Hamostaseologie 1998; 18(S 04): S19-S26
DOI: 10.1055/s-0038-1655357
Übersichtsarbeiten/Review Article
Schattauer GmbH

Anticoagulation Strategies in Ischemic Stroke: Evidence Based on Experimental Research

G. J. del Zoppo
1   Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California USA
› Author Affiliations
Supported in part by grant R01 NS26945 from the National Institutes of Neurological Diseases and Stroke
Further Information

Publication History

Publication Date:
27 June 2018 (online)

Summary

Anticoagulation has not been shown unequivocally to confer benefit to patients with TIAs, stroke-in-evolution, partial stable stroke, or completed stroke. One unconfirmed study of subcutaneous LMWH (nadroparin) applied in early stroke appears to reduce mortality at 6 months. Anticoagulation has been shown to significantly decrease the frequency of cerebral embolism in patients with a signal myocardial infarction, atrial fibrillation in the absence of a valvular abnormality, and mechanical cardiac valve prosthesis, or xenograft (bio)prostheses. The use of LMWH or low molecular weight heparinoids to reduce stroke-related disability and/or mortality is currently under rigorous study, although outcomes are conflicting. However, the contributions of fibrin and platelet deposition to microvascular occlusion following middle cerebral artery occlusion provides an experimental basis for considering the use of antithrombins to maintain microvascular patency and therefore potentially reduce tissue injury during acute focal cerebral ischemia.

 
  • REFERENCES

  • 1 Adams Jr HP. Trial of Org 10172 in Acute Stroke Treatment (TOAST). Amsterdam, 29 May, 1997, 6th European Stroke Conference..
  • 2 Akbarian M, Austen WG, Yurchak PM, Scanneil JG. Thromboembolic complications of prosthetic cardiac valves. Circulation 1986; 37: 826-31.
  • 3 Altman R, Boullon F, Rouvier J, Raca R, de la Fuente L, Favaloro R. Aspirin and prophylaxis of thromboembolic complications in patients with substitute heart valves. J Thorac Cardiovasc Surg 1976; 72: 127-9.
  • 4 Anonymous 4th American College of Chest Physicians Consensus Conference on Antithrombotic Therapy. Tuscon, Arizona, April 1995. Proceedings. Chest 1995; 108: 225S-522S.
  • 5 Baker RN. An evaluation of anticoagulant therapy in the treatment of cerebrovascular disease: Report of the Veterans Administration Cooperative Study of Atherosclerosis, Neurology Section. Neurology 1961; 11: 132-8.
  • 6 Baker RN, Broward JA, Fang HC, Fisher CM, Groch SN, Heyman A, Karp HR, McDevitt E, Scheinberg P, Schwartz W, Toole JF. Anticoagulant therapy in cerebral infarction. Neurology 1962; 12: 823-35.
  • 7 Baker RN, Schwartz WS, Rose AS. Transient ischemic attacks. Neurology 1966; 16: 841-7.
  • 8 Barnhorst DA, Oxman HA, Connolly DC. et al. Long-term follow-up of isolated replacement of the aortic or mitral valve with the Starr-Edwards prosthesis. Am J Cardiol 1975; 35: 228-33.
  • 9 Biller J, Bruno A, Adams Jr HP, Godersky JC, Loftus CM, Mitchell VL, Banwart KJ, Jones MP. A randomized trial of aspirin and heparin in hospitalized patients with recent transient ischemic attacks: A pilot study. Stroke 1989; 20: 441-7.
  • 10 Brust JCM. Transient ischemic attacks: Natural history and anticoagulation. Neurology 1977; 27: 107-707.
  • 11 Cairns JA, Connolly SJ. Nonrheumatic atrial fibrillation. Risk of stroke and role of antithrombotic therapy. Circulation 1991; 84: 469-81.
  • 12 Campbell MH. Basilar artery syndrome. Can Med Assoc J 1953; 69: 314-5.
  • 13 Carter AB. Anticoagulant treatment in progressing stroke. Br Med J 1961; 02: 70-3.
  • 14 Chesebro JH, Fuster V, Elveback LR, McGoon DC, Pluth JR, Puga FJ, Wallace RB, Danielson GK, Orszulak TA, Piehler JM, Schaff HV. Trial of combined warfarin plus dipyridamole or aspirin therapy in prosthetic heart valve replacement: Danger of aspirin compared with dipyridamole. Am J Cardiol 1983; 51: 1537-41.
  • 15 Cohn LH, Allred EN, DiSesa VJ, Sawtelle K, Sherman RJ, Collins Jr JJ. Early and late risk of aortic valve replacement. A 12-year concomitant comparison of the porcine bioprosthetic and tilting disc prosthetic aortic valves. J Thorac Cardiovasc Surg 1984; 88: 695-705.
  • 16 Connolly SJ, Laupacis A, Gent M, Roberts RS, Cairns JA, Joyner C. for the DAFA Study Coinvestigators. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol 1991; 18: 349-55.
  • 17 Coulshed N, Epstein EJ, McKendrick CS, Galloway RW, Walker E. Systemic embolism in mitral valve disease. Br Med J 1970; 32: 26-34.
  • 18 Crowell RM, Olsson Y, Klatzo I, Ommaya A. Temporary occlusion of the middle cerebral artery in monkeys. Clinical and pathological observations. Stroke 1970; 01: 439-48.
  • 19 Crowell RM, Olsson Y. Impaired microvascular filling after focal cerebral ischemia in the monkey. Neurology 1972; 22: 500-4.
  • 20 Dale J, Myhre E, Storstein O, Stormorker H, Efskind L. Prevention of artherial thromboembolism with acetylsalicylic acid. A controlled clinical study in patients with aortic ball valves. Am Heart J 1977; 94: 101-11.
  • 21 Dalen JE, Hirsh J. Second ACCP Conference on Antithrombotic Therapy. Chest 1991; 95: 5S-169S.
  • 22 Daley R, Mattingly TW, Holt Cl, Bland EF, Whit PD. Systemic arterial embolism in rheumatic heart disease. Am Heart J 1981; 42: 566-81.
  • 23 Davoiser GE, Brandenburg RO, McGoon DC. Factors affecting thromboembolism associated with prosthetic heart valves. Circulation (Suppl) 1967; 35/36: 170-6.
  • 24 del Zoppo G, Yu J-Q, Copeland BR, Thomas WS, Schneiderman J, Morrissey J. Tissue factor location in non-human primate cerebral tissue. Thromb Haemost 1992; 68: 642-7.
  • 25 del Zoppo GJ, Copeland BR, Harker LA, Waltz TA, Zyroff J, Hanson SR, Battenberg E. Experimental acute thrombotic stroke in baboons. Stroke 1986; 17: 1254-65.
  • 26 del Zoppo GJ, Schmid-Schönbein GW, Mori E, Copeland BR, Chang C-M. Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons. Stroke 1991; 22: 1276-83.
  • 27 del Zoppo GJ. Antithrombotic therapy in cerebrovascular disease. In: Thrombosis and Hemorrhage. Loscalzo J, Schafer AI. eds), Boston, Blackwell: Scientific Publications; 1994: 1225-52.
  • 28 Duke RJ, Turpie AGG, Bloch RF, Trebilcock RG. Clinical trial of low-dose subcutaneous heparin for the prevention of stroke progression: Natural history of acute partial stable stroke. In: Cerebrovascular Disease. Reivich M, Hurtig HI. eds New York: Raven Press; 1983: 399-405.
  • 29 Duke RJ, Block RF, Turpie AG, Trebilcock R, Bayer N. Intravenous heparin for the prevention of stroke progression in acute partial stable stroke: A randomized controlled trial. Arch Intern Med 1986; 105: 825-8.
  • 30 Enger E, Boyesen S. Long-term anticoagulant therapy in patients with cerebral infarction: A controlled clinical study. Acta Med Scand 1965; 179 (Suppl): 1-61.
  • 31 Estol CJ, Pessin MS. Anticoagulation: Is there still a role in atherothrombotic stroke?. Stroke 1990; 21: 820-4.
  • 32 Fazekas JF, Alman RW, Sullivan JF. Vertebrobasilar insufficiency. Arch Neurol 1963; 08: 115-20.
  • 33 Fihn SD, Callahan CM, Martin DC, McDonell MB, Henikoff JG, White RH. for The National Consortium of Anticoagulation Clinics. The risk for and severity of bleeding complications in elderly patients treated with warfarin. Ann Intern Med 1996; 124: 970-9.
  • 34 Fisher CM. The use of anticoagulants in cerebral thrombosis. Neurology 1958; 08: 311-32.
  • 35 Fisher CM. Anticoagulant therapy in cerebral thrombosis and cerebral embolism: A national cooperative study, interim report. Neurology 1961; 11: 119-31.
  • 36 Friedman GD, Wilson WS, Mosier JM, Colandrea MA, Nichaman MZ. Transient ischemic attacks in a community. JAMA 1969; 210: 1428-34.
  • 37 Gaidai KS, Lyberg T, Evensen SA, Nilsen E, Prydz H. Thrombin induces thromboplastin synthesis in cultured vascular endothelial cells. Thromb Haemost 1985; 54: 373-6.
  • 38 Garcia JH, Yoshida Y, Lian J, Chen S, Chen H, Li Y, Chopp M. Experimental occlusion of a middle cerebral artery (MCA) is accompanied by early polymorphonuclear leukocyte infiltration. Stroke 1993; 24: 166 (Abstract).
  • 39 Garcia JH, Liu KF, Yoshida Y, Lian J, Chen S, del Zoppo GJ. Influx of leukocytes and platelets in an evolving brain infarct (Wistar rat). Am J Pathol 1994; 144: 188-99.
  • 40 Hanson SR, Harker LA. Baboon models of acute arterial thrombosis. Thromb Haemost 1987; 58: 801-5.
  • 41 Haring H-P, Berg EL, Tsurushita N, Tagaya M, del Zoppo GJ. E-selectin appears in non-ischemic tissue during experimental focal cerebral ischemia. Stroke 1996; 27: 1386-92.
  • 42 Harker LA, Hanson SR. Experimental arterial thromboembolism in baboons: Mechanism, quantitation and pharmacologic prevention. J Clin Invest 1979; 64: 559-69.
  • 43 Hart RG. Cerebral Embolism Study Group: Timing of hemorrhagic transformation of cardioembolic stroke. In: Central Nervous System Control of the Heart. Stober T, Schimrigk K, Ganten D, Sherman DG. eds Boston: Martinus Nijhoff Publishing; 1986: 229-32.
  • 44 Hart RG, Coull BM, Hart D. Early recurrent embolism associated with nonvalvular atrial fibrillation: A retrospective study. Stroke 1983; 14: 688-93.
  • 45 Hart RG, Putnam C. Hemorrhagic transformation of cardioembolic stroke. Stroke 1989; 20: 1117.
  • 46 Hatashita S, Hoff JT. Role of bloodbrain barrier permeability in focal ischemic brain edema. Adv Neurol 1990; 52: 327-33.
  • 47 Hill AB, Marshall J, Shaw DA. Cerebrovascular disease: Trial of long-term anticoagulant therapy. Br Med 1962; 02: 1003-6.
  • 48 International Stroke Trial Collaborative Group. The International Stroke Trial (1ST): A randomised trial of aspirin, subcutaneous heparin, both, or neither among 19,435 patients with acute ischaemic stroke. Lancet 1997; 349: 1569-681.
  • 49 Ionescu MI, Smith DR, Hasan SS, Chidambaram M, Tandon AP. Clinical durability of the pericardial xenograft valve: Ten years experience with mitral replacement. Ann Thorac Surg 1982; 34: 265-77.
  • 50 Joint Committee for Stroke Resources. Cerebral ischemia: The role of thrombosis and of antithrombotic therapy. Stroke 1977; 08: 150-75.
  • 51 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: 1588-93.
  • 52 Kopf GS, Hammond GL, Geha AS, Elefberiades J, Hashim SW. Long-term performance of the St. Jude Medical valve: Low incidence of thromboembolism and hemorrhagic complications with modest doses of warfarin. Circulation 1987; 76 (Suppl): 132-6.
  • 53 Levine HJ, Pauker SG, Salzman EW. Antithrombotic therapy in valvular heart disease. Chest 1989; 95 (Suppl): 98S-106S.
  • 54 Liu T, McDonnell PC, Young PR, White RF, Siren AL, Hallenbeck JM, Barone FC, Feuerstein GZ. Interleukin-lb mRNA expression in ischemic rat cortex. Stroke 1993; 24: 1746-51.
  • 55 Loddick SA, Rothwell NJ. Neuroprotective effects of human recombinant interleukin-1 receptor antagonist in focal cerebral ischaemia in the rat. J Cereb Blood Flow Metab 1996; 16: 932-40.
  • 56 Loeliger EA, Poller L, Samama M, Thomson JM, Van den Besselar AMHP, Vermyler J, Verstraete M. Questions and answers on prothrombin time standardization in oral anticoagulant control. Thromb Haemost 1985; 54: 515-7.
  • 57 Loeliger EA. Therapeutic target values in oral anticoagulation Justification of Dutch policy and a warning against the so-called moderate-intensity regimens. Ann Hematol 1992; 64: 60-5.
  • 58 Marshall J, Shaw DA. Anticoagulant therapy in acute cerebrovascular accidents: A controlled trial. Lancet 1960; 01: 995-8.
  • 59 Massey EW, Biller J, Dairs JN, Adams Jr HP, Marler JR, Goldstein LB, Alberts M, Bruno A. Large-dose infusions of heparinoid ORG 10172 in ischemic stroke. Stroke 1990; 21: 1289-92.
  • 60 Maynard JR, Dreyer BE, Stemerman MB, Pitlick FA. Tissue-factor coagulant activity of cultured human endothelial and smooth muscle cells and fibroblasts. Blood 1977; 50 (3): 387-95.
  • 61 McCarron RM, Uematsu S, Merkel N, Long D, Bembry J, Spatz M. The role of arachidonic acid and oxygen radicals on cerebromicrovascular endothelial permeability. Acta Neurochir 1990; 51: 61-4.
  • 62 McDowell F, McDevitt E. Treatment of the completed stroke with long-term anticoagulant. Six and one-half years’ experience. In: Cerebral Vascular Diseases, Fourth Princeton Conference. Siekert RH, Whisnant JR. eds New York: Grune and Stratton; 1965: 185-99.
  • 63 Miller VT. Transient ischemic attacks and ischemic stroke: Indications for anticoagulation. Clin Cardiol 1990; 13: VI-29-VI-30.
  • 64 Millikan CH. Anticoagulant therapy in cerebrovascular disease. In: Cerebral Vascular Diseases. Millikan CH, Siekert RG, Whisnant JP. eds New York: Grune and Stratton; 1965: 183.
  • 65 Millikan CH, Siekert RG, Shick RM. Studies in cerebrovascular disease: III. The use of anticoagulant drugs in the treatment of insufficiency or thrombosis within the basilar arterial system. Mayo Clin Proc 1955; 30: 116-26.
  • 66 Moggio RA, Hammond GL, Stansel Jr HL, Glenn WWL. Incidence of emboli with cloth-covered Starr-Edwards value without anticoagulation and with varying forms of anticoagulation. J Thorac Cardiovasc Surg 1978; 75: 296-9.
  • 67 Mori E, Chambers JD, Copeland BR, Arfors K-E, del Zoppo GJ. Inhibition of polymorphonuclear leukocyte adherence suppresses non-reflow after focal cerebral ischemia. Stroke. 1992. 23 712-8.
  • 68 Muhlfelder TW, Niemetz J, Kreutzer D, Beebe D, Ward PA, Rosenfeld SI. C5 chemotactic fragment induces monocyte production of tissue factor activity. J Clin Invest 1979; 63: 147-50.
  • 69 Nawrath PP, Stern DM. Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med 1986; 163: 740-5.
  • 70 Niemetz J. Coagulant activity of monocytes. J Clin Invest 1972; 51: 307-13.
  • 71 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: 1847-54.
  • 72 Okada Y, Copeland BR, Mori E, Tung M-M, Thomas WS, del Zoppo GJ. P-selectin and intercellular adhesion molecule-1 expression after focal brain ischemia and reperfusion. Stroke 1994b; 25: 202-11.
  • 73 Olsson JE, Müller R, Benneli S. Longterm anticoagulant therapy for transient ischemic attacks and minor strokes with minimum residuum. Stroke 1976; 07: 444-51.
  • 74 Oyer PE, Stinson EB, Griepp RB, Shumway NE. Valve replacement with the Starr-Edwards and Hancock prostheses. Comparative analysis of late morbidity and mortality. Ann Surg 1977; 186: 301-9.
  • 75 Pearce JMS, Gubbay SS, Walton JN. Long-term anticoagulant therapy in transient cerebral ischemic attacks. Lancet 1965; 01: 6-9.
  • 76 Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B. Placebocontrolled randomized trial of warfarin and aspirin to prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK Study. Lancet 1989; 01: 175-9.
  • 77 Poller L. Oral anticoagulant therapy. In: Haemostasis and Thrombosis. Bloom AL, Thomas DP. eds Edinburgh: ChurchillLivingstone; 1987: 870-85.
  • 78 Putnam SF, Adams HP. Usefulness of heparin in initial management of patients with recent transient ischemic attacks. Arch Neurol 1985; 42: 960-2.
  • 79 Risau W, Wolburg H. Development of the blood-brain barrier. TINS 1990; 13: 174-8.
  • 80 Rothwell NJ. Functions and mechanism of interleukin-1 in the brain. Trends Pharmacol Sci 1991; 12: 430-5.
  • 81 Sage JL, Van Uitert RL. Recurrent stroke in patients with atrial fibrillation and nonvalvular heart disease. Stroke 1983; 14: 537-40.
  • 82 Saöur JN, Sleek JO, Mamo LAR, Gallus AS. Trial of different intensities of patients with prosthetic heart valves. N Engl J Med 1990; 322: 428-32.
  • 83 Schorer AE, Kaplan ME, Rao GHR, Moldow CF. Interleukin 1 stimulates endothelial cell tissue factor production and expression by a prostaglandin-independent mechanism. Thromb Haemost 1986; 56: 256-9.
  • 84 Schwartz BS, Edgington TS. Immune complex-induced human monocyte procoagulant activity. J Exp Med 1981; 154: 892-906.
  • 85 Siekert RG, Whisnant JP, Millikan CH. Surgical and anticoagulant therapy of occlusive cerebrovascular disease. Ann Intern Med 1963; 58: 637-41.
  • 86 Stein PD, Kantrowitz A. Antithrombotic therapy in mechanical and biological prosthetic heart valves and saphenous vein bypass grafts. Chest 1989; 95 (Suppl): 107S-17S.
  • 87 Stroke Prevention in Atrial Fibrillation Study Group Investigators. Preliminary report of the Stroke Prevention in Atrial Fibrillation Study. N Engl J Med 1990; 322: 863-8.
  • 88 Stroke Prevention in Atrial Fibrillation Investigators. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet 1994; 343: 687-91.
  • 89 Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke prevention in atrial fibrillation III randomised clinical trial. Lancet 1996; 348: 633-8.
  • 90 Sullivan JM, Harken DE, Gorlin R. Effect of dipyridamole on the incidence of arterial emboli after cardiac valve replacement. Circulation 1969; 39/40 (Suppl): I-149-I-153.
  • 91 Sullivan JM, Harken DE, Gorlin R. Pharmacologic control of thromboembolic complications of cardiac valve replacement. N Engl J Med 1971; 284: 1391-4.
  • 92 Szekely P. Systemic embolism and anticoagulant prophylaxis in rheumatic heart disease. Br Med J 1964; 01: 1209-12.
  • 93 Tagaya M, Liu K-F, Copeland B, Seiffert D, Engler R, Garcia JH, del Zoppo GJ. DNA scission following focal brain ischemia: Temporal differences in two species. Stroke 1997; 28: 1245-54.
  • 94 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: 268-70.
  • 95 The Boston Area Anticoagulation Trial/Atrial Fibrillation Investigators. The effect of low-dose warfarin on the risk of stroke in patients with non-rheumatic atrial fibrillation. N Engl J Med 1990; 323: 1505-11.
  • 96 Thomas WS, Mori E, Copeland BR, Yu J-Q, Morrissey JH, del Zoppo GJ. Tissue factor contributes to microvascular defects following cerebral ischemia. Stroke 1993; 24: 847-53.
  • 97 Toole JF, Janeway R, Choi K, Cordell R, Davis C, Johnston F, Muller HS. Transient ischemic attacks due to atherosclerosis. A prospective study of 160 patients. Arch Neurol 1975; 32: 5-12.
  • 98 Turpie AGG, Gunstensen J, Hirsh J, Nelson H, Gent M. Randomized comparison of two intensities of oral anticoagulant therapy after tissue heart valve placement. Lancet 1988; 01: 1242-5.
  • 99 Villacara A, Kempski O, Spatz M. Arachiconic acid and cerebromicrovascular endothelial permeability. Adv Neurol 1990; 52: 195-201.
  • 100 Walker AM, Jick H. Predictors of bleeding during heparin therapy. JAMA 1980; 244: 1209-12.
  • 101 Wang XK, Yue T-L, Barone FC, White RF, Gagnon RC, Feuerstein GZ. Concommitant cortical expression of TNF-a and IL-lb mRNA following transient focal ischemia. Mol Chem Neuropathol 1994; 23: 103-14.
  • 102 Wharram BL, Fitting K, Kunkel SL, Remick DG, Merritt SE, Wiggins RC. Tissue factor expression in endothelial cell/monocyte cocultures stimulated by lipopolysaccharide and/or aggregated IgG. J Immunol 1991; 146: 1437-45.
  • 103 Williams JB, Karp RB, Kirklin JW, Kouchoukos NT, Pacifico AD, Zorn GL. et al. Considerations in selection and management of patients undergoing valve replacement with gluteraldehyde-fixed porcine bioprostheses. Ann Thorac Surg 1980; 30: 247-58.
  • 104 Wong D, Dorovini-Zis K. Up-regulation of intercellular adhesion molecule-1 (ICAM-1) expression in primary cultures of human brain microvessel endothelial cells by cytokines and lipopolysaccharide. J Neuroimmunol 1992; 39: 11-22.
  • 105 Yamakawa T, Yamaguchi S, Niimi H. Cerebral microcirculatory hemodynamics after microembolization with fluorescently labelled microspheres: In vivo studies using a fluorescence TV microscope. In: Microcirculatory Disorders in the Heart and Brain. Niimi H, Hori M, Naritomi H. eds Amsterdam: Harwood Academic Pub; 1991: 103-19.
  • 106 Yang GY, Betz AL. Reperfusioninduced injury to the blood-brain barrier after middle cerebral artery occlusion in rats. Stroke 1994; 25: 1658-64.