Thromb Haemost 2000; 83(03): 496-502
DOI: 10.1055/s-0037-1613843
Review Article
Schattauer GmbH

Inhibition of Platelet Thrombosis Using an Activated Protein C-loaded Stent: In Vitro and In Vivo Results

Roger S.-Y. Foo
1   From the Division of Cardiology, Department of Medicine and Therapeutics, Leicester University
,
Anthony H. Gershlick
1   From the Division of Cardiology, Department of Medicine and Therapeutics, Leicester University
,
Kai Hogrefe
1   From the Division of Cardiology, Department of Medicine and Therapeutics, Leicester University
,
Julia H. Baron
1   From the Division of Cardiology, Department of Medicine and Therapeutics, Leicester University
,
Thomas W. Johnston
2   From the PPL Therapeutics, Roslin, Edinburgh, UK
,
Amanda J. Hussey
2   From the PPL Therapeutics, Roslin, Edinburgh, UK
,
Ian Garner
2   From the PPL Therapeutics, Roslin, Edinburgh, UK
,
David P. de Bono
1   From the Division of Cardiology, Department of Medicine and Therapeutics, Leicester University
› Author Affiliations
Further Information

Publication History

Received 23 June 1999

Accepted after resubmission 03 November 1999

Publication Date:
14 December 2017 (online)

Summary

In high-risk and complicated coronary intervention, the risk of acute closure is unpredictable. Thrombus and platelet deposition at the intervention site may also have further effects on subsequent restenosis. In vivo infusion of activated protein C has previously been shown to achieve potent anticoagulation without any haemostatic side effects. We now evaluated the in vitro and in vivo efficacy of polymer-coated coronary stents loaded with purified rabbit Activated Protein C (APC). By measuring 125I-fibrinogen/fibrin deposition APC-loaded stent-wires were antithrombotic compared to albumin-loaded, inhibited-APCloaded, plain polymer-coated and stainless steel stent-wires. In a balloon injury rabbit iliac artery model, APC-loaded stents did not occlude (0/14) compared to plain stents (9/15) and BSA-loaded stents (2/4). Relative 111In-labelled platelet deposition showed a similarly significant degree of inhibition. In conclusion, APC-loading could render stents significantly less thrombotic. Whether an effective antithrombogenic stent like this effectively reduces restenosis rates warrants further evaluation.

 
  • References

  • 1 More RS, Rutty G, Underwood MJ, Brack MJ, Gershlick AH. A time sequence of vessel wall changes in an experimental model of angioplasty. J Pathol 1994; 172: 287-92.
  • 2 Bergelson BA, Fishman RF, Tommaso CL. Abrupt vessel closure: Changing importance, management, and consequences. Am Heart J 1997; 134: 362-81.
  • 3 Leon MB, Baim DS, Gordon P, Giambartolomei A, Williams DO, Diver DD, Senerchia C, Fitzpatrick M, Popma JJ, Kuntz RE. Clinical and angiographic results from the STent Anticoagulation Regimen Study (STARS). Circulation 1996; 94 (suppl I): I-685 Abstract.
  • 4 Sawada Y, Nokasa H, Kimura T, Nobuyoshi M. Initial and six months outcome of Palmaz-Schartz stent implantation: STRESS/BENESTENT equivalent vs non-equivalent lesions. J Am Coll Cardiol 1996; 27 (suppl A|): 252A. Abstract.
  • 5 Schwartz RS, Holmes DR, Topol EJ. The restenosis paradigm revisited: An alternative proposal for cellular mechanisms. J Am Coll Cardiol 1992; 20: 1284-93.
  • 6 Gershlick AH. Endovascular manipulation to restrict restenosis. Vasc Med 1998; 03: 177-88.
  • 7 Baykal D, Schmedtje Jr JF, Runge MS. Role of the thrombin receptor in restenosis and atherosclerosis. Am J Cardiol 1995; 75: 82B-7B.
  • 8 McNamara CA, Sarembock IJ, Bachhuber BG, Stouffer GA, Ragosta M, Barry W, Gimple LW, Powers ER, Owens GK. Thrombin and vascular smooth muscle cell proliferation: implications for atherosclerosis and restenosis. Semin Thromb Haemost 1996; 22: 139-44.
  • 9 Maruyama I, Shigeta K, Miyahara H, Makajima T, Shin H, Ide S, Kitajima I. Thrombin activates NF-kappa B through thrombin receptor and results in proliferation of vascular smooth muscle cells: role of thrombin in atherosclerosis and restenosis. Ann N Y Acad Sci 1997; 811: 429-36.
  • 10 Salvioni A, Galli S, Marenzi G, Lauri G, Perego GB, Assanelli E, Guazzi MD. Thrombin activation and late restenosis after percutaneous transluminal coronary angioplasty. Am Heart J 1998; 135: 503-9.
  • 11 Gallo R, Padurean A, Toschi V, Bichler J, Fallon JT, Chesebro JH, Fuster V, Badimon JJ. Prolonged thrombin inhibition reduces restenosis after balloon angioplasty in porcine coronary arteries. Circulation 1998; 97: 581-8.
  • 12 Abendschein DR, Recchia D, Meng YY, Oltrona L, Wickline SA, Eisenberg PR. Inhibition of thrombin attenuates stenosis after arterial injury in minipigs. J Am Coll Cardiol 1996; 28: 1849-55.
  • 13 Dabbagh K, Laurent GJ, McAnulty RJ, Chambers RC. Thrombin stimulates smooth muscle cell procollagen synthesis and mRNA levels via a PAR-1 mediated mechanism. Thromb Haemost 1998; 79: 405-9.
  • 14 Larsson R, Larm O, Olsson O. The search for thromboresistance using immobilized heparin. Ann N Y Acad Sci 1987; 516: 102-15.
  • 15 Hardhammar PA, van Beusekom HMM, Emanuelsson HU, Hofma SH, Albertsson PA, Verdouw PD, Boersma E, Serruys PW, van der Giessen WJ. Reduction in thrombotic events with heparin-coated Palmaz-Schartz stents in normal porcine coronary arteries. Circulation 1996; 93: 423-30.
  • 16 Serruys PW, Emanuelsson H, van der Giessen W, Lunn AC, Kiemeney F, Macaya C, Rutsch W, Heyndrickx G, Suryapranta H, Legrand V, Goy JJ, Materne P, Bonnier H, Morice MC, Fajadet J, Belardi J, Colombo A, Garcia E, Ruygrok P, de Jaegere P, Morel MA. on behalf of the BENESTENT II Study Group. Heparin-coated Palmaz-Schatz stents in human coronary arteries: early outcome of the BENESTENT II Pilot Study. Circulation 1996; 93: 412-22.
  • 17 Dahlbäck B, Stenflo J. The protein C anticoagulant system. In: The Molecular Basis of Blood Diseases. Stamatoyannopoulos G, Nienhuis AW, Majerus PW, Varmus H. eds. Philadelphia, USA: WB Saunders; 1994: 599-628.
  • 18 Davie EW. Biochemical and molecular aspects of the coagulation cascade. Thromb Haemost 1995; 74: 1-6.
  • 19 Arnljots B, Dahlbäck B. Antithrombotic effects of activated protein C and protein S in a rabbit model of microarterial thrombosis. Arterioscler Thromb Vasc Biol 1995; 15: 937-41.
  • 20 Arnljots B, Bergqvist D, Dahlbäck B. Inhibition of microarterial thrombosis by activated protein C in a rabbit model. Thromb Haemost 1994; 72: 415-20.
  • 21 Gruber A, Hanson SR, Kelly AB, Yan BS, Bang N, Griffin JH, Harker LA. Inhibition of thrombus formation by activated recombinant protein C in a primate model of arterial thrombosis. Circulation 1990; 82: 578-85.
  • 22 Gruber A, Harker LA, Hanson SR, Griffin JH. Inhibition of platelet-dependent thrombus formation by human activated protein C in a primate model. Blood 1989; 73: 639-42.
  • 23 Sakamoto T, Ogawa H, Yasue H, Oda Y, Kitajima S, Tsumoto K, Mizokami H. Prevention of arterial reocclusion after thrombolysis with activated protein C. Circulation 1994; 90: 427-32.
  • 24 Lincoff SG, Topol E, Ellis SG. Local drug delivery for the prevention of restenosis. Fact, fancy and future. Circulation 1994; 90: 207-8.
  • 25 Topol EJ, Serruys PW. Frontiers in interventional cardiology. Circulation 1998; 98: 1802-20.
  • 26 Fraker PJ, Speck JC. Protein and cell membrane iodinations with a sparingly soluble chloroamide 1,3,4,6-tetrachloro-3α,6α-diphenylgylcolouril. Biochem Biophys Res Comms 1978; 80: 849-57.
  • 27 Hawker RJ. Indium (111In)-labelled human platelets: optimal method. Clin Sci 1980; 58: 243-8.
  • 28 Aggarwal RK, Ireland DC, Azrin MA, Ezekowitz MD, de Bono D, Gershlick AH. Antithrombotic potential of polymer-coated stents eluting platelet glycoprotein IIb/IIIa receptor antibody. Circulation 1996; 94: 3311-7.
  • 29 Dreyfus M, Magny JF, Bridey F, Schwarz HP, Planche C, Dehan M, Tchernia G. Treatment of homozygous protein C deficiency and neonatal purpura fulminans with a purified protein C concentrate. N Engl J Med 1991; 325: 1565-8.