Hyperreactive platelet phenotypes: Relationship to altered serotonin transporter number, transport kinetics and intrinsic response to adrenergic co-stimulation

 

 Buy Article Permissions and Reprints

Summary

The mechanism underlying a hyperreactive platelet phenotype remains unknown. Since serotonin has been shown to influence platelet biology and atherothrombosis, we sought to investigate the association of platelet serotonin transporter number, binding affinity, and uptake kinetics with platelet aggregation. A total of 542 healthy volunteers had light transmittance platelet aggregometry measured in response to varying concentrations of epinephrine, serotonin, epinephrine plus serotonin, ADP and collagen. Transporter-dependent serotonin uptake rate was determined (V_max), as were serotonin transporter number (B_max) and binding affinity (Kd) using ³H paroxetine binding in a homologous displacement assay, nonlinear regression and validated algorithms for kinetic modelling. Stimulation with submaximal (2μM) epinephrine concentration elicited a distinct, bimodal pattern of platelet aggregation in this population. In contrast, subjects exhibited minimal aggregation in response to serotonin alone. Co-stimulation with submaximal epinephrine and serotonin induced platelet aggregation to a level beyond that observed with either agonist alone and maintained a bimodal response distribution. Subjects with heightened (>60%) platelet aggregation to both epinephrine alone and epinephrine plus serotonin exhibited increased platelet serotonin uptake, and transporter number and affinity. In a population of healthy subjects, co-stimulation with submaximal concentrations of epinephrine and serotonin identifies a subset of individuals with a hyperreactive platelet aggregation profile that is associated with changes in platelet serotonin function.

• References

• 1 Davi G, Patrono C. Platelet activation and atherothrombosis. New Engl J Med 2007; 357: 2482-2494. DOI:10.1056/NEJMra071014.
  CrossrefPubMedGoogle Scholar
• 2 Ruggeri ZM. Platelets in atherothrombosis. Nature Med 2002; 08: 1227-1234. DOI:10.1038/nm1102-1227.
  CrossrefPubMedGoogle Scholar
• 3 Vorchheimer DA, Becker R. Platelets in atherothrombosis. Mayo Clin Proc 2006; 81: 59-68. DOI:10.4065/81.1.59.
  CrossrefPubMedGoogle Scholar
• 4 Elwood PC, Renaud S, Sharp DS. et al. Ischemic heart disease and platelet aggregation. The Caerphilly Collaborative Heart Disease Study. Circulation 1991; 83: 38-44. DOI:10.1161/01.CIR.83.1.38.
  CrossrefPubMedGoogle Scholar
• 5 Gurbel PA, Becker RC, Mann KG. et al. Platelet function monitoring in patients with coronary artery disease. J Am Coll Cardiol 2007; 50: 1822-1834. DOI:10.1016/j.jacc.2007.07.051.
  CrossrefPubMedGoogle Scholar
• 6 Trip MD, Cats VM, van Capelle FJ. et al. Platelet hyperreactivity and prognosis in survivors of myocardial infarction. New Engl J Med 1990; 322: 1549-1554. DOI:10.1056/NEJM199005313222201.
  CrossrefPubMedGoogle Scholar
• 7 Michelson AD. Platelet function testing in cardiovascular diseases. Circulation 2004; 110: e489-493. DOI:10.1161/01.CIR.0000147228.29325.F9.
  CrossrefPubMedGoogle Scholar
• 8 Sharma G, Berger JS. Platelet activity and cardiovascular risk in apparently healthy individuals: a review of the data. J Thromb Thrombolysis 2011; 32: 201-208. DOI:10.1007/s11239-011-0590-9.
  CrossrefPubMedGoogle Scholar
• 9 Yee DL, Sun CW, Bergeron AL. et al. Aggregometry detects platelet hyperreactivity in healthy individuals. Blood 2005; 106: 2723-2729. DOI:10.1182/blood-2005-03-1290.
  CrossrefPubMedGoogle Scholar
• 10 Yee DL, Bergeron AL, Sun CW. et al. Platelet hyperreactivity generalizes to multiple forms of stimulation. J Thromb Haemost 2006; 04: 2043-2050. DOI:10.1111/j.1538-7836.2006.02089.x.
  CrossrefPubMedGoogle Scholar
• 11 Yoshida N, Aoki N. Potentiation by collagen or epinephrine of platelet responsiveness to aggregation. The possible role of substance(s) released from platelet membranes. J Lab Clin Med 1977; 89: 603-614.
  PubMedGoogle Scholar
• 12 Huang EM, Detwiler TC. Characteristics of the synergistic actions of platelet agonists. Blood 1981; 57: 685-691.
  PubMedGoogle Scholar
• 13 Kinlough-Rathbone RL, Packham MA, Mustard JF. Synergism between platelet aggregating agents: the role of the arachidonate pathway. Thrombosis Res 1977; 11: 567-580. DOI:10.1016/0049-3848(77)90016-0.
  CrossrefPubMedGoogle Scholar
• 14 De Clerck F. The role of serotonin in thrombogenesis. Clin Physiol Biochemy 1990; 08 (03) 40-49.
  PubMedGoogle Scholar
• 15 Li N, Wallen NH, Ladjevardi M. et al. Effects of serotonin on platelet activation in whole blood. Blood Coagul Fibrinol 1997; 08: 517-523. DOI:10.1097/00001721-199711000-00006.
  CrossrefPubMedGoogle Scholar
• 16 Eidt JF, Ashton J, Golino P. et al. Thromboxane A2 and serotonin mediate coronary blood flow reductions in unsedated dogs. Am J Physiol 1989; 257: H873-882.
  PubMedGoogle Scholar
• 17 Ashton JH, Benedict CR, Fitzgerald C. et al. Serotonin as a mediator of cyclic flow variations in stenosed canine coronary arteries. Circulation 1986; 73: 572-578. DOI:10.1161/01.CIR.73.3.572.
  CrossrefPubMedGoogle Scholar
• 18 Flad HD, Brandt E. Platelet-derived chemokines: pathophysiology and therapeutic aspects. Cell Mol Life Sci 2010; 67: 2363-2386. DOI:10.1007/s00018-010-0306-x.
  CrossrefPubMedGoogle Scholar
• 19 Otterdal K, Smith C, Oie E. et al. Platelet-derived LIGHT induces inflammatory responses in endothelial cells and monocytes. Blood 2006; 108: 928-935. DOI:10.1182/blood-2005-09-010629.
  CrossrefPubMedGoogle Scholar
• 20 Zarbock A, Polanowska-Grabowska RK, Ley K. Platelet-neutrophil-interactions: linking hemostasis and inflammation. Blood Rev 2007; 21: 99-111. DOI:10.1016/j.blre.2006.06.001.
  CrossrefPubMedGoogle Scholar
• 21 Walker RF, Codd EE. Neuroimmunomodulatory interactions of norepinephrine and serotonin. J Neuroimmunol 1985; 10: 41-58. DOI:10.1016/0165-5728(85)90033-5.
  CrossrefPubMedGoogle Scholar
• 22 Thompson NT, Scrutton MC, Wallis RB. Synergistic responses in human platelets. Comparison between aggregation, secretion and cytosolic Ca2+ concentration. Eur J Biochem 1986; 161: 399-408. DOI:10.1111/j.1432-1033.1986.tb10459.x.
  CrossrefPubMedGoogle Scholar
• 23 Tofler GH, Brezinski D, Schafer AI. et al. Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl J Med 1987; 316: 1514-1518. DOI:10.1056/NEJM198706113162405.
  CrossrefPubMedGoogle Scholar
• 24 Nemeroff CB, Knight DL, Krishnan RR. et al. Marked reduction in the number of platelet-tritiated imipramine binding sites in geriatric depression. Arch Gen Psychiatry 1988; 45: 919-923. DOI:10.1001/archpsyc.1988.01800340045006.
  CrossrefPubMedGoogle Scholar
• 25 Slotkin TA, McCook EC, Ritchie JC. et al. Serotonin transporter expression in rat brain regions and blood platelets: aging and glucocorticoid effects. Biol Psych 1997; 41: 172-183. DOI:10.1016/S0006-3223(96)00215-6.
  CrossrefPubMedGoogle Scholar
• 26 Chatterjee MS, Purvis JE, Brass LF. et al. Pairwise agonist scanning predicts cellular signaling responses to combinatorial stimuli. Nat Biotechnol 2010; 28: 727-732. DOI:10.1038/nbt.1642.
  CrossrefPubMedGoogle Scholar
• 27 Offermanns S. Activation of platelet function through G protein-coupled receptors. Circ Res 2006; 99: 1293-1304. DOI:10.1161/01.RES.0000251742.71301.16.
  CrossrefPubMedGoogle Scholar
• 28 Ishida T, Hirata K, Sakoda T. et al. Identification of mRNA for 5-HT1 and 5-HT2 receptor subtypes in human coronary arteries. Cardiovasc Res 1999; 41: 267-274. DOI:10.1016/S0008-6363(98)00162-X.
  CrossrefPubMedGoogle Scholar
• 29 Vikenes K, Farstad M, Nordrehaug JE. Serotonin is associated with coronary artery disease and cardiac events. Circulation 1999; 100: 483-489. DOI:10.1161/01.CIR.100.5.483.
  CrossrefPubMedGoogle Scholar
• 30 Greenberg BD, Tolliver TJ, Huang SJ. et al. Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets. Am J Med Genet 1999; 88: 83-87. DOI:10.1002/(SICI)1096-8628(19990205)88:1<83::AID-AJMG15>3.0.CO;2-0.
  CrossrefPubMedGoogle Scholar
• 31 Fumeron F, Betoulle D, Nicaud V. et al. Serotonin transporter gene polymorphism and myocardial infarction: Etude Cas-Temoins de l’Infarctus du Myocarde (ECTIM). Circulation 2002; 105: 2943-2945. DOI:10.1161/01.CIR.0000022603.92986.99.
  CrossrefPubMedGoogle Scholar
• 32 Arinami T, Ohtsuki T, Yamakawa-Kobayashi K. et al. A synergistic effect of serotonin transporter gene polymorphism and smoking in association with CHD. Thromb Haemost 1999; 81: 853-856.
  Article in Thieme ConnectPubMedGoogle Scholar
• 33 Coto E, Reguero JR, Alvarez V. et al. 5-Hydroxytryptamine 5-HT2A receptor and 5-hydroxytryptamine transporter polymorphisms in acute myocardial infarction. Clin Sci 2003; 104: 241-245. DOI:10.1042/CS20020246.
  PubMedGoogle Scholar
• 34 Carneiro AM, Cook EH, Murphy DL. et al. Interactions between integrin alphaIIbbeta3 and the serotonin transporter regulate serotonin transport and platelet aggregation in mice and humans. J Clin Invest 2008; 118: 1544-1552. DOI:10.1172/JCI33374.
  CrossrefPubMedGoogle Scholar
• 35 Lesperance F, Frasure-Smith N, Koszycki D. et al. Effects of citalopram and interpersonal psychotherapy on depression in patients with coronary artery disease: the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial. J Am Med Assoc 2007; 297: 367-379. DOI:10.1001/jama.297.4.367.
  CrossrefPubMedGoogle Scholar
• 36 Taylor CB, Youngblood ME, Catellier D. et al. Effects of antidepressant medication on morbidity and mortality in depressed patients after myocardial infarction. Arch Gen Psychiatry 2005; 62: 792-798. DOI:10.1001/archpsyc.62.7.792.
  CrossrefPubMedGoogle Scholar
• 37 Galan AM, Lopez-Vilchez I, Diaz-Ricart M. et al. Serotonergic mechanisms enhance platelet-mediated thrombogenicity. Thromb Haemost 2009; 102: 511-519.
  Article in Thieme ConnectPubMedGoogle Scholar
• 38 Tseng YL, Chiang ML, Huang TF. et al. A selective serotonin reuptake inhibitor, citalopram, inhibits collagen-induced platelet aggregation and activation. Thromb Res 2010; 126: 517-523. DOI:10.1016/j.thromres.2010.09.017.
  CrossrefPubMedGoogle Scholar
• 39 Jiang W, Velazquez EJ, Samad Z. et al. Responses of mental stress-induced myocardial ischemia to escitalopram treatment: background, design, and method for the Responses of Mental Stress Induced Myocardial Ischemia to Escitalopram Treatment trial. Am Heart J 2012; 163: 20-26. DOI:10.1016/j.ahj.2011.09.018.
  CrossrefPubMedGoogle Scholar