Scholar 

  • Ricciotti E, Yu Y, Grosser T, FitzGerald GA (2013) COX-2, the dominant source of prostacyclin. Proc Natl Acad Sci U S A 110(3):E183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rimon G, Sidhu RS, Lauver DA, Lee JY, Sharma NP, Yuan C, Frieler RA, Trievel RC, Lucchesi BR, Smith WL (2010) Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1. Proc Natl Acad Sci U S A 107(1):28–33

    Article  CAS  PubMed  Google Scholar 

  • Rocca B, Secchiero P, Ciabattoni G, Ranelletti FO, Catani L, Guidotti L, Melloni E, Maggiano N, Zauli G, Patrono C (2002) Cyclooxygenase-2 expression is induced during human megakaryopoiesis and characterizes newly formed platelets. PNAS 99(11):7634–7639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rosenstock M, Danon A, Rubin M, Rimon G (2001) Prostaglandin H synthase-2 inhibitors interfere with prostaglandin H synthase-1 inhibition by nonsteroidal anti-inflammatory drugs. Eur J Pharmacol 412(1):101–108

    Article  CAS  PubMed  Google Scholar 

  • Schlagenhauf A, Haidl H, Leschnik B, Leis HJ, Heinemann A, Muntean W (2015) Prostaglandin E2 levels and platelet function are different in cord blood compared to adults. Thromb Haemost 113(1):97–106

    Article  PubMed  Google Scholar 

  • Schror K, Bretschneider E, Fischer K, Fischer JW, Pape R, Rauch BH, Rosenkranz AC, Weber AA (2010) Thrombin receptors in vascular smooth muscle cells - function and regulation by vasodilatory prostaglandins. Thromb Haemost 103(5):884–890

    Article  PubMed  CAS  Google Scholar 

  • Seta F, Chung AD, Turner PV, Mewburn JD, Yu Y, Funk CD (2009) Renal and cardiovascular characterization of COX-2 knockdown mice. Am J Physiol Regul Integr Comp Physiol 296(6):R1751–R1760

    Article  CAS  PubMed  Google Scholar 

  • Smith WL, DeWitt DL, Garavito RM (2000) Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem 69:145–182

    Article  CAS  PubMed  Google Scholar 

  • Smith WL, Urade Y, Jakobsson PJ (2011) Enzymes of the cyclooxygenase pathways of prostanoid biosynthesis. Chem Rev 111(10):5821–5865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smyth EM, Burke A, FitzGerald GA (2005) Lipid-derived autacoids. In: Brunton LL, Lazo JS, Parker KL (eds) Goodman & Gilman’s the pharmacological basis of therapeutics. McGraw-Hill, New-York, pp 653–670

    Google Scholar 

  • Smyth EM, Grosser T, Wang M, Yu Y, Fitzgerald GA (2008) Prostanoids in health and disease. J Lipid Res 50(Suppl):S423–S428

    Article  PubMed  CAS  Google Scholar 

  • So OY, Scarafia LE, Mak AY, Callan OH, Swinney DC (1998) The dynamics of prostaglandin H synthases. Studies with prostaglandin H synthase 2 Y355F unmask mechanisms of time-dependent inhibition and allosteric activation. J Biol Chem 273(10):5801–5807

    Article  CAS  PubMed  Google Scholar 

  • Song WL, FitzGerald GA (2013) Niacin, an old drug with a new twist. J Lipid Res 54(10):2586–2594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song WL, Stubbe J, Ricciotti E, Alamuddin N, Ibrahim S, Crichton I, Prempeh M, Lawson JA, Wilensky RL, Rasmussen LM, Pure E, FitzGerald GA (2012) Niacin and biosynthesis of PGD2 by platelet COX-1 in mice and humans. J Clin Invest 122(4):1459–1468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Svensson J, Hamberg M, Samuelsson B (1975) Prostaglandin endoperoxides IX. Characterization of rabbit aorta contracting substance (RCS) from guinea pig lung and human platelets. Acta Physiol Scand 94(2):222–228

    Article  CAS  PubMed  Google Scholar 

  • Thomas DW, Mannon RB, Mannon PJ, Latour A, Oliver JA, Hoffman M, Smithies O, Koller BH, Coffman TM (1998) Coagulation defects and altered hemodynamic responses in mice lacking receptors for thromboxane A2. J Clin Invest 102:1994–2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tilly P, Charles AL, Ludwig S, Slimani F, Gross S, Meilhac O, Geny B, Stefansson K, Gurney ME, Fabre JE (2014) Blocking the EP3 receptor for PGE2 with DG-041 decreases thrombosis without impairing haemostatic competence. Cardiovasc Res 101(3):482–491

    Article  CAS  PubMed  Google Scholar 

  • Vezza R, Habib A, FitzGerald GA (1999) Differential signaling by the thromboxane receptor isoforms via the novel GTP-binding protein, Gh. J Biol Chem 274(18):12774–12779

    Article  CAS  PubMed  Google Scholar 

  • Vree TB, van den Biggelaar-Martea M, Verwey-van Wissen CP, Vree JB, Guelen PJ (1993) Pharmacokinetics of naproxen, its metabolite O-desmethylnaproxen, and their acyl glucuronides in humans. Biopharm Drug Dispos 14(6):491–502

    Article  CAS  PubMed  Google Scholar 

  • Willingale HL, Gardiner NJ, McLymont N, Giblett S, Grubb BD (1997) Prostanoids synthesized by cyclo-oxygenase isoforms in rat spinal cord and their contribution to the development of neuronal hyperexcitability. Br J Pharmacol 122(8):1593–1604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wilson SJ, Roche AM, Kostetskaia E, Smyth EM (2004) Dimerization of the human receptors for prostacyclin and thromboxane facilitates thromboxane receptor-mediated cAMP generation. J Biol Chem 279(51):53036–53047

    Article  CAS  PubMed  Google Scholar 

  • Woodward DF, Jones RL, Narumiya S (2011) International Union of Basic and Clinical Pharmacology. LXXXIII: classification of prostanoid receptors, updating 15 years of progress. Pharmacol Rev 63(3):471–538

    Article  CAS  PubMed  Google Scholar 

  • Wu KK, Liou JY (2005) Cellular and molecular biology of prostacyclin synthase. Biochem Biophys Res Commun 338(1):45–52

    Article  CAS  PubMed  Google Scholar 

  • Yamagata K, Andreasson KI, Kaufmann WE, Barnes CA, Worley PF (1993) Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron 11(2):371–386

    Article  CAS  PubMed  Google Scholar 

  • Yu Y, Ricciotti E, Grosser T, Fitzgerald GA (2009) The translational therapeutics of prostaglandin inhibition in atherothrombosis. J Thromb Haemost 7(Suppl 1):222–226

    Article  CAS  PubMed  Google Scholar 

  • Yu Y, Ricciotti E, Scalia R, Tang SY, Grant G, Yu Z, Landesberg G, Crichton I, Wu W, Pure E, Funk CD, FitzGerald GA (2012) Vascular COX-2 modulates blood pressure and thrombosis in mice. Sci Transl Med 4(132):132ra154

    Article  Google Scholar 

  • Yuan C, Rieke CJ, Rimon G, Wingerd BA, Smith WL (2006) Partnering between monomers of cyclooxygenase-2 homodimers. Proc Natl Acad Sci U S A 103(16):6142–6147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zagol-Ikapite I, Sosa IR, Oram D, Judd A, Amarnath K, Amarnath V, Stec D, Oates JA, Boutaud O (2015) Modification of platelet proteins by malondialdehyde: prevention by dicarbonyl scavengers. J Lipid Res 56(11):2196–2205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zimmermann N, Wenk A, Kim U, Kienzle P, Weber AA, Gams E, Schror K, Hohlfeld T (2003) Functional and biochemical evaluation of platelet aspirin resistance after coronary artery bypass surgery. Circulation 108(5):542–547

    Article  CAS  PubMed  Google Scholar 

  • Zou H, Yuan C, Dong L, Sidhu RS, Hong YH, Kuklev DV, Smith WL (2012) Human cyclooxygenase-1 activity and its responses to COX inhibitors are allosterically regulated by nonsubstrate fatty acids. J Lipid Res 53(7):1336–1347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA, 19104-6084, USA

    Susanne Fries M.D. & Tilo Grosser M.D.

Authors
  1. Susanne Fries M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tilo Grosser M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tilo Grosser M.D. .

Editor information

Editors and Affiliations

  1. Department of Medicine, Section of Internal and Cardiovascular Medicine, University of Perugia , Perugia, Italy

    Paolo Gresele

  2. Houston Methodist Hospital , Houston, Texas, USA

    Neal S. Kleiman

  3. Bloodworks Northwest, University of Washington , Seattle, Washington, USA

    José A. Lopez

  4. Sackler Inst of Pulmonary Pharmacol, King’s College London, London, United Kingdom

    Clive P. Page

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Fries, S., Grosser, T. (2017). Platelet Prostanoids and their receptors. In: Gresele, P., Kleiman, N., Lopez, J., Page, C. (eds) Platelets in Thrombotic and Non-Thrombotic Disorders. Springer, Cham. https://doi.org/10.1007/978-3-319-47462-5_15

Download citation

Publish with us

Policies and ethics

Search

Navigation