- Email: [email protected]
Anticoagulation and restenosis after percutaneous transluminal coronary angioplasty
Anticoagulation and RestenosisAfter PercutaneousTransluminalCoronary Angioplasty MICHAEL
A.
BETTMANN,
Restenosis after angioplasty is probably related to 2 processes: thrombosis and recurrence of atherosclerosis. Many approaches to altering these processes are available, but to date none has shown a high rate of success. Heparin has properties relevant to both processes; this makes it an attractive compound for further study. The anticoagulant action. of heparin is well known. It is mediated primarily though complex formation with antithrombin Ill, which leads to a conformational change and an increased rate of thrombin inactivation. Heparin has additional antithrombotic actions, largely mediated through the formation of the same complex, but involving precursor elements such as factor Xa. These
MD
actions of heparin can be localized to different portions of the large, complex motecule. Additionally, experimental studies have demonstrated an antiproliferative action of heparin, a property that may be relevant to smooth muscle cell’ proliferation afler angiopiasty. This is mediated by a fairly small, functionally distinct nonanticoagulant portion of the heparin molecule. Fragments of heparin possessing particular actions are being investigated experimentally and clinically. Continued investigations of the structure and function of heparin promise to lead to a decreased rate of restenosis and a better understanding of the mechanisms of (Am J Cardiol 1987;80:17B-19B) angioplasty.
A
considered here. The primary focus of this article is heparin. Heparin is a relatively large and complex molecule with a variety of actions and effects.12-l4 Clinically, heparin is used routinely during coronary angiography in many, if not most, centers. The rationale for its use in coronary angiography, as in PTCA, is to prevent thrombosis induced through the coagulation cascade. It does this without significant risk during coronary angiography, as indicated in several large studies.15J6 Although bleeding is a major consideration in instituting heparin therapy, l7 the incidence of bleeding complications after routine, single dose administration during coronary angiography is ~ow.*~J~J~On the other hand, the incidence of coronary angiography complications is, somewhat surprisingly, essentially identical whether or not heparin is administered.15J6 This may indicate that certain thrombotic complications are less frequent with heparin while bleeding complications are more common. If heparin use during routine coronary angiography is of marginal value, however, its use during PTCA is widely if not universally accepted. The usual dose administered is 5,000 to 10,000units, often 5,000 units at the time the guiding catheter is introduced and an additional 5,000 units at the time the lesion is traversed with the guidewire. Because the effect is rapidly established systemically, the site of administration-of the heparin is probably of little con-
nticoagulation plays a large but incompletely understood role in angioplasty in general, and specifically in preventing restenosis. The anticoagulation regimens currently in use have evolved from a number of factors, ranging from personal experience to experimental studies to clinical results. It is perhaps simplest to consider anticoagulation and restenosis from the point of view of specific drugs-most notably heparin-and their proven and putative actions. From the current understanding of the mechanism of restenosis and the mechanism of vessel wall healing after injury, 2 factors are operative: thrombosis and recurrence of atherosclerotic lesions.l-lo Because thrombosis is far more likely to occur acutely rather than days or weeks after percutaneous transluminal coronary angioplasty (PTCA), it is unlikely that warfarin therapy has a significant role to play. Tentative confirmation of this has come from a clinical study.ll The same reasoning probably applies to volume expanding agents such as dextran. The role of antiplatelet agents is a different topic, and will not be directly
From the Department of Radiology, Harvard Medical School, and the Department of Cardiovasctilar and Interventional Radiology, Brigham and Women’s Hospital, Boston, Massachusetts. Address for reprints: Michael A. Bettmann, MD, Department of Radiology, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115. 178
18B
A SYMPOSIUM:
RESTENOSIS
AFTER
PERCUTANEOUS
TRANSLUMINAL
sequence. The biologic half-life of parenteral heparin is 60 to 80 minutes,lg with fairly wide individual variations After routine angiography, it is usual in many centers to reverse the effect with a slow infusion of protamine sulfate at a dose of 10 mg/l,OOO units of heparin. In patients undergoing PTCA, protamine is generally not given. It is conventional to continue heparin via infusion for 24 to 48 hours after the procedure, mainly because of fear of thrombosis at the site of the dilatation. Much has been learned about heparin over the last few years that is relevant in both practical and theoretical terms to PTCA. The anticoagulant effect of heparin derives from the complex formed by this drug and circulating antithrombin III.13Jo This interaction leads to a shape change in antithrombin III, which in simple terms makes the active site more accessible. This in turn leads to an increased rate of complex formation of antithrombin III with thrombin, resultant inactivation of thrombin and suppressed conversion of fibrinogen to fibrin. The antithrombin III-thrombin complex is stable, but the heparin molecule is released to combine with other antithrombin III molecules. The suppression of thrombin activity leads to the measured alterations in the activated partial thromboplastin time. The primary aim of heparinization, then, is anticoagulation, as reflected in an increase of the partial thromboplastin time to 1 to 2 times normal, usually 40 to 55 seconds. Heparin, however, clearly has additional effects. Through the same mechanism, the formation of the heparin-antithrombin III complex, other clotting factors are inactivated.13,20J1These inactivations may take place with doses of heparin lower than those normally considered necessary. In 1 study, for example, it was found that the incidence of venous thrombosis after orthopedic surgery was significantly lower in patients in whom the partial thromboplastin time was titrated to a level at the upper limits of normal compared with untreated control patients.22 In other words, low doses afforded protection, without the bleeding risk associated with full anticoagulation.17 Of equal or greater relevance to PTCA are other effects of heparin. A variety of interactions of this drug with platelets, with other clotting factors and with the arterial wall have been demonstrated. Thrombocytopenia often occurs, either immediately or 6 to 7 days after the infusion has begun, With delayed thrombocytopenia, the mechanism may be allergic. With immediate thrombocytopenia, which is usually transient and relatively mild, the mechanism is thought to relate to specific platelet binding sites on the molecule.13 The reaction is probably responsible for some of the bleeding complications that occur. This binding site for platelets is thought to be separate from the antithrombin III binding site. It may, therefore, be possible to fractionate heparin to a form that binds with antithrombin III but not with platelets. The concept of fractionated heparin is currently under investigation, using a variety of approaches. By fractionating this complex, heterogeneous molecule on the basis of molecular weight, it is possible to isolate fragments that have little or no thrombin-inactivating activity.lsJs These fragments appear to act by com-
CORONARY
ANGIOPLASTY
plexing with antithrombin III and then with factor Xa, thereby intervening higher in the coagulation cascade. The postulated value of such low molecular weight fragments has been primarily in regard to venous thrombosis, and there have been several reports of the use of such preparations for prophylaxis, with promising results.21,23J4Two problems arise, however, in dealing with such heparin fractions. First, it is difficult to establish appropriate dosages, in large part because the partial thromboplastin time cannot be used for monitoring, and other rapid and inexpensive tests for measuring effect are not yet readily available. Second, it is not yet clear to what extent different heparin fractions possess or lack specific effects such as platelet interaction. Despite such problems, and notwithstanding that experience to date has been limited primarily to venous thrombosis, such fractionated heparin preparations are theoretically likely to be beneficial during and after PTCA. They provide the advantage of lower risk of bleeding but continued protection against formation of thrombus at the PTCA site and, therefore, the possibility of longer but safer heparin administration. As this implies, anticoagulation in PTCA is based on the idea that acute reocclusion as well as delayed restenosis may be related to thrombus formations-10 Intimal damage, which clearly accompanies angioplasty, may lead to thrombus formation by both platelet activation and the coagulation cascade. Heparin as well as antiplatelet medications are then theoretically of value during and after PTCA. It is likely, however, that other mechanisms play a role in restenosis. These may include both spasm and, perhaps more importantly, regrowth of atherosclerotic plaque. It is not clear yet what the pathology of recurrent stenosis is, and more than one mechanism is likely to be involved.6~8-10~2s-27 Nonetheless, studies of vessel wall damage and healing shed some light on possible mechanisms. It has long been known, for example, that the normal, intact endothelial lining of arteries is nonthrombogenic. If the endothelium is removed, which can easily be accomplished by gentle rubbing with a balloon catheter, platelets accumulate on the subendothelium. They release numerous factors, among them platelet factor 4 (PF4, which is an antiheparin factor), and plateletderived growth factor. 27~8Platelet-derived growth factor stimulates migration of smooth muscle cells from the media to the intima and their proliferation, with the resultant formation of a fibromusculoelastic plaque. This experimentally induced lesion resembles the earliest plaques found in human arteries, and is thought to be the precursor of full-blown atheroma. The injury to the wall induced by PTCA is similar to the experimental injury that results in the fibromusculoelastic plaque. It is possible that a reaction encountered experimentally also occurs clinically, and is, at least in a certain percentage of patients, the cause of the recurrent stenosis. This theory is in part the reason for the use of antiplatelet agents during and after PTCA. It is thought that suppression of platelet aggregation may limit platelet-derived growth factor release, and therefore limit the proliferative response. A major reason for the use of heparin during and subse-
July
31, 1987
quent to PTCA is this theory and supporting experimental work. Heparin is known to be present normally in the endothelium, and has been shown experimentally to have antiproliferative effects.29J0It suppresses the smooth muscle cell proliferation that occurs after endothelial removal in a carotid animal model. The mechanism of this action is not yet clear. Experimentally, the suppression of proliferation can be achieved with a heparin fraction that does not possessnormal antithrombotic activity. This fraction is derived not by separation on the basis of molecular weight, as mentioned earlier, but rather on the basis of function, by complexing with antithrombin 11131and deriving a fragment essentially devoid of anticoagulant activity. In practical terms, then, different portions of the heparin molecule may have distinct functions. This raises the possibility of using different heparin fragments for specific functional aims, with a lower likelihood of complications. Much remains to be clarified concerning the antiproliferative effect, in regard to both mechanism and clinical relevance, but the experimental results to date are clearly encouraging. In summary, the role that anticoagulation plays or may play in preventing restenosis is not yet clear. From experience as well as from clinical and experimental studies, it is likely that warfarin therapy after PTCA, even in combination with antiplatelet agents, is unlikely to significantly reduce the restenosis rate. Heparin is conventionally used and probably useful during the procedure, but neither the optimal dose nor the duration of heparinization after PTCA is well defined. Currently, the dosage varies from a single dose of 5,000 to 10,000 units at the start of the procedure, to a S-day, full anticoagulant infusion. Because of both safety and cost considerations, it is desirable to limit the duration of anticoagulation. In light of the findings of the antiproliferative properties of heparin, however, longer administration may be advantageous. Much remains to be learned before the optimal role of anticoagulation, and specifically of heparin, can be defined. This definition will depend on continued studies with various heparin fragments, as well as on improved understanding of both the mechanism of angioplasty and the pathophysiology of restenosis.
References 1. Block PC, Baughman KL, Pasternak RC, Fallon JT. Transluminal angiopfasty: correlation of morphologic and ongiographic findings in an experimental model. Circulation 1980;61:778-785, 2. Block PC, Myler RK, Stertzer S, Fallon JT. Morphology after tronsluminal angioplasty in human beings. N Engl J Med 1981;305:382-385. 3. Waller BF, McManus BM, Garfinkel J. Kishel JC, Schmidt ECH, Kent KM, Roberts WC. Status of the major epicardia1 coronary arteries 80 to 150 days after percutaneous transluminal angioplasty. Am J CardioJ 1983;51:81-84. 4. Leimgruber PP. Roubin GS, Anderson V, Bredlau CB, Whitworth HB, Douglas JS Jr, King SB III, Gruentzig AR. Influence of intimal dissection on reStenOSisafter SUCCessfuf coronary angioplasty. Circulation 1985; 72:530-535. 5. Leimgruber PP, Roubin GS. Hollman J, Cotsonis GA, Meir R, Douglas JS,
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume 60
19B
King SB III, Gruentzig AR. &stenosis after successful coronary angioplasty in patients with single vessel disease. Circulation 1986:73:710-717, 6. Ross R. The pathogenesis of atherosclerosis-an update. N Engl J Med 1986;314:488-500. 7. Stemerman MB, Spaet TH, Pitlick F, Cintron J, Lejniecks I, Tie11 ML. Intimal hearing. The pattern of re-endothelialization and intimal thickening. Am J Path01 1977;87:125-142. 8. Park JH, Bethann MA, Adelman B, Levin DC, Miller R, Finkelstein J,Hunt M. In vivo imaging and evaluation of platelet accumulation vs. time at arterial injury site. Invest Radio1 1985; 20:287-292. 9. Faxon DP, Sanborn TA, Haudenschild CC, Ryan TJ. Effect of antiplatelet therapy on restenosis after experimental angioplasty. Am J CardioJ 1984; 53:72C-76C.
10. Steele PM, Chesebro JH, Stanson AW, Holmes DR Jr, Dewanjee MK, Badimon L, Fuster V. Balloon angioplasty. Natural history of the pathophysiological response to injury in a pig model. Circ Res 1985;57:105-xz 11. Thornton MA, Gruentzig AR, Hollman J, King SB III, Douglas JS.Coumadin and aspirin in prevention of recurrence after transluminal coronary angioplasty: a randomized study. Circulation 1984;69:721-727. 12. Rosenberg RD. Lam L. Correlation between structure and function of heparin. Proc Nat1 Acad Sci USA 1979;76:1218-1222, 13. Rosenberg RD. Heparin-antithrombin system. In: Colman RW, Hirsh J. Marder VJ, Salzman EW, eds. Hemostasis and Thrombosis. Philadelphia: JB Lippincott, 1982:962-985. 14. Fareed J, Walenga JM, Williamson K, Emanuele RM, Kumar A, Hopenseadt DA. Studies on the antithrombotic effects and pharmacokinetics of heparin fractions and fragments. Semin Thromb Hemost 1985;11:56-74. 15. Davis K, Kennedy JW, Kemp HG Jr, Judkins MP, Gosselin AJ, Killip T. CompJications of coronary arteriography from the collaborative study of coronary artery surgery (CA,%‘). Circulation 1979;59:1105-1112. 16. Adams DF, Abrams HL. Complications of coronary arteriography: a follow-up report. Cardiovasc Intervent Radio1 1979;2:89-96. 17. Walker AM, Jick H. Predictors of bleeding during heparin therapy. JAMA 1980;244:1209-1212. 18. Walker WJ, Mundall SL. Broderick HG, Prasad B, Kim J,Ravi JM. Systemic heparinization for femoral percutaneous coronary arteriography. N EngJ J Med 1973;288:826-828. 19. Hirsh J, van Aken WG, Gallus AS, Dollery CT, Cade JF, Yung WL. Heparin kinetics in venous thrombosis and pulmonary embolism. Circulation 1976;53:691-695. 20. Salzman EW. Low molecular weight heparin. Editorial. N EngJ J Med 1986;315:957-959. 21. Turpie AGG, Levine MN, Hirsh J, Carter CJ, Jay RM, Powers PJ,Andrew M, Hull RD, Gent M. A randomized controlled trial of low-molecular-weight heparin (enoxaparin) to prevent deep vein thrombosis in patients undergoing elective hip surgery. N EngI J Med 1986;315:925-929. 22. Leyvraz PF, Richard J, Bachmann F, Van Mel1 G, Treynaud J-M, Leiro J-J, Candardjis G. Adjusted versus fixed dose subcutaneous heparin in the prevention of deep-vein thrombosis after total hip replacement. N EngJ J Med 1983;309:954-958. 23. Lund T. Heimdal A, Ulvik NM. A low molecular weight heparin fragment in prophylaxis of post-operative deep vein thrombosis after major abdominal surgery (abstr]. Thromb Haemost 1985;54:552. 24. Kakker VV. Murray WJG. Efficacy and safety of low-molecular-weight heparin (CY 216) in preventing postoperative venous thrombo-embolism: a co-operative study. Br J Surg 1985;72:786-791. 25. Stine RA, Magorien RD. Bush CA, Kolibash AJ, Leier CV, Fertel RH, Brandt J, Unverferth DV. Failure of percutaneous transhminal coronary angioplasty to stimulate platelet and prostaglandin activity. Cathet Cardiovast Diagn 1985;11:247-254. 26. Peterson MB, Machaj V, Block PC, Palacios I, Philbin D, Watkins WD. Thromboxane release during percutaneous transluminal coronary angioplasty. Am Heart J 1986;111:1-5. 27. Ross R, Glomsei JA. The pathophysiology of atherosclerosis. N EngJ J Med 1976:295:362-376.420-425. 28. Harker LA, Ross R, Glomset JA. The role of endothelial cell injury and platelet response in atherogenesis. Thromb Haemost 1978;39:312-321. 29. Clowes AW, Clowes MM. Kinetics of cellular proliferation after arterial injury. II. Inhibition of smooth muscle growth by heparin. Lab Invest 1985; 52:611-616.
30. Clowes AW, Clowes MM. Kinetics of cellular proliferation after arterial injury. IV. Heparin inhibits rat smooth muscle mitogenesis and migration. Circ Res 1986;58:839-845. 31. Guyton JR, Rosenberg RD. Clowes AW, Karnovsky MJ. Inhibition of rat arterial smooth muscle cell proliferation by heporin. In vivo studies with anticoagulant and nonanticoagulant heparin. Circ Res 1980;46:625-634.
A.
BETTMANN,
Restenosis after angioplasty is probably related to 2 processes: thrombosis and recurrence of atherosclerosis. Many approaches to altering these processes are available, but to date none has shown a high rate of success. Heparin has properties relevant to both processes; this makes it an attractive compound for further study. The anticoagulant action. of heparin is well known. It is mediated primarily though complex formation with antithrombin Ill, which leads to a conformational change and an increased rate of thrombin inactivation. Heparin has additional antithrombotic actions, largely mediated through the formation of the same complex, but involving precursor elements such as factor Xa. These
MD
actions of heparin can be localized to different portions of the large, complex motecule. Additionally, experimental studies have demonstrated an antiproliferative action of heparin, a property that may be relevant to smooth muscle cell’ proliferation afler angiopiasty. This is mediated by a fairly small, functionally distinct nonanticoagulant portion of the heparin molecule. Fragments of heparin possessing particular actions are being investigated experimentally and clinically. Continued investigations of the structure and function of heparin promise to lead to a decreased rate of restenosis and a better understanding of the mechanisms of (Am J Cardiol 1987;80:17B-19B) angioplasty.
A
considered here. The primary focus of this article is heparin. Heparin is a relatively large and complex molecule with a variety of actions and effects.12-l4 Clinically, heparin is used routinely during coronary angiography in many, if not most, centers. The rationale for its use in coronary angiography, as in PTCA, is to prevent thrombosis induced through the coagulation cascade. It does this without significant risk during coronary angiography, as indicated in several large studies.15J6 Although bleeding is a major consideration in instituting heparin therapy, l7 the incidence of bleeding complications after routine, single dose administration during coronary angiography is ~ow.*~J~J~On the other hand, the incidence of coronary angiography complications is, somewhat surprisingly, essentially identical whether or not heparin is administered.15J6 This may indicate that certain thrombotic complications are less frequent with heparin while bleeding complications are more common. If heparin use during routine coronary angiography is of marginal value, however, its use during PTCA is widely if not universally accepted. The usual dose administered is 5,000 to 10,000units, often 5,000 units at the time the guiding catheter is introduced and an additional 5,000 units at the time the lesion is traversed with the guidewire. Because the effect is rapidly established systemically, the site of administration-of the heparin is probably of little con-
nticoagulation plays a large but incompletely understood role in angioplasty in general, and specifically in preventing restenosis. The anticoagulation regimens currently in use have evolved from a number of factors, ranging from personal experience to experimental studies to clinical results. It is perhaps simplest to consider anticoagulation and restenosis from the point of view of specific drugs-most notably heparin-and their proven and putative actions. From the current understanding of the mechanism of restenosis and the mechanism of vessel wall healing after injury, 2 factors are operative: thrombosis and recurrence of atherosclerotic lesions.l-lo Because thrombosis is far more likely to occur acutely rather than days or weeks after percutaneous transluminal coronary angioplasty (PTCA), it is unlikely that warfarin therapy has a significant role to play. Tentative confirmation of this has come from a clinical study.ll The same reasoning probably applies to volume expanding agents such as dextran. The role of antiplatelet agents is a different topic, and will not be directly
From the Department of Radiology, Harvard Medical School, and the Department of Cardiovasctilar and Interventional Radiology, Brigham and Women’s Hospital, Boston, Massachusetts. Address for reprints: Michael A. Bettmann, MD, Department of Radiology, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115. 178
18B
A SYMPOSIUM:
RESTENOSIS
AFTER
PERCUTANEOUS
TRANSLUMINAL
sequence. The biologic half-life of parenteral heparin is 60 to 80 minutes,lg with fairly wide individual variations After routine angiography, it is usual in many centers to reverse the effect with a slow infusion of protamine sulfate at a dose of 10 mg/l,OOO units of heparin. In patients undergoing PTCA, protamine is generally not given. It is conventional to continue heparin via infusion for 24 to 48 hours after the procedure, mainly because of fear of thrombosis at the site of the dilatation. Much has been learned about heparin over the last few years that is relevant in both practical and theoretical terms to PTCA. The anticoagulant effect of heparin derives from the complex formed by this drug and circulating antithrombin III.13Jo This interaction leads to a shape change in antithrombin III, which in simple terms makes the active site more accessible. This in turn leads to an increased rate of complex formation of antithrombin III with thrombin, resultant inactivation of thrombin and suppressed conversion of fibrinogen to fibrin. The antithrombin III-thrombin complex is stable, but the heparin molecule is released to combine with other antithrombin III molecules. The suppression of thrombin activity leads to the measured alterations in the activated partial thromboplastin time. The primary aim of heparinization, then, is anticoagulation, as reflected in an increase of the partial thromboplastin time to 1 to 2 times normal, usually 40 to 55 seconds. Heparin, however, clearly has additional effects. Through the same mechanism, the formation of the heparin-antithrombin III complex, other clotting factors are inactivated.13,20J1These inactivations may take place with doses of heparin lower than those normally considered necessary. In 1 study, for example, it was found that the incidence of venous thrombosis after orthopedic surgery was significantly lower in patients in whom the partial thromboplastin time was titrated to a level at the upper limits of normal compared with untreated control patients.22 In other words, low doses afforded protection, without the bleeding risk associated with full anticoagulation.17 Of equal or greater relevance to PTCA are other effects of heparin. A variety of interactions of this drug with platelets, with other clotting factors and with the arterial wall have been demonstrated. Thrombocytopenia often occurs, either immediately or 6 to 7 days after the infusion has begun, With delayed thrombocytopenia, the mechanism may be allergic. With immediate thrombocytopenia, which is usually transient and relatively mild, the mechanism is thought to relate to specific platelet binding sites on the molecule.13 The reaction is probably responsible for some of the bleeding complications that occur. This binding site for platelets is thought to be separate from the antithrombin III binding site. It may, therefore, be possible to fractionate heparin to a form that binds with antithrombin III but not with platelets. The concept of fractionated heparin is currently under investigation, using a variety of approaches. By fractionating this complex, heterogeneous molecule on the basis of molecular weight, it is possible to isolate fragments that have little or no thrombin-inactivating activity.lsJs These fragments appear to act by com-
CORONARY
ANGIOPLASTY
plexing with antithrombin III and then with factor Xa, thereby intervening higher in the coagulation cascade. The postulated value of such low molecular weight fragments has been primarily in regard to venous thrombosis, and there have been several reports of the use of such preparations for prophylaxis, with promising results.21,23J4Two problems arise, however, in dealing with such heparin fractions. First, it is difficult to establish appropriate dosages, in large part because the partial thromboplastin time cannot be used for monitoring, and other rapid and inexpensive tests for measuring effect are not yet readily available. Second, it is not yet clear to what extent different heparin fractions possess or lack specific effects such as platelet interaction. Despite such problems, and notwithstanding that experience to date has been limited primarily to venous thrombosis, such fractionated heparin preparations are theoretically likely to be beneficial during and after PTCA. They provide the advantage of lower risk of bleeding but continued protection against formation of thrombus at the PTCA site and, therefore, the possibility of longer but safer heparin administration. As this implies, anticoagulation in PTCA is based on the idea that acute reocclusion as well as delayed restenosis may be related to thrombus formations-10 Intimal damage, which clearly accompanies angioplasty, may lead to thrombus formation by both platelet activation and the coagulation cascade. Heparin as well as antiplatelet medications are then theoretically of value during and after PTCA. It is likely, however, that other mechanisms play a role in restenosis. These may include both spasm and, perhaps more importantly, regrowth of atherosclerotic plaque. It is not clear yet what the pathology of recurrent stenosis is, and more than one mechanism is likely to be involved.6~8-10~2s-27 Nonetheless, studies of vessel wall damage and healing shed some light on possible mechanisms. It has long been known, for example, that the normal, intact endothelial lining of arteries is nonthrombogenic. If the endothelium is removed, which can easily be accomplished by gentle rubbing with a balloon catheter, platelets accumulate on the subendothelium. They release numerous factors, among them platelet factor 4 (PF4, which is an antiheparin factor), and plateletderived growth factor. 27~8Platelet-derived growth factor stimulates migration of smooth muscle cells from the media to the intima and their proliferation, with the resultant formation of a fibromusculoelastic plaque. This experimentally induced lesion resembles the earliest plaques found in human arteries, and is thought to be the precursor of full-blown atheroma. The injury to the wall induced by PTCA is similar to the experimental injury that results in the fibromusculoelastic plaque. It is possible that a reaction encountered experimentally also occurs clinically, and is, at least in a certain percentage of patients, the cause of the recurrent stenosis. This theory is in part the reason for the use of antiplatelet agents during and after PTCA. It is thought that suppression of platelet aggregation may limit platelet-derived growth factor release, and therefore limit the proliferative response. A major reason for the use of heparin during and subse-
July
31, 1987
quent to PTCA is this theory and supporting experimental work. Heparin is known to be present normally in the endothelium, and has been shown experimentally to have antiproliferative effects.29J0It suppresses the smooth muscle cell proliferation that occurs after endothelial removal in a carotid animal model. The mechanism of this action is not yet clear. Experimentally, the suppression of proliferation can be achieved with a heparin fraction that does not possessnormal antithrombotic activity. This fraction is derived not by separation on the basis of molecular weight, as mentioned earlier, but rather on the basis of function, by complexing with antithrombin 11131and deriving a fragment essentially devoid of anticoagulant activity. In practical terms, then, different portions of the heparin molecule may have distinct functions. This raises the possibility of using different heparin fragments for specific functional aims, with a lower likelihood of complications. Much remains to be clarified concerning the antiproliferative effect, in regard to both mechanism and clinical relevance, but the experimental results to date are clearly encouraging. In summary, the role that anticoagulation plays or may play in preventing restenosis is not yet clear. From experience as well as from clinical and experimental studies, it is likely that warfarin therapy after PTCA, even in combination with antiplatelet agents, is unlikely to significantly reduce the restenosis rate. Heparin is conventionally used and probably useful during the procedure, but neither the optimal dose nor the duration of heparinization after PTCA is well defined. Currently, the dosage varies from a single dose of 5,000 to 10,000 units at the start of the procedure, to a S-day, full anticoagulant infusion. Because of both safety and cost considerations, it is desirable to limit the duration of anticoagulation. In light of the findings of the antiproliferative properties of heparin, however, longer administration may be advantageous. Much remains to be learned before the optimal role of anticoagulation, and specifically of heparin, can be defined. This definition will depend on continued studies with various heparin fragments, as well as on improved understanding of both the mechanism of angioplasty and the pathophysiology of restenosis.
References 1. Block PC, Baughman KL, Pasternak RC, Fallon JT. Transluminal angiopfasty: correlation of morphologic and ongiographic findings in an experimental model. Circulation 1980;61:778-785, 2. Block PC, Myler RK, Stertzer S, Fallon JT. Morphology after tronsluminal angioplasty in human beings. N Engl J Med 1981;305:382-385. 3. Waller BF, McManus BM, Garfinkel J. Kishel JC, Schmidt ECH, Kent KM, Roberts WC. Status of the major epicardia1 coronary arteries 80 to 150 days after percutaneous transluminal angioplasty. Am J CardioJ 1983;51:81-84. 4. Leimgruber PP. Roubin GS, Anderson V, Bredlau CB, Whitworth HB, Douglas JS Jr, King SB III, Gruentzig AR. Influence of intimal dissection on reStenOSisafter SUCCessfuf coronary angioplasty. Circulation 1985; 72:530-535. 5. Leimgruber PP, Roubin GS. Hollman J, Cotsonis GA, Meir R, Douglas JS,
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume 60
19B
King SB III, Gruentzig AR. &stenosis after successful coronary angioplasty in patients with single vessel disease. Circulation 1986:73:710-717, 6. Ross R. The pathogenesis of atherosclerosis-an update. N Engl J Med 1986;314:488-500. 7. Stemerman MB, Spaet TH, Pitlick F, Cintron J, Lejniecks I, Tie11 ML. Intimal hearing. The pattern of re-endothelialization and intimal thickening. Am J Path01 1977;87:125-142. 8. Park JH, Bethann MA, Adelman B, Levin DC, Miller R, Finkelstein J,Hunt M. In vivo imaging and evaluation of platelet accumulation vs. time at arterial injury site. Invest Radio1 1985; 20:287-292. 9. Faxon DP, Sanborn TA, Haudenschild CC, Ryan TJ. Effect of antiplatelet therapy on restenosis after experimental angioplasty. Am J CardioJ 1984; 53:72C-76C.
10. Steele PM, Chesebro JH, Stanson AW, Holmes DR Jr, Dewanjee MK, Badimon L, Fuster V. Balloon angioplasty. Natural history of the pathophysiological response to injury in a pig model. Circ Res 1985;57:105-xz 11. Thornton MA, Gruentzig AR, Hollman J, King SB III, Douglas JS.Coumadin and aspirin in prevention of recurrence after transluminal coronary angioplasty: a randomized study. Circulation 1984;69:721-727. 12. Rosenberg RD. Lam L. Correlation between structure and function of heparin. Proc Nat1 Acad Sci USA 1979;76:1218-1222, 13. Rosenberg RD. Heparin-antithrombin system. In: Colman RW, Hirsh J. Marder VJ, Salzman EW, eds. Hemostasis and Thrombosis. Philadelphia: JB Lippincott, 1982:962-985. 14. Fareed J, Walenga JM, Williamson K, Emanuele RM, Kumar A, Hopenseadt DA. Studies on the antithrombotic effects and pharmacokinetics of heparin fractions and fragments. Semin Thromb Hemost 1985;11:56-74. 15. Davis K, Kennedy JW, Kemp HG Jr, Judkins MP, Gosselin AJ, Killip T. CompJications of coronary arteriography from the collaborative study of coronary artery surgery (CA,%‘). Circulation 1979;59:1105-1112. 16. Adams DF, Abrams HL. Complications of coronary arteriography: a follow-up report. Cardiovasc Intervent Radio1 1979;2:89-96. 17. Walker AM, Jick H. Predictors of bleeding during heparin therapy. JAMA 1980;244:1209-1212. 18. Walker WJ, Mundall SL. Broderick HG, Prasad B, Kim J,Ravi JM. Systemic heparinization for femoral percutaneous coronary arteriography. N EngJ J Med 1973;288:826-828. 19. Hirsh J, van Aken WG, Gallus AS, Dollery CT, Cade JF, Yung WL. Heparin kinetics in venous thrombosis and pulmonary embolism. Circulation 1976;53:691-695. 20. Salzman EW. Low molecular weight heparin. Editorial. N EngJ J Med 1986;315:957-959. 21. Turpie AGG, Levine MN, Hirsh J, Carter CJ, Jay RM, Powers PJ,Andrew M, Hull RD, Gent M. A randomized controlled trial of low-molecular-weight heparin (enoxaparin) to prevent deep vein thrombosis in patients undergoing elective hip surgery. N EngI J Med 1986;315:925-929. 22. Leyvraz PF, Richard J, Bachmann F, Van Mel1 G, Treynaud J-M, Leiro J-J, Candardjis G. Adjusted versus fixed dose subcutaneous heparin in the prevention of deep-vein thrombosis after total hip replacement. N EngJ J Med 1983;309:954-958. 23. Lund T. Heimdal A, Ulvik NM. A low molecular weight heparin fragment in prophylaxis of post-operative deep vein thrombosis after major abdominal surgery (abstr]. Thromb Haemost 1985;54:552. 24. Kakker VV. Murray WJG. Efficacy and safety of low-molecular-weight heparin (CY 216) in preventing postoperative venous thrombo-embolism: a co-operative study. Br J Surg 1985;72:786-791. 25. Stine RA, Magorien RD. Bush CA, Kolibash AJ, Leier CV, Fertel RH, Brandt J, Unverferth DV. Failure of percutaneous transhminal coronary angioplasty to stimulate platelet and prostaglandin activity. Cathet Cardiovast Diagn 1985;11:247-254. 26. Peterson MB, Machaj V, Block PC, Palacios I, Philbin D, Watkins WD. Thromboxane release during percutaneous transluminal coronary angioplasty. Am Heart J 1986;111:1-5. 27. Ross R, Glomsei JA. The pathophysiology of atherosclerosis. N EngJ J Med 1976:295:362-376.420-425. 28. Harker LA, Ross R, Glomset JA. The role of endothelial cell injury and platelet response in atherogenesis. Thromb Haemost 1978;39:312-321. 29. Clowes AW, Clowes MM. Kinetics of cellular proliferation after arterial injury. II. Inhibition of smooth muscle growth by heparin. Lab Invest 1985; 52:611-616.
30. Clowes AW, Clowes MM. Kinetics of cellular proliferation after arterial injury. IV. Heparin inhibits rat smooth muscle mitogenesis and migration. Circ Res 1986;58:839-845. 31. Guyton JR, Rosenberg RD. Clowes AW, Karnovsky MJ. Inhibition of rat arterial smooth muscle cell proliferation by heporin. In vivo studies with anticoagulant and nonanticoagulant heparin. Circ Res 1980;46:625-634.