Download PDF
Thromb Haemost 1999; 82(02): 938-946
DOI: 10.1055/s-0037-1615936
Research Article
Schattauer GmbH

Antithrombotic Treatments in Acute Ischemic Stroke

Gregory J. del Zoppo
1   Department of Molecular and Experimental Medicine, The Scripps Research Institute and Division of Hematology/Medical Oncology, Scripps Clinic and Research Foundation, La Jolla, CA, USA
› Author Affiliations
Further Information

Publication History

Publication Date:
09 December 2017 (online)

    Permissions and Reprints

Introduction

Stroke may be defined as a syndrome of thrombohemorrhagic disorders affecting the central nervous system. In this setting, considerable efforts have been directed to improve clinical outcome with antithrombotic agents, including platelet inhibitors, anticoagulants, and plasminogen activators. The search for a role for antithrombotic agents in ischemic stroke rests on the observation that, overall, 75% to 80% of strokes involve thrombotic events. Recent experience with plasminogen activators (PAs) in acute ischemic stroke indicates that, in select patients, clinical improvement is associated with shorter interval from symptom onset to treatment, while clinically significant hemorrhagic transformation increases with delays in treatment. The time-dependence and the subpopulation characteristics of outcomes following PA exposure is entirely compatible with an evolution of brain injury and varies individually, but where microvascular integrity in the ischemic bed decreases with time. These relationships have not been developed or explored with other antithrombotic agents, including antiplatelet agents or anticoagulants. Thus, among antithrombotic agents, only certain PAs have been used in a strictly “acute” setting, that is within 6 to 8 hours of symptom onset. This presentation summarizes current experience with antithrombotic interventions in focal cerebral ischemia in the acute and early (>8) hours following symptom onset.

 

  • References

  • 1 del Zoppo GJ. The role of platelets in ischemic stroke. Neurology 1998; 51 (Suppl. 03) S9-S14.
    PubMedGoogle Scholar
  • 2 Fieschi C, Argentino C, Lenzi GL, Sacchetti ML, Toni D, Bozzao L. Clinical and instrumental evaluation of patients with ischemic stroke within the first six hours. J Neurol Sci 1989; 91: 311-321.
    CrossrefPubMedGoogle Scholar
  • 3 del Zoppo GJ, Poeck K, Pessin MS, Wolpert SM, Furlan AJ, Ferbert A, Alberts MJ, Zivin JA, Wechsler L, Busse O, Greenlee Jr. R, Brass L, Mohr JP, Feldmann E, Hacke W, Kase CS, Biller J, Gress D, Otis SM. Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke. Ann Neurol 1992; 32: 78-86.
    CrossrefPubMedGoogle Scholar
  • 4 del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M. and the PROACT Investigators. PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. Stroke 1998; 29: 4-11.
    CrossrefPubMedGoogle Scholar
  • 5 Solis OJ, Roberson GR, Taveras JM, Mohr J, Pessin MS. Cerebral angiography in acute cerebral infarction. Revist Interam Radiol 1977; 2: 19-25.
    PubMedGoogle Scholar
  • 6 Fieschi C, Bozzao L. Transient embolic occlusion of the middle cerebral and internal carotid arteries in cerebral apoplexy. J Neurol Neurosurg Psychiatry 1969; 32: 236-240.
    CrossrefPubMedGoogle Scholar
  • 7 Irino T, Taneda M, Minami T. Angiographic manifestations in post-recanalized cerebral infarction. Neurology 1977; 27: 471-475.
    CrossrefPubMedGoogle Scholar
  • 8 Yamaguchi T. Intravenous tissue plasminogen activator in acute thromboembolic stroke: a placebo-controlled, double-blind trial. In: del Zoppo GJ, Mori E, Hacke W. eds. Thrombolytic Therapy in Acute Ischemic Stroke II. Springer-Verlag; Heidelberg: 1993: 59-65.
    Google Scholar
  • 9 Mori E, Yoneda Y, Tabuchi M, Yoshida T, Ohkawa S, Ohsumi Y, Kitano K, Tsutsumi A, Yamadori A. Intravenous recombinant tissue plasminogen activator in acute carotid artery territory stroke. Neurology 1992; 42: 976-982.
    CrossrefPubMedGoogle Scholar
  • 10 Mori E. Fibrinolytic recanalization therapy in acute cerebrovascular thromboembolism. In: Hacke W, del Zoppo GJ, Hirschberg M. eds. Thrombolytic Therapy in Acute Ischemic Stroke. Springer-Verlag; Heidelberg: 1991: 137-146.
    Google Scholar
  • 11 Fisher CM, Adams RD. Observations on brain embolism with special reference to the mechanism of hemorrhagic infarction. J Neuropathol Exp Neurol 1951; 10: 92-94.
    PubMedGoogle Scholar
  • 12 Okada Y, Yamaguchi T, Minematsu K, Miyashita T, Sawada T, Sadoshima S, Fujishima M, Omae T. Hemorrhagic transformation in cerebral embolism. Stroke 1989; 20: 598-603.
    CrossrefPubMedGoogle Scholar
  • 13 Hornig CR, Dorndorf W, Agnoli AL. Hemorrhagic cerebral infarction: a prospective study. Stroke 1986; 17: 179-185.
    CrossrefPubMedGoogle Scholar
  • 14 Babikian VL, Kase CS, Pessin MS, Norrving B, Gorelick PB. Intracerebral hemorrhage in stroke patients anticoagulated with heparin. Stroke 1989; 29: 1500-1503.
    PubMedGoogle Scholar
  • 15 Furlan AJ, Cavalier SJ, Hobbs RE, Weinstein MA, Modic MI. Hemorrhage and anticoagulation after nonseptic embolic brain infarction. Neurology 1982; 32: 280-282.
    CrossrefPubMedGoogle Scholar
  • 16 International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. The Lancet 1997; 349: 1569-1581.
    CrossrefPubMedGoogle Scholar
  • 17 CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: randomised placebo-controlled trial of early aspirin use in 20 000 patients with acute ischaemic stroke. The Lancet 1997; 349: 1641-1649.
    CrossrefPubMedGoogle Scholar
  • 18 del Zoppo GJ, Ferbert A, Otis S, Brückmann H, Hacke W, Zyroff J, Harker LA, Zeumer H. Local intra-arterial fibrinolytic therapy in acute carotid territory stroke: a pilot study. Stroke 1988; 19: 307-313.
    CrossrefPubMedGoogle Scholar
  • 19 Mori E, Tabuchi M, Yoshida T, Yamadori A. Intracarotid urokinase with thromboembolic occlusion of the middle cerebral artery. Stroke 1988; 19: 802-812.
    CrossrefPubMedGoogle Scholar
  • 20 Ogata J, Yutani C, Imakita M, Ishibashi-Ueda H, Saku Y, Minematsu K, Sawada T, Yamaguchi T. Hemorrhagic infarct of the brain without a reopening of the occluded arteries in cardioembolic stroke. Stroke 1989; 20: 876-883.
    CrossrefPubMedGoogle Scholar
  • 21 Wityk RJ, Pessin MS, Kaplan RF, Caplan LR. Serial assessment of acute stroke using the NIH stroke scale. Stroke 1994; 25: 362-365.
    CrossrefPubMedGoogle Scholar
  • 22 The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995; 333: 1581-1587.
    CrossrefPubMedGoogle Scholar
  • 23 Rankin J. Cerebral vascular accidents in patients over the age of 60. II. Prognosis. Scott Med J 1957; 2: 200-215.
    CrossrefPubMedGoogle Scholar
  • 24 Loewen SC, Anderson BA. Reliability of the modified motor assessment scale and the Barthel index. Phys Ther 1988; 68: 1077-1081.
    CrossrefPubMedGoogle Scholar
  • 25 Saito I, Segawa H, Shiokawa Y, Taniguchi M, Tsutsumi K. Middle cerebral artery occlusion: Correlation of computed tomography and angiography with clinical outcome. Stroke 1987; 18: 863-868.
    CrossrefPubMedGoogle Scholar
  • 26 Baron JC, von Kummer R, del Zoppo GJ. Treatment of acute ischemic stroke. Challenging the concept of a rigid and universal time window (Editorial). Stroke 1995; 26: 2219-2221.
    CrossrefPubMedGoogle Scholar
  • 27 Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy- I: Prevention of death, myocardial infarction, and stroke by prolongedm antiplatelet therapy in various categories of patients. Br Med J 1995; 308: 81-106.
    PubMedGoogle Scholar
  • 28 Hass WK, Easton J, D. Adams Jr. HP. et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for prevention of stroke in high-risk patients. N Engl J Med 1989; 321: 501-507.
    CrossrefPubMedGoogle Scholar
  • 29 Gent M, Blakely JA, Easton JD, Ellis DJ, Hachinski VC, Harbison JW, Panak E, Roberts RS, Sicurella J, Turpie AG. The Canadian-American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989; 1: 1215-1220.
    PubMedGoogle Scholar
  • 30 Diener H, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996; 143: 1-13.
    CrossrefPubMedGoogle Scholar
  • 31 Okada Y, Copeland BR, Fitridge R, Koziol JA, del Zoppo GJ. Fibrin contributes to microvascular obstructions and parenchymal changes during early focal cerebral ischemia and reperfusion. Stroke 1994; 25: 1847-1854.
    CrossrefPubMedGoogle Scholar
  • 32 Turpie AG. Prophylaxis of venous thromboembolism in stroke patients. Semin Thromb Hemost 1997; 23: 155-157.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 ten Cate H, Henny CP, Buller HR, ten Cate JLO, Magnani H. Use of a heparinoid in patients with hemorrhagic stroke and thromboembolic disease. Ann Neurol 1984; 15: 268-270.
    CrossrefPubMedGoogle Scholar
  • 34 Turpie AG. Orgaran in the prevention of deep vein thrombosis in stroke patients. Hemostasis 1992; 22: 92-98.
    PubMedGoogle Scholar
  • 35 Turpie AG, Gent M, Cote R, Levine MN, Ginsberg JS, Powers PJ, Leclerc J, Geerts W, Jay R, Neemeh J. et al. A low-molecular weight heparinoid compared with unfractionated heparin in the prevention of deep vein thrombosis in patients with acute ischemic stroke. A randomized, double-blind study. Ann Intern Med 1992; 117: 353-357.
    CrossrefPubMedGoogle Scholar
  • 36 Low molecular weight heparinoid, Org 10172 (danaparoid), and outcome after acute ischemic stroke: A randomised controlled trial. The Publications’ Committee for the Trial of Org 10172 in Acute Stroke Treatment (TOAST) Investigators. JAMA 1998; 279: 1265-1272.
    CrossrefPubMedGoogle Scholar
  • 37 Kay R, Wong KA, Yu YL, Chan YW, Tsoi TH, Ahuja AT, Chan FL, Fong KY, Law CB, Wong A, Woo J. Low-molecular weight heparin in the treatment of acute ischemic stroke. N Engl J Med 1995; 333: 1588-1593.
    CrossrefPubMedGoogle Scholar
  • 38 del Zoppo GJ, Zeumer H, Harker LA. Thrombolytic therapy in acute stroke: possibilities and hazards. Stroke 1986; 17: 595-607.
    CrossrefPubMedGoogle Scholar
  • 39 Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, Boysen G, Bluhmki E, Höxter G, Mahagne M -H, Hennerici M. for the ECASS Study Group. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA 1995; 274: 1017-1025.
    CrossrefPubMedGoogle Scholar
  • 40 Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S, Donnan G, Schneider D, Diez-Tejedor E, Trouillas P. for the Second European-Australasian acute Stroke Study Investigators. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). The Lancet 1998; 352: 1245-1251.
    CrossrefPubMedGoogle Scholar
  • 41 Hommel M, Boissel JP, Cornu C, Boutitie F, Lees KR, Bessorn G, Leys D, Amarenio P, Bogart M. for the MAST Group. Termination of trial of streptokinase in severe acute ischemic stroke (Letter). Lancet 1995; 345: 578-579.
    CrossrefPubMedGoogle Scholar
  • 42 Donnan GA, Davis SM, Chambers BR, Gates PC, Hankey GJ, McNeil JJ, Rosen D, Stewart-Wynne EG, Tuck RR. for the Australian Streptokinase (ASK) Trial Study Group. Streptokinase for acute ischemic stroke with relationship to time of administration. JAMA 1996; 276: 961-966.
    CrossrefPubMedGoogle Scholar
  • 43 Multicentre Acute Stroke Trial-Italy (MAST-I) Group. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Lancet 1995; 346: 1509-1514.
    CrossrefPubMedGoogle Scholar
  • 44 Matsumoto K, Satoh K. Topical intraarterial urokinase infusion for acute stroke. In: Hacke W, del Zoppo GJ, Hirschberg M. eds. Thrombolytic Therapy in Acute Ischemic Stroke. Springer-Verlag; Heidelberg: 1991: 207-212.
    Google Scholar
  • 45 Hacke W, Zeumer H, Ferbert A, Brückmann H, del Zoppo GJ. Intra-arterial thrombolytic therapy improves outcome in patients with acute vertebrobasilar occlusive disease. Stroke 1988; 19: 1216-1222.
    CrossrefPubMedGoogle Scholar
  • 46 Zeumer H, Freitag H-J, Zanella F, Thie A, Arnig C. Local intra-arterial fibrinolytic therapy in patients with stroke: Urokinase vs recombinant tissue plasminogen activator (rt-PA). Neuroradiology 1993; 35: 159-162.
    CrossrefPubMedGoogle Scholar
  • 47 Zeumer H. Survey of progress: .ascular recanalizing techniques in interventional neuroradiology. J Neurol 1985; 231: 287-294.
    CrossrefPubMedGoogle Scholar
  • 48 Nenci GG, Gresele P, Taramelli M, Agnelli G, Signorini E. Thrombolytic therapy for thromboembolism of vertebrobasilar artery. Angiology 1983; 34: 561-571.
    CrossrefPubMedGoogle Scholar
  • 49 del Zoppo GJ, Higashida RT, Furlan AJ. The case for a phase III trial of cerebral intraarterial fibrinolysis. AJNR 1994; 15: 1217-1222.
    PubMedGoogle Scholar
  • 50 von Kummer R, Hacke W. Safety and efficacy of intravenous tissue plasminogen activator and heparin in acute middle cerebral artery. Stroke 1992; 23: 646-652.
    CrossrefPubMedGoogle Scholar
  • 51 Yamaguchi T. Intravenous rt-PA in acute embolic stroke. In: Hacke W, del Zoppo GJ, Hirschberg M. eds. Thrombolytic Therapy in Acute Ischemic Stroke. Springer-Verlag; Heidelberg: 1991: 168-174.
    Google Scholar
  • 52 Levy DE, Brott TG, Haley Jr. EC, Marler JR, Sheppard GL, Barsan W, Broderick JP. Factors related to intracranial hematoma formation in patients receiving tissue-type plasminogen activator for acute ischemic stroke. Stroke 1994; 25: 291-297.
    CrossrefPubMedGoogle Scholar
  • 53 Larrue V, von Kummer R, del Zoppo GJ, Bluhmki E. Hemorrhagic transformation in acute ischemic stroke: Potential contributing factors in the European Cooperative Acute Stroke Study. Stroke 1997; 28: 957-960.
    CrossrefPubMedGoogle Scholar
  • 54 The NINDS t-PA Stroke Study Group. Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. Stroke 1997; 28: 2109-2118.
    CrossrefPubMedGoogle Scholar