High-shear- and-thrombin-inducible platelet adhesion and aggregation in patients undergoing percutaneous coronary intervention

 

 Buy Article Permissions and Reprints

Summary

Thrombin-generation and activation of platelets during percutaneous coronary intervention (PCI) play a key role for early thrombotic events. Heparin and bivalirudin are approved anticoagulants for PCI. We examined the specific effects of these anticoagulants on platelet adhesion and aggregation under high shear conditions, and the presence of excess thrombin. To simulate in vivo conditions that may precipitate a bleeding/thrombotic event, we added thrombin in vitro to blood samples from 89 stable patients who had been randomly assigned to receive heparin or bivalirudin for elective PCI and examined thrombininducible platelet adhesion and aggregation under high shear conditions. Platelet adhesion increased by 10% of baseline with heparin, but decreased by 20% with bivalirudin (p=0.0047). Thrombin-inducible platelet adhesion and size of aggregates was equally inhibited by heparin and bivalirudin. Thus, under high shear conditions and excessive thrombin generation as they occur in atherosclerotic vascular compartments and acute vascular syndromes, heparin and bivalirudin inhibit thrombin-induced platelet adhesion and aggregation to a similar extent, while they have opposite effects on platelet adhesion in the absence of thrombin.

This study was part of the doctorial thesis of NR at the Department of Blood Group Serology and Transfusion Medicine.

^* I. Lang and S. Panzer share senior authorship.

• References

• 1 Kahn ML, Nakanishi-Matsui M, Shapiro MJ. et al. Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin. J Clin Invest 1999; 103: 879-887.
  CrossrefPubMedGoogle Scholar
• 2 Leger AJ, Covic L, Kuliopulos A. Protease-Activated Receptors in Cardiovascular Diseases. Circulation 2006; 114: 1070-1077.
  CrossrefPubMedGoogle Scholar
• 3 Dormann D, Clemetson KJ, Kehrel BE. The GPIb thrombin-binding site is essential for thrombin-induced platelet procoagulant activity. Blood 2000; 96: 2469-2478.
  PubMedGoogle Scholar
• 4 Soslau G, Class R, Morgan DA. et al. Unique pathway of thrombin-induced platelet aggregation mediated by glycoprotein Ib. J Biol Chem 2001; 276: 21173-21183.
  CrossrefPubMedGoogle Scholar
• 5 Adam F, Guillin MC, Jandrot-Perrus M. Glycoprotein Ib-mediated platelet activation. A signalling pathway triggered by thrombin. Eur J Biochem 2003; 270: 2959-2970.
  CrossrefPubMedGoogle Scholar
• 6 Jurk K, Jahn UR, Van Aken H. et al. Platelets in patients with acute ischemic stroke are exhausted and refractory to thrombin, due to cleavage of the seven-trans-membrane thrombin receptor (PAR-1). Thromb Haemost 2004; 91: 334-344.
  Article in Thieme ConnectPubMedGoogle Scholar
• 7 Yano Y, Ohmori T, Hoshide S. et al. Determinants of thrombin generation, fibrinolytic activity, and endothelial dysfunction in patients on dual antiplatelet therapy: involvement of factors other than platelet aggregability in Virchow‘s triad. Eur Heart J 2008; 29: 1729-1738.
  CrossrefPubMedGoogle Scholar
• 8 Becker RC, Moliterno DJ, Jennings LK. et al. TRA-PCI Investigators.. Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study. Lancet 2009; 373: 919-928.
  CrossrefPubMedGoogle Scholar
• 9 Dardik R, Varon D, Eskaraev R. et al. Recombinant fragment of von Willebrand factor AR545C inhibits platelet binding to thrombin and platelet adhesion to thrombin-treated endothelial cells. Br J Haematol 2000; 109: 512-518.
  CrossrefPubMedGoogle Scholar
• 10 Warkentin TE, Greinacher A, Koster A. Bivalirudin. Thromb Haemost 2008; 99: 830-839.
  Article in Thieme ConnectPubMedGoogle Scholar
• 11 De Luca G, Cassetti E, Verdoia M. et al. Bivalirudin as compared to unfractionated heparin among patients undergoing coronary angioplasty: A meta-analyis of randomised trials. Thromb Haemost 2009; 102: 428-436.
  Article in Thieme ConnectPubMedGoogle Scholar
• 12 Xiao Z, Theroux P. Platelet activation with unfractionated heparin at therapeutic concentrations and comparisons with a low-molecular-weight heparin and with a direct thrombin inhibitor. Circulation 1998; 97: 251-256.
  CrossrefPubMedGoogle Scholar
• 13 Schneider DJ, Keating F, Sobel BE. Greater inhibitory effects of bivalirudin compared with unfractionated heparin plus eptifibitide on thrombin-induced platelet activation. Coron Artery Dis 2006; 17: 471-476.
  CrossrefPubMedGoogle Scholar
• 14 Keating FK, Dauerman HL, Whitaker DA. et al. Increased expression of platelet P-selectin and formation of platelet-leukocyte aggregates in blood from patients treated with unfractionated heparin plus eptifibatide compared with bivalirudin. Thromb Res 2006; 118: 361-369.
  CrossrefPubMedGoogle Scholar
• 15 Harding SA, Din JN, Sarma J. et al. Promotion of proinflammatory interactions between platelets and monocytes by unfractionated heparin. Heart 2006; 92: 1635-1638.
  CrossrefPubMedGoogle Scholar
• 16 Sobel M, Fish WR, Toma N. et al. Heparin modulates integrin function in human platelets. J Vasc Surg 2001; 33: 587-594.
  CrossrefPubMedGoogle Scholar
• 17 Anand SX, Kim MC, Kamran M. et al. Comparison of platelet function and morphology in patients undergoing percutaneous coronary intervention receiving bivalirudin versus unfractionated heparin versus clopidogrel pretreatment and bivalirudin. Am J Cardiol 2007; 100: 417-424.
  CrossrefPubMedGoogle Scholar
• 18 Reiter R, Derhaschnig U, Spiel A. et al. Regulation of protease-activated receptor 1 (PAR1) on platelets and responsiveness to thrombin receptor activating peptide (TRAP) during systemic inflammation in humans. Thromb Haemost 2003; 90: 898-903.
  Article in Thieme ConnectPubMedGoogle Scholar
• 19 Lincoff AM, Bittl JA, Harrington RA. et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. J Am Med Assoc 2003; 289: 853-863.
  CrossrefPubMedGoogle Scholar
• 20 Stone GW, White HD, Ohman EM. et al. Bivalirudin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a subgroup analysis from the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial. Lancet 2007; 369: 907-919.
  CrossrefPubMedGoogle Scholar
• 21 Stone GW, Witzenbichler B, Guagliumi G. et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358: 2218-2230.
  CrossrefPubMedGoogle Scholar
• 22 White HD, Chew DP, Hoekstra JW. et al. Safety and efficacy of switching from either unfractionated heparin or enoxaparin to bivalirudin in patients with nonST-segment elevation acute coronary syndromes managed with an invasive strategy: results from the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial. J Am Coll Cardiol 2008; 51: 1734-1741.
  CrossrefPubMedGoogle Scholar
• 23 Eslam RB, Reiter N, Kaider A. et al. Regulation of PAR-1 in patients undergoing percutaneous coronary intervention: effects of unfractionated heparin and bivalirudin. Eur Heart J 2009; 30: 1831-1836.
  CrossrefPubMedGoogle Scholar
• 24 Savion N, Varon D. Impact--the cone and plate(let) analyzer: testing platelet function and anti-platelet drug response. Pathophysiol Haemost Thromb 2006; 35: 83-88.
  CrossrefPubMedGoogle Scholar
• 25 Shenkman B, Matetzky S, Fefer P. et al. Variable responsiveness to clopidogrel and aspirin among patients with acute coronary syndrome as assessed by platelet function tests. Thromb Res 2008; 122: 336-345.
  CrossrefPubMedGoogle Scholar
• 26 Gremmel T, Steiner S, Seidinger D. et al. Comparison of methods to evaluate clopidogrel-mediated platelet inhibition after percutaneous intervention with stent implantation. Thromb Haemost 2009; 101: 333-339.
  Article in Thieme ConnectPubMedGoogle Scholar
• 27 Storey RF, May JA, Heptinstall S. Potentiation of platelet aggregation by heparin in human whole blood is attenuated by P2Y12 and P2Y1 antagonists but not aspirin. Thromb Res 2005; 115: 301-307.
  CrossrefPubMedGoogle Scholar
• 28 Goto S, Salomon DR, Ikeda Y. et al. Characterization of the unique mechanism mediating the shear-dependent binding of soluble von Willebrand factor to platelets. J Biol Chem 1995; 270: 23352-23361.
  CrossrefPubMedGoogle Scholar
• 29 Goto S, Tamura N, Li M. et al. Different effects of various anti-GPIIb-IIIa agents on shear-induced platelet activation and expression of procoagulant activity. J Thromb Haemost 2003; 1: 2022-2030.
  CrossrefPubMedGoogle Scholar
• 30 Panzer S, Eichelberger B, Koren D. et al. Monitoring survival and function of transfused platelets in Bernard-Soulier syndrome by flow cytometry and a cone and plate(let) analyzer (Impact-R). Transfusion 2007; 47: 103-106.
  CrossrefPubMedGoogle Scholar
• 31 Panzer S, Badr Eslam R, Schneller A. et al. Loss of high-molecular-weight von Willebrand factor multimers mainly affects platelet aggregation in patients with aortic stenosis. Thromb Haemost 2010; 103: 408-414.
  Article in Thieme ConnectPubMedGoogle Scholar
• 32 Ikeda Y, Handa M, Kamata T. et al. Transmembrane calcium influx associated with von Willebrand factor binding to GP Ib in the initiation of shear-induced platelet aggregation. Thromb Haemost 1993; 69: 496-502.
  Article in Thieme ConnectPubMedGoogle Scholar
• 33 Reiter N, Eichelberger B, Kaider A. et al. Thrombin-inducible platelet adhesion and regulation of the platelet seven-transmembrane thrombin receptor-1 (PAR-1): effects of unfractionated heparin and lepirudin. Platelets 2009; 20: 582-587.
  CrossrefPubMedGoogle Scholar