[Skip to Content]
[Skip to Content Landing]
February 1990

Retinal Toxicity of Recombinant Tissue Plasminogen Activator in the Rabbit

Author Affiliations

From the Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami (Fla) School of Medicine. Dr R. Johnson is now in private practice in San Francisco, Calif.

Arch Ophthalmol. 1990;108(2):259-263. doi:10.1001/archopht.1990.01070040111042

• We studied the dose-dependent retinal toxicity of the available commercial preparation of human recombinant tissue plasminogen activator in the normal rabbit eye. Tissue plasminogen activator was injected into the midvitreous cavity of albino rabbits in doses (per 100 μL) of 25, 50, 75, and 100 μg. Control eyes received 100 μL of balanced salt solution or tissue plasminogen activator vehicle. No evidence of a retinal toxic reaction was seen in eyes receiving 25 μg of tissue plasminogen activator. One of four eyes injected with 50 μg showed loss of photoreceptor cells by light microscopy. Severe retinal damage was seen by ophthalmoscopy, electroretinography, and light microscopy in three of four eyes receiving 75 μg of tissue plasminogen activator and in all eyes treated with 100 μg of tissue plasminogen activator or equivalent vehicle. These results suggest that the commercial recombinant tissue plasminogen activator formulation has a narrow margin of safety in nonvitrectomized eyes and that a component of the vehicle is the toxic factor.

Pennica D, Holmes WE, Kohr WJ, et al.  Cloning and expression of human tissue-type plasminogen activator cDNA in E coli . Nature . 1983;301:214-221.Article
Collen D, Stassen JM, Marafino BJ Jr, et al.  Biological properties of human tissue-type plasminogen activator obtained by expression of recombinant DNA in mammalian cells . J Pharmacol Exp Ther . 1984;231:146-152.
Rogers SD, Riemersma LB, Clements SD.  Tissue plasminogen activator: an evaluation of clinical efficacy in acute myocardial infarction . Pharmacotherapy . 1987;7:111-121.
Hoylaerts M, Rijken DC, Lijnen HR, Collen D.  Kinetics of the activation of plasminogen by human tissue plasminogen activator: role of fibrin . J Biol Chem . 1982;257:2912-2919.
Collen D, Lijnen HR.  Tissue-type plasminogen activator: mechanism of action and thrombolytic properties . Haemostasis . 1986;16( (suppl 3) ):25-32.
Tiefenbrunn AJ, Robison AK, Kurnik PB, Ludbrook PA, Sobel BE.  Clinical pharmacology in patients with evolving myocardial infarction of tissue-type plasminogen activator produced by recombinant DNA technology . Circulation . 1985;71:110-116.Article
Agnelli G, Buchanan MR, Fernandez F, et al.  A comparison of the thrombolytic and hemorrhagic effects of tissue-type plasminogen activator and streptokinase in rabbits . Circulation . 1985;72:178-182.Article
Mueller HS, Roberts R, Teichman SL, Sobel BE.  Thrombolytic therapy in acute myocardial infarction, II: rt-PA . Med Clin North Am . 1989;73:387-407.
 Tissue-type plasminogen activator for acute coronary thrombosis . Med Lett Drugs Ther . 1987;29:107-109.
Loscalzo J, Braunwald E.  Tissue plasminogen activator . N Engl J Med . 1988;319:925-931.Article
Snyder RW, Lambrou FH, Williams GA.  Intraocular fibrinolysis with recombinant human tissue plasminogen activator: experimental treatment in a rabbit model . Arch Ophthalmol . 1987;105:1277-1280.Article
Lambrou FH, Snyder RW, Williams GA, Lewandowski M.  Treatment of experimental intravitreal fibrin with tissue plasminogen activator . Am J Ophthalmol . 1987;104:619-623.
Johnson RN, Olsen KR, Hernandez E.  Tissue plasminogen activator treatment of postoperative intraocular fibrin . Ophthalmology . 1988;95:592-596.Article
Williams GA, Lambrou FH, Jaffe GA, et al.  Treatment of postvitrectomy fibrin formation with intraocular tissue plasminogen activator . Arch Ophthalmol . 1988;106:1055-1058.Article
Ortiz JR, Walker SD, McManus PE, Martinez LA, Brown RH, Jaffe GJ.  Filtering bleb thrombolysis with tissue plasminogen activator . Am J Ophthalmol . 1988;106:624-625.Article
Ozment RR, Liaw ZC, Krug J, Melamed S, Latina M.  Use of tissue plasminogen activator in experimental filtration surgery . Invest Ophthalmol Vis Sci . 1989;30( (suppl) ):418.
Vaid K, Fourman S.  Effects of human tissue plasminogen activator (tPA) on glaucoma filter blebs in rabbits . Invest Ophthalmol Vis Sci . 1989;30( (suppl) ):416.
Williams AS, Latina MA.  Use of tPA to treat post-cyclocryotherapy pressure elevation . Invest Ophthalmol Vis Sci . 1989;30( (suppl) ):354.
Lambrou FH, Snyder RW, Williams GA.  Use of tissue plasminogen activator in experimental hyphema . Arch Ophthalmol . 1987;105:995-997.Article
Vine AK, Maguire PT, Martonyi C, Kincaid MC.  Recombinant tissue plasminogen activator to lyse experimentally induced retinal arterial thrombi . Am J Ophthalmol . 1988;105:266-270.
Oncel M, Peyman GA, Khoobehi B.  Tissue plasminogen activator in the treatment of experimental retinal vein occlusion . Retina . 1989;9:1-7.Article
Elman MJ, Quinlan P, Fine SL, et al.  Thrombolytic therapy for central retinal vein occlusion . Invest Ophthalmol Vis Sci . 1988;29( (suppl) ):68.
Kreutzer A, Brunner R, Schäfer HJ, Sickel W, Auel H, Hossmann V.  Lysetherapie mit rt-PA bei Patienten mit Stammoder Zentralvenenocclusion der Retina . Fortschr Ophthalmol . 1988;85:511-513.
Reim M, Bertram B, Wolf S.  Behandlungs-versuche der Zentralvenenthrombose der Netzhaut mit Plasminogen-Aktivator (rt-PA) . Klin Wochenschr . 1988;66( (suppl 12) ):143-149.
Johnson RN, Olsen KR, Hernandez E.  Intravitreal tissue plasminogen activator treatment of experimental vitreous hemorrhage . Arch Ophthalmol . 1989;107:891-894.Article
Jaffe GJ, Green GDJ, McKay BS, Hartz A, Williams GA.  Intravitreal clearance of tissue plasminogen activator in the rabbit . Arch Ophthalmol . 1988;106:969-972.Article
Dabbs CK, Aaberg TM, Aguilar H, Sternberg P, Meredith TA.  Complications of the treatment of severe fibrinous response following diabetic vitrectomy with tissue plasminogen activator . Invest Ophthalmol Vis Sci . 1989;30( (suppl) ):273.
McDermott ML, Edelhauser HF, Hyndiuk RA, Koenig SB.  Tissue plasminogen activator and the corneal endothelium . Am J Ophthalmol . 1989;108:91-92.
Olney JW.  The toxic effects of glutamate and related compounds in the retina and brain . Retina . 1982;2:341-359.Article
Sisk DR, Kuwabara T.  Histologic changes in the inner retina of albino rats following intravitreal injection of monosodium L-glutamate . Graefes Arch Clin Exp Ophthalmol . 1985;223:250-258.Article
Lucas DR, Newhouse JP.  The toxic effect of sodium L-glutamate on the inner layers of the retina . Arch Ophthalmol . 1957;58:193-201.Article
Greenberger LM, Besharse JC.  Stimulation of photoreceptor disc shedding and pigment epithelial phagocytosis by glutamate, aspartate, and other amino acids . J Comp Neurol . 1985;239:361-372.Article
Ishikawa Y, Kuwabara T, Kaiser-Kupfer MI.  Toxic effects of ornithine and its related compounds on the retina . Adv Exp Med Biol . 1982;153:371-378.
Van Herreveld A, Fifkova E.  Effects of amino acids on the isolated chicken retina, and on its response to glutamate stimulation . J Neurochem . 1973;20:947-962.Article