Download PDF
Thromb Haemost 2000; 84(05): 858-864
DOI: 10.1055/s-0037-1614128
Review Article
Schattauer GmbH

Successful Attenuation of Venous Thrombus Growth in Rabbits after the Administration of a Novel Oral Thrombin Inhibitor

Philip W. Friederich
1   From the Departments of Vascular Medicine, University of Amsterdam, Amsterdam, The Netherlands
2   Internal Medicine, University of Amsterdam, Amsterdam, The Netherlands
,
Tymen T. Keller
1   From the Departments of Vascular Medicine, University of Amsterdam, Amsterdam, The Netherlands
,
Bart J. Biemond
1   From the Departments of Vascular Medicine, University of Amsterdam, Amsterdam, The Netherlands
2   Internal Medicine, University of Amsterdam, Amsterdam, The Netherlands
,
Ron J. G. Peters
3   Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Wilfried Hornberger
4   Department of Experimental and Cardiovascular Research, Knoll AG, Ludwigshafen, Germany
,
Harry R. Büller
1   From the Departments of Vascular Medicine, University of Amsterdam, Amsterdam, The Netherlands
,
Marcel Levi
1   From the Departments of Vascular Medicine, University of Amsterdam, Amsterdam, The Netherlands
2   Internal Medicine, University of Amsterdam, Amsterdam, The Netherlands
› Author AffiliationsMarcel Levi is a fellow of the Royal Netherlands Academy of Arts and Sciences; Harry Büller is an established investigator of the Netherlands Heart Foundation and Philip Friederich is supported by a grant from the Netherlands Organization for Scientific Research (NWO).
Further Information

Publication History

Received 07 February 2000

Accepted after resubmission 24 May 2000

Publication Date:
13 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

Current antithrombotic compounds have several limitations in clinical practice. The present study was designed to investigate a novel orally available direct thrombin inhibitor, BSF 208791. Intravenous administration of BSF 208791 showed superior antithrombotic properties as compared with Polyethylenglycol-Hirudin (PEG-Hirudin) and low molecular weight heparin (LMWH) in a model of venous thrombosis in rabbits. The thrombus growth was 22%, 30%, 37% and 50% after BSF 208791, PEG-Hirudin, LMWH, and saline administration, respectively. Moreover, bleeding time was less affected after administration of BSF 208791 as compared with PEG-Hirudin. The oral administration of BSF 208791 resulted in adequate bioavailability and significantly reduced venous thrombus growth to 36% as compared with 60% in the saline treated rabbits. The antithrombotic effect of BSF 208791 appears to be superior to PEG-Hirudin and LMWH without affecting the bleeding time. BSF 208791 is an orally available agent that might be a promising candidate for future antithrombotic therapy.

Key words

Anticoagulants - thrombosis - coagulation - rabbits - thrombin inhibitor
 

  • References

  • 1 Verstraete M, Arnold AE, Brower RW, Collen D, de Bono DP, De Zwaan C, Erbel R, Hillis WS, Lennane RJ, Lubsen J. Acute coronary thrombolysis with recombinant human tissue-type plasminogen activator: initial patency and influence of maintained infusion on reocclusion rate. Am J Cardiol 1987; 60: 231-7.
    CrossrefPubMedSearch in Google Scholar
  • 2 Williams DO, Borer J, Braunwald E, Chesebro JH, Cohen LS, Dalen J, Dodge HT, Francis CK, Knatterud G, Ludbrook P. Intravenous recombinant tissue-type plasminogen activator in patients with acute myocardial infarction: a report from the NHLBI thrombolysis in myocardial infarction trial. Circulation 1986; 73: 338-46.
    CrossrefPubMedSearch in Google Scholar
  • 3 Yasuda T, Gold HK, Fallon JT, Leinbach RC, Garabedian HD, Guerrero JL, Collen D. A canine model of coronary artery thrombosis with superimposed high grade stenosis for the investigation of rethrombosis after thrombolysis. J Am Coll Cardiol 1989; 13: 1409-14.
    CrossrefPubMedSearch in Google Scholar
  • 4 Topol EJ, Califf RM, George BS, Kereiakes DJ, Rothbaum D, Candela RJ, Abbotsmith CW, Pinkerton CA, Stump DC, Collen D. Coronary arterial thrombolysis with combined infusion of recombinant tissue-type plasminogen activator and urokinase in patients with acute myocardial infarction. Circulation 1988; 77: 1100-7.
    CrossrefPubMedSearch in Google Scholar
  • 5 Weitz JI, Leslie B, Hudoba M. Thrombin binds to soluble fibrin degradation products where it is protected from inhibition by heparin-antithrombin but susceptible to inactivation by antithrombin-independent inhibitors. Circulation 1998; 97: 544-52.
    CrossrefPubMedSearch in Google Scholar
  • 6 Hogg PJ, Jackson CM. Fibrin monomer protects thrombin from inactivation by heparin-antithrombin III: implications for heparin efficacy. Proc Natl Acad Sci USA 1989; 86: 3619-23.
    CrossrefPubMedSearch in Google Scholar
  • 7 Bar-Shavit R, Eldor A, Vlodavsky I. Binding of thrombin to subendothelial extracellular matrix. Protection and expression of functional properties. J Clin Invest 1989; 84: 1096-104.
    CrossrefPubMedSearch in Google Scholar
  • 8 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 III-independent inhibitors. J Clin Invest 1990; 86: 385-91.
    CrossrefPubMedSearch in Google Scholar
  • 9 Hanson SR, Harker LA. Interruption of acute platelet-dependent thrombosis by the synthetic antithrombin D-phenylalanyl-L-prolyl-L-arginyl chloromethyl ketone. Proc Natl Acad Sci USA 1988; 85: 3184-8.
    CrossrefPubMedSearch in Google Scholar
  • 10 van den Bos AA, Deckers JW, Heyndrickx GR, Laarman GJ, Suryapranata H, Zijlstra F, Close P, Rijnierse JJ, B¸ller HR, Serruys PW. Safety and efficacy of recombinant hirudin (CGP 39 393) versus heparin in patients with stable angina undergoing coronary angioplasty. Circulation 1993; 88: 2058-66.
    CrossrefPubMedSearch in Google Scholar
  • 11 Eriksson BI, Ekman S, Kalebo P, Zachrisson B, Bach D, Close P. Prevention of deep-vein thrombosis after total hip replacement: direct thrombin inhibition with recombinant hirudin, CGP 39393. Lancet 1996; 347: 635-9.
    CrossrefPubMedSearch in Google Scholar
  • 12 The OASIS Investigators. Comparison of the effects of two doses of recombinant hirudin compared with heparin in patients with acute myocardial ischemia without ST elevation: a pilot study. Organization to Assess Strategies for Ischemic Syndromes (OASIS) Investigators. Circulation 1997; 96: 769-77.
    CrossrefPubMedSearch in Google Scholar
  • 13 Nurmohamed MT, Rosendaal FR, Buller HR, Dekker E, Hommes DW, Vandenbroucke JP, BriÎt E. Low-molecular-weight heparin versus standard heparin in general and orthopaedic surgery: a meta-analysis. Lancet 1992; 340: 152-6.
    CrossrefPubMedSearch in Google Scholar
  • 14 Azar AJ, Cannegieter SC, Deckers JW, BriÎt E, van Bergen PF, Jonker JJ, Rosendaal FR. Optimal intensity of oral anticoagulant therapy after myocardial infarction. J Am Coll Cardiol 1996; 27: 1349-55.
    CrossrefPubMedSearch in Google Scholar
  • 15 Rosendaal FR, Cannegieter SC, van der Meer FJ, BriÎt E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993; 69: 236-9.
    Thieme ConnectPubMedSearch in Google Scholar
  • 16 Forfar JC. A 7-year analysis of haemorrhage in patients on long-term anticoagulant treatment. Br Heart J 1979; 42: 128-32.
    CrossrefPubMedSearch in Google Scholar
  • 17 Petitti DB, Strom BL, Melmon KL. Duration of warfarin anticoagulant therapy and the probabilities of recurrent thromboembolism and hemorrhage. Am J Med 1986; 81: 255-9.
    CrossrefPubMedSearch in Google Scholar
  • 18 van der Meer FJ, Rosendaal FR, Vandenbroucke JP, Briët E. Bleeding complications in oral anticoagulant therapy. An analysis of risk factors. Arch Intern Med 1993; 153: 1557-62.
    CrossrefPubMedSearch in Google Scholar
  • 19 The ASPECT Investigators. Effect of long-term oral anticoagulant treatment on mortality and cardiovascular morbidity after myocardial infarction. Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis (ASPECT) Research Group. Lancet 1994; 343: 499-503.
    PubMedSearch in Google Scholar
  • 20 Bleske BE, Welage LS, Warren EW, Brown MB, Shea MJ. Variations in prothrombin time and international normalized ratio over 24 hours in warfarin-treated patients. Pharmacotherapy 1995; 15: 709-12.
    PubMedSearch in Google Scholar
  • 21 Biemond BJ, Friederich PW, Koschinsky ML, Levi M, Sangrar W, Xia J, B¸ller HR, ten Cate JW. Apolipoprotein(a) attenuates endogenous fibrinolysis in the rabbit jugular vein thrombosis model in vivo. Circulation 1997; 96: 1612-5.
    CrossrefPubMedSearch in Google Scholar
  • 22 Friederich PW, Levi M, Biemond BJ, Charlton P, Templeton D, van Zonneveld AJ, Bevan P, Pannekoek H, ten Cate JW. Novel low-molecularweight inhibitor of PAI-1 (XR5118) promotes endogenous fibrinolysis and reduces postthrombolysis thrombus growth in rabbits. Circulation 1997; 96: 916-21.
    PubMedSearch in Google Scholar
  • 23 Esslinger HU, Haas S, Maurer R, Lassmann A, Dubbers K, Muller P. Pharmacodynamic and safety results of PEG-Hirudin in healthy volunteers. Thromb Haemost 1997; 77: 911-9.
    Thieme ConnectPubMedSearch in Google Scholar
  • 24 Rubsamen K, Kirchengast M. Thrombin inhibition and intracoronary thrombus formation: effect of polyethylene glycol-coupled hirudin in the stenosed, locally injured canine coronary artery. Coron Artery Dis 1998; 09: 35-42.
    CrossrefPubMedSearch in Google Scholar
  • 25 Humphries J, Lattimer C, Smith A, McGuinness CL, Whitton C, Gaffney PJ, Burnand KG. High and constant plasma levels of tissue plasminogen activator and PEG-hirudin can be achieved by subcutaneous delivery. Thromb Research 1997; 87: 123-9.
    CrossrefPubMedSearch in Google Scholar
  • 26 Frydman AM, Bara L, Le Roux Y, Woler M, Chauliac F, Samama MM. The antithrombotic activity and pharmacokinetics of enoxaparine, a low molecular weight heparin, in humans given single subcutaneous doses of 20 to 80 mg. J Clin Pharmacol 1988; 28: 609-18.
    CrossrefPubMedSearch in Google Scholar
  • 27 Biemond BJ, Levi M, Nurmohamed MT, B¸ller HR, ten Cate JW. Additive effect of the combined administration of low molecular weight heparin and recombinant hirudin on thrombus growth in a rabbit jugular vein thrombosis model. Thromb Haemost 1994; 72: 377-80.
    Thieme ConnectPubMedSearch in Google Scholar
  • 28 Hull RD, Raskob GE, Pineo GF, Green D, Trowbridge AA, Elliott CG, Lerner RG, Hall J, Sparling T, Brettell HR. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med 1992; 326: 975-82.
    CrossrefPubMedSearch in Google Scholar
  • 29 Koopman MM, Prandoni P, Piovella F, Ockelford PA, Brandjes DP, van der Meer J, Gallus AS, Simonneau G, Chesterman CH, Prins MH. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecularweight heparin administered at home. The Tasman Study Group. N Engl J Med 1996; 334: 682-7.
    CrossrefPubMedSearch in Google Scholar
  • 30 Prandoni P, Lensing AW, B¸ller HR, Carta M, Cogo A, Vigo M, Casara D, Ruol A, ten Cate JW. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet 1992; 339: 441-5.
    CrossrefPubMedSearch in Google Scholar
  • 31 Callas DD, Fareed J. Comparative anticoagulant effects of various thrombin inhibitors, as determined in the ecarin clotting time method. Thromb Research 1996; 83: 463-8.
    CrossrefPubMedSearch in Google Scholar
  • 32 Nowak G, Bucha E. A New Method for Therapeutical Monitoring of Hirudin. Thromb Haemost 1993; 69: 1306-6.
    PubMedSearch in Google Scholar
  • 33 Nurmohamed MT, Berckmans RJ, Morrien-Salomons WM, Berends F, Hommes DW, Rijnierse JJ, Sturk A. Monitoring anticoagulant therapy by activated partial thromboplastin time: hirudin assessment. An evaluation of native blood and plasma assays. Thromb Haemost 1994; 72: 685-92.
    Thieme ConnectPubMedSearch in Google Scholar
  • 34 ten Cate H, Lamping RJ, Henny CP, Prins A, ten Cate JW. Automated amidolytic method for determining heparin, a heparinoid, and a low-Mr heparin fragment, based on their anti-Xa activity. Clin Chem 1984; 30: 860-4.
    PubMedSearch in Google Scholar
  • 35 Levi M, Friederich PW, Middleton S, de Groot PG, Wu YP, Harris R, Biemond BJ, Heijnen HG, Levin J, ten Cate JW. Fibrinogen-coated albumin microcapsules reduce bleeding in severely thrombocytopenic rabbits. Nature Med 1999; 05: 107-11.
    CrossrefPubMedSearch in Google Scholar
  • 36 Schulman S, Rhedin AS, Lindmarker P, Carlsson A, Larfars G, Nicol P, Loogna E, Svensson E, Ljungberg B, Walter H. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. Duration of Anticoagulation Trial Study Group. N Engl J Med 1995; 332: 1661-5.
    CrossrefPubMedSearch in Google Scholar
  • 37 Schulman S, Lockner D, Juhlin-Dannfelt A. The duration of oral anticoagulation after deep vein thrombosis. A randomized study. Act Med Scan 1985; 217: 547-52.
    PubMedSearch in Google Scholar
  • 38 Levine MN, Hirsh J, Gent M, Turpie AG, Weitz J, Ginsberg J, Geerts W, LeClerc J, Neemeh J, Powers P. Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis. Thromb Haemost 1995; 74: 606-11.
    Thieme ConnectPubMedSearch in Google Scholar
  • 39 Schulman S, Granqvist S, Holmstrom M, Carlsson A, Lindmarker P, Nicol P, Eklund SG, Nordlander S, Larfars G, Leijd B, Linder O, Loogna E. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. The Duration of Anticoagulation Trial Study Group. N Engl J Med 1997; 336: 393-8.
    CrossrefPubMedSearch in Google Scholar
  • 40 Li WX, Kaplan AV, Grant GW, Toole JJ, Leung LL. A novel nucleotidebased thrombin inhibitor inhibits clot-bound thrombin and reduces arterial platelet thrombus formation. Blood 1994; 83: 677-82.
    PubMedSearch in Google Scholar
  • 41 De Caterina R, Lanza M, Manca G, Strata GB, Maffei S, Salvatore L. Bleeding time and bleeding: an analysis of the relationship of the bleeding time test with parameters of surgical bleeding. Blood 1994; 84: 3363-70.
    PubMedSearch in Google Scholar
  • 42 Rodgers RP, Levin J. A critical reappraisal of the bleeding time. Seminars in Thromb Haemost 1990; 16: 1-20.
    Thieme ConnectPubMedSearch in Google Scholar
  • 43 Cousins GR, Friedrichs GS, Sudo Y, Rebello SS, Rote WE, Vlasuk GP, Nolan TG, Mendoza C, Lucchesi BR. Orally effective CVS-1123 prevents coronary artery thrombosis in the conscious dog. Circulation 1996; 94: 1705-12.
    CrossrefPubMedSearch in Google Scholar
  • 44 Bagdy D, Szabo G, Barabas E, Bajusz S. Inhibition by D-MePhe-Pro-Arg- H (GYKI-14766) of thrombus growth in experimental models of thrombosis. Thromb Haemost 1992; 68: 125-9.
    Thieme ConnectPubMedSearch in Google Scholar
  • 45 Hussain MA, Knabb R, Aungst BJ, Kettner C. Anticoagulant activity of a peptide boronic acid thrombin inhibitor by various routes of administration in rats. Peptides 1991; 12: 1153-4.
    CrossrefPubMedSearch in Google Scholar
  • 46 Mehta JL, Chen L, Nichols WW, Mattsson C, Gustafsson D, Saldeen TG. Melagatran, an oral active-site inhibitor of thrombin, prevents or delays formation of electrically induced occlusive thrombus in the canine coronary artery. J Cardiovasc Pharmacol 1998; 31: 345-51.
    CrossrefPubMedSearch in Google Scholar