Download PDF
Thromb Haemost 1993; 70(01): 208-211
DOI: 10.1055/s-0038-1646192
State-of-the-Art Lecture
Anticoagulation
Schattauer GmbH Stuttgart

Thrombin, Thrombin Inhibitors, and the Arterial Thrombotic Process

John M Maraganore
Department of Biological Research, Biogen, Inc., Cambridge, MA, USA
› Author Affiliations
Further Information

Publication History

Publication Date:
03 July 2018 (online)

  PDF Download  Permissions and Reprints
 

  • References

  • 1 Mann K, Jenny RJ, Krishnaswamy S. Cofactor proteins in the assembly and expression of blood clotting enzyme complexes. Ann Rev Biochem 1988; 57: 915-956
    CrossrefPubMedGoogle Scholar
  • 2 Vu TKH, Hung DT, Wheaton VI, Coughlin SR. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 1991; 64: 1057-1068
    CrossrefPubMedGoogle Scholar
  • 3 Hanson SR, Harker LA. Interruption of acute platelet-dependent thrombosis by the synthetic antithrombin D-phenylalanyl-L-prolyl-L-arginyl chloromethylketone. Proc Natl Acad Sci USA 1988; 85: 3184
    CrossrefPubMedGoogle Scholar
  • 4 Heras M, Chesebro JH, Penny WJ, Bailey KR, Badimon L, Fuster V. Effects of thrombin inhibition on the development of acute platelet-thrombus deposition during angioplasty in pigs: heparin versus recombinant hirudin, a specific thrombin inhibitor. Circulation 1989; 79: 657-665
    CrossrefPubMedGoogle Scholar
  • 5 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
  • 6 Klement P, Borm A, Hirsh J, Maraganore JM, Wilson G, Weitz J. The effects of thrombin inhibitors on tissue plasminogen activator induced thrombolysis in a rat model. Thromb Haemostas 1992; 68: 64
    PubMedGoogle Scholar
  • 7 Kelly A, Maraganore JM, Bourdon P, Harker LA. Antithrombotic effects of synthetic peptides targeting different functional domains of thrombin. Proc Natl Acad Sci USA 1992; 89: 6040-6044
    CrossrefPubMedGoogle Scholar
  • 8 Yao SK, McNatt J, Anderson HV, Eidt J, Cui KX, Golino P, Glas-Greenwalt P, Maraganore JM, Buja LM, Willerson JT. Thrombin inhibition enhances tissue-type plasminogen activator-induced thrombolysis and delays reocclusion. Am J Physiol 1992; 262: 374-379
    CrossrefPubMedGoogle Scholar
  • 9 Walsmann P, Markwardt F. Biochemische and pharmakologische aspekte des thrombininhibitors hirudin. Pharmazie 1981; 43: 737-744
    PubMedGoogle Scholar
  • 10 Eidt JF, Allison P, Noble S, Ashton J, Golino P, McNatt J, Buja LM, Willerson JT. Thrombin is an important mediator of platelet aggregation in stenosed canine coronary arteries with endothelial injury. J Clin Invest. 1989; 84: 18-27
    PubMedGoogle Scholar
  • 11 Stone SR, Maraganore JM. Hirudin interactions with thrombin. In: Thrombin: Structure and Function. Berliner LJ. (ed). Plenum Press; New York: 1992. pp. 219; -256
    Google Scholar
  • 12 Fenton JW, Villaneuva GB, Ofosu FA, Maraganore JM. Thrombin inhibition by hirudin: how hirudin inhibits thrombin. Haemostasis 1991; 21: 27-31
    PubMedGoogle Scholar
  • 13 Maraganore JM, Chao B, Joseph ML, Jablonski J, Ramachandran KL. Anticoagulant activity of synthetic hirudin peptides. J Biol Chem 1989; 264: 8692-8698
    PubMedGoogle Scholar
  • 14 Maraganore JM, Bourdon P, Jablonski J, Ramachandran KL, Fenton JW. Design and characterization of hirulogs: a novel class of bivalent peptide inhibitors of thrombin. Biochemistry 1990; 29: 7095-7101
    CrossrefPubMedGoogle Scholar
  • 15 Kline T, Hammond C, Bourdon P, Maraganore JM. Hirulog peptides with scissile bond replacements resistant to thrombin cleavage. Biochem Biophys Res Comm 1991; 177: 1049-1055
    CrossrefPubMedGoogle Scholar
  • 16 Bourdon P, Jablonski JA, Chao BH, Maraganore JM. Structure-function relationships of hirulog peptide interactions with thrombin. FEBS Lett. 1991; 294: 163-166
    CrossrefPubMedGoogle Scholar
  • 17 DiMaio JB, Gibbs D, Munn J, Lefebvre J, Ni F, Konishi Y. Bifunc-tional thrombin inhibitors based on the sequence of hirudin 45-65. J Biol Chem 1990; 265: 21698-21703
    PubMedGoogle Scholar
  • 18 Fenton JW, Olson TA, Zabinski MP, Wilner GD. Anion-binding exosite of human alpha-thrombin and fibrin(ogen) recognition. Biochemistry 1988; 27: 7106-7112
    CrossrefPubMedGoogle Scholar
  • 19 Stone SR, Hofsteenge J. Kinetics of the inhibition of thrombin by hirudin. Biochemistry 1986; 25: 4622-4628
    CrossrefPubMedGoogle Scholar
  • 20 Naski MC, Fenton JW, Maraganore JM, Olson ST, Shafer JA. The COOH-terminal domain of hirudin. An exosite-directed competitive inhibitor of the action of alpha-thrombin on fibrinogen. J Biol Chem 1990; 265: 11766-11772
    PubMedGoogle Scholar
  • 21 Jakubowski JA, Maraganore JM. Inhibition of coagulation and thrombin-induced platelet activities by a synthetic dodecapeptide modeled on the carboxy-terminus of hirudin. Blood 1990; 75: 399-406
    PubMedGoogle Scholar
  • 22 Vu TKH, Wheaton VI, Hung DT, Charo I, Coughlin SR. Domains specifying thrombin-receptor interaction. Nature 1991; 353: 674-677
    CrossrefPubMedGoogle Scholar
  • 23 Rydel TJ, Ravichandran KG, Tulinsky A, Bode W, Huber R, Roitsch C, Fenton JW. The structure of a complex of recombinant hirudin and human alpha-thrombin. Science 1990; 249: 277-280
    CrossrefPubMedGoogle Scholar
  • 24 Bourdon P, Fenton JW, Maraganore JM. Affinity labeling of lysine-149 in the anion-binding exosite of human alpha-thrombin with an N-alpha-(dinitrofluorobenzyl) hirudin C-terminal peptide. Biochemistry 1990; 29: 6379-6384
    CrossrefPubMedGoogle Scholar
  • 25 Furie B, Bing DH, Feldmann RJ, Robinson DJ, Burnier JP, Furie BC. Computer-generated models of blood coagulation factor X a factor IXa, and thrombin based on structural homology with other serine proteases. J Biol Chem 1982; 257: 3875-3882
    PubMedGoogle Scholar
  • 26 Ofosu FA, Fenton JW, Maraganore JM, Blajchman MA, Yang X, Smith L, Anvari N, Buchanan NR, Hirsh J. Inhibition of the amplification reactions of blood coagulation by site-specific inhibitors of alpha-thrombin. Biochem J 1992; 283: 893-897
    CrossrefPubMedGoogle Scholar
  • 27 Skrzypczak-Jankun E, Carperos VE, Ravichandran KG, Tulinsky A, Westbrook M, Maraganore JM. Structure of the hirugen and Hirulog 1 complexes of alpha-thrombin. J Mol Biol 1991; 221: 1379-1393
    CrossrefPubMedGoogle Scholar
  • 28 Qiu X, Padmanaban K, Carperos VE, Tulinsky A, Kline T, Maraganore JM, Fenton JW. The structure of the hirulog3-thrombin complex and the nature of the S' subsites of substrates and inhibitors. Biochemistry 1992; 31: 11689-11697
    CrossrefPubMedGoogle Scholar
  • 29 Liu CY, Nossel HL, Kaplan KL. The binding of thrombin by fibrin. J Biol Chem 1979; 254: 10421-10425
    PubMedGoogle Scholar
  • 30 Francis CW, Markham RE, Barlow GH, Florack TM, Dobrzynski DM, Marder VJ. Thrombin activity of fibrin thrombi and soluble plasmic derivatives. J Lab Clin Med 1983; 102: 220-230
    PubMedGoogle Scholar
  • 31 Hogg PJ, Jackson CM. Fibrin monomer protects thrombin from inac-tivation by heparin-antithrombin III: implications for heparin efficacy. Proc Natl Acad Sci USA 1989; 86: 3619
    CrossrefPubMedGoogle Scholar
  • 32 Weitz JI, Hudoba M, Massel D, Maraganore JM, 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: 385-391
    CrossrefPubMedGoogle Scholar
  • 33 Mirshani M, Soria J, Soria C, Faivre R, Lu H, Courtney M, Roitsch C, Tripier D, Caen JP. Evaluation of the inhibition by heparin andhirudin of coagulation activation during r-tPA-induced thrombolysis. Blood 1989; 74: 1025-1030
    PubMedGoogle Scholar
  • 34 Bar-Shavit R, Eldor A, Vlodavsky I. Binding of thrombin to subendo-thelial extracellular matrix. Protection and expression of functional properties. J Clin Invest 1989; 84: 1096-1104
    CrossrefPubMedGoogle Scholar
  • 35 Lane DA, Denton J, Flynn L, Thunberg L, Lindahl U. Anticoagulant activities of heparin oligosaccharides and their neutralization by platelet factor 4. Biochem J 1984; 218: 725-732
    CrossrefPubMedGoogle Scholar
  • 36 Maraganore JM, Chao BH, Weitz JI, Hirsh J. Comparison of antithrombin activities of heparin and Hirulog-1—basis for improved antithrombotic properties of direct thrombin inhibitors. Thromb Haemostas 1991; 65: 829 (abstr)
    PubMedGoogle Scholar
  • 37 Muller TH, Koch V, Gerster U, Maraganore JM. Hirulog, a synthetic hirudin-based peptide, is superior to heparin in prevention of arterial thrombus formation. Thromb Haemostas 1991; 65: 735 (abstr)
    PubMedGoogle Scholar
  • 38 Hirsh J. Heparin. New Engl J Med. 1991; 324: 1565-1574
    CrossrefPubMedGoogle Scholar
  • 39 Basu D, Gallus A, Hirsh J, Cade J. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. New Engl J Med 1972; 287: 324-327
    CrossrefPubMedGoogle Scholar
  • 40 Fox I, Dawson A, Loynds P, Eisner J, Findlen K, Levin E, Hanson D, Mant T, Wagner J, Maraganore JM. Anticoagulant activity ofHirulog, a direct thrombin inhibitor, in humans. Thromb Haemostas 1993; 69: 157-163
    PubMedGoogle Scholar
  • 41 Young E, Prins M, Levine MN, Hirsh J. Heparin binding to plasma proteins, an important mechanism for heparin resistance. Thromb Haemostas 1992; 67: 639-643
    PubMedGoogle Scholar
  • 42 Maraganore JM, Bourdon P, Adelman B, Cannon C, Theroux P. Heparin variability and resistance: Comparisons with a direct thrombin inhibitor. Circulation 1992; 86: 386 (abstr)
    PubMedGoogle Scholar
  • 43 Cannon CP, Maraganore JM, Loscalzo J, McAllister A, Eddings K, George D, Selwyn AP, Adelman B, Fox I, Braunwald E, Ganz P. Anticoagulant effects of Hirulog, a novel thrombin inhbitor, in patients with coronary artery disease. Am J Cardiol (in press).
    PubMedGoogle Scholar
  • 44 Ginsberg JS, Hirsh J, Gent M, McKinnon B, Turpie AGG, Levine M, Powers P, Weitz J, Findlen K, Neemeh J, Buller H, Adelman B, Maraganore JM, Fox I. A phase II study of Hirulog in the prevention of venous thrombosis after major hip or knee surgery. Circulation 1992; 86: 409 (abstr)
    PubMedGoogle Scholar
  • 45 Topol EJ, Bonan R, Jewitt D, Sigwart U, Kakkar VV, Rothman M, deBono D, Ferguson J, Willerson J, Strony J, Ganz P, Cohen M, Raymond R, Fox I, Maraganore JM, Adelman B. Use of a direct antithrombin, Hirulog, in place of heparin during coronary angioplasty. Circulation (in press).
    PubMedGoogle Scholar
  • 46 Lidon RM, Theroux P, Juneau M, Adelman B, Maraganore JM. Initial experience with a direct antithrombin, Hirulog, in unstable angina: anticoagulant, antithrombotic, and clinical effects. Circulation. (in press)
    PubMedGoogle Scholar