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The role of aspirin in enhancing arterial graft patency

1986; Elsevier BV; Volume: 3; Issue: 2 Linguagem: Inglês

10.1016/0741-5214(86)90028-5

1097-6809

Alexander W. Clowes,

Antiplatelet Therapy and Cardiovascular Diseases

As the disciplines of cardiac and peripheral vascular surgery have matured, the ability of surgeons to reconstruct even the most severely diseased vessels has improved. For example, approximately 95% of patients with lower extremity occlusive disease are suitable candidates for reconstruction.1Maini BS Mannick JA. The effect of arterial reconstruction on limb salvage—a ten-year appraisal.Arch Surg. 1978; 113: 1297-1304Crossref PubMed Scopus (76) Google Scholar Nevertheless, many grafts fail on account of early thrombosis or, at later times, graft stenosis.2Whittemore AD Clowes AW Couch NP Mannick JA. Secondary femoropopliteal reconstruction.Ann Surg. 1981; 193: 35-42Crossref PubMed Scopus (346) Google Scholar, 3Szilagyi DE Elliott JP Hageman JH Smith RF Dall'olmo CA. Biological fate of autogenous vein implants as arterial substitutes.Am J Surg. 1973; 178: 232-246Google Scholar Some of these can be salvaged by further surgical intervention. In addition, adjuvant antithrombotic drug therapy (e.g., aspirin) has been introduced in an attempt to reduce the rate of graft thrombosis. Aspirin inhibits platelet aggregation by blocking cyclooxygenase and therefore the generation of thromboxane A2 from arachidonic acid.4Salzman EW. Aspirin to prevent arterial thrombosis.N Engl J Med. 1982; 307: 113-115Crossref PubMed Scopus (27) Google Scholar, 5Packham MA. Mode of action of acetylsalicylic acid.in: Acetylsalicylic acid: New uses for an old drug. Raven Press, New York1982: 63-82Google Scholar This effect is achieved by acetylation of a serine residue in the active site of the enzyme. The aspirin effect is present for the life of the platelet since circulating platelets are incapable of synthesizing new enzyme. Cyclooxygenase is also found in endothelium and is responsible for the synthesis by these cells of the prostaglandin inhibitor of platelet aggregation, prostacyclin (PGI2). Endothelial cyclooxygenase can be inactivated by aspirin although it is less sensitive than the platelet enzyme and can be rapidly regenerated. Because PGI2 and thromboxane A2 exert opposite effects on stimulated platelets, much effort has been directed toward exploiting the differential sensitivity of platelet and endothelial cyclooxygenase to aspirin to achieve a net balance that favors PGI2 production and inhibition of thromboxane A2 synthesis. Although early investigations indicated that this objective could be met with very low doses of aspirin, more recent studies have demonstrated that the two forms of cyclooxygenase exhibit too much overlap in their aspirin sensitivity. Moreover, the theoretical benefit of low-dose aspirin may be more apparent than real since no differences in clinical efficacy can be detected when drug trials with low- or high-dose aspirin are compared. A number of other pharmacologic effects of aspirin have been described.5Packham MA. Mode of action of acetylsalicylic acid.in: Acetylsalicylic acid: New uses for an old drug. Raven Press, New York1982: 63-82Google Scholar In many of the studies on the effect of pharmacologic interventions on graft patency, aspirin has been used together with dipyridamole. In animals and in man dipyridamole appears to potentiate the antiaggregating effect of aspirin. Moncada and Korbut6Moncada S Korbut R. Dipyridamole and other phospho-diesterase inhibitors act as antithrombotic agents by potentiating endogenous prostacyclin.Lancet. 1978; 1: 1286-1289Abstract PubMed Scopus (290) Google Scholar have suggested that this potentiation is due to an inhibition of platelet phosphodiesterase and an increase in platelet cyclic AMP. Aspirin given with or without dipyridamole to nonhuman primates reduced platelet consumption after placement of Dacron grafts and reduced intimal thickening in vein and polytetrafluoroethylene (PTFE) grafts.7Harker LA Slichter SJ Sauvage LR. Platelet consumption by arterial prostheses: The effects of endothelialization and pharmacologic inhibition of platelet function.Ann Surg. 1977; 186: 594-601Crossref PubMed Scopus (138) Google Scholar, 8McCann RL Hagen PO Fuchs JCA. Aspirin and dipyridamole decrease intimal hyperplasia in experimental vein grafts.Ann Surg. 1980; 191: 238-243Crossref PubMed Scopus (90) Google Scholar, 9Hagen PO Wang ZG Mikat EM Hackel DB. Antiplatelet therapy reduces aortic intimal hyperplasia distal to small-diameter vascular prostheses (PTFE) in nonhuman primates.Ann Surg. 1982; 195: 328-339Crossref PubMed Scopus (69) Google Scholar The optimal dosages of aspirin (20 mg/kg/day) and dipyridamole (5 mg/kg/day) in baboons have been established in experiments in which the accumulation of indium 111-labeled platelets on Dacron arteriovenous shunts was measured.10Hanson SR Harker LA Bjornsson TD. Effects of platelet modifying drugs on arterial thromboembolism in baboons. Aspirin potentiates the antithrombotic actions of dipyridamole and sulfinpyrazone by mechanisms independent of platelet cyclooxygenase inhibition.J Clin Invest. 1985; 75: 1591-1599Crossref PubMed Scopus (83) Google Scholar In addition to having an antithrombotic effect, aspirin and dipyridamole have also been shown to reduce lipid incorporation into primate vein grafts; whether this is a secondary effect of inhibition of platelet aggregation has not been established.11Bonchek LI Boerboom LE Olinger GN Pepper JR Munns J Hutchinson L Kissebah AH. Prevention of lipid accumulation in experimental vein bypass grafts by antiplatelet therapy.Circulation. 1982; 66: 338-341Crossref PubMed Scopus (31) Google Scholar It is apparent from these studies that aspirin with or without dipyridamole reduces platelet aggregation and to some extent intimal thickening in grafts. Clinical data (discussed later) indicate that antithrombotic therapy may be expected to offer more protection against acute graft failure caused by thrombosis than against late failure caused by intimal thickening and smooth muscle proliferation. This conclusion is evident from a comparison of rates of occlusion early (within the first month) and late after surgery. The relationship between platelet deposition and subsequent intimal thickening has not been clearly defined. Thrombus accumulation at suture lines immediately after surgery may become organized by the infiltration and proliferation of underlying smooth muscle cells. However, smooth muscle cells can proliferate in injured and atherosclerotic vessels in the absence of significant thrombus. For example, in rabbit aorta stripped of endothelium by the passage of a balloon catheter, platelets attach to the denuded surface as a monolayer only during the first hour after surgery.12Groves HM Kinlough-Rathbone RL Richardson M Moore S Mustard JF. Platelet interaction with damaged rabbit aorta.Lab Invest. 1979; 40: 194-200PubMed Google Scholar Despite the absence of endothelium, platelet accumulation ceases after the first day. On the other hand, smooth muscle proliferation begins between 24 and 48 hours after surgery and continues for several weeks.13Clowes AW Reidy MA Clowes MM. Kinetics of cellular proliferation after arterial injury. I. Smooth muscle growth in the absence of endothelium.Lab Invest. 1983; 49: 327-333PubMed Google Scholar The evidence supporting a role for specific platelet-derived growth factors in the stimulation of smooth muscle cell growth in vivo is sparse and rests primarily on the observation that animals rendered thrombocytopenic exhibit markedly reduced intimal thickening in response to arterial injury.14Friedman RJ Stemerman MB Wenz B Moore S Gauldie J Gent M Tiell MJ Spaeth TH. The effect of thrombocy-topenia on experimental atherosclerotic lesion formation in rabbits. Smooth muscle proliferation and reendothelialization.J Clin Invest. 1977; 60: 1191-1201Crossref PubMed Scopus (202) Google Scholar, 15Moore S Friedman RJ Singal DP Gauldie J Blajchman MA Roberts RS. Inhibition of injury-induced thromboathero-sclerotic lesions by antiplatelet serum in rabbits.Thromb Haemost. 1976; 35: 70-81PubMed Google Scholar Antithrombotic drugs do not appear to affect the process of injury-induced intimal thickening and may even retard endothelial repair of the damaged wall.16Clowes AW Karnovsky MJ. Failure of certain antiplatelet drugs to affect myointimal thickening following arterial injury.Lab Invest. 1977; 36: 452-458PubMed Google Scholar, 17Bomberger RA DePalma RG Ambrose TA Manalo P. Aspirin and dipyridamole inhibit endothelial healing.Arch Surg. 1982; 117: 1459-1464Crossref PubMed Scopus (32) Google Scholar These data taken together with the observations made in experimental models of arterial grafting support the view that aspirin and dipyridamole may be acting primarily to limit the early accumulation of thrombus in vascular grafts and to some extent may limit platelet turnover on chronically thrombogenic synthetic surfaces. From the experimental studies in animals, it has become apparent that aspirin with or without dipyridamole can protect against the formation of mural thrombus and to some degree limit intimal thickening. Similar studies in man have confirmed these observations. Various investigators have demonstrated that synthetic aortofemoral or femoropopliteal grafts continue to accumulate platelets even as late as a decade after surgery and that platelet accumulation can be reduced by the administration of antithrombotic drugs.18Stratton JR Thiele BL Ritchie JL. Platelet deposition on Dacron aortic bifurcation grafts in man: Quantitation with indium 111 platelet imaging.Circulation. 1982; 66: 1287-1293Crossref PubMed Scopus (40) Google Scholar, 19Goldman MD Norcott HC Hawker RJ Drolc Z McCollum CN. Platelet accumulation on mature Dacron grafts in man.Br J Surg. 1982; 69 (Suppl): 38-40Crossref PubMed Scopus (45) Google Scholar, 20Goldman MD Simpson D Hawker RJ Norcott HC McCollum CN. Aspirin and dipyridamole reduce platelet deposition on prosthetic femoropopliteal grafts in man.Ann Surg. 1983; 198: 713-716Crossref PubMed Scopus (60) Google Scholar, 21Pumphrey CW Chesebro JH Dewanjee MK Wahner HW Hollier LH Pairolero PC Fuster V. In vivo quantitation of platelet deposition on human peripheral arterial bypass grafts using indium-111-labeled platelets. Effect of dipyridamole and aspirin.Am J Cardiol. 1983; 51: 796-801Abstract Full Text PDF PubMed Scopus (57) Google Scholar, 22Stratton JR Ritchie JL. Aspirin plus dipyridamole reduces platelet deposition on chronic Dacron arterial grafts in man.J Am Coll Cardiol. 1985; 5 (abstract): 470Abstract Full Text PDF Scopus (38) Google Scholar In femoropopliteal saphenous vein grafts platelet accumulation as detected by the indium-labeled platelet technique was observed to be low at 7 days after surgery and was not affected by aspirin and dipyridamole.20Goldman MD Simpson D Hawker RJ Norcott HC McCollum CN. Aspirin and dipyridamole reduce platelet deposition on prosthetic femoropopliteal grafts in man.Ann Surg. 1983; 198: 713-716Crossref PubMed Scopus (60) Google Scholar A number of clinical trials examining the effectiveness of antithrombotic agents (mainly aspirin with or without dipyridamole) in preventing aortocoronary or femoropopliteal graft failure have now been reported (Tables I and II).23Mayer Jr, JE Lindsay WG Castaneda W Nicoloff DM. Influence of aspirin and dipyridamole on patency of coronary artery bypass grafts.Ann Thorac Surg. 1981; 31: 204-210Abstract Full Text PDF PubMed Scopus (71) Google Scholar, 24Chesebro JH Fuster V Elveback LR Clements JP Smith HC Holmes DR Bardsley WT Pluth JR Wallace RB Puga JF Orszulak JA Pichler JM Danielson GK Schaff HV Frye RL. Effect of dipyridamole and aspirin on late vein-graft patency after coronary bypass operations.N Engl J Med. 1984; 310: 209-214Crossref PubMed Scopus (402) Google Scholar, 25Brown BG Cukingnan RA DeRouen T Goede LV Wong M Fee HF Roth JA Carey JS. Improved graft patency in patients treated with platelet inhibiting therapy following coronary bypass surgery.Circulation. 1985; 72: 138-146Crossref PubMed Scopus (118) Google Scholar, 26Lorenz RL Weber M Kotzur J Thiesen K Schacky CV Meister W Reichardt B Weber PC. Improved aortocoronary bypass patency by low-dose aspirin (100 mg daily). Effects on platelet aggregation and thromboxane formation.Lancet. 1984; 1: 1261-1264Abstract PubMed Scopus (225) Google Scholar, 27Chevigne M David JL Rigo P Limet R. Effect of ticlopidine on saphenous vein bypass patency rates: A double-blind study.Ann Thorac Surg. 1984; 37: 371-378Abstract Full Text PDF PubMed Scopus (56) Google Scholar, 28Pantely GA Goodnight Jr, SH Rahimtoola SH Harlan BJ DeMots H Calvin L Rosch J. Failure of antiplatelet and anticoagulant therapy to improve patency of grafts after coronary-artery bypass. A controlled, randomized study.N Engl J Med. 1979; 301: 962-966Crossref PubMed Scopus (115) Google Scholar, 29Sharma GVRK Khuri SF Josa M Folland ED Parisi AF. The effect of antiplatelet therapy on saphenous vein coronary artery bypass graft patency.Circulation. 1983; 68: 218-221Google Scholar, 30Brooks N Wright J Sturridge M Pepper J Magee P Walesby R Layton C Honey M Balcon R. Randomized placebo-controlled trial of aspirin and dipyridamole in the prevention of coronary vein graft occlusion.Br Heart J. 1985; 53: 201-207Crossref PubMed Scopus (42) Google ScholarTable IEffect of antithrombotic drugs on aortocoronary vein graft patencyPatencyInvestigatorsDrugAdministration started (days)TreatedPlaceboStudies demonstrating benefit Mayer et al.23Mayer Jr, JE Lindsay WG Castaneda W Nicoloff DM. Influence of aspirin and dipyridamole on patency of coronary artery bypass grafts.Ann Thorac Surg. 1981; 31: 204-210Abstract Full Text PDF PubMed Scopus (71) Google ScholarASA/DP1, postop92%77%at 3-6 months (113 patients) Chesebro et al.24Chesebro JH Fuster V Elveback LR Clements JP Smith HC Holmes DR Bardsley WT Pluth JR Wallace RB Puga JF Orszulak JA Pichler JM Danielson GK Schaff HV Frye RL. Effect of dipyridamole and aspirin on late vein-graft patency after coronary bypass operations.N Engl J Med. 1984; 310: 209-214Crossref PubMed Scopus (402) Google ScholarASA7 hr, postop89%75%DP2, preopat 12 months (407 patients) Brown et al.25Brown BG Cukingnan RA DeRouen T Goede LV Wong M Fee HF Roth JA Carey JS. Improved graft patency in patients treated with platelet inhibiting therapy following coronary bypass surgery.Circulation. 1985; 72: 138-146Crossref PubMed Scopus (118) Google ScholarASA/DP2-3, postop86%79%ASA88%79%at 12 months (147 patients) Lorenz et al.26Lorenz RL Weber M Kotzur J Thiesen K Schacky CV Meister W Reichardt B Weber PC. Improved aortocoronary bypass patency by low-dose aspirin (100 mg daily). Effects on platelet aggregation and thromboxane formation.Lancet. 1984; 1: 1261-1264Abstract PubMed Scopus (225) Google ScholarLow-dose ASA1, postop90%68%at 4 months (83 patients) Chevigne et al.27Chevigne M David JL Rigo P Limet R. Effect of ticlopidine on saphenous vein bypass patency rates: A double-blind study.Ann Thorac Surg. 1984; 37: 371-378Abstract Full Text PDF PubMed Scopus (56) Google ScholarTiclopidine1, postop90%80%at 3 months (150 patients)Studies demonstrating no benefit Pantely et al.28Pantely GA Goodnight Jr, SH Rahimtoola SH Harlan BJ DeMots H Calvin L Rosch J. Failure of antiplatelet and anticoagulant therapy to improve patency of grafts after coronary-artery bypass. A controlled, randomized study.N Engl J Med. 1979; 301: 962-966Crossref PubMed Scopus (115) Google ScholarASA/DP3, postop82%82%Warfarin3, postop78%82%at 6 months (50 patients) Sharma et al.29Sharma GVRK Khuri SF Josa M Folland ED Parisi AF. The effect of antiplatelet therapy on saphenous vein coronary artery bypass graft patency.Circulation. 1983; 68: 218-221Google ScholarASA/DP3-5, postop83%80%ASA3-5, postop78%80%at 12 months (176 patients) Brooks et al.30Brooks N Wright J Sturridge M Pepper J Magee P Walesby R Layton C Honey M Balcon R. Randomized placebo-controlled trial of aspirin and dipyridamole in the prevention of coronary vein graft occlusion.Br Heart J. 1985; 53: 201-207Crossref PubMed Scopus (42) Google Scholar*ASA/DP2-3, postop89%87%at 12 months (266 patients)*Both treated and placebo patients received warfarin for the first 3 months.ASA = aspirin; DP = dipyridamole. Open table in a new tab Table IIEffect of antithrombotic drugs on femoropopliteal graft patencyInvestigatorsGraftDrugAdministration startedPatencyGreen et al.31Green RM Roedersheimer LR DeWeese JA. Effects of aspirin and dipyridamole on expanded polytetrafluoroethylene graft patency.Surgery. 1982; 92: 1016-1026PubMed Google ScholarPTFEASA/DP or ASA1-2 days preopImproved only for above-knee bypasses at 12 months (49 patients)Kohler et al.32Kohler TF Kaufman JL Kacoyanis G Clowes A Donaldson MC Kelly E Skillman J Couch NP Whittemore AD Mannick JA Salzman EW. Effect of aspirin and dipyridamole on the patency of lower extremity bypass grafts.Surgery. 1984; 96: 462-466PubMed Google ScholarPTFE or veinASA/DP1 day postopNo benefit at 24 months (100 patients)PTFE = polytetrafluoroethylene; ASA = aspirin; DP = dipyridamole. Open table in a new tab In the aorto-coronary bypass studies, saphenous vein grafts were used, whereas in the femoropopliteal studies both saphenous vein and synthetic grafts were employed. The administered dosage of drugs in these studies varied but in most circumstances was 325 mg of aspirin and 75 mg of dipyridamole three times each day. In the aortocoronary drug trials graft occlusion was assessed by angiography. ASA = aspirin; DP = dipyridamole. PTFE = polytetrafluoroethylene; ASA = aspirin; DP = dipyridamole. Several overall conclusions emerge from a comparison of the data provided by these clinical trials. (1) In all reports demonstrating improved patency in the treated group, the drugs were administered either preoperatively or immediately after surgery. If the initiation of drug therapy was delayed beyond 2 days after surgery, no benefit could be detected. (2) No clear advantage of aspirin and dipyridamole over aspirin alone was apparent. (3) These studies do not establish an optimal dose of aspirin; however, there appears to be no marked difference between normal (975 mg daily) and low-dose (100 mg daily) aspirin treatment. (4) In particular trials such as the one reported by Chesebro et al.,24Chesebro JH Fuster V Elveback LR Clements JP Smith HC Holmes DR Bardsley WT Pluth JR Wallace RB Puga JF Orszulak JA Pichler JM Danielson GK Schaff HV Frye RL. Effect of dipyridamole and aspirin on late vein-graft patency after coronary bypass operations.N Engl J Med. 1984; 310: 209-214Crossref PubMed Scopus (402) Google Scholar drug therapy was of most benefit in preventing early graft failure (occlusion rates at 1 month after surgery: placebo, 10%; treated, 2%). Less benefit could be demonstrated at late times (studied at a median time of 12 months) for grafts patent at 1 month (new occlusion rates after 1 month: placebo, 14%; treated, 9%). Overall, aspirin and dipyridamole reduced graft occlusion from 25% to 10% at 1 year. (5) Grafts into arteries already well supplied by competing collateral branches were at high risk for thrombosis and benefited from drug treatment. The studies conducted in patients undergoing femoropopliteal bypass have not provided definitive conclusions regarding the benefits of aspirin and dipyridamole. Green, Roedersheimer, and DeWeese31Green RM Roedersheimer LR DeWeese JA. Effects of aspirin and dipyridamole on expanded polytetrafluoroethylene graft patency.Surgery. 1982; 92: 1016-1026PubMed Google Scholar randomized 49 patients undergoing PTFE grafting into groups treated with aspirin and dipyridamole, aspirin alone, or placebo. There was a significant benefit at 1 year from aspirin or aspirin and dipyridamole treatment in patients undergoing above-knee bypass but not below-knee bypass. Drug treatment was started before surgery. A similar study comparing aspirin and dipyridamole to placebo treatment was reported by Kohler et al.32Kohler TF Kaufman JL Kacoyanis G Clowes A Donaldson MC Kelly E Skillman J Couch NP Whittemore AD Mannick JA Salzman EW. Effect of aspirin and dipyridamole on the patency of lower extremity bypass grafts.Surgery. 1984; 96: 462-466PubMed Google Scholar for patients receiving either saphenous vein or PTFE grafts and could not demonstrate a benefit from drug therapy. In this trial drug administration was begun during the first postoperative day. The reasons for the different outcome between the two studies are not evident. One possibility is that antithrombotic agents need to be given to patients before surgery. Both studies suffered from having small numbers of patients in subgroups particularly prone to thrombosis; for example, there was a trend toward significant improvement in femorotibial graft patency in the treated group reported by Kohler et al.,32Kohler TF Kaufman JL Kacoyanis G Clowes A Donaldson MC Kelly E Skillman J Couch NP Whittemore AD Mannick JA Salzman EW. Effect of aspirin and dipyridamole on the patency of lower extremity bypass grafts.Surgery. 1984; 96: 462-466PubMed Google Scholar but the numbers were too small for a statistical comparison to be made. These studies, particularly the recent aortocoronary ones, identify early graft failure on account of accretion and accumulation of platelets and thrombus as a significant problem. Marked improvement in early graft patency can be achieved by inhibiting platelet aggregation with aspirin (with or without dipyridamole) but only if the drugs are given during the immediate postoperative period at a time when thrombotic activity is pronounced. Which combination and dosages of medications will produce the best result remain to be determined; on the basis of the available evidence the precise regulation of aspirin dosage and the preservation of PGI2 synthesis does not seem as clinically important as it was once thought to be. How long should antithrombotic therapy be continued? The answer to this question must address the problem of the mechanism of late graft failure. Late graft failure has been attributed to either myointimal thickening or progressive atherosclerosis. Does platelet aggregation play a role in this process, and therefore should antithrombotic drugs be expected to inhibit it? Animal and human studies demonstrate that synthetic grafts not covered by endothelium continue to consume platelets, but these regions do not develop significant intimal thickening and luminal stenosis. Our own studies and those of others in animal models of PTFE and vein graft healing have tended to demonstrate that intimal thickening because of smooth muscle proliferation develops in regions covered by endothelium where thrombotic activity has ceased.33Clowes AW Gown AM Hanson SR Reidy MA. Mechanisms of arterial graft failure. I. Role of cellular proliferation in early healing of PTFE prostheses.Am J Pathol. 1985; 118: 43-54PubMed Google Scholar These findings taken together with the clinical observation that antithrombotic drugs are ineffective if started more than 2 days after surgery suggest that factors other than those derived from platelets may control the late proliferative process. One possibility is that endothelial cells, smooth muscle cells, or blood-borne leukocytes (e.g., macrophages) might synthesize and secrete growth factors; support for this new hypothesis comes from both in vitro and in vivo work demonstrating that these cells can synthesize a platelet-derived growth factor-like protein.34Gajdusek CM DiCorleto P Ross R Schwartz S. An endothelial cell—derived growth factor.J Cell Biol. 1980; 85: 467-472Crossref PubMed Scopus (198) Google Scholar, 35Fox PL DiCorleto PE. Regulation of production of a platelet-derived growth factor-like protein by cultured bovine aortic endothelial cells.J Cell Physiol. 1984; 121: 298-308Crossref PubMed Scopus (115) Google Scholar, 36Seifert RA Schwartz SM Bowen-Pope DF. Developmentally regulated production of platelet-derived factor-like molecules.Nature. 1984; 311: 669-671Crossref PubMed Scopus (250) Google Scholar, 37Walker LN Bowen-Pope DF Reidy MA. Secretion of platelet-derived growth factor (PDGF)-like activity by arterial smooth muscle cells is induced as a response to injury (abstract).J Cell Biol. 1984; 99: 416Google Scholar, 38Barrett TB Gajdusek CM Schwartz SM McDougall JK Benditt EP. Expression of the sis gene by endothelial cells in culture and in vivo.Proc Natl Acad Sci USA. 1984; 81: 6772-6774Crossref PubMed Scopus (137) Google Scholar, 39Barrett TB Benditt EP. The sis gene is expressed in human atherosclerotic lesions suggesting atherosclerosis may be an autocrine/paracrine disorder.Fed Proc. 1985; 44 (abstract): 737Google Scholar If this hypothesis proves to be correct, then pharmacologic research and therapy will need to address directly the problem of cell growth control. One such growth-inhibiting agent exhibiting specificity for smooth muscle cells is heparin40Clowes AW Clowes MM. Kinetics of cellular proliferation after arterial injury. II. Inhibition of smooth muscle growth by heparin.Lab Invest. 1985; 52: 611-616PubMed Google Scholar; heparin and related nonanticoagulant molecules are now under intensive investigation. Adjuvant therapy in the future may comprise both antithrombotic and antiproliferative components. Despite our ability to bypass arteriosclerotic occlusive disease, thrombosis both in the early and the late periods after surgery poses a major obstacle to the long-term success of these grafts. Aspirin given in the perioperative period provides significant protection against early graft failure. Whether it will prove to be of benefit in the prevention of late occlusion remains to be determined.