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Thromb Haemost 2009; 102(03): 511-519
DOI: 10.1160/TH08-12-0810
Platelets and Blood Cells
Schattauer GmbH

Serotonergic mechanisms enhance platelet-mediated thrombogenicity

Ana M. Galan
1   Servicio Hemoterapia-Hemostasia, Hospital Clinic, CDB, IDIBAPS, UB, Barcelona, Spain
,
Irene Lopez-Vilchez
1   Servicio Hemoterapia-Hemostasia, Hospital Clinic, CDB, IDIBAPS, UB, Barcelona, Spain
,
Maribel Diaz-Ricart
1   Servicio Hemoterapia-Hemostasia, Hospital Clinic, CDB, IDIBAPS, UB, Barcelona, Spain
,
Fulgencio Navalon
1   Servicio Hemoterapia-Hemostasia, Hospital Clinic, CDB, IDIBAPS, UB, Barcelona, Spain
,
Esther Gomez
2   Instituto Clínic de Psiquiatría, Hospital Clinic, ICN, Barcelona, Spain
,
Cristobal Gasto
2   Instituto Clínic de Psiquiatría, Hospital Clinic, ICN, Barcelona, Spain
,
Gines Escolar
1   Servicio Hemoterapia-Hemostasia, Hospital Clinic, CDB, IDIBAPS, UB, Barcelona, Spain
› Author AffiliationsFinancial support: This work was partially supported by grants FISPI040887, FISCP04/00112, FIS PI060260, FIS PI050153, SAF 2006–08003, PETRI 2007-0169 and Red HERACLES RD06/0009, from the Spanish government, and SGR 2005–00952 from the Generalitat of Catalunya.
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Publication History

Received: 18 December 2008

Accepted after minor revision: 07 May 2009

Publication Date:
22 November 2017 (online)

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Summary

Although it is generally acknowledged that serotonin (5-HT) is a weak agonist for human platelets, recent information suggests an association between serotonergic mechanisms and cardiovascular risk. We investigated the action of 5-HT on adhesive, cohesive and procoagulant properties of human platelets. Impact of 5-HT on whole blood coagulation and thrombin generation was measured by modified thromboelastometry (TEM) and specific fluorogenic assays. We evaluated the effects of 5-HT on thrombus formation in an in-vitro model of thrombosis using human flowing blood. In platelet-rich plasma (PRP), 5-HT favoured the expression of CD62-P, and procoagulant molecules on platelet membranes. These effects were potentiated in the presence of Ca++ and/or ADP. Incubation with 5-HT accelerated clotting times and augmented clot strength in whole blood TEM, and enhanced thrombin generation in PRP. In perfusion studies, 5-HT significantly increased fibrin deposition at low shear (300s-1) and enhanced platelet thrombus formation on the damaged vascular surface at high shear (1,200s-1). Selective inhibition of serotonin reuptake (SSRI) attenuated effects of 5-HT on platelet activation and downregulated the prothrombotic tendencies observed in the previous experimental conditions. In general, reductions of thrombogenic patterns observed with SSRI were more evident under shear conditions (aggregation and perfusion systems) and less evident under steady conditions (TEM and thrombin generation assays). In conclusion, 5-HT is not a weak agonist for human platelets; instead it accentuates platelet activation, potentiates procoagulant responses on human blood and increases thrombogenesis on damaged vascular surfaces. The remarkable antithrombotic actions achieved through SSRI deserve further mechanistic and clinical investigations.

Keywords

Platelet physiology - platelet pharmacology - serotonin - thrombogenesis
 

  • References

  • 1 White JG. Platelet secretory granules and associated proteins. Lab Invest 1993; 68: 497-498.
    PubMedGoogle Scholar
  • 2 Mcnicol A, Israels SJ. Platelet dense granules: Structure, function and implications for haemostasis. Thromb Res 1999; 95: 1-18.
    CrossrefPubMedGoogle Scholar
  • 3 Hoyer D, Hannon JP, Martin GR. Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 2002; 71: 533-554.
    CrossrefPubMedGoogle Scholar
  • 4 Stratz C, Trenk D, Bhatia HS. et al. Identification of 5-HT3 receptors on human platelets: increased surface immunoreactivity after activation with adenosine diphosphate (ADP) and thrombin receptor-activating peptide (TRAP). Thromb Haemost 2008; 99: 784-786.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Carneiro AM, Blakely RD. Serotonin-, protein kinase C-, and Hic-5-associated redistribution of the platelet serotonin transporter. J Biol Chem 2006; 281: 24769-24780.
    CrossrefPubMedGoogle Scholar
  • 6 Nagatomo T, Rashid M, Abul MH. et al. Functions of 5-HT(2A) receptor and its antagonists in the cardiovascular system. Pharmacol Ther 2004; 104: 59-81.
    CrossrefPubMedGoogle Scholar
  • 7 Jin JG, Kunapuli SP. Coactivation of two different G protein-coupled receptors is essential for ADP-induced platelet aggregation. Proc Nat Acad Sci USA 1998; 95: 8070-8074.
    CrossrefPubMedGoogle Scholar
  • 8 Gomez-Gil E, Gasto C, Diaz-Ricart M. et al. Platelet 5-HT2A-receptor-mediated induction of aggregation is not altered in major depresion. Hum Psychopharmacol 2002; 17: 419-424.
    CrossrefPubMedGoogle Scholar
  • 9 Carney RM, Blumenthal JA, Catellier D. et al. Depression as a risk factor for mortality after acute myocardial infarction. Am J Cardiol 2003; 92: 1277-1281.
    CrossrefPubMedGoogle Scholar
  • 10 Carney RM, Freedland KE, Jaffe AS. et al. Depression as a risk factor for post-MI mortality. J Am Coll Cardiol 2004; 44: 472-474.
    PubMedGoogle Scholar
  • 11 Escolar G, Diaz-Ricart M, Gomez-Gil E. et al. Serotonergic mechanisms: a potential link between affective disorders and cardiovascular risk. Drugs Today (Barc) 2005; 41: 721-743.
    CrossrefPubMedGoogle Scholar
  • 12 Carney RM, Freedland KE. Depression, mortality, and medical morbidity in patients with coronary heart disease. Biol Psychiatry 2003; 54: 241-247.
    CrossrefPubMedGoogle Scholar
  • 13 Schlienger RG, Meier CR. Effect of selective serotonin reuptake inhibitors on platelet activation : can they prevent acute myocardial infarction?. Am J Cardiovasc Drugs 2003; 03: 149-162.
    CrossrefPubMedGoogle Scholar
  • 14 Maurer-Spurej E, Pittendreigh C, Solomons K. The influence of selective serotonin reuptake inhibitors on human platelet serotonin. Thromb Haemost 2004; 91: 119-128.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Sauer WH, Berlin JA, Kimmel SE. Effect of antidepressants and their relative affinity for the serotonin transporter on the risk of myocardial infarction. Circulation 2003; 108: 32-36.
    CrossrefPubMedGoogle Scholar
  • 16 Hron G, Kollars M, Binder BR. et al. Identification of patients at low risk for recurrent venous thromboembolism by measuring thrombin generation. J Am Med Assoc 2006; 296: 397-402.
    CrossrefPubMedGoogle Scholar
  • 17 Varadi K, Turecek PL, Schwarz HP. Thrombin generation assay and other universal tests for monitoring haemophilia therapy. Haemophilia 2004; 10 (Suppl. 02) 17-21.
    PubMedGoogle Scholar
  • 18 Anderson L, Quasim I, Soutar R. et al. An audit of red cell and blood product use after the institution of thromboelastometry in a cardiac intensive care unit. Transfus Med 2006; 16: 31-39.
    PubMedGoogle Scholar
  • 19 Galan AM, Tonda R, Pino M. et al. Increased local procoagulant action: a mechanism contributing to the favorable hemostatic effect of recombinant FVIIa in PLT disorders. Transfusion 2003; 43: 885-892.
    CrossrefPubMedGoogle Scholar
  • 20 Escolar G, Bastida E, Castillo R. et al. Development of a computer program to analyze the parameters of plateletvessel wall interaction. Haemostasis 1986; 16: 8-14.
    PubMedGoogle Scholar
  • 21 Galan AM, Reverter JC, Bozzo J. et al. Assessment of potential thrombogenicity of coagulation factor IX concentrates in an in vitro model of human thrombogenesis. Thromb Res 1999; 96: 383-389.
    CrossrefPubMedGoogle Scholar
  • 22 Schins A, Honig A, Crijns H. et al. Increased coronary events in depressed cardiovascular patients: 5-HT2A receptor as missing link?. Psychosom Med 2003; 65: 729-737.
    CrossrefPubMedGoogle Scholar
  • 23 Dale GL. Coated-platelets: an emerging component of the procoagulant response. J Thromb Haemost 2005; 03: 2185-2192.
    CrossrefPubMedGoogle Scholar
  • 24 Packham MA, Bryant NL, Guccione MA. et al. Effect of the concentration of Ca2+ in the suspending medium on the responses of human and rabbit platelets to aggregating agents. Thromb Haemost 1989; 62: 968-976.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Schneider DJ, Tracy PB, Mann KG. et al. Differential effects of anticoagulants on the activation of platelets ex vivo. Circulation 1997; 96: 2877-2883.
    CrossrefPubMedGoogle Scholar
  • 26 Kessels H, Beguin S, Andree H. et al. Measurement of thrombin generation in whole blood - the effect of heparin and aspirin. Thromb Haemost 1994; 72: 78-83.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Altman R, Scazziota A, DE Lourdes HM. et al. Recombinant factor VIIa reverses the inhibitory effect of aspirin or aspirin plus clopidogrel on in vitro thrombin generation. J Thromb Haemost 2006; 04: 2022-2027.
    CrossrefPubMedGoogle Scholar
  • 28 Escolar G, Galan AM, Mazzara R. et al. Measurement of platelet interactions with subendothelial substrata: relevance to transfusion medicine. Transfus Med Rev 2001; 15: 144-156.
    CrossrefPubMedGoogle Scholar
  • 29 Tonda R, Lopez-Vilchez I, Navalon F. et al. Platelets interact with tissue factor immobilized on surfaces: effects of shear rate. Eur J Clin Invest 2008; 38: 34-42.
    PubMedGoogle Scholar
  • 30 Stahl SM. The human platelet. A diagnostic and research tool for the study of biogenic amines in psychiatric and neurologic disorders. Arch Gen Psychiatry 1977; 34: 509-516.
    CrossrefPubMedGoogle Scholar
  • 31 Rao GH, Escolar G, White JG. Epinephrine reverses the inhibitory influence of aspirin on plateletvessel wall interactions. Thromb Res 1986; 44: 65-74.
    CrossrefPubMedGoogle Scholar
  • 32 Roux SP, Sakariassen KS, Turitto VT. et al. Effect of aspirin and epinephrine on experimentally induced thrombogenesis in dogs. A parallelism between in vivo and ex vivo thrombosis models. Arterioscler Thromb 1991; 11: 1182-1191.
    CrossrefPubMedGoogle Scholar
  • 33 Ressler KJ, Nemeroff CB. Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders. Depress Anxiety 2000; 12 (Suppl. 01) 2-19.
    CrossrefPubMedGoogle Scholar
  • 34 Nutt D, Demyttenaere K, Janka Z. et al. The other face of depression, reduced positive affect: the role of catecholamines in causation and cure. J Psychopharmacol 2007; 21: 461-471.
    CrossrefPubMedGoogle Scholar
  • 35 Belcher PR, Drake-Holland AJ, Hynd J. et al. Dispersion of coronary artery thrombi by antagonism of platelet serotonin receptor in the dog. Cardiovasc Res 1992; 26: 292-296.
    CrossrefPubMedGoogle Scholar
  • 36 Nishihira K, Yamashita A, Tanaka N. et al. Inhibition of 5-hydroxytryptamine(2A) receptor prevents occlusive thrombus formation on neointima of the rabbit femoral artery. J Thromb Haemost 2006; 04: 247-255.
    CrossrefPubMedGoogle Scholar
  • 37 Uchiyama S, Ozaki Y, Satoh K. et al. Effect of sarpogrelate, a 5-HT(2A) antagonist, on platelet aggregation in patients with ischemic stroke: clinical-pharmacological dose-response study. Cerebrovasc Dis 2007; 24: 264-270.
    CrossrefPubMedGoogle Scholar
  • 38 Shinohara Y, Nishimaru K, Sawada T. et al. Sarpogrelate-Aspirin Comparative Clinical Study for Efficacy and Safety in Secondary Prevention of Cerebral Infarction (S-ACCESS): A randomized, double-blind, aspirin-controlled trial. Stroke 2008; 39: 1827-1833.
    CrossrefPubMedGoogle Scholar
  • 39 Celada P, Puig M, Amargos-Bosch M. et al. The therapeutic role of 5-HT1A and 5-HT2A receptors in depression. J Psychiatry Neurosci 2004; 29: 252-265.
    PubMedGoogle Scholar
  • 40 Shelton RC, Tollefson GD, Tohen M. et al. A novel augmentation strategy for treating resistant major depression. Am J Psychiatry 2001; 158: 131-134.
    CrossrefPubMedGoogle Scholar
  • 41 Li Q, Ma L, Innis RB. et al. Pharmacological and genetic characterization of two selective serotonin transporter ligands: 2-[2-(dimethylaminomethylphenylthio)]-5-fluoromethylphenylamine (AFM) and 3-amino-4-[2-(dimethylaminomethyl-phenylthio)] benzonitrile (DASB). J Pharmacol Exp Ther 2004; 308: 481-486.
    PubMedGoogle Scholar
  • 42 Shimbo D, Davidson KW, Haas DC. et al. Negative impact of depression on outcomes in patients with coronary artery disease: mechanisms, treatment considerations, and future directions. J Thromb Haemost 2005; 03: 897-908.
    CrossrefPubMedGoogle Scholar
  • 43 Atar D, Malinin A, Takserman A. et al. Escitalopram, but not its major metabolites, exhibits antiplatelet activity in humans. J Clin Psychopharmacol 2006; 26: 172-177.
    CrossrefPubMedGoogle Scholar
  • 44 Lichtman JH, Bigger Jr JT, Blumenthal JA. et al. Depression and coronary heart disease: recommendations for screening, referral, and treatment: a science advisory from the American Heart Association Prevention Committee of the Council on Cardiovascular Nursing, Council on Clinical Cardiology, Council on Epidemiology and Prevention, and Interdisciplinary Council on Quality of Care and Outcomes Research: endorsed by the American Psychiatric Association. Circulation 2008; 118: 1768-1775.
    CrossrefPubMedGoogle Scholar
  • 45 Maurer-Spurej E. Serotonin reuptake inhibitors and cardiovascular diseases: a platelet connection. Cell Mol Life Sci 2005; 62: 159-170.
    CrossrefPubMedGoogle Scholar
  • 46 van der Heijden FM, Tuinier S, Fekkes D. et al. Atypical antipsychotics and the relevance of glutamate and serotonin. Eur Neuropsychopharmacol 2004; 14: 259-265.
    CrossrefPubMedGoogle Scholar
  • 47 Sherwood A, Blumenthal JA, Trivedi R. et al. Relationship of depression to death or hospitalization in patients with heart failure. Arch Intern Med 2007; 167: 367-373.
    CrossrefPubMedGoogle Scholar
  • 48 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.
    CrossrefPubMedGoogle Scholar
  • 49 Glassman AH, O’connor CM, Califf RM. et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. J Am Med Assoc 2002; 288: 701-709.
    CrossrefPubMedGoogle Scholar
  • 50 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.
    CrossrefPubMedGoogle Scholar
  • 51 Serebruany VL, Glassman AH, Malinin AI. et al. Selective serotonin reuptake inhibitors yield additional antiplatelet protection in patients with congestive heart failure treated with antecedent aspirin. Eur J Heart Fail 2003; 05: 517-521.
    CrossrefPubMedGoogle Scholar
  • 52 Meijer WE, Heerdink ER, Nolen WA. et al. Association of risk of abnormal bleeding with degree of serotonin reuptake inhibition by antidepressants. Arch Intern Med 2004; 164: 2367-2370.
    CrossrefPubMedGoogle Scholar
  • 53 de Abajo FJ, Montero D, Rodriguez LA. et al. Antidepressants and risk of upper gastrointestinal bleeding. Basic Clin Pharmacol Toxicol 2006; 98: 304-310.
    CrossrefPubMedGoogle Scholar
  • 54 Atar D, Malinin A, Pokov A. et al. Antiplatelet properties of escitalopram in patients with the metabolic syndrome: a dose-ranging in vitro study. Neuropsychopharmacology 2007; 32: 2369-2374.
    CrossrefPubMedGoogle Scholar
  • 55 Steiner JA, Carneiro AM, Blakely RD. Going with the Flow: Trafficking-Dependent and -Independent Regulation of Serotonin Transport. Traffic 2008; 09: 1393-1402.
    CrossrefPubMedGoogle Scholar
  • 56 Blakely RD, Ramamoorthy S, Schroeter S. et al. Regulated phosphorylation and trafficking of antidepressant-sensitive serotonin transporter proteins. Biol Psychiatry 1998; 44: 169-178.
    CrossrefPubMedGoogle Scholar
  • 57 Frankhauser P, Baranyai R, Ahrens T. et al. Platelet surface P-selectin expression is highly correlated with serotonin transporter density in human subjects. Thromb Haemost 2008; 100: 1201-1203.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 58 Quick MW. Regulating the conducting states of a mammalian serotonin transporter. Neuron 2003; 40: 537-549.
    CrossrefPubMedGoogle Scholar
  • 59 Ren Q, Barber HK, Crawford GL. et al. Endobrevin/VAMP-8 is the primary v-SNARE for the platelet release reaction. Mol Biol Cell 2007; 18: 24-33.
    CrossrefPubMedGoogle Scholar
  • 60 Walther DJ, Peter JU, Winter S. et al. Serotonylation of Small GTPases Is a Signal Transduction Pathway that Triggers Platelet [alpha]-Granule Release. Cell 2003; 115: 851-862.
    CrossrefPubMedGoogle Scholar
  • 61 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.
    CrossrefPubMedGoogle Scholar