655
Editorial Comment Prevention of Thrombosis and Rethrombosis New Approaches Marschall S. Runge, MD, PhD R ecent clinical experience with plasminogen activator therapy and percutaneous transluminal coronary angioplasty (PTCA) and a growing understanding of the pathophysiology of coronary artery thrombosis have led to the hypothesis that to successfully prevent coronary thrombotic complications, it is necessary to prevent platelet activation and aggregation. Though there are many potential mechanisms by which coronary thrombosis might be prevented, the data presented by Gruber et al' suggest an alternative approach, that is, the use of recombinant activated protein C (rAPC), an agent suitable for clinical use that effectively inhibits platelet-dependent thrombosis without impairing hemostasis. While it is not known how the activity of rAPC in primates will translate into the use of rAPC in man, this study justifies further evaluation. See p 578 Thrombosis is a clinically observable end point that results from an alteration in the delicate balance between procoagulant and anticoagulant activities in plasma, platelets, and vascular cells. Modern approaches to treating the consequences of coronary thrombosis have focused on either mechanical interventions (such as coronary artery bypass surgery, PTCA, or other related procedures), amplification of natural anticoagulant or fibrinolytic mechanisms, or a combination of these approaches. The frequency of rethrombosis after such an intervention remains a major limitation regardless of the route of treatment chosen, despite the improvements made by manipulating dosages of the clinically available antiplatelet agents (aspirin) and anticoagulant (heparin) therapy.2,3 In the treatment of cardiovascular disease, for example, the reported incidence of acute thrombosis after PTCA ranges from 2% to 10%,4,5 and the incidence of reocclusion after successful thrombolytic therapy for acute myocardial infarction is approxiThe opinions expressed in this editorial comment are not necessarily those of the editors or of the American Heart Association. From the Cardiology Division, Emory University School of Medicine, Atlanta, Ga. Supported in part by National Institutes of Health grants HL-41808 and HL-02414. Address for correspondence: Marschall S. Runge, MD, PhD, Cardiology Division, Emory University, P.O. Drawer LL, Atlanta, GA 30322.
mately 12-18%.6,7 Current evidence suggests that the pathophysiology of unstable angina involves platelet recruitment and thrombosis and that at least 10% of patients with unstable angina progress to myocardial infarction (complete thrombotic occlusion).8'9 Gruber et al report potent antithrombotic effects of rAPC for arterial thrombus formation in a primate model. APC is an active enzyme, a serine protease that inhibits thrombin formation by cleaving and degrading coagulation factors Va and Villa,10 the two important plasma cofactors involved in the generation of thrombin. There is a significant body of clinical data showing a marked correlation between the hereditary deficiency of protein C and thrombotic events," implicating APC in the physiological downregulation of thrombin and prevention of pathological thrombosis in normal individuals. In the Gruber et al study, intravenous rAPC was given to baboons in doses that greatly exceed the normal physiological range. The investigators then quantified the effect of intravenous rAPC on the accretion of platelets and fibrin onto a thrombogenic segment incorporated into an exteriorized chronic femoral arteriovenous shunt. Perhaps the most striking finding presented in this study is that at doses of rAPC that effectively prevent arterial thrombus formation, there was no measurable effect on the template bleeding time, implying that APC produces antithrombotic effects without impairing hemostatic plug formation. These observations suggest that the administration of APC in a clinical setting might be less likely to cause bleeding than the administration of other available platelet antagonists or thrombin inhibitors. To appreciate fully the potential importance of these observations, it would be helpful to consider some of the other approaches that are currently under study. Of the many strategies to prevent reocclusion, post-PTCA thrombosis, and unstable angina, the majority focus on blocking the activation and aggregation of platelets. There are at least five known physiological agonists of platelet aggregation (ADP, epinephrine, thromboxane A2, collagen, and thrombin). The local concentration of three of these (ADP, epinephrine, and thromboxane A2) is probably platelet derived in that they are released by platelets on activation. Collagen is present in the subendothelium and in the intercellular matrix, and thrombin may be formed on the surface of platelets, monocytes or
Downloaded from http://circ.ahajournals.org/ at BIBL DE L'UNIV LAVAL on July 1, 2015
656
Circulation Vol 82 No 2, August 1990
macrophages, and connective tissue. The use of the nonspecific platelet antagonist aspirin reduces the frequency of some platelet-mediated events35,9 but has less effect on others. Recent experimental approaches have focused on more specific ways to intervene. Some lines of evidence lead to the conclusion that the inhibition of thrombin is a particularly attractive way to prevent undesired thrombosis. Thrombin plays a central role in several important areas: 1) it converts fibrinogen into fibrin; 2) it facilitates crosslinking of fibrin by activation of factor XIII; 3) it is a potent stimulus for platelet activation (by a mechanism that is independent of ADP, thromboxane A2, and fibrin generation); and 4) this platelet activation results in marked positive feedback for activation of factors V and VIII. In fact, there is a putative receptor for thrombin on the platelet surface, and continuous occupancy of this "receptor" is required for phosphatate synthesis, a granule, and acid hydrolase secretion. Thrombin formation is markedly amplified (280,000-fold) by the formation of the prothrombinase complex (formed by the binding of factors Va and Xa and Ca2 to the phospholipid of the platelet membrane). The list of antithrombins that have been evaluated continues to grow. The agent with which the most clinical experience is available is heparin. Heparin is a coenzyme of circulating antithrombin III (AT III), which greatly accelerates the interaction of AT III with thrombin, resulting in thrombin inhibition. However, heparin only modestly reduces platelet deposition after angioplasty in a porcine model.12,13 Low molecular weight heparins (which have more anti-Xa activity on a molar basis) have an equal effect on arterial thrombosis. Hirudin is a potent antithrombin that binds directly to and inhibits thrombin and thrombin-catalyzed activation of factors V, VIII, and XIII and prevents fibrinogen clotting. Hirudin has been shown to be more effective than heparin or heparin plus aspirin in the reduction of platelet-thrombus deposition in an experimental angioplasty model.13 Other antithrombins that have been evaluated include many synthetic antithrombins evaluated in animal models, such as the tripeptide D-phenylalanine-proline-arginine-chloromethyl ketone,14 MD805 (or argipidine),1516 derivatives of the serine protease inhibitor benzamidine,17 and others. All inhibit thrombin by antithrombin III-independent mechanisms and prevent platelet aggregation and thrombus formation in animal models. Although there is some variation among these different agents, the administration of effective antithrombotic doses of each results in impairment of normal hemostasis and prolongation of bleeding times. It is important to compare the mechanism of action of these thrombin inhibitors with that of APC. The direct thrombin inhibitors listed here inhibit any generated thrombin and thereby prevent its action in platelet activation and fibrin generation. APC also mediates its effect by decreasing the amount of active thrombin locally. However,
instead of a direct inhibition, APC down-regulates the normal amplification of thrombin by factors Vllla and Va. One might predict that this would allow for the generation of small amounts of thrombin, which would be adequate to facilitate the formation of hemostatic plugs but would prevent intravascular thrombosis. The data of Gruber et al' support this hypothesis. Specific inhibitors of the cell surface receptor for thromboxane A2 have also been tested in animal models designed to represent unstable angina.18'19 It is unknown whether the observations from the canine model can be generalized to platelet-dependent processes such as unstable angina in humans. They do show, however, that thromboxane A2 receptor antagonists in combination with serotonin receptor antagonists prevent the epinephrine-induced cyclical occlusions that occur in a canine model of coronary artery stenosis.'8 In addition, this combined thromboxane A2 and serotonin receptor blockade enhances thrombolysis and markedly reduces the tendency toward reocclusion after tissue-type plasminogen activator administration in a canine model of coronary thrombosis.'9 Finally, it has been suggested that it might be possible to block the "final common pathway" for platelet aggregation by inhibiting the interaction of fibrinogen with its specific receptor found on the platelet glycoprotein lIb/IIIa complex. Many molecules have been evaluated that block this interaction by binding to glycoprotein IIb/IIIa at or near its fibrinogen receptor site. In theory, the effects on platelet aggregation of ADP, epinephrine, thrombin, thromboxane A2, and collagen are all mediated through glycoprotein lIb/Illa. There are three categories of molecules that have been evaluated: 1) several monoclonal antibodies that specifically bind to and inhibit glycoprotein lIb/Illa have been developed20"21; 2) there are also many small synthetic peptides that contain one or more arginine-glycineaspartic acid (RGD) peptide sequences (it is thought that two domains on the fibrinogen a-chain that interact with glycoprotein lIb/IIIa contain this RGD sequence22); and 3) "natural" RGD-containing proteins (trigramin,'3 echistatin,'4 bitistatin,'5 applagin,'6 and kistrin'7) have been isolated from the venom of several vipers. Representatives from each of these three groups have been shown to be effective in preventing platelet aggregation, thrombus formation, and cyclical occlusions in canine models such as those described above. The theoretically significant limitation of this approach is the duration of platelet inhibition, and the possibility that thrombus formation will be inhibited to such an extent that bleeding complications will result. As with potent antithrombins, Hanson et al'4 have shown significant prolongation of the template bleeding time associated with doses sufficient to prevent thrombus formation. Intracoronary thrombosis after thrombolytic therapy or occurring acutely after PTCA are undoubtedly very complex processes. Although there are morpho-
Downloaded from http://circ.ahajournals.org/ at BIBL DE L'UNIV LAVAL on July 1, 2015
Runge Prevention of Thrombosis and Rethrombosis
logical similarities between these processes and unstable angina, none are fully understood, and it is not known how closely they are related mechanistically. There are probably many stimuli for the formation and propagation of intravascular thrombi, some of which may reside in the abnormal substrate responsible for the stenotic or occlusive lesion that initially brought the patient to medical attention. There has been an intensive effort to develop pharmacological ways to intervene in these processes, and the data of Gruber et al,1 using rAPC, represents the most recent approach described in animal models. The use of rAPC is distinctive when compared with other approaches that have been summarized here because at therapeutically effective doses, there is no measurable effect on the ability to form normal hemostatic plugs, suggesting that the use of rAPC may avoid the bleeding complications likely to occur with other potent agents that inhibit thrombus formation. References 1. Gruber A, Hanson SR, Kelly AB, Yan BS, Bang N, Griffin JH, Harker L: Inhibition of thrombus formation by activated recombinant protein C in a primate model of arterial thrombosis. Circulation 1990;82:578-585 2. Randomized controlled trial of subcutaneous calcium-heparin in acute myocardial infarction: The SCATI Group. Lancet
1989;2:182-186 3. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group: Randomized trial of intravenous streptokinase, oral aspirin, both or neither among 17,187 cases of suspected myocardial infarction: ISIS-2. Lancet 1988; 2:349-360 4. Holmes DR, Vlietstra RE, Smith HC, Vetrovec GW, Kent KM, Cowley MJ, et al: Restenosis after percutaneous transluminal angioplasty (PTCA): A report from the PTCA registry of the National Heart, Lung, and Blood Institute. Am J Cardiol 1984;53:77C-81C 5. Barnathan ES, Schwartz JS, Taylor L, Laskey WK, Kleaveland JP, et al: Aspirin and dipyridamole in the prevention of acute coronary thrombosis complicating coronary angioplasty. Circulation 1987;76:125-134 6. Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen LS, et al: Thrombolysis in Myocardial Infarction (TIMI) Trial: Phase 1. A comparison between intravenous tissue plasminogen activator and intravenous streptokinase: Clinical findings through hospital discharge. Circulation 1987;76:142-154 7. Topol EJ, Morris DC, Smalling RW, Schumacher RR, Taylor CR, et al: A multicenter, randomized, placebo-controlled trial of a new form of intravenous recombinant tissue-type plasminogen activator (activase) in acute myocardial infarction. JAm Coll Cardiol 1987;9:1205-1213 8. Freeman MR, Williams AE, Chisholm RJ, Armstrong PW: Intracoronary thrombus and complex morphology in unstable angina: Relation to timing of angiography and in-hospital cardiac events. Circulation 1989;80:17-23 9. Becker RC, Gore JM, Alpert JS: Postinfarction unstable angina: Pathophysiologic basis for current treatment modalities. Cardiology 1989;76:144-157 10. Marlar RA, Kleiss AJ, Griffin JH: Mechanism of action of human activated protein C, a thrombin-dependent anticoagulant enzyme. Blood 1982;59:1067-1072 11. Bovill EG, Bauer KA, Dickerman JD, Callas P, West B: The clinical spectrum of heterozygous protein C deficiency in a large New England kindred. Blood 1989;73:712-717
657
12. Heras M, Chesebro JH, Penny WJ, Bailey KR, Lam JYT, Holmes DR, Reeder GS, Badimon L, Fuster V: Importance of adequate heparin dosage in arterial angioplasty in a porcine model. Circulation 1988;78:654-660 13. 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. Circulation 1989;79:657-665 14. Hanson S, Harker L: Interception of acute platelet-dependent thrombosis by the synthetic antithrombin D-phenylalanylL-prolyl-L-arginyl chloromethyl ketone. Proc Natl Acad Sci USA 1988;85:3184-3188 15. 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 16. Jang I, Gold HK, Leinbach RC, McNary JE, Fallon JT, Collen D: Acceleration of reperfusion by combination of rt-PA and a selective thrombin inhibitor, argatroban. Circulation 1989; 80(suppl II):II-217 17. Sturzebecher J, Sturzebecher U, Vieweg H, Wagner G, Hauptmann J, Markwardt F: Synthetic inhibitors of bovine factor Xa and thrombin comparison of their anticoagulant efficiency. Thromb Res 1989;54:245-252 18. Ashton JH, Golino P, McNatt JM, Buja LM, Willerson JT: Serotonin S2 and thromboxane A2-prostaglandin H2 receptor blockade provide protection against epinephrine-induced cyclic flow variations in severely narrowed canine coronary arteries. JAm Coll Cardiol 1989;13:755-763 19. Golino P, Ashton JH, McNatt J, Glas-Greenwalt P, ShengKun Y, O'Brien RA, Buja LM, Willerson JT: Simultaneous administration of thromboxane A2- and serotonin S2-receptor antagonists markedly enhances thrombolysis and prevents or delays reocclusion after tissue-type plasminogen activator in a canine model of coronary thrombosis. Circulation 1989; 79:911-919 20. Gold HK, Coller BS, Yasuda T, Saito T, Fallon JT, Guerrero JL, Leinbach RC, Ziskind AA, Collen D: Rapid and sustained coronary artery recanalization with combined bolus injection of recombinant tissue-type plasminogen activator and monoclonal antiplatelet GPIIb/IIIa antibody in a canine preparation. Circulation 1988;77:670-677 21. Hanson SR, Pareti FI, Ruggeri ZM, Marzec UM, Kunicki TJ, Montgomery RR, Zimmerman RS, Harker LA: Effects of monoclonal antibodies against the platelet glycoprotein Ilb/ IIIa complex on thrombosis and hemostasis in the baboon. J Clin Invest 1988;81:149-158 22. Shebuski RJ, Berry DE, Bennett DB, Romoff T, Storer BL, Ali F, Samanen J: Demonstration of ac-arg-gly-asp-ser-NH2 as an antiaggregatory agent in the dog by intracoronary administration. Thromb Haemost 1989;61:183-188 23. Huang TF, Holt JC, Kirby EP, Niewiarowski S: Trigramin: Primary structure and its inhibition of von Willebrand factor binding to glycoprotein 1Ib/IIIa complex on human platelets.
Biochemistry 1989;28:661-666 24. Gan Z-R, Gould RJ, Jacobs JW, Friedman PA, Polokoff MA: Echistatin: A potent platelet aggregation inhibitor from the venom of the viper, Echis carinatus. J Biol Chem 1988; 263:19827-19832 25. Shebuski RJ, Ramjit DR, Bencen GH, Polokoff MA: Characterization and platelet inhibitory activity of bitistatin, a potent arginine-glycine-aspartic acid-containing peptide from the venom of the viper Bitis arietans. J Biol Chem 1989; 264:21550-21556 26. Chao BH, Jakubowski JA, Savage B, Chow EP, et al: Agkistrodon piscivorus piscivorus platelet aggregation inhibitor: A potent inhibitor of platelet activation. Proc NatlAcad Sci USA
1989;86:8050-8054 27. Dennis MS, Henzel WJ, Pitti RM, Lipari MT, Napier MA, Peisher TA, Bunting S: Platelet glycoprotein Ilb/IIa protein antagonists from snake venoms: Evidence for a family of platelet aggregation inhibitors. Blood 1989;74:129a
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Prevention of thrombosis and rethrombosis. New approaches. M S Runge Circulation. 1990;82:655-657 doi: 10.1161/01.CIR.82.2.655 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1990 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
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Editorial Comment Prevention of Thrombosis and Rethrombosis New Approaches Marschall S. Runge, MD, PhD R ecent clinical experience with plasminogen activator therapy and percutaneous transluminal coronary angioplasty (PTCA) and a growing understanding of the pathophysiology of coronary artery thrombosis have led to the hypothesis that to successfully prevent coronary thrombotic complications, it is necessary to prevent platelet activation and aggregation. Though there are many potential mechanisms by which coronary thrombosis might be prevented, the data presented by Gruber et al' suggest an alternative approach, that is, the use of recombinant activated protein C (rAPC), an agent suitable for clinical use that effectively inhibits platelet-dependent thrombosis without impairing hemostasis. While it is not known how the activity of rAPC in primates will translate into the use of rAPC in man, this study justifies further evaluation. See p 578 Thrombosis is a clinically observable end point that results from an alteration in the delicate balance between procoagulant and anticoagulant activities in plasma, platelets, and vascular cells. Modern approaches to treating the consequences of coronary thrombosis have focused on either mechanical interventions (such as coronary artery bypass surgery, PTCA, or other related procedures), amplification of natural anticoagulant or fibrinolytic mechanisms, or a combination of these approaches. The frequency of rethrombosis after such an intervention remains a major limitation regardless of the route of treatment chosen, despite the improvements made by manipulating dosages of the clinically available antiplatelet agents (aspirin) and anticoagulant (heparin) therapy.2,3 In the treatment of cardiovascular disease, for example, the reported incidence of acute thrombosis after PTCA ranges from 2% to 10%,4,5 and the incidence of reocclusion after successful thrombolytic therapy for acute myocardial infarction is approxiThe opinions expressed in this editorial comment are not necessarily those of the editors or of the American Heart Association. From the Cardiology Division, Emory University School of Medicine, Atlanta, Ga. Supported in part by National Institutes of Health grants HL-41808 and HL-02414. Address for correspondence: Marschall S. Runge, MD, PhD, Cardiology Division, Emory University, P.O. Drawer LL, Atlanta, GA 30322.
mately 12-18%.6,7 Current evidence suggests that the pathophysiology of unstable angina involves platelet recruitment and thrombosis and that at least 10% of patients with unstable angina progress to myocardial infarction (complete thrombotic occlusion).8'9 Gruber et al report potent antithrombotic effects of rAPC for arterial thrombus formation in a primate model. APC is an active enzyme, a serine protease that inhibits thrombin formation by cleaving and degrading coagulation factors Va and Villa,10 the two important plasma cofactors involved in the generation of thrombin. There is a significant body of clinical data showing a marked correlation between the hereditary deficiency of protein C and thrombotic events," implicating APC in the physiological downregulation of thrombin and prevention of pathological thrombosis in normal individuals. In the Gruber et al study, intravenous rAPC was given to baboons in doses that greatly exceed the normal physiological range. The investigators then quantified the effect of intravenous rAPC on the accretion of platelets and fibrin onto a thrombogenic segment incorporated into an exteriorized chronic femoral arteriovenous shunt. Perhaps the most striking finding presented in this study is that at doses of rAPC that effectively prevent arterial thrombus formation, there was no measurable effect on the template bleeding time, implying that APC produces antithrombotic effects without impairing hemostatic plug formation. These observations suggest that the administration of APC in a clinical setting might be less likely to cause bleeding than the administration of other available platelet antagonists or thrombin inhibitors. To appreciate fully the potential importance of these observations, it would be helpful to consider some of the other approaches that are currently under study. Of the many strategies to prevent reocclusion, post-PTCA thrombosis, and unstable angina, the majority focus on blocking the activation and aggregation of platelets. There are at least five known physiological agonists of platelet aggregation (ADP, epinephrine, thromboxane A2, collagen, and thrombin). The local concentration of three of these (ADP, epinephrine, and thromboxane A2) is probably platelet derived in that they are released by platelets on activation. Collagen is present in the subendothelium and in the intercellular matrix, and thrombin may be formed on the surface of platelets, monocytes or
Downloaded from http://circ.ahajournals.org/ at BIBL DE L'UNIV LAVAL on July 1, 2015
656
Circulation Vol 82 No 2, August 1990
macrophages, and connective tissue. The use of the nonspecific platelet antagonist aspirin reduces the frequency of some platelet-mediated events35,9 but has less effect on others. Recent experimental approaches have focused on more specific ways to intervene. Some lines of evidence lead to the conclusion that the inhibition of thrombin is a particularly attractive way to prevent undesired thrombosis. Thrombin plays a central role in several important areas: 1) it converts fibrinogen into fibrin; 2) it facilitates crosslinking of fibrin by activation of factor XIII; 3) it is a potent stimulus for platelet activation (by a mechanism that is independent of ADP, thromboxane A2, and fibrin generation); and 4) this platelet activation results in marked positive feedback for activation of factors V and VIII. In fact, there is a putative receptor for thrombin on the platelet surface, and continuous occupancy of this "receptor" is required for phosphatate synthesis, a granule, and acid hydrolase secretion. Thrombin formation is markedly amplified (280,000-fold) by the formation of the prothrombinase complex (formed by the binding of factors Va and Xa and Ca2 to the phospholipid of the platelet membrane). The list of antithrombins that have been evaluated continues to grow. The agent with which the most clinical experience is available is heparin. Heparin is a coenzyme of circulating antithrombin III (AT III), which greatly accelerates the interaction of AT III with thrombin, resulting in thrombin inhibition. However, heparin only modestly reduces platelet deposition after angioplasty in a porcine model.12,13 Low molecular weight heparins (which have more anti-Xa activity on a molar basis) have an equal effect on arterial thrombosis. Hirudin is a potent antithrombin that binds directly to and inhibits thrombin and thrombin-catalyzed activation of factors V, VIII, and XIII and prevents fibrinogen clotting. Hirudin has been shown to be more effective than heparin or heparin plus aspirin in the reduction of platelet-thrombus deposition in an experimental angioplasty model.13 Other antithrombins that have been evaluated include many synthetic antithrombins evaluated in animal models, such as the tripeptide D-phenylalanine-proline-arginine-chloromethyl ketone,14 MD805 (or argipidine),1516 derivatives of the serine protease inhibitor benzamidine,17 and others. All inhibit thrombin by antithrombin III-independent mechanisms and prevent platelet aggregation and thrombus formation in animal models. Although there is some variation among these different agents, the administration of effective antithrombotic doses of each results in impairment of normal hemostasis and prolongation of bleeding times. It is important to compare the mechanism of action of these thrombin inhibitors with that of APC. The direct thrombin inhibitors listed here inhibit any generated thrombin and thereby prevent its action in platelet activation and fibrin generation. APC also mediates its effect by decreasing the amount of active thrombin locally. However,
instead of a direct inhibition, APC down-regulates the normal amplification of thrombin by factors Vllla and Va. One might predict that this would allow for the generation of small amounts of thrombin, which would be adequate to facilitate the formation of hemostatic plugs but would prevent intravascular thrombosis. The data of Gruber et al' support this hypothesis. Specific inhibitors of the cell surface receptor for thromboxane A2 have also been tested in animal models designed to represent unstable angina.18'19 It is unknown whether the observations from the canine model can be generalized to platelet-dependent processes such as unstable angina in humans. They do show, however, that thromboxane A2 receptor antagonists in combination with serotonin receptor antagonists prevent the epinephrine-induced cyclical occlusions that occur in a canine model of coronary artery stenosis.'8 In addition, this combined thromboxane A2 and serotonin receptor blockade enhances thrombolysis and markedly reduces the tendency toward reocclusion after tissue-type plasminogen activator administration in a canine model of coronary thrombosis.'9 Finally, it has been suggested that it might be possible to block the "final common pathway" for platelet aggregation by inhibiting the interaction of fibrinogen with its specific receptor found on the platelet glycoprotein lIb/IIIa complex. Many molecules have been evaluated that block this interaction by binding to glycoprotein IIb/IIIa at or near its fibrinogen receptor site. In theory, the effects on platelet aggregation of ADP, epinephrine, thrombin, thromboxane A2, and collagen are all mediated through glycoprotein lIb/Illa. There are three categories of molecules that have been evaluated: 1) several monoclonal antibodies that specifically bind to and inhibit glycoprotein lIb/Illa have been developed20"21; 2) there are also many small synthetic peptides that contain one or more arginine-glycineaspartic acid (RGD) peptide sequences (it is thought that two domains on the fibrinogen a-chain that interact with glycoprotein lIb/IIIa contain this RGD sequence22); and 3) "natural" RGD-containing proteins (trigramin,'3 echistatin,'4 bitistatin,'5 applagin,'6 and kistrin'7) have been isolated from the venom of several vipers. Representatives from each of these three groups have been shown to be effective in preventing platelet aggregation, thrombus formation, and cyclical occlusions in canine models such as those described above. The theoretically significant limitation of this approach is the duration of platelet inhibition, and the possibility that thrombus formation will be inhibited to such an extent that bleeding complications will result. As with potent antithrombins, Hanson et al'4 have shown significant prolongation of the template bleeding time associated with doses sufficient to prevent thrombus formation. Intracoronary thrombosis after thrombolytic therapy or occurring acutely after PTCA are undoubtedly very complex processes. Although there are morpho-
Downloaded from http://circ.ahajournals.org/ at BIBL DE L'UNIV LAVAL on July 1, 2015
Runge Prevention of Thrombosis and Rethrombosis
logical similarities between these processes and unstable angina, none are fully understood, and it is not known how closely they are related mechanistically. There are probably many stimuli for the formation and propagation of intravascular thrombi, some of which may reside in the abnormal substrate responsible for the stenotic or occlusive lesion that initially brought the patient to medical attention. There has been an intensive effort to develop pharmacological ways to intervene in these processes, and the data of Gruber et al,1 using rAPC, represents the most recent approach described in animal models. The use of rAPC is distinctive when compared with other approaches that have been summarized here because at therapeutically effective doses, there is no measurable effect on the ability to form normal hemostatic plugs, suggesting that the use of rAPC may avoid the bleeding complications likely to occur with other potent agents that inhibit thrombus formation. References 1. Gruber A, Hanson SR, Kelly AB, Yan BS, Bang N, Griffin JH, Harker L: Inhibition of thrombus formation by activated recombinant protein C in a primate model of arterial thrombosis. Circulation 1990;82:578-585 2. Randomized controlled trial of subcutaneous calcium-heparin in acute myocardial infarction: The SCATI Group. Lancet
1989;2:182-186 3. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group: Randomized trial of intravenous streptokinase, oral aspirin, both or neither among 17,187 cases of suspected myocardial infarction: ISIS-2. Lancet 1988; 2:349-360 4. Holmes DR, Vlietstra RE, Smith HC, Vetrovec GW, Kent KM, Cowley MJ, et al: Restenosis after percutaneous transluminal angioplasty (PTCA): A report from the PTCA registry of the National Heart, Lung, and Blood Institute. Am J Cardiol 1984;53:77C-81C 5. Barnathan ES, Schwartz JS, Taylor L, Laskey WK, Kleaveland JP, et al: Aspirin and dipyridamole in the prevention of acute coronary thrombosis complicating coronary angioplasty. Circulation 1987;76:125-134 6. Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen LS, et al: Thrombolysis in Myocardial Infarction (TIMI) Trial: Phase 1. A comparison between intravenous tissue plasminogen activator and intravenous streptokinase: Clinical findings through hospital discharge. Circulation 1987;76:142-154 7. Topol EJ, Morris DC, Smalling RW, Schumacher RR, Taylor CR, et al: A multicenter, randomized, placebo-controlled trial of a new form of intravenous recombinant tissue-type plasminogen activator (activase) in acute myocardial infarction. JAm Coll Cardiol 1987;9:1205-1213 8. Freeman MR, Williams AE, Chisholm RJ, Armstrong PW: Intracoronary thrombus and complex morphology in unstable angina: Relation to timing of angiography and in-hospital cardiac events. Circulation 1989;80:17-23 9. Becker RC, Gore JM, Alpert JS: Postinfarction unstable angina: Pathophysiologic basis for current treatment modalities. Cardiology 1989;76:144-157 10. Marlar RA, Kleiss AJ, Griffin JH: Mechanism of action of human activated protein C, a thrombin-dependent anticoagulant enzyme. Blood 1982;59:1067-1072 11. Bovill EG, Bauer KA, Dickerman JD, Callas P, West B: The clinical spectrum of heterozygous protein C deficiency in a large New England kindred. Blood 1989;73:712-717
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Prevention of thrombosis and rethrombosis. New approaches. M S Runge Circulation. 1990;82:655-657 doi: 10.1161/01.CIR.82.2.655 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1990 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
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