Download PDF
Thromb Haemost 1996; 76(01): 105-110
DOI: 10.1055/s-0038-1650531
Original Article
Schattauer GmbH Stuttgart

Prevention of Early Reocclusion after Thrombolysis of Copper Coil-induced Thrombi in the Canine Carotid Artery: Comparison of PEG-Hirudin and Unfractionated Heparin

Klaus Rübsamen
The Knoll AG, Research and Development, Preclinical Angiology, Ludwigshafen, Germany
,
Wilfried Hornberger
The Knoll AG, Research and Development, Preclinical Angiology, Ludwigshafen, Germany
› Author Affiliations
Further Information

Publication History

Received 11 August 1995

Accepted after resubmission 27 March 1996

Publication Date:
10 July 2018 (online)

  PDF Download  Permissions and Reprints

Summary

Cofactor-independent thrombin inhibitors as adjunctive treatment to thrombolysis have been found to enhance reperfusion and reduce the incidence of early reocclusion more effectively than heparins. However, all thrombin inhibitors presently available are rapidly cleared from the circulation which may cause rebound effects after cessation of treatment. To evaluate the effect of PEG-hirudin (LU 87981) a new, long acting derivative of hirudin as adjunctive treatment to rt-PA, a thrombotic occlusion of the carotid artery was induced in mongrel dogs by means of a copper coil. Vessel patency was continuously monitored with an electromagnetic flow probe. Thrombolysis of the occluded artery was induced by administration of 40 Μg × kg−1 + 240 Μg × kg−1 × h−1 rt-PA (low dose) or 80 Μg × kg−1 + 480 Μg × kg−1 × h−1 rt-PA (high dose). With high dose rt-PA treatment, patency was achieved in all animals within 50 min (range 24 to 75), with low dose rt-PA treatment only in 6 out of 8 animals after 73 min (range 26 to 117). Concomitant administration of PEG-hirudin (0.3 mg × kg−1 bolus + 0.15 mg × kg−1 × h−1 infusion) increased the incidence of reperfusion in the low dose rt-PA group to 100% while the reperfusion time was shortened from 73 min in the corresponding control group to 38 min (range 20 to 75 min) in the group given PEG-hirudin (p = 0.065, Mann-Whitney U-test). The carotid artery blood flow, which rapidly declined to zero within 18 to 27 min after discontinuing low or high dose rt-PA infusions remained at a sustained level for the whole observation period of 4 h only in the group given PEG-hirudin. Only one animal reoccluded after 229 min. Unfractionated heparin (UFH) given at a dose of 0.3 mg × kg−1 bolus + 0.3 mg × kg−1 × h−1 infusion did not improve the incidence of reperfusion or lower the incidence of reocclusion. Buccal bleeding time was prolonged after high dose rt-PA treatment and after low dose rt-PA with adjunctive UFH- or PEG-hirudin treatment. Buccal blood loss was not significantly affected by either treatment.

In conclusion, these experiments indicate that early reocclusion after thrombolysis can effectively be diminished by concomitant treatment with the long acting thrombin inhibitor PEG-hirudin with moderate effects on bleeding time and aPTT.

 

  • References

  • 1 White HD, Norris RM, Browns MA, Takayama M, Maslowski A, Bass NM, Ormiston JA, Whitlock T. Effect of intravenous streptokinase on left ventricular function and early survival after acute myocardial infarction. N Engl J Med 1987; 317: 850-855
    CrossrefPubMedGoogle Scholar
  • 2 Sobel BE. Thrombolysis in the treatment of acute myocardial infarction. In: Fuster V, Verstraete M. eds Thrombosis in cardiovascular disorders. Philadelphia: WB Saunders: 1992: 289-326
  • 3 Hoffmann JJML, Janssen WCM. Interactions between thrombolytic agents and platelets: Effects of plasmin on glycoproteins lb and Ilb/IIIa. Thromb Res 1992; 67: 711-719
    CrossrefPubMedGoogle Scholar
  • 4 Rapold HJ, de Bono D, Arnold AER, Amout J, De Cock F, Collen D, Verstraete M. Plasma fibrinopeptide A levels in patients with acute myocardial infarction treated with alteplase. Correlation with concomitant heparin, coronary artery patency, and recurrent ischemia. Circulation 1992; 85: 928-34
    CrossrefPubMedGoogle Scholar
  • 5 Szezeklik A, Dropinski J, Radwan J, Krzanowski M. Persistent generation of thrombin after acute myocardial infarction. Arterioscl Thromb 1992; 12: 548-553
    CrossrefPubMedGoogle Scholar
  • 6 Mirshahi M, Soria J, Soria C, Faivre R, Lu H, Courtney M, Roitsch C, Tripier D, Caen JP. Evaluation of the inhibition by heparin and hirudin of coagulation activation during rt-PA-induced thrombolysis. Blood 1989; 74: 1025-1030
    PubMedGoogle Scholar
  • 7 Gold HK, Yasuda T, Jang IK, Guerrero JJ, Fallon JT, Leinbach RC, Collen D. Animal models for arterial thrombolysis and prevention of reocclusion. Erythrocyte-rich versus platelet-rich thrombus. Circulation 1991; 83 Suppl (Suppl. 04) IV-26-IV-40
    CrossrefPubMedGoogle Scholar
  • 8 Yasuda T, Gold HK, Yaoita H, Leinbach RC, Guerrero JL, Jang IK, Holt R, Fallon JT, Collen D. Comparative effects of aspirin, a synthetic thrombin inhibitor and a monoclonal antiplatelet glycoprotein Ilb/IIIa antibody on coronary artery reperfusion, reocclusion and bleeding with recombinant tissue-type plasminogen activator in a canine preparation. J Am Coll Cardiol 1990; 16: 714-22
    CrossrefPubMedGoogle Scholar
  • 9 Haskel EJ, Prager NA, Sobel BE, Abendschein DR. Relative efficacy of antithrombin compared with antiplatelet agents in accelerating coronary thrombolysis and preventing early reocclusion. Circulation 1991; 83: 1048-56
    CrossrefPubMedGoogle Scholar
  • 10 Yao SK, Ober JC, Ferguson JJ, Anderson HV, Maragonore J, Buja LM, Willerson JT. Combination of inhibition of thrombin and blockade of thromboxane A2 synthetase and receptors enhances thrombolysis and delays reocclusion in canine coronary arteries. Circulation 1992; 86: 1993-1999
    CrossrefPubMedGoogle Scholar
  • 11 Kelly AB, Marzec UM, Krupski W, Bass A, Cadroy Y, Hanson SR, Harker LA. Hirudin interruption of heparin-resistant arterial thrombus formation in baboons. Blood 1991; 77: 1006-1012
    PubMedGoogle Scholar
  • 12 Heras M, Chesebro JH, Webster MWI, Mruk JS, Grill DE, Penny WJ, Bowie EJW, Badimon L, Fuster V. Hirudin, heparin, and placebo during deep arterial injury in the pig. The in vivo role of thrombin in platelet-mediated thrombosis. Circulation 1990; 82: 1476-1484
    CrossrefPubMedGoogle Scholar
  • 13 Buchwald AB, Sandrock D, Unterberg C, Ebbecke M, Nebendahl K, Liiders S, Munz D, Wiegand V. Platelet and fibrin deposition on coronary stents in minipigs: Effect of hirudin versus heparin. J Am Coll Cardiol 1993; 21: 249-254
    CrossrefPubMedGoogle Scholar
  • 14 Schumacher WA, Heran CH, Steinbacher TE, Megill JR, Bird JE, Giancar-li MR, Durham SK. Thrombin inhibition compared with other antithrombotic drugs in rats. Thromb Res 1992; 68: 157-166
    CrossrefPubMedGoogle Scholar
  • 15 Sitko GR, Ramjit DR, Stabilito II, Lehman D, Lynch JJ, Vlasuk GP. Conjunctive enhancement of enzymatic thrombolysis and prevention of thrombotic reocclusion with the selective factor Xa inhibitor, tick anticoagulant peptide. Comparison to hirudin and heparin in a canine model of acute coronary artery thrombosis. Circulation 1992; 85: 805-815
    CrossrefPubMedGoogle Scholar
  • 16 Klement P, Borm A, Hirsh J, Maraganore J, Wilson G, Weitz J. The effect of thrombin inhibitors on tissue plasminogen activator induced thrombolysis in a rat model. Thromb Haemost 1992; 68: 64-68
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin Ill-independent inhibitors. J Clin Invest 1990; 86: 385-91
    CrossrefPubMedGoogle Scholar
  • 18 Kaiser B, Hauptmann J. Pharmacology of synthetic thrombin inhibitors of the tripeptide type. Cardiovasc Drug Rev 1992; 10: 71-87
    CrossrefPubMedGoogle Scholar
  • 19 Markwardt F, Richter M, Walsmann P, Riesener G, Paintz M. Preparation of dextran-bound recombinant hirudin and its pharmacokinetic behaviour. Biomed Biochim Acta 1990; 49: 1103-1108
    PubMedGoogle Scholar
  • 20 Riibsamen K, Homberger W, Laux V, Schwarz M, Schweden J. Antithrombotic efficacy of the polyethyleneglycol-coupled hirudin mutein LU 57291 in experimentally induced venous and arterial thrombosis. Thromb Haemost 1993; 69: 2717 Abstr
    PubMedGoogle Scholar
  • 21 Kordenat RK, Kezdi P, Stanley EL. A new catheter technique for producing experimental coronary thrombosis and selective coronary visualization. Amer Heart J 1972; 83: 360-364
    CrossrefPubMedGoogle Scholar
  • 22 Folts J. An in vivo model of experimental arterial stenosis, intimal damage, and periodic thrombosis. Circulation 1991; 83 (Suppl. 04) IV-3-IV-14
    PubMedGoogle Scholar
  • 23 Brassard JA, Meyers KM. Evaluation of the buccal bleeding time and platelet glass bead retention as assays of hemostasis in the dog: The effects of acetylsalicylic acid, warfarin and von Willebrand factor deficiency. Thromb Haemost 1991; 65: 191-195
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Spannagl M, Bichler J, Birg A, Lill H, Schramm W. Development of a chromogenic substrate assay for the determination of hirudin in plasma. Blood Coagulation Fibrinolysis 1991; 2: 121-127
    CrossrefPubMedGoogle Scholar
  • 25 Ohman EM, Califf RM, Topol EJ, Candela R, Abbottsmith C, Ellis S, Sigmon KN, Kereakes D, George B, Stack R. TAMI study group: Consequences of reocclusion after successful reperfusion therapy in acute myocardial infarction. Circulation 1990; 82: 781-91
    CrossrefPubMedGoogle Scholar
  • 26 Rigel DF, Olson RW, Lappe RW. Comparison of hirudin and heparin as adjuncts to streptokinase thrombolysis in a canine model of coronary thrombosis. Circulation Res 1993; 72: 1091-1102
    CrossrefPubMedGoogle Scholar
  • 27 Lynch JJ, Sitk GR, Mellott MJ, Nutt EM, Lehman ED, Friedman PA, Dunwiddie CT, Vlasuk GP. Maintenance of canine coronary artery patency following thrombolysis with front loaded plus low dose maintenance conjunctive therapy. A comparison of factor Xa versus thrombin inhibition. Cardiovasc Res 1994; 28: 78-85
    CrossrefPubMedGoogle Scholar
  • 28 Jang IK, Gold HK, Leinbach RC, Fallon JT, Collen D. In vivo thrombin inhibition enhances and sustains arterial recanalization with recombinant tissue-type plasminogen activator. Circulation Res 1990; 67: 1552-1561
    CrossrefPubMedGoogle Scholar
  • 29 Jackson CV, Wilson HC, Growe VG, Shuman RT, Gesellchen PD. Reversible tripeptide thrombin inhibitors as adjunctive agents to coronary thrombolysis: A comparison with heparin in a canine model of coronary artery thrombosis. J Cardiovasc Pharmacol 1993; 21: 587-94
    CrossrefPubMedGoogle Scholar
  • 30 Yao SK, McNatt J, Anderson HV, Eidt J, Cui K, Golino P, Glas-Greenwalt P, Maraganore J, Buja LM, Willerson JT. Thrombin inhibition enhances tissue-type plasminogen activator-induced thrombolysis and delays reocclusion. Am J Physiol 1992; 262: H374-H379
    CrossrefPubMedGoogle Scholar
  • 31 Voytik S, Badylak SF, Burke S, Klabunde RE, Henkin J, Simmons A. The protective effect of heparin in a dog model of rethrombosis following pharmacologic thrombolysis. Thromb Haemost 1990; 64: 438-444
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 Rudd MA, George D, Johnstone MT, Moore RT, Collins L, Rabbani LE, Loscalzo J. Effect of thrombin inhibition on the dynamics of thrombolysis and on platelet function during thrombolytic therapy. Circulation Res 1992; 70: 829-834
    CrossrefPubMedGoogle Scholar
  • 33 Theroux P, Perez-Villa F, Waters D, Lesperance J, Shabani F, Bonan R. Randomized double-blind comparison of two doses of hirulog with heparin as adjunctive therapy to streptokinase to promote early patency of the infarct-related artery in acute myocardial infarction. Circulation 1995; 91: 2132-2139
    CrossrefPubMedGoogle Scholar
  • 34 Cannon CP, McCabe CH, Henry TD, Schweiger MJ, Gibson RS, Mueller HS. A pilot study of recombinant desulfatohirudin compared with heparin in conjunction with tissue-type plasminogen activator factor and aspirin for acute myocardial infarction: Results of the thrombolysis in myocardial infarction (TIMI) 5 trial. J Am Coll Cardiol 1994; 23: 993-1003
    CrossrefPubMedGoogle Scholar
  • 35 Rote WE, Mu DX, Bates ER, Nedelman MA, Lucchesi BR. Prevention of rethrombosis after coronary thrombolysis in a chronic canine model.II. Adjunctive therapy with r-hirudin. J Cardiovasc Pharmacol 1994; 23: 203-211
    CrossrefPubMedGoogle Scholar
  • 36 Gold HK, Torres FW, Garabedian HD, Werner W, Jang IK, Khan A, Hagstrom JN, Yasuda T, Leinbach RC, Newell JB, Bovill EG, Stump DC, Collen D. Evidence for a rebound phenomenon after cessation of a 4-hour infusion of a specific thrombin inhibitor in patients with unstable angina pectoris. JACC 1993; 21: 1039-1047
    CrossrefPubMedGoogle Scholar
  • 37 Nicolini FA, Lee P, Rios G, Kottke-Marchant K, Topol EJ. Combination of platelet fibrinogen receptor antagonist and direct thrombin inhibitor at low doses markedly improves thrombolysis. Circulation 1994; 89: 1802-1809
    CrossrefPubMedGoogle Scholar
  • 38 Prager NA, Torr-Brown SR, Sobel BE, Abendschein DR. Maintenance of patency after thrombolysis in stenotic coronary arteries requires combined inhibition of thrombin and platelets. JACC 1993; 22: 296-301
    CrossrefPubMedGoogle Scholar
  • 39 Antmann EM. for the TIMI 9A Investigators. Hirudin in acute myocardial infarction. Safety report from the thrombolysis and thrombin inhibition in myocardial infarction (TIMI) 9A trial. Circulation 1994; 90: 1624-1630
    CrossrefPubMedGoogle Scholar
  • 40 The global use of strategies to open occluded arteries (GUSTO) Ha investigators. Randomized trial of intravenous heparin versus recombinant hirudin for acute coronary syndromes. Circulation 1994; 90: 1631-1637
    CrossrefPubMedGoogle Scholar
  • 41 Neuhaus KL, Essen Rv, Tebbe U, Jessel A, Heinrichs H, Maurer W, Doring W, Harmjanz D, Kotter V, Kalhammer E, Simon H, Horacek T. Safety observations from the pilot phase of the randomized r-hirudin for improvement of thrombolysis (HIT-III) study. A study of the Arbeitsgemein-schaft Leitender Kardiologischer Krankenhausarzte (ALKK). Circulation 1994; 90: 1638-1642
    CrossrefPubMedGoogle Scholar
  • 42 Riibsamen K, Homberger W, Ruf A, Bode C. The ecarin clotting time, a rapid and simple coagulation assay for monitoring hirudin and PEG-Hiru-din in blood. Ann Hematol 1996; 72: A56
    PubMedGoogle Scholar
  • 43 Esslinger HU, Diibbers K, Miiller-Peltzer H. First data on safety and anticoagulant activity after single i.v. and s.c. PEG-himdin-administration in healthy volunteers. Thromb Haemost 1995; 73: 2109
    PubMedGoogle Scholar