- Email: [email protected]
Expanded Use of Thrombolytic Therapy
Editorial Expanded Use of Thrombolytic Therapy
tients, consistent with the action of thrombin or another similar enzyme. Other authors have found depressed endogenous fibrinolysis in patients with this disease.' Some small series. have demonstrated the effective use of antiplatelet Thrombolytic Therapy for Myocardial lnfarction.-AI- therapies such as aspirin, dipyridamole, and ticlopidine hythough our understanding of the pathogenesis of acute myo- drochloride." Finally, ethylestrenol and phenformin hydrocardial infarction is incomplete, acute occlusive coronary chloride, two drugs that are known to enhance fibrinolysis, thrombi are thought to be responsible in most cases. Re- had previously produced good results in patients with markably, only slightly more than a decade ago DeWood and atrophie blanche.' associates I reported on the high frequency of coronary Effects on Microcirculation.-Although thrombolytic thrombi in transmural myocardial infarction, at a time when agents have frequently been used as therapy for limb spasm was considered to have an important role.' In fact, ischemia through recanalization of peripheral arteries and thrombolytic therapy for acute myocardial infarction was arterioles," their success in the treatment of atrophie blanche initiated in the late 1960s, but the results of the early studies apparently is related to an effect on the microcirculation. were inconclusive and difficult to interpret, in part because Perhaps a parallel exists in cardiac disease, in which the of the time delays in administration and because of the benefits from thrombolytic agents may include not only the variation in the doses that were used. Since the study by opening of epicardial arteries and the preservation of left Rentrop and colleagues- in 1979, when intracoronary admin- ventricular function but also an enhancement of the coronary istration of streptokinase was used in patients with acute microcirculation. For example, in the western Washington myocardial infarction, thrombolytic agents have become trial of intracoronary administration of streptokinase," the standard treatment for acute infarction. In addition, mortality rate was considerably lower among patients in thrombolytic therapy has been applied to other cardiovascu- whom complete reperfusion of epicardial arteries was establar diseases with thrombotic mechanisms, such as pulmonary lished through use of the thrombolytic agent. Of interest, embolism and peripheral thrombosis. this effect was noted even after adjustments were made for Thrombolytic Therapy for Dermatologic Disorders.- minor differences in left ventricular ejection fraction, which The study by Klein and Pittelkow reported in this issue of the is usually considered one of the best predictors of mortality. Mayo Clinic Proceedings (pages 923 to 933) expands the One hypothesis is that decreased mortality may be related to use of thrombolytic agents into the realm of dermatologic a reduction in abnormal electrical activity (late potentials) in disease. The authors suggest that low-dose thrombolytic patients with open arteries,'? which, in turn, may result from therapy can be tested in various dermatologic disorders in a more intact microcirculation. which thrombus may have an important role, such as livedo Previous investigators have shown an abundance of platevasculitis (also called atrophie blanche), Interestingly, a let microthrombi in the hearts of patients who have died striking similarity has been noted between the cardiologic suddenly from coronary artery disease." Furthermore, an and the dermatologic literature on the evolution of anti- intriguing report described several patients who had comthrombotic and fibrinolytic therapy-beginning, of course, pletely asymptomatic skin mottling, in association with no with the debate over which underlying mechanisms are most other abnormalities on physical examination, electrocardiimportant. Although many investigators consider livedo ography, or laboratory testing, and who died soon thereafter vasculitis an immune-mediated inflammatory disease, accu- while asleep. 12 Although the cause of these deaths was mulating evidence suggests that extensive thrombosis is a unexplained, an association may exist between livedo primary factor. Recently, McCalmont and co-workers' re- reticularis and some cases of sudden death, linked by the ported their findings of normal levels of complement and the common mechanism of thrombotic microvascular occlusion. absence of circulating immune complexes in patients with Conceivably, thrombolytic agents may be exerting some "livedo vasculopathy," and they also noted substantially in- positive effects at this level. creased levels of fibrinopeptide A in each of their six paPotential Complications.-As suggested by Klein and Pittelkow, expansion of the use of thrombolytic agents can be expected as more is learned about the pathogenesis of Address reprint requests to Dr. Valentin Fuster, Cardiac Unit, vascular diseases." For widespread use of such potent Bu1finch One, Massachusetts General Hospital, 32 Fruit Street, drugs, however, a prudent approach is necessary because severe bleeding complications can occur, especially when a Boston, MA 02114. Mayo Clin Proc 67:1004-1005.1992
1004
Mayo Clin Proc, October 1992, Vol 67
thrombolytic agent is used in conjunction with aspirin, heparin, or warfarin. Regardless of the manifestation of disease (whether the heart, brain, lung, or skin is affected), therapy should be directed toward the biologic process. A thorough understanding of the cause of a particular disease will refine treatment further and decrease the incidence of complications. For example, although fibrin and erythrocytes may be more important than platelets in atrophie blanche, the relative importance of platelets is unclear. Thus, a combination of tissue plasminogen activator and heparin (and subsequent long-term use of warfarin) without aspirin may be both effective and safe because it decreases the possibility of bleeding complications by avoiding an interaction between heparin and aspirin." Conclusion.-Overall, a better understanding of the pathogenetic mechanisms of occlusive and thrombotic disorders will help to optimize further therapy and minimize complications. Thrombolytic agents are an important therapeutic option for such conditions. Jay Curwin, M.D. Ik-Kyung Jang, M.D., Ph.D. Valentin Fuster, M.D., Ph.D. Cardiac Unit Massachusetts General Hospital Boston, Massachusetts
REFERENCES 1.
2.
DeWood MA, Spores J, Notske R, Mouser LT, Burroughs R, Golden MS, Lang HT: Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 303:897-902,1980 Maseri A, L' Abbate A, Baroldi G, Chierchia S, Marzilli M, Ballestra AM, Severi S, Parodi 0, Biagini A, Distante A, Pesola A: Coronary vasospasm as a possible cause of myocardial infarction: a conclusion derived from the study of "preinfarction" angina. N Engl J Med 299:1271-1277, 1978
EDITORIAL
3.
4. 5. 6. 7. 8.
9.
10.
11. 12. 13.
14.
1005
Rentrop KP, Blanke H, Karsch KR, Kreuzer H: Initial experience with transluminal recanalization of the recently occluded infarct-related coronary artery in acute myocardial infarction-i-comparison with conventionally treated patients. Clin Cardiol 2:92-105,1979 McCalmont CS, McCalmont TH, Jorizzo JL, White WL, Leshin B, Rothberger H: Livedo vasculitis: vasculitis or thrombotic vascu1opathy? Clin Exp Dermatol 17:4-8, 1992 Pizzo SV, Murray JC, Gonias SL: Atrophie blanche: a disorder associated with defective release of tissue plasminogen activator. Arch Pathol Lab Med 110:517-519, 1986 Yamamoto M, Danno K, Shio H, Imamura S: Antithrombotic treatment in livedo vasculitis. JAm Acad Dermatol 18:5762, 1988 Gilliam IN, Herndon JH, Prystowsky SD: Fibrinolytic therapy for vasculitis of atrophie blanche. Arch Dermatol 109:664-667,1974 Verhaeghe R, Bounameaux H: Peripheral arterial occlusion: thromboembolism and anti thrombotic therapy. In Thrombosis in Cardiovascular Disorders. Edited by V Fuster, M Verstraete. Philadelphia, WB Saunders Company, 1992, pp 423-449 Kennedy JW, Ritchie JL, Davis KB, Stadius ML, Maynard C, Fritz IK: The western Washington randomized trial of intracoronary streptokinase in acute myocardial infarction: a 12month follow-up report. NEnglJMed 312:1073-1078,1985 Eldar M, Leor J, Hod H, Rotstein Z, Truman S, Kap1inskyE, Abboud S: Effect of thrombolysis on the evolution of late potentials within 10 days of infarction. Br Heart I 63:273276, 1990 Haerem JW: Mural platelet microthrombi and major acute lesions of main epicardial arteries in sudden coronary death. Atherosclerosis 19:529-541, 1974 Brandt JL: Intermittent skin mottling in elderly patients (letter to the editor). JAm Geriatr Soc 35:478,1987 Fritzler MJ, Hart DA: Prolonged improvement of Raynaud's phenomenon and scleroderma after recombinant tissue plasminogen activator therapy. Arthritis Rheum 33:274-276, 1990 Garabedian HD, Gold HK, Leinbach RC, Svizzero TA, Finkelstein DM, Guerrero JL, Collen D: Bleeding time prolongation and bleeding during infusion of recombinant tissuetype plasminogen activator in dogs: potentiation by aspirin and reversal with aprotinin. J Am Coll Cardiol 17:12131222, 1991
tients, consistent with the action of thrombin or another similar enzyme. Other authors have found depressed endogenous fibrinolysis in patients with this disease.' Some small series. have demonstrated the effective use of antiplatelet Thrombolytic Therapy for Myocardial lnfarction.-AI- therapies such as aspirin, dipyridamole, and ticlopidine hythough our understanding of the pathogenesis of acute myo- drochloride." Finally, ethylestrenol and phenformin hydrocardial infarction is incomplete, acute occlusive coronary chloride, two drugs that are known to enhance fibrinolysis, thrombi are thought to be responsible in most cases. Re- had previously produced good results in patients with markably, only slightly more than a decade ago DeWood and atrophie blanche.' associates I reported on the high frequency of coronary Effects on Microcirculation.-Although thrombolytic thrombi in transmural myocardial infarction, at a time when agents have frequently been used as therapy for limb spasm was considered to have an important role.' In fact, ischemia through recanalization of peripheral arteries and thrombolytic therapy for acute myocardial infarction was arterioles," their success in the treatment of atrophie blanche initiated in the late 1960s, but the results of the early studies apparently is related to an effect on the microcirculation. were inconclusive and difficult to interpret, in part because Perhaps a parallel exists in cardiac disease, in which the of the time delays in administration and because of the benefits from thrombolytic agents may include not only the variation in the doses that were used. Since the study by opening of epicardial arteries and the preservation of left Rentrop and colleagues- in 1979, when intracoronary admin- ventricular function but also an enhancement of the coronary istration of streptokinase was used in patients with acute microcirculation. For example, in the western Washington myocardial infarction, thrombolytic agents have become trial of intracoronary administration of streptokinase," the standard treatment for acute infarction. In addition, mortality rate was considerably lower among patients in thrombolytic therapy has been applied to other cardiovascu- whom complete reperfusion of epicardial arteries was establar diseases with thrombotic mechanisms, such as pulmonary lished through use of the thrombolytic agent. Of interest, embolism and peripheral thrombosis. this effect was noted even after adjustments were made for Thrombolytic Therapy for Dermatologic Disorders.- minor differences in left ventricular ejection fraction, which The study by Klein and Pittelkow reported in this issue of the is usually considered one of the best predictors of mortality. Mayo Clinic Proceedings (pages 923 to 933) expands the One hypothesis is that decreased mortality may be related to use of thrombolytic agents into the realm of dermatologic a reduction in abnormal electrical activity (late potentials) in disease. The authors suggest that low-dose thrombolytic patients with open arteries,'? which, in turn, may result from therapy can be tested in various dermatologic disorders in a more intact microcirculation. which thrombus may have an important role, such as livedo Previous investigators have shown an abundance of platevasculitis (also called atrophie blanche), Interestingly, a let microthrombi in the hearts of patients who have died striking similarity has been noted between the cardiologic suddenly from coronary artery disease." Furthermore, an and the dermatologic literature on the evolution of anti- intriguing report described several patients who had comthrombotic and fibrinolytic therapy-beginning, of course, pletely asymptomatic skin mottling, in association with no with the debate over which underlying mechanisms are most other abnormalities on physical examination, electrocardiimportant. Although many investigators consider livedo ography, or laboratory testing, and who died soon thereafter vasculitis an immune-mediated inflammatory disease, accu- while asleep. 12 Although the cause of these deaths was mulating evidence suggests that extensive thrombosis is a unexplained, an association may exist between livedo primary factor. Recently, McCalmont and co-workers' re- reticularis and some cases of sudden death, linked by the ported their findings of normal levels of complement and the common mechanism of thrombotic microvascular occlusion. absence of circulating immune complexes in patients with Conceivably, thrombolytic agents may be exerting some "livedo vasculopathy," and they also noted substantially in- positive effects at this level. creased levels of fibrinopeptide A in each of their six paPotential Complications.-As suggested by Klein and Pittelkow, expansion of the use of thrombolytic agents can be expected as more is learned about the pathogenesis of Address reprint requests to Dr. Valentin Fuster, Cardiac Unit, vascular diseases." For widespread use of such potent Bu1finch One, Massachusetts General Hospital, 32 Fruit Street, drugs, however, a prudent approach is necessary because severe bleeding complications can occur, especially when a Boston, MA 02114. Mayo Clin Proc 67:1004-1005.1992
1004
Mayo Clin Proc, October 1992, Vol 67
thrombolytic agent is used in conjunction with aspirin, heparin, or warfarin. Regardless of the manifestation of disease (whether the heart, brain, lung, or skin is affected), therapy should be directed toward the biologic process. A thorough understanding of the cause of a particular disease will refine treatment further and decrease the incidence of complications. For example, although fibrin and erythrocytes may be more important than platelets in atrophie blanche, the relative importance of platelets is unclear. Thus, a combination of tissue plasminogen activator and heparin (and subsequent long-term use of warfarin) without aspirin may be both effective and safe because it decreases the possibility of bleeding complications by avoiding an interaction between heparin and aspirin." Conclusion.-Overall, a better understanding of the pathogenetic mechanisms of occlusive and thrombotic disorders will help to optimize further therapy and minimize complications. Thrombolytic agents are an important therapeutic option for such conditions. Jay Curwin, M.D. Ik-Kyung Jang, M.D., Ph.D. Valentin Fuster, M.D., Ph.D. Cardiac Unit Massachusetts General Hospital Boston, Massachusetts
REFERENCES 1.
2.
DeWood MA, Spores J, Notske R, Mouser LT, Burroughs R, Golden MS, Lang HT: Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 303:897-902,1980 Maseri A, L' Abbate A, Baroldi G, Chierchia S, Marzilli M, Ballestra AM, Severi S, Parodi 0, Biagini A, Distante A, Pesola A: Coronary vasospasm as a possible cause of myocardial infarction: a conclusion derived from the study of "preinfarction" angina. N Engl J Med 299:1271-1277, 1978
EDITORIAL
3.
4. 5. 6. 7. 8.
9.
10.
11. 12. 13.
14.
1005
Rentrop KP, Blanke H, Karsch KR, Kreuzer H: Initial experience with transluminal recanalization of the recently occluded infarct-related coronary artery in acute myocardial infarction-i-comparison with conventionally treated patients. Clin Cardiol 2:92-105,1979 McCalmont CS, McCalmont TH, Jorizzo JL, White WL, Leshin B, Rothberger H: Livedo vasculitis: vasculitis or thrombotic vascu1opathy? Clin Exp Dermatol 17:4-8, 1992 Pizzo SV, Murray JC, Gonias SL: Atrophie blanche: a disorder associated with defective release of tissue plasminogen activator. Arch Pathol Lab Med 110:517-519, 1986 Yamamoto M, Danno K, Shio H, Imamura S: Antithrombotic treatment in livedo vasculitis. JAm Acad Dermatol 18:5762, 1988 Gilliam IN, Herndon JH, Prystowsky SD: Fibrinolytic therapy for vasculitis of atrophie blanche. Arch Dermatol 109:664-667,1974 Verhaeghe R, Bounameaux H: Peripheral arterial occlusion: thromboembolism and anti thrombotic therapy. In Thrombosis in Cardiovascular Disorders. Edited by V Fuster, M Verstraete. Philadelphia, WB Saunders Company, 1992, pp 423-449 Kennedy JW, Ritchie JL, Davis KB, Stadius ML, Maynard C, Fritz IK: The western Washington randomized trial of intracoronary streptokinase in acute myocardial infarction: a 12month follow-up report. NEnglJMed 312:1073-1078,1985 Eldar M, Leor J, Hod H, Rotstein Z, Truman S, Kap1inskyE, Abboud S: Effect of thrombolysis on the evolution of late potentials within 10 days of infarction. Br Heart I 63:273276, 1990 Haerem JW: Mural platelet microthrombi and major acute lesions of main epicardial arteries in sudden coronary death. Atherosclerosis 19:529-541, 1974 Brandt JL: Intermittent skin mottling in elderly patients (letter to the editor). JAm Geriatr Soc 35:478,1987 Fritzler MJ, Hart DA: Prolonged improvement of Raynaud's phenomenon and scleroderma after recombinant tissue plasminogen activator therapy. Arthritis Rheum 33:274-276, 1990 Garabedian HD, Gold HK, Leinbach RC, Svizzero TA, Finkelstein DM, Guerrero JL, Collen D: Bleeding time prolongation and bleeding during infusion of recombinant tissuetype plasminogen activator in dogs: potentiation by aspirin and reversal with aprotinin. J Am Coll Cardiol 17:12131222, 1991