Thromb Haemost 1996; 75(05): 820-826
DOI: 10.1055/s-0038-1650373
Original Article
Schattauer GmbH Stuttgart

An Experimental Model of Intracranial Hemorrhage during Thrombolytic Therapy with t-PA

Nicholas F Paoni
The Department of Cardiovascular Research, Genentech Inc., South San Francisco, CA, USA
,
Hope G Steinmetz
The Department of Cardiovascular Research, Genentech Inc., South San Francisco, CA, USA
,
Nancy Gillett
1   The Departments of Pathobiology and Toxicology, Genentech Inc., South San Francisco, CA, USA
,
Canio J Refino
The Department of Cardiovascular Research, Genentech Inc., South San Francisco, CA, USA
,
Julie M Badillo
The Department of Cardiovascular Research, Genentech Inc., South San Francisco, CA, USA
,
Stuart Bunting
The Department of Cardiovascular Research, Genentech Inc., South San Francisco, CA, USA
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Received 06. November 1995

Accepted after revision 23. Januar 1996

Publikationsdatum:
10. Juli 2018 (online)

Summary

Multiple clinical trials have proven that thrombolytic therapy is an effective treatment for acute myocardial infarction. Spontaneous intracranial hemorrhage (ICH) occurs in a small percentage of patients as a result of the treatment. The etiology of the ICH is unknown and there is currently no established experimental model for this side effect. A model of ICH during thrombolytic therapy has been developed using spontaneously hypertensive rats (SHR). The SHR were made susceptible to ICH during thrombolytic therapy by bilateral ligation of the external jugular veins. This procedure produced asymptomatic hemorrhagic lesions in the brains of the animals in the hours preceding the administration of t-PA/heparin. The incidence of ICH following the administration of test substances was assessed by histological examination and by measuring the red blood cell count in a sample of cerebrospinal fluid taken from the atlanto-occipital space. t-PA administration produced a low frequency of ICH in this model. The incidence and severity of ICH were dramatically increased, and significant mortality at 24 h was observed, by combining heparin with the t-PA. No fewer hemorrhages were observed if the t-PA and heparin were administered sequentially rather than simultaneously. Furthermore, ICHs were observed whether the t-PA dose was administered over 4 h, 1 h, or as a double bolus 30 min apart. The potentiation of ICH by heparin was dose dependent and proportional to the prolongation of the aPTT. Although the precise mechanism of ICH during thrombolytic therapy is unknown, many similarities exist between the observations made in this model and in the human clinical experience.

 
  • References

  • 1 Sobel BE. Intracranial bleeding, fibrinolysis, and anticoagulation: causal connections and clinical implications. Circulation 1994; 90: 2147-2151
  • 1 Lyden PD, Madden KP, Clark WM, Sasse KC, Zivin JA. Incidence of cerebral hemorrhage after antifibrinolytic treatment for embolic stroke in rabbits. Stroke 1990; 21: 1589-1593
  • 3 Clark WM, Madden KP, Lyden PD, Zivin JA. Cerebral hemorrhage risk of aspirin or heparin therapy with thrombolytic treatment in rabbits. Stroke 1991; 22: 872-876
  • 4 Thomas GR, Thibodeaux H, Bennett WF, Refino CJ, Badillo JM, Errett CJ, Zivin JA. Optimized thrombolysis of cerebral clots with tissue-type plasminogen activator in a rabbit model of embolic stroke. J Pharm Exp Ther 1993; 264: 67-73
  • 5 Thomas GR, Thibodeau H, Errett CJ, Badillo JM, Keyt BA, Refino CJ, Zivin JA, Bennett WF. A long-half-life and fibrin-specific form of tissue plasminogen activator in rabbit models of embolic stroke and peripheral bleeding. Stroke 1994; 25: 2072-2079
  • 6 De Bono DP, Pringle S, Underwood I. Differential effects of aprotinin and tranexamic acid on cerebral bleeding and cutaneous bleeding time during rt-PA infusion. Thromb Res 1991; 61: 159-163
  • 7 O'Connor CM, Califf RM, Massey EW, Mark DB, Kereiakes DJ, Candela RJ, Abbottsmith C, George B, Stack RS, Aronson L, Mantell S, Topol EJ. Stroke and acute myocardial infarction in the thrombolytic era: clinical correlates and long-term prognosis. J Am Coll Cardiol 1990; 16: 533-540
  • 8 Gore JM, Sloan M, Price TR, Randall AM, Bovill E, Collen D, Forman S, Knatterud GL, Sopko G, Terrin ML. the TIMI Investigators. Intracerebral hemorrhage, cerebral infarction, and subdural hematoma after acute myocardial infarction and thrombolytic therapy in the Thrombolysis in Myocardial Infarction study. Circulation 1991; 83: 448-459
  • 9 Califf RM, Fortin DF, Tenaglia AN, Sane DC. Clinical risks of thrombolytic therapy. Am J Cardiol 1992; 69: 12A-20A
  • 10 De Jaegere PP, Arnold AA, Balk AH, Simoons ML. Intracranial hemorrhage in association with thrombolytic therapy: incidence and clinical predictive factors. J Am Coll Cardiol 1992; 19: 289-294
  • 11 Anderson JL, Karagounis L, Allen A, Bradford MJ, Menlove RH, Pryor TA. Older age and elevated blood pressure are risk factors for intracerebral hemorrhage after thrombolysis. Am J Cardiol 1991; 68: 166-170
  • 12 Longstreth WTJ, Litwin PE, Weaver WD. Myocardial infarction, thrombolytic therapy, and stroke: a community-based study. Stoke 1993; 24: 587-590
  • 13 Alpert JS. Intracranial hemorrhage after thrombolytic therapy: a therapeutic conflict. J Am Coll Cardiol 1992; 19: 295-296
  • 14 Selker HP, Beshansky JR, Schmid CH, Griffith JL, Longstreth WTJ, O'Connor CM, Caplan LR, Massey W, D'Agostino RB, Laks MM, Lee KL, Maynard C, Wagner GS, Weaver WD, Califf RM. Presenting pulse pressure predicts thrombolytic therapy-related intracranial hemorrhage: thrombolytic predictive instrument (TPI) project results. Circulation 1994; 90: 1657-1661
  • 15 Sloan MA, Price TR, Petito CK, Solomon RE, Terrin ML, Gore J, Collen D, Kleiman N, Feit F, Babb J, Herman M, Roberts WC, Sopko G, Bovill E, Forman S, Knatterud GL. for the TIMI Investigators.Clinical features and pathogenesis of intracerebral hemorrhage after rt-PA and heparin therapy for acute myocardial infarction: the Thrombolysis in Myocardial Infarction (TIMI) II Pilot and Randomized Clinical Trial combined experience. Neurology 1995; 45: 649-658
  • 16 Antman EM. Hirudin in acute myocardial infarction: safety report from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A trial. Circulation 1994; 90: 1624-1630
  • 17 The Global Use of Strategies to Open Occluded Arteries (GUSTO) Ha Investigators. Randomized trial of intravenous heparin versus recombinant hirudin for acute coronary syndromes. Circulation 1994; 90: 1631-1637
  • 18 Paoni NF, Refino CJ, Brady K, Pena LC, Nguyen HV, Kerr EM, Johnson AC, Wurm FM, van Reis R, Botstein D, Bennett WF. Involvement of residues 296-299 in the enzymatic activity of tissue-type plasminogen activator. Protein Engineering 1992; 5: 259-266
  • 19 Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acto Haematol (Basel) 1957; 17: 237-240
  • 20 Soria J, Soria C, Samama MM. Chemical Fibrinolysis and Thrombolysis. In: Davidson JF, Samama MM, Desnoyers PC. eds. A Plasminogen Assay Using a Chromo-genic Synthetic Substrate: Results From Clinical Work and Studies of Thrombolysis. New York: Raven Press; 1978: 337-346
  • 21 Bovill EG, Terrin ML, Stump DC, Berke AD, Frederick M, Collen D, Feit F, Gore JM, Hillis LD, Lambrew CT, Leiboff R, Man KG, Markis JE, Pratt CM, Sharkey SW, Sopko G, Tracy RP, Chesebro JH. for the TIMI Investigators. Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI), phase II trial. Ann Int Med 1991; 115: 256-265
  • 22 The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993; 329: 673-682
  • 23 Rogers WJ, Bowlby LJ, Chandra NC, French WJ, Gore JM, Lambrew CT, Rubison M, Tiefenbrunn AJ, Weaver WD. for the Participants in the National Registry of Myocardial Infarction. Treatment of myocardial infarction in the United States (1990-1993): observations from the National Registry of Myocardial Infarction. Circulation 1994; 90: 2103-2114
  • 24 Lindgren A, Roijer A, Rudling O, Norrving B, Larsson E-M, Eskilsson J, Wallin L, Olsson B, Johansson BB. Cerebral lesions on magnetic resonance imaging, heart disease, and vascular risk factors in subjects without stroke. Stroke 1994; 25: 929-934