Accumulation of radiolabelled platelets and fibrin on the carotid artery of rabbits after angioplasty: effects of heparin and dipyridamole

Summary

We investigated the dynamic accumulation of platelets and fibrin after balloon injury of the carotid arteries in rabbits in vivo. In addition, effects of heparin and dipyridamole treatment were also tested. Autologous ^99mTc-labelled platelet and ¹²³I-labelled fibrin accumulation was measured at one minute intervals for 4 hours following balloon injury of the carotid artery. Platelet accumulation occurred rapidly, with a ~125% increase occurring within 30 min after injury. There was no further activity for up to 4 hours. This accumulation could be inhibited with an intravenous infusion of PGI₂ (500 ng/kg/hr). Fibrin accumulation occurred slowly and continuously over the 4 hour measurement period. Injection of an anti-fibrin antibody inhibited fibrin accumulation. Heparin (25 U/kg/hr for 4 hrs) administration resulted in a significant 82 ± 19% and 68 ± 13% reduction in platelet and fibrin accumulation, respectively. This dose of heparin was associated with a 2-fold prolongation of the aPTT. Dipyridamole (0.45 mg/kg/hr for 4 hrs) resulted in a 46 ± 12% and 70 ± 25% reduction of platelet and fibrin accumulation, respectively. Thus, we demonstrated that the dynamics of platelet and fibrin accumulation following balloon injury in rabbits are very different. The vessel wall continues to be thrombogenic for fibrin up to 4 hours after injury even though platelet accumulation has ceased after one hour. We conclude that the local thrombotic events following balloon injury are complex and that not only platelets but also fibrin is important in regulating responses to injury.

Keywords

Animal models - platelet pharmacology - fibrin - vascular injury - dipyridamole

• References

• 1 Popma JJ, Ohman EM, Weitz J. et al. Antithrombotic therapy in patients undergoing percutaneous coronary intervention. Chest 2001; 119: 321S-36S.
• 2 Narins CR, Hillegass WB, Nelson CL. et al. Relation between activated clotting time during angioplasty and abrupt closure. Circulation 1996; 93: 667-71.
• 3 Gerns GAA, Stewart-Lee AL, Änggård EE. Arterial response to mechanical injury: balloon catheter de-endothelialization. Atherosclerosis 1992; 92: 89-104.
• 4 Virmani R, Farb A, Burke AP. Coronary angioplasty from the perspective of atherosclerotic plaque: Morphologic predictors of immediate success and restenosis. Am Heart J 1994; 127: 163-79.
• 5 Mintz GS, Pichard AD, Kent KM. et al. Axial plaque redistribution as a mechanism of percutaneous transluminal coronary angioplasty. Amer J Cardiol 1996; 77: 427-30.
• 6 De Feyter PJ, van den Brand M, Jaarman GJ. et al. Acute coronary artery occlusion during and after percutaneous transluminal coronary angioplasty. Circulation 1991; 83: 927-36.
• 7 Plante S, Laarman GJ, de Feyter P. et al. Acute complications of percutaneous transluminal coronary angioplasty for total occlusion. Am Heart J 1991; 121: 417-26.
• 8 Hirsh J, Anand SS, Halperin JL. et al. Guide to anticoagulant therapy: Heparin: A statement for healthcare professionals from the American Heart Association. Circulation 2001; 103: 2994-3018.
• 9 Gargan PE, Gaffney PJ, Pleasants JR. et al. A monoclonal antibody which recognises an epi-topic region unique to the intact fibrin polymeric structure. Fibrinolysis 1993; 7: 275-83.
• 10 Regoeczi E. Fibrinogen catabolism: Kinetics of catabolism following sudden elevation of the pool with exogenous fibrinogen. Clin Sci 1970; 38: 111-21.
• 11 Greenwood FC, Hunter WM, Glovers JS. The preparation of 131I-labelled human growth hormone of high specific radioactivity. Biochem J 1963; 89: 114-21.
• 12 Becker W, Borst U, Krahe T. et al. Tc-99m-HMPAO labelled human platelets: in vitro and in vivo results. Eur J Nucl Med 1989; 15: 296-301.
• 13 Lorenz M, Van Ryn J, Merk H. et al. Portable gamma spectroscopy system for simultaneously monitoring radiotracers in vivo using CdTe and CdZnTe radiation detector probes. Nucl Instr and Meth in Phys Res 1994; A353: 448-52.
• 14 Proctor RR, Rappaport I S. The partial thromboplastin time with kaolin. Am J Clin Pathol 1961; 36: 212-18.
• 15 Bruning JL, Kintz BL. Computational Handbook of Statistics. Glenview, IL. Scott: Fores-man and Company; 1977
• 16 Steele PM, Chesebro JH, Stanson AW. et al. Balloon Angioplasty. Natural history of the pathophysiological response to injury in a pig model. Circ Res 1985; 57: 105-112.
• 17 Groves HM, Kinlough-Rathbone RL, Richard-son M. et al. Platelet interaction with damaged rabbit aorta. Lab Invest 1979; 40: 194-200.
• 18 Kelly AB, Marzec UM, Krupski W. et al. Hirudin interruption of heparin-resistant arterial thrombus formation in baboons. Blood 1991; 77: 1006-12.
• 19 Heras M, Chesebro JH, Penny WJ. et al. Effects of thrombin inhibition on the development of acute platelet-thrombus deposition during angioplasty in pigs. Circulation 1989; 79: 657-65.
• 20 Harker LA, Kelly AB, Hanson SR. Experimental arterial thrombosis in nonhuman primates.Circulation. 1991: 83suppl IV IV41-IV55.
• 21 Richardson M, Hatton MWC, Buchanan MR. et al. Wound healing in the media of the nor-molipemic rabbit carotid artery injured by air drying or by balloon catheter de-endothelialization. Am J Pathol 1990; 137: 1453-65.
• 22 Weksler BB, Marcus AJ, Jaffe EA. Synthesis of prostaglandin I₂ (prostacyclin) by cultured human and bovine endothelial cells. Proc Natl Acad Sci USA 1997; 74: 3922-6.
• 23 McAdam BF, Catella-Lawson F, Mardini IA. et al. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: The human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci USA 1999; 96: 272-7.
• 24 Ofosu FA, Sie P, Modi G. et al. The inhibition of thrombin-dependent positive-feedback reactions is critical to the expression of the anticoagulant effect of heparin. Biochem J 1987; 243: 579-88.
• 25 Hatton MWC, Moar SL, Richardson M. Enhanced binding of fibrinogen by the subendothelium after treatment of the rabbit aorta with thrombin. J Lab Clin Med 1990; 115: 356-64.
• 26 Patrono C, Coller B, Dalen JE. et al. Platelet-Active Drugs. Relationship among dose, effectiveness and side effects. Chest 2001; 119: 39S-63S.
• 27 Eisert WG. Dipyridamole. In: Platelets. A Michelson, ed. Academic Press, San Diego, 2002. In Press.
• 28 Diener HC, Cuhna L, Forbes C. et al. European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996; 143: 1-13.
• 29 Ahn HS, Crim W, Romano M. et al. Effects of selective inhibitors on cyclic nucleotide phosphodiesterase of rabbit aorta. Biochem Pharma-col 1989; 38: 3331-9.
• 30 Gillespie PG, Beavo JA. Inhibition and stimulation of photoreceptor phosphodiesterases by dipyridamole and M&B 22, 948. Mol Pharma-col 1989; 36: 773-81.
• 31 Buchanan MR, Hirsh J. A comparison of the effects of aspirin and dipyridamole on platelet aggregation in vivo and ex vivo. Thromb Res 1978; 13: 517-29.
• 32 Gresele P, Zojy C, Deckmyn H. et al. Dipyridamole inhibits platelet aggregation in whole blood. Thromb Haemost 1983; 50: 852-6.
• 33 Neri Serneri GG, Masotti G, Poggesi L. et al. Enhanced prostacyclin production by dipyrida-mole in man. Eur J Clin Pharmacol 1981; 21: 9-15.
• 34 Weber E, Haas TA, Muller TH. et al. Relationship between vessel wall 13-HODE synthesis and vessel wall thrombogenicity following injury: influence of salicylate and dipyridamole treatment. Thromb Res 1990; 57: 383-92.