Advertisement

Prothrombotic and antithrombotic pathways in acute coronary syndromes

  • Andrew P Selwyn
    Correspondence
    Address for reprints: Andrew P. Selwyn, MD, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA.
    Affiliations
    From the Cardiovascular Division and the Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
    Search for articles by this author

      Abstract

      The acute coronary syndromes arise from procoagulant changes in complex plaques, which trigger both platelet activation and coagulation pathways. These 2 pathways intersect at a number of points that form positive-feedback loops to sustain and accelerate thrombus formation. In normal hemostasis and with a healthy endothelium, intravascular thrombosis is prevented, and vascular patency is protected by the fibrinolytic system and a number of antithrombotic factors, such as antithrombin, thrombomodulin, and tissue factor pathway inhibitor. However, atherosclerosis is characterized by a hypercoagulable state, and the fibrinolytic balance is skewed toward occlusive thrombus formation at critical sites on vulnerable plaques. This review focuses on cellular and humoral mechanisms and the antithrombotic strategies that are important during the acute phase of an ischemic coronary syndrome, both in patients managed conservatively and in patients scheduled for an interventional procedure. These strategies include fibrinolytic therapy, antiplatelet therapies (aspirin, clopidogrel, glycoprotein IIb/IIIa receptor inhibitors), and low–molecular-weight heparin.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to American Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Libby P.
        Current concepts of the pathogenesis of the acute coronary syndromes.
        Circulation. 2001; 104: 365-372
        • Edelman E.R.
        • Rogers C.
        Pathobiologic responses to stenting.
        Am J Cardiol. 1998; 81: 4E-6E
        • Orford J.L.
        • Selwyn A.P.
        • Ganz P.
        • Popma J.J.
        • Rogers C.
        The comparative pathobiology of atherosclerosis and restenosis.
        Am J Cardiol. 2000; 86: 6H-11H
        • Rosenberg R.D.
        • Lam L.
        Correlation between structure and function of heparin.
        Proc Natl Acad Sci U S A. 1979; 76: 1218-1222
        • Hirsh J.
        • Anand S.S.
        • Halperin J.L.
        • Fuster V.
        Guide to anticoagulant therapy. Heparin.
        Circulation. 2001; 103: 2994-3018
        • Tollefsen D.M.
        • Majerus D.W.
        • Blank M.K.
        Heparin cofactor II.
        J Biol Chem. 1982; 257: 2162-2169
        • Sadler J.E.
        Thrombomodulin structure and function.
        Thromb Haemost. 1997; 78: 392-395
        • Cines D.B.
        • Pollak E.S.
        • Buck C.A.
        • Loscalzo J.
        • Zimmerman G.A.
        • McEver R.P.
        • Pober J.S.
        • Wick T.M.
        • Konkle B.A.
        • Schwartz B.S.
        • et al.
        Endothelial cells in physiology and in the pathophysiology of vascular disorders.
        Blood. 1998; 91: 3527-3561
        • Fair D.S.
        • Marlar R.A.
        • Levin E.G.
        Human endothelial cells synthesize protein S.
        Blood. 1986; 67: 1168-1171
        • Broze Jr, G.J.
        Tissue factor pathway inhibitor.
        Thromb Haemost. 1995; 74: 90-93
        • Hoylaerts M.
        • Rijken D.C.
        • Lijnen H.R.
        • Collén D.
        Kinetics of the activation of plasminogen by human tissue plasminogen activator.
        J Biol Chem. 1982; 257: 2912-2919
        • Higgins D.L.
        • Vehar G.A.
        Interaction of one-chain and two-chain tissue plasminogen activator with intact and plasmin-degraded fibrin.
        Biochemistry. 1987; 26: 7786-7791
        • Schafer A.I.
        • Ali N.M.
        • Levine G.N.
        Hemostasis, thrombosis, fibrinolysis, and cardiovascular disease.
        in: Braunwald E. Zipes D.P. Libby P. Heart Disease. 6th ed. WB Saunders, Philadelphia2001: 2099-2132
        • Hajjar K.A.
        • Jakovina A.T.
        • Chacko J.
        An endothelial cell receptor for plasminogen/tissue plasminogen activator. I.
        J Biol Chem. 1994; 269: 21191-21197
        • Husain S.S.
        • Hasan A.A.
        • Budzynski A.Z.
        Differences between binding of one-chain and two-chain tissue plasminogen activators to non-cross-linked and cross-linked fibrin clots.
        Blood. 1989; 74: 999-1006
        • Lindahl T.L.
        • Ohlsson P.I.
        • Wiman B.
        The mechanism of the reaction between human plasminogen-activator 1 and tissue plasminogen activator.
        Biochem J. 1990; 265: 109-113
        • Owensby D.A.
        • Morton P.A.
        • Wun T.C.
        • Schwartz A.L.
        Binding of plasminogen activator inhibitor type-1 to extracellular matrix of Hep G2 cells.
        J Biol Chem. 1991; 266: 4334-4340
        • Bajzar L.
        • Morser J.
        • Nesheim M.
        TAFI, or plasma procarboxypeptidase-B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex.
        J Biol Chem. 1996; 271: 16603-16608
        • Mosnier L.O.
        • Meijers J.C.
        • Bouma B.N.
        The role of protein S in the activation of thrombin activatable fibrinolysis inhibitor (TAFI) and regulation of fibrinolysis.
        Thromb Haemost. 2001; 86: 1040-1046
        • Chatterjee T.
        • Schroeder V.
        • Fleisch M.
        • Windecker S.
        • Seiler C.
        • Eberli F.R.
        • Meier B.
        • Kohler H.P.
        Thrombin activatable fibrinolysis inhibitor (TAFI) levels in patients with coronary artery disease investigated by angiography [abstract].
        J Am Coll Cardiol. 2002; 39 (Abstract 1007MP-130): 204A
        • Sase K.
        • Michel T.
        Expression of constitutive endothelial nitric oxide synthase in human blood platelets.
        Life Sci. 1995; 57: 2049-2055
        • Pigazzi A.
        • Fabian A.
        • Johnson J.
        • Upchurch G.R.
        • Loscalzo J.
        Identification of nitric oxide synthases in human magakaryocytes and platelets.
        Circulation. 1995; 92: I365
        • Zhou Q.
        • Hellermann G.R.
        • Solomonson L.P.
        Nitric oxide release from resting human platelets.
        Thromb Res. 1995; 77: 87-96
        • Freedman J.E.
        • Loscalzo J.
        • Barnard M.R.
        • Alpert C.
        • Keaney Jr, J.F.
        • Michelson A.D.
        Nitric oxide release from activated platelets inhibits platelet recruitment.
        J Clin Invest. 1997; 100: 350-356
        • Katoh A.
        • Ikeda H.
        • Takajo Y.
        • Haramaki N.
        • Murohara T.
        • Shintani S.
        • Kanaya S.
        • Yokoyama S.
        • Ueno T.
        • Honma T.
        • Imaizumi T.
        Coexistence of impairment of endothelium-derived nitric oxide and platelet-derived nitric oxide in patients with coronary risk factors.
        Circ J. 2002; 66: 837-840
        • Freedman J.E.
        • Ting B.
        • Hankin B.
        • Loscalzo J.
        • Keaney Jr, J.F.
        • Vita J.A.
        Impaired platelet production of nitric oxide predicts presence of acute coronary syndromes.
        Circulation. 1998; 98: 1481-1486
      1. Crane MS, Ollosson R, Moore KP, Rossi AG, Megson IL. Novel role for low molecular weight plasma thiols in nitric oxide mediated control of platelet function. J Biol Chem [serial online]. 2002;277:46858–46863. Available at: http://www.jbc.org/cgi/reprint/277/49/46858.pdf. Accessed October 15, 2002

        • Benjamin N.
        • Dutton J.A.E.
        • Ritter J.M.
        Human vascular smooth muscle cells inhibit platelet aggregation when incubated with glyceryl trinitrate.
        Br J Pharmacol. 1991; 102: 847-850
        • Moncada S.
        • Vane J.R.
        Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2 and prostacyclin.
        Pharmacol Rev. 1979; 30: 293-331
        • Marcus A.J.
        • Broekman M.J.
        • Drosopoulos J.H.F.
        • Islam N.
        • Alyoncheva T.N.
        • Safier L.B.
        • Hajjar K.A.
        • Posnett D.N.
        • Schoenborn M.A.
        • Schooley K.A.
        • Gayle R.B.
        • Maliszewski C.R.
        The endothelial cell ecto-ADPase responsible for inhibition of platelet function is CD39.
        J Clin Invest. 1997; 99: 1351-1360
        • Mertens K.
        • Bertina R.M.
        The contribution of Ca2+ and phospholipids to the activation of human blood-coagulation factor X by activated factor VII.
        Biochem J. 1984; 223: 607-615
        • Krishnaswamy S.
        • Jones K.C.
        • Mann K.G.
        Prothrombinase complex assembly.
        J Biol Chem. 1988; 263: 3823-3834
        • Bom V.J.
        • Bertina R.M.
        The contributions of Ca2+, phospholipids and tissue-factor apoprotein to the activation of human blood-coagulation factor X by activated factor VII.
        Biochem J. 1990; 265: 327-336
        • Hoffman M.
        • Monroe D.M.
        A cell-based model of hemostasis.
        Thromb Haemost. 2001; 85: 958-965
        • Kroll M.H.
        • Hellums J.D.
        • McIntire L.V.
        • Schafer A.I.
        • Moake J.L.
        Platelets and shear stress.
        Blood. 1996; 88: 1525-1541
        • Nakamura T.
        • Kambayashi J.
        • Okuma M.
        • Tandon N.N.
        Activation of the GP IIb-IIIa complex induced by platelet adhesion to collagen is mediated by both α2β1 integrin and GP VI.
        J Biol Chem. 1999; 274: 11897-11903
        • Frenette P.S.
        • Wagner D.D.
        Adhesion molecules, part II.
        N Engl J Med. 1996; 335: 43-45
        • Pakala R.
        • Willerson J.T.
        • Benedict C.R.
        Effect of serotonin, thromboxane A2, and specific receptor antagonists on vascular smooth muscle cell proliferation.
        Circulation. 1997; 96: 2280-2286
        • Ross R.
        The pathogenesis of atherosclerosis.
        Nature. 1993; 362: 801-809
        • Forrester J.S.
        • Fishbein M.
        • Helfant R.
        • Fagin J.
        A paradigm for restenosis based on cell biology.
        J Am Coll Cardiol. 1991; 17: 758-769
        • Shebuski R.J.
        • Kilgore K.S.
        Role of inflammatory mediators in thrombogenesis.
        J Pharmacol Exp Ther. 2002; 300: 729-735
        • Loppnow H.
        • Bil R.
        • Hirt S.
        • Schonbeck U.
        • Herzberg M.
        • Werdan K.
        • Rietschel E.T.
        • Brandt E.
        • Flad H.D.
        Platelet-derived interleukin-1 induces cytokine production but not proliferation of human vascular smooth muscle cells.
        Blood. 1998; 91: 134-141
        • Marti F.
        • Bertran E.
        • Llucia M.
        • Villen E.
        • Peiro M.
        • Garcia J.
        • Rueda F.
        Platelet factor 4 induces human natural killer cells to synthesize and release interleukin-8.
        J Leukoc Biol. 2002; 72: 590-597
        • Freedman J.E.
        • Frei B.
        • Welch G.N.
        • Loscalzo J.
        Glutathione peroxidase potentiates the inhibition of platelet function by S-nitrosothiols.
        J Clin Invest. 1995; 96: 394-400
        • Jahn B.
        • Hansch G.M.
        Oxygen radical generation in human platelets.
        Int Arch Allergy Immunol. 1990; 93: 73-79
        • Harrison P.
        • Cramer E.M.
        Platelet alpha-granules.
        Blood Rev. 1993; 7: 52-62
        • Wilcox J.N.
        • Smith K.M.
        • Schwartz S.M.
        • Gordon D.
        Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque.
        Proc Natl Acad Sci U S A. 1989; 86: 2839-2843
        • Drake T.A.
        • Morrissey J.H.
        • Edgington T.S.
        Selective cellular expression of tissue factor in human tissue.
        Am J Pathol. 1989; 134: 1087-1097
        • Mosesson M.W.
        Fibrinogen and fibrin polymerization.
        Blood Coagul Fibrinolysis. 1997; 8: 257-267
        • Pieters J.
        • Lindhout T.
        • Hemker H.C.
        In situ-generated thrombin is the only enzyme that effectively activates factor VIII and factor V in thromboplastin-activated plasma.
        Blood. 1989; 74: 1021-1024
        • Alberio L.
        • Safa O.
        • Cletson K.J.
        • Esmon C.T.
        • Dale G.L.
        Surface expression and functional characterization of alpha-granule factor V in human platelets.
        Blood. 1987; 69: 1188-1195
        • Viskup R.W.
        • Tracy P.B.
        • Mann K.G.
        The isolation of human platelet factor V.
        Blood. 1987; 69: 1188-1195
        • Monroe D.M.
        • Hoffman M.
        • Roberts H.R.
        Platelets and thrombin generation.
        Arterioscler Thromb Vasc Biol. 2002; 22: 1381-1389
        • Annex B.H.
        • Denning S.M.
        • Channon K.M.
        • Sketch M.H.
        • Stack R.S.
        • Morrissey J.H.
        • Peters K.G.
        Differential expression of tissue factor protein in directional atherectomy specimens from patients with stable and unstable coronary syndromes.
        Circulation. 1995; 91: 619-622
        • Ardissino D.
        • Merlini P.A.
        • Ariens R.
        • Coppola R.
        • Bramucci E.
        • Mannucci P.M.
        Tissue-factor antigen and activity in human coronary atherosclerotic plaques.
        Lancet. 1997; 349: 769-771
        • Siegbahn A.
        • Johnell M.
        • Rorsman C.
        • Ezban M.
        • Heldin C.-H.
        • Rönnstrand L.
        Binding of factor VIIa to tissue factor on human fibroblasts leads to activation of phospholipase C and enhanced PDGF-BB-stimulated chemotaxis.
        Blood. 2000; 96: 3452-3458
        • Bar-Shavit R.
        • Kahn A.
        • Wilner G.D.
        • Fenton 2nd, J.W.
        Monocyte chemotaxis.
        Science. 1983; 220: 728-731
        • Bar-Shavit R.
        • Kahn A.J.
        • Mann K.G.
        • Wilner G.D.
        Identification of a thrombin sequence with growth factor activity on macrophages.
        Proc Natl Acad Sci U S A. 1986; 83: 976-980
        • McNamara C.A.
        • Sarembock I.J.
        • Gimple L.W.
        • Fenton 2nd, J.W.
        • Coughlin S.R.
        • Owens G.K.
        Thrombin stimulates proliferation of cultured rat aortic smooth muscle cells by a proteolytically activated receptor.
        J Clin Invest. 1993; 91: 94-98
        • Bar-Shavit R.
        • Benezra M.
        • Eldor A.
        • Hy-Am E.
        • Fenton 2nd, J.W.
        • Wilner G.D.
        • Vlodavsky I.
        Thrombin immobilized to extracellular matrix is a potent mitogen for vascular smooth muscle cells.
        Cell Regul. 1990; 1: 453-463
        • Kranzhofer R.
        • Clinton S.K.
        • Ishii K.
        • Coughlin S.R.
        • Fenton 2nd, J.W.
        • Libby P.
        Thrombin potently stimulates cytokine production in human vascular smooth muscle cells but not in mononuclear phagocytes.
        Circ Res. 1996; 79: 286-294
        • Dabbagh K.
        • Laurent G.J.
        • McAnulty R.J.
        • Chambers R.C.
        Thrombin stimulates smooth muscle cell procollagen synthesis and mRNA levels via a PAR-1 mediated mechanism.
        Thromb Haemost. 1998; 79: 405-409
        • Coughlin S.R.
        Thrombin signaling and protease-activated receptors.
        Nature. 2000; 407: 258-264
        • Nelken N.A.
        • Soifer S.J.
        • O’Keefe J.
        • Vu T.-K.
        • Charo I.
        • Coughlin S.
        Thrombin receptor expression in normal and atherosclerotic human arteries.
        J Clin Invest. 1992; 90: 1614-1621
        • Armstrong P.W.
        • Collen D.
        Fibrinolysis for acute myocardial infarction.
        Circulation. 2001; 103: 2862-2866
        • Armstrong P.W.
        • Collen D.
        Fibrinolysis for acute myocardial infarction.
        Circulation. 2001; 103: 2987-2992
      2. Ryan TJ, Antman EM, Brooks N, Califf RM, Hillis LD, Hiratzka LF, Rapaport E, Riegel B, Russell RO, Smith EE III, Weaver WD. 1999 update: ACC/AHA guidelines for the management of patients with acute myocardial infarction. 1999 update: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). Available at: http://www.acc.org/clinical/guidelines/nov96/1999/index.htm Accessed: May 2003

        • Quinn M.J.
        • Plow E.F.
        • Topol E.J.
        Platelet glycoprotein IIb/IIIa inhibitors.
        Circulation. 2002; 106: 379-385
        • Antithrombotic Trialists’ Collaboration
        Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high-risk patients.
        BMJ. 2002; 324: 71-86
        • Mangano D.T.
        • Multicenter Study of Perioperative Ischemia Research Group
        Aspirin and mortality from coronary bypass surgery.
        N Engl J Med. 2002; 347: 1309-1317
        • Chignard M.
        • Lalau Keraly C.
        • Delautier D.
        • Sebag C.
        • Bouloux C.
        • Motte G.
        • Benveniste J.
        Reduced sensitivity of human platelets to PAF-acether following ticlopidine intake.
        Haemostasis. 1989; 19: 213-218
        • Heptinstall S.
        • May J.A.
        • Glenn J.R.
        • Sanderson H.M.
        • Dickinson J.P.
        • Wilcox R.G.
        Effects of ticlopidine administered to healthy volunteers on platelet function in whole blood.
        Thromb Haemost. 1995; 74: 1310-1315
        • Orford J.L.
        • Kinlay S.
        • Adams M.R.
        • Simon D.I.
        • Selwyn A.P.
        Clopidogrel inhibits shear-induced platelet function.
        Platelets. 2002; 13: 187-189
        • Klinkhardt U.
        • Graff J.
        • Harder S.
        Clopidogrel, but not abciximab, reduces platelet leukocyte conjugates and P-selectin expression in a human ex vivo in vitro model.
        Clin Pharmacol Ther. 2002; 71: 176-185
        • Quinn M.J.
        • Fitzgerald D.J.
        Ticlopidine and clopidogrel.
        Circulation. 1999; 100: 1667-1672
      3. Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, Jones RH, Keriakes D, Kupersmith J, Levin TN, et al. ACC/AHA guideline update for the management of patients with unstable angina and non–ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Unstable Angina). Available at: http://www.acc.org/clinical/guidelines/unstable/unstable.pdf. Accessed May 2002

        • Yusuf S.
        • Zhao F.
        • Mehta S.R.
        • Chrolaricivius S.
        • Tognoni G.
        • Fox K.K.
        • Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators
        Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
        N Engl J Med. 2001; 345: 494-502
        • Mehta S.R.
        • Yusuf S.
        • Peters R.J.G.
        • Bertrand M.E.
        • Lewis B.S.
        • Natarajan M.K.
        • Malmberg K.
        • Rupprecht H.-J.
        • Zhao F.
        • Chrolavicius S.
        • Copland I.
        • Fox K.A.A.
        • Clopidogrel in Unstable Angina to Prevent Recurrent Events trial (CURE) Investigators
        Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention.
        Lancet. 2001; 358: 527-533
        • Boersma E.
        • Harrington R.A.
        • Moliterno D.J.
        • White H.
        • Théroux P.
        • Van de Werf F.
        • de Torbal A.
        • Armstrong P.W.
        • Wallentin L.C.
        • Wilcox R.G.
        • et al.
        Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes.
        Lancet. 2002; 359: 189-198
        • Coller B.S.
        Monitoring GP IIb/IIIa antagonist therapy.
        Circulation. 1997; 96: 3828-3832
        • Topol E.J.
        • Moliterno D.J.
        • Herrmann H.C.
        • Powers E.R.
        • Grines C.L.
        • Cohen D.J.
        • Cohen E.A.
        • Bertrand M.
        • Neumann F.-J.
        • Stone G.W.
        • DiBattiste P.M.
        • Demopoulis L.
        • TARGET Investigators
        Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization.
        N Engl J Med. 2001; 344: 1888-1894
        • Newby L.K.
        • Califf R.M.
        • White H.D.
        • Harrington R.A.
        • Van de Werf F.
        • Granger C.B.
        • Simes R.J.
        • Hasselblad V.
        • Armstrong P.W.
        The failure of orally administered glycoprotein IIb/IIIa inhibitors to prevent recurrent cardiac events.
        Am J Med. 2002; 112: 647-658
        • Weitz J.I.
        Low-molecular-weight heparins.
        N Engl J Med. 1997; 337: 688-698
        • Sandset P.M.
        • Abildgaard U.
        • Larsen M.L.
        Heparin induces release of extrinsic coagulation pathway inhibitor (EPI).
        Thromb Res. 1988; 50: 803-813
        • Broze Jr, G.J.
        Tissue factor pathway inhibitor.
        Thromb Haemost. 1995; 74: 90-93
        • Huang Z.F.
        • Wun T.-C.
        • Broze Jr, G.J.
        Kinetics of factor Xa inhibition by tissue factor pathway inhibitor.
        J Biol Chem. 1993; 268: 26950-26955
        • Hansen J.B.
        • Sandset P.M.
        • Huseby K.R.
        • Huseby N.E.
        • Bendz B.
        • Ostergaard P.
        • Nordoy A.
        Differential effect of unfractionated heparin and low molecular weight heparin on intravascular tissue factor pathway inhibitor.
        Br J Haematol. 1998; 101: 638-646
        • Montalescot G.
        • Philippe F.
        • Ankri A.
        • Vicaut E.
        • Bearez E.
        • Poulard J.E.
        • Carrie D.
        • Flammang D.
        • Dutoit A.
        • Carayon A.
        • et al.
        • French Investigators of the ESSENCE trial
        Early increase of von Willebrand factor predicts adverse outcome in unstable coronary artery disease.
        Circulation. 1998; 98: 294-299
        • Montalescot G.
        • Collet J.P.
        • Lison L.
        • Choussat R.
        • Ankri A.
        • Vicaut E.
        • Perlemuter K.
        • Philippe F.
        • Drobinski G.
        • Thomas D.
        Effects of various anticoagulant treatments on von Willebrand factor release in stable angina.
        J Am Coll Cardiol. 2000; 36: 110-114
        • Turpie A.G.G.
        • Antman E.M.
        Low-molecular-weight heparins in the treatment of acute coronary syndromes.
        Arch Intern Med. 2001; 161: 1484-1490
        • Manduteanu I.
        • Voinea M.
        • Capraru M.
        • Dragomir E.
        • Simionescu M.
        A novel attribute of enoxaparin.
        Pharmacology. 2002; 65: 32-37
        • Cohen M.
        • Demers C.
        • Gurfinkel E.P.
        • Turpie A.G.G.
        • Fromell G.J.
        • Goodman S.
        • Langer A.
        • Califf R.M.
        • Fox K.A.A.
        • Premmereur J.
        • Bigonzi F.
        • Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-Wave Coronary Events Study Group
        A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease.
        N Engl J Med. 1997; 337: 447-452
        • Antman E.M.
        • McCabe C.H.
        • Gurfinkel E.P.
        • Turpie A.G.G.
        • Bernink P.J.
        • Salein D.
        • Bayers De Luna A.
        • Fox K.
        • Lablanche J.-M.
        • Radley D.
        • Premmereur J.
        • Braunwald E.
        • TIMI 11B Investigators
        Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction.
        Circulation. 1999; 100: 1593-1601
        • Michalis L.K.
        • Papamichail N.
        • Katsouras C.S.
        • Karahaliou A.
        • Souria E.
        • Novas J.
        • Sioros L.
        • Papalambrakopoulos A.
        • Goudenos J.A.
        • Sideris D.A.
        Enoxaparin versus tinzaparin in the management of unstable coronary artery disease (EVET study).
        J Am Coll Cardiol. 2001; 37: 365A
        • Klein W.
        • Buchwald A.
        • Hillis S.E.
        • Monrad S.
        • Sanz G.
        • Turpie A.G.
        • van der Meer J.
        • Olaisson E.
        • Undeland S.
        • Ludwig K.
        Comparison of low-molecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease.
        Circulation. 1997; 96: 61-68
        • FRAXIS Study Group
        Comparison of two treatment duration (6 days and 14 days) of a low molecular weight heparin with a 6-day treatment of unfractionated heparin in the initial management of unstable angina or non-Q wave myocardial infarction.
        Eur Heart J. 1999; 20: 1553-1562
        • Kereiakes D.J.
        • Kleiman N.S.
        • Fry E.
        • Mwawasi G.
        • Lengerich R.
        • Maresh K.
        • Burkert M.L.
        • Aquilina J.W.
        • DeLoof M.
        • Broderick T.M.
        • Shimshak T.M.
        Dalteparin in combination with abciximab during percutaneous coronary intervention.
        Am Heart J. 2001; 141: 348-352
        • Collet J.P.
        • Montalescot G.
        • Lison L.
        • Choussat R.
        • Ankri A.
        • Drobinski G.
        • Sotirov I.
        • Thomas D.
        Percutaneous coronary intervention after subcutaneous enoxaparin pretreatment in patients with unstable angina pectoris.
        Circulation. 2001; 103: 658-663
        • Chen W.-H.
        • Lau C.-P.
        • Lau Y.-K.
        • Ng W.
        • Lee P.-Y.
        • Yu C.-M.
        • Ma E.
        Stable and optimal anticoagulation is achieved with a single dose of intravenous enoxaparin in patients undergoing percutaneous coronary intervention.
        J Invasive Cardiol. 2002; 14: 439-442
        • Aslam M.S.
        • Sundberg S.
        • Sabri M.N.
        • Cooke D.
        • Lakier J.B.
        Pharmacokinetics of intravenous/subcutaneous enoxaparin in patients with acute coronary syndrome undergoing percutaneous coronary interventions.
        Catheter Cardiovasc Interv. 2002; 57: 187-190
        • Fox K.A.
        • Antman E.M.
        • Cohen M.
        • Bigonzi F.
        • ESSENCE/TIMI 11 B Investigators
        Comparison of enoxaparin versus unfractionated heparin in patients with unstable angina pectoris/non-ST-segment elevation acute myocardial infarction having subsequent percutaneous coronary intervention.
        Am J Cardiol. 2002; 90: 477-482
        • Cohen M.
        • Theroux P.
        • Frey M.J.
        • White H.D.
        • Borzak S.
        • Weber S.
        • Senatore F.
        • Espenshade M.
        • Mukherjee R.
        • Thornton A.
        • Bigonzi F.
        • Sax F.L.
        Antithrombotic combination using tirofiban and enoxaparin.
        Circulation. 2000; 102: II826
        • Ferguson J.J.
        • Antman E.M.
        • Bates E.R.
        • Cohen M.
        • Every N.R.
        • Harrington R.A.
        • Pepine C.J.
        • Theroux P.
        • NICE 3 Investigators
        The use of enoxaparin and IIb/IIIa antagonists in acute coronary syndromes, including PCI.
        J Am Coll Cardiol. 2001; 37: 365A
        • Williams E.S.
        • Miller J.M.
        Results from late-breaking clinical trial sessions at the American College of Cardiology 51st Annual Scientific Session.
        J Am Coll Cardiol. 2002; 40: 1-18
        • Kereiakes D.J.
        • Grines C.
        • Fry E.
        • Esente P.
        • Hoppensteadt D.
        • Midei M.
        • Barr L.
        • Matthai W.
        • Todd M.
        • Broderick T.
        • et al.
        • NICE 1 and NICE 4 Investigators
        National Investigators Collaborating on Enoxaparin.
        Enoxaparin and abciximab adjunctive pharmacotherapy during percutaneous coronary intervention. J Invasive Cardiol. 2001; 13: 272-278
        • Kereiakes D.J.
        • Montalescot G.
        • Antman E.M.
        • Cohen M.
        • Darius H.
        • Ferguson H.H.
        • Grines C.
        • Karsch K.R.
        • Kleinman N.S.
        • Moliterno D.J.
        • et al.
        Low-molecular-weight heparin therapy for non-ST-elevation acute coronary syndromes and during percutaneous coronary intervention.
        Am Heart J. 2002; 144: 615-624
        • Ross A.M.
        • Molhoek P.
        • Lundergan C.L.
        • Knudtson M.
        • Draoui Y.
        • Regalado L.
        • Le Louer V.
        • Bigonzi F.
        • Schwartz W.
        • de Jong E.
        • Coyne K.
        Randomized comparison of enoxaparin, a low-molecular-weight heparin, with unfractionated heparin adjunctive to recombinant tissue plasminogen activator thrombolysis and aspirin.
        Circulation. 2001; 104: 648-652
        • Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT-3) Investigators
        Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin.
        Lancet. 2001; 358: 605-613
        • Antman E.M.
        • Louwererenburg H.W.
        • Baars H.F.
        • Wesdorp J.C.L.
        • Hamer B.
        • Bassand J.-P.
        • Bigonzi F.
        • Pisapia G.
        • Gibson C.M.
        • Heidbuchel H.
        • Braunwald E.
        • Van de Werf F.
        • ENTIRE-TIMI 23 Investigators
        Enoxaparin as adjunctive antithrombin therapy for ST-elevation myocardial infarction.
        Circulation. 2002; 105: 1642-1649
        • Simoons M.L.
        • Krzemiñska-Pakula M.
        • Alonso A.
        • Goodman S.G.
        • Kali A.
        • Loos U.
        • Gosset F.
        • Louer V.
        • Bigonzi F.
        • AMI-SK Investigators
        Improved reperfusion and clinical outcome with enoxaparin as an adjunct to streptokinase thrombolysis in acute myocardial infarction.
        Eur Heart J. 2002; 23: 1282-1290
        • Bittl J.A.
        • Strony J.
        • Brinker J.A.
        • Ahmed W.H.
        • Meckel C.R.
        • Chaitman B.R.
        • Maraganore J.
        • Deutsch E.
        • Adelman B.
        • Hirulog Angioplasty Study Investigators
        Treatment with bivalirudin (Hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina.
        N Engl J Med. 1995; 333: 764-769
        • Serruys P.W.
        • Herrman J.-P.R.
        • Simon R.
        • Rutsch W.
        • Bode C.
        • Laarman G.-J.
        • van Dijk R.
        • van den Bos A.
        • Umans V.A.W.M.
        • Fox K.A.A.
        • Close P.
        • Deckers J.W.
        • HELVETICA Investigators
        A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty.
        N Engl J Med. 1995; 333: 757-763
        • Lincoff A.M.
        • Kleiman N.S.
        • Kottker-Marchant K.
        • Maierson E.S.
        • Maresh K.
        • Wolski K.E.
        • Topol E.J.
        Bivalirudin with planned or provisional abciximab versus low-dose heparin and abciximab during percutaneous coronary revascularization.
        Am Heart J. 2002; 143: 847-853
        • Schwartz G.G.
        • Olsson A.G.
        • Ezekowitz M.D.
        • Ganz P.
        • Oliver M.F.
        • Waters D.
        • Zeiher A.
        • Chaitman B.R.
        • Leslie S.
        • Stern T.
        • Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators
        Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes.
        JAMA. 2001; 285: 1711-1718
        • Colivicchi F.
        • Guido V.
        • Tubaro M.
        • Ammirati F.
        • Montefoschi N.
        • Varveri A.
        • Santini M.
        Effects of atorvastatin 80 mg daily early after onset of unstable angina pectoris or non-Q-wave myocardial infarction.
        Am J Cardiol. 2002; 90: 872-874
        • ACE Inhibitor Myocardial Infarction Collaborative Group
        Indications for ACE inhibitors in the early treatment of acute myocardial infarction.
        Circulation. 1998; 97: 2202-2212
        • Badimon L.
        • Turitto V.
        • Rosemark J.A.
        • Badimon J.J.
        • Fuster V.
        Characterization of a tubular flow chamber for studying platelet interaction with biologic and prosthetic materials.
        J Lab Clin Med. 1987; 110: 706-718
        • Bourcier T.
        • Libby P.
        HMG-CoA reductase inhibitors reduce plasminogen activator inhibitor-1 expression by human vascular smooth muscle and endothelial cells.
        Arterioscler Thromb Vasc Biol. 2000; 20: 556-562
        • Eto M.
        • Kozai T.
        • Cosentino F.
        • Joch H.
        • Lüscher T.
        Statin prevents tissue factor expression in human endothelial cells.
        Circulation. 2002; 105: 1756-1759
        • Kinlay S.
        • Rifai N.
        • Libby P.
        • Ganz P.
        • MIRACL Investigators
        Effect of atorvastatin on C-reactive protein in patients with acute coronary syndromes.
        J Am Coll Cardiol. 2002; 39 (Abstract 822-3): 308A
        • Wagner A.
        • Herkner H.
        • Schreiber W.
        • Bur A.
        • Woisetschlager C.
        • Stix G.
        • Laggner A.N.
        • Hirschl M.M.
        Ramipril prior to thrombolysis attenuates the early increase of PAI-1 in patients with acute myocardial infarction.
        Thromb Haemost. 2002; 88: 180-185