点击显示 收起
University of South Carolina School of Medicine, Columbia, SC, USA
Past, present, and future
Keywords: tissue plasminogen activator
The systemic (intravenous) administration of genetically modified (recombinant) tissue plasminogen activator (tPA) for thrombolysis in coronary arteries was approved by the US Federal Drug Administration in 1988. Since then, use of this approved drug has been extended to many non-approved indications, especially in the eye.1
Tissue plasminogen activator is a naturally occurring serine protease produced by a variety of mammalian tissues, especially endothelial cells. Ocular tissues that contain tPA include the conjunctiva, cornea, trabecular meshwork, lens, vitreous, and retina.1–3 In normal adult human eyes, the aqueous humour contains a significant amount of tPA that is some 30 times more than in plasma.4 The major enzymatic action of tPA is the conversion of plasminogen (a zymogen) into plasmin, an active serine protease that hydrolyses fibrin. Compared to other fibrinolytic agents (for example, urokinase and streptokinase), tPA has several advantages: fibrin forms a ternary complex with tPA and plasminogen, which increases the rate of plasminogen activation several hundred-fold; in addition, tPA serves to protect plasmin from antiplasmin inhibitors until complete clot lysis is achieved.5–7 Even though cost effective, urokinase and streptokinase did not gain popularity because of their toxicity.8,9,10,11
Since fibrin clots can occur in several sites of the body, including the eye, the notion was conceived that tPA therapy could be effective for the rapid dissolution of fibrin clots in the anterior chamber of the human eye,1,4,12,13 as well as for lysis of fibrin clots after vitrectomy14–17 and failed blebs after glaucoma filtering surgery.1,18–20
As clinicians, we have to weigh the possible risks versus the benefits in deciding whether to pursue the prophylactic use of tPA
In this issue of the BJO (p 1458), Siatiri and colleagues report the results of a prospective, double masked randomised clinical trial in paediatric patients to evaluate the efficacy of 20 μg tPA, administered intracamerally at the completion of congenital cataract surgery, with the aim of preventing severe fibrinous effusion and its sequelae. The rationale for this approach is based on the frequent occurrence of fibrin exudation in paediatric patients, which may cause complications including delayed visual recovery, after an otherwise successful cataract surgery.21,22 The randomisation in the study presumes that all patients would develop a fibrinous reaction after the surgical procedure, irrespective of tissue manipulation. The results show that compared to controls, the number of eyes that had anterior chamber reaction and fibrin formation was significantly reduced (p = 0.02 to 0.01) on days 1, 3, 7, and 14 after surgery and intracameral delivery of tPA. However, after 1–3 months of follow up, the difference between the two groups was statistically insignificant.
Prophylactic use of tPA is akin to the concept of using antibiotics preoperatively or intraoperatively to prevent postoperative infection of the eye. As clinicians, we have to weigh the possible risks versus the benefits in deciding whether to pursue such an approach. Because of the reactivity of ocular tissues and fibrinous exudation, especially in children, and in view of the fact that post-surgical intracameral administration of tPA in a child’s eye requires general anaesthesia or short sedation,23,24 it may be reasonable to use tPA prophylactically. The half life of tPA in the blood circulation is short (about 5 minutes).7,25 However, it is possible that in the closed cavity of the anterior chamber of the eye, and with the low daily turnover of aqueous humour, tPA persists for several hours,1 which may justify intracameral delivery at the conclusion of surgery. We must also consider that paediatric patients who require surgical removal of congenital cataract often have many other ocular and systemic disorders and therefore warrant careful individual evaluation before administration of prophylactic tPA.
An amount of 25 μg or more of tPA has been widely used intracamerally or intravitreally.13–16,19,26–29 Based on extrapolation of the therapeutic serum concentration of tPA achieved with intravenous therapy for coronary thrombolysis, we advocated that 10 μg would be an equivalent and safe dose for intracameral administration.1 Several reports in the literature support the effectiveness of 10 μg tPA for rapid (within minutes to a few hours) fibrinolysis in the anterior chamber and some investigators even recommend a dose as low as 3 μg.1,20,30–35 Indeed, untoward side effects such as intraocular haemorrhage/rebleed/hyphaema, especially after surgical trauma, as well as corneal and retinal toxicity, have been reported with the use of 25 μg or higher doses of tPA.13,15–17,26,32,33,35–38 Although an optimal intracameral therapeutic or prophylactic dose of this very potent drug has not been determined, 10 μg or less of TPA appears to achieve the desired fibrinolytic action in the anterior chamber with potentially minimal complications of rebleed and toxicity to the cornea and retina.
The topical application of tPA to dissolve fibrin clot in the anterior chamber has been advocated by several investigators, although studies in human eyes and experimental animal models have produced equivocal results.39–42 Because of the large molecular size (68 kDa) of tPA, its penetration across the intact cornea may be limited.1 Transconjunctival or subconjunctival, sub-Tenon’s capsule and trans-scleral routes deserve consideration, especially if clinicians prefer to initiate tPA therapy postoperatively after paediatric or adult cataract surgery. With this approach, the need for a short duration of general anaesthesia or sedation for intracameral injection especially in children, can be avoided and tPA could be administered in the postoperative follow up period on an as needed basis. This concept poses a challenge to clinicians and the pharmaceutical industry interested in developing novel methods for tPA drug delivery.
REFERENCES
Tripathi RC, Tripathi BJ, Bornstein S, et al. Use of tissue plasminogen activator for rapid dissolution of fibrin and blood clots in the eye after surgery for glaucoma and cataract in humans. Drug Dev Res 1992;27:147–59.
Park JK, Tripathi RC, Tripathi BJ, et al. Tissue plasminogen activator in the trabecular endothelium. Invest Ophthalmol Vis Sci 1987;28:1341–5.
Geanon JD, Tripathi BJ, Tripathi RC, et al. Tissue plasminogen activator in avascular tissues of the eye: a quantitative study of its activity in the cornea, lens, and aqueous and vitreous humors of dog, calf, and monkey. Exp Eye Res 1987;44:55–63.
Tripathi RC, Park JK, Tripathi BJ, et al. Tissue plasminogen activator in human aqueous humor and its possible therapeutic significance. Am J Ophthalmol 1988;106:719–22.
Kwaan HC, Samama MM, Nguyen G. Fibrinolytic systems. In: Kwaan HC, Samama MM, eds. Clinical thrombosis. Boca Raton: CRC Press, 1989:23–31.
Weitz JI, Stewart RJ, Fredenburgh JC. Mechanism of action of plasminogen activators. Thromb Haemost 1999;82:974–82.
Collen D, Lijen HR. Tissue-type plasminogen activator: a historical perspective and personal account. J Thromb Haemost 2004;2:541–6.
Forrester JV, Williamson J. Lytic therapy in vitreous haemorrhage. Trans Ophthalmol Soc UK 1974;94:583–6.
Bramsen T. The effect of urokinase on central corneal thickness and vitreous haemorrahge. Acta Ophthalmol 1978;56:1006–12.
Textorius O, Stenkula S. Toxic ocular effects of two fibrinolytic drugs: an experimental electroretinographic study on albino rabbits. Arch Ophthalmol 1983;61:322–31.
Mindel JS. Special topics. Part 2: Drugs affecting blood. In: Duane TD, ed. Biomedical foundations of ophthalmology Philadelphia, Harper and Row 1991;41:1–26.
Tripathi RC, Tripathi BJ, Park JK, et al. Intracameral tissue plasminogen activator for resolution of fibrin clots after glaucoma filtering procedures. Am J Ophthalmol 1991;111:247–28.
Snyder RW, Sherman MD, Allinson RW. Intracameral tissue plasminogen activator for treatment of excessive fibrin response after penetrating keratoplasty. Am J Ophthalmol 1990;109:483–4.
Williams GA, Lambrou FH, Jaffe GJ, et al. Treatment of postvitrectomy fibrin formation with intraocular tissue plasminogen activator. Arch Ophthalmol 1988;106:1055–8.
Jaffe GJ, Lewis H, Han DP, et al. Treatment of postvitrectomy fibrin pupillary block with tissue plasminogen activator. Am J Ophthalmol 1989;108:170–5.
Jaffe GJ, Abrams GW, Williams GA, et al. Tissue plasminogen activator for postvitrectomy fibrin formation. Ophthalmology 1990;97:184–9.
Dabbs CK, Aaberg TM, Aguilar HE, et al. Complications of tissue plasminogen activator therapy after vitrectomy for diabetes. Am J Ophthalmol 1990;110:354–60.
Ortiz JR, Walker SD, McManus PE, et al. Filtering bleb thrombolysis with tissue plasminogen activator. Am J Ophthalmol 1988;106:624–65.
Baker ND, Lehman DM, Weber PA, et al. Tissue plasminogen activator treatment of failing glaucoma filtering surgery. ARVO ABSTRACT. Invest Ophthalmol Vis Sci 1991;32 (suppl 4) :1122.
Smith MF, Doyle JW. Use of tissue plasminogen activator to revive blebs following intraocular surgery. Arch Ophthalmol 2001;119:809–12.
Jameson NA, Good WV, Hoyt CS. Inflammation after cataract surgery in children. Ophthalmic Surg Lasers 1992;23:99–102.
Fallaha N, Lambert SR. Pediatric cataracts. Ophthalmol Clin N Am 2001;14:479–92.
Klais CM, Hattenbach LO, Steinkamp GW, et al. Intraocular recombinant tissue-plasminogen activator fibrinolysis of fibrin formation after cataract surgery in children. J Cataract Refract Surg 1999;25:357–62.
Mehta JS, Adams GGW. Recombinant tissue plasminogen activator following paediatric cataract surgery. Br J Ophthalmol 2000;84:983–6.
Rijken DC, Otter M, Kuiper J, et al. Receptor-mediated endocytosis of tissue-type plasminogen activator (t-PA) by liver cells. Thromb Res Suppl 1990;10:63–71.
Wedrich A, Menapace R, Muhlbauer-Ries E. The use of recombinant tissue plasminogen activator for intracameral fibrinolysis following cataract surgery. Int Ophthalmol. 1994–95 18:277–80.
Wedrich A, Menapace R, Reis E, et al. Intracameral tissue plasminogen activator to treat severe fibrinous effusion after cataract surgery. J Cataract Refract Surg 1997;23:873–7.
Georgiadis N, Bobiridis K, Halvatzis N, et al. Low-dose tissue plasminogen activator in the management of anterior chamber fibrin formation. J Cataract Refract Surg 2003;29:729–32.
Erol N, Ozer A, Topbas S, et al. Treatment of intracameral fibrinous membranes with tissue plasminogen activator. Ophthalmic Surg Lasers Imaging 2003;34:451–6.
Williams DF, Bennett SR, Abrams GW, et al. Low-dose intraocular tissue plasminogen activator for treatment of postvitrectomy fibrin formation. Am J Ophthalmol 1990;109:606–7.
Abrams GW, Murray TG, Boldt HC, et al. Tissue plasminogen activator (t-PA): determination of clinical limits of efficacy for intracameral delivery. ARVO abstract. Invest Ophthalmol Vis Sci 1991;32 (suppl 4) :1226.
Starck T, Hopp L, Held KS, et al. Low-dose intraocular tissue plasminogen activator treatment for traumatic total hyphema, postcataract, and penetrating keratoplasty fibrinous membranes. J Cataract Refract Surg 1995;21:219–24.
Lundy DC, Sidoti P, Winarko T, et al. Intracameral tissue plasminogen activator after glaucoma surgery. Indications, effectiveness, and complications. Ophthalmology 1996;103:274–82.
Heiligenhaus A, Steinmetz B, Lapuente R, et al. Recombinant tissue plasminogen activator in cases with fibrin formation after cataract surgery: a prospective randomised multicentre study. Br J Ophthalmol 1998;82:810–15.
Kim MH, Koo TH, Sah WJ, et al. Treatment of total hyphema with relatively low-dose tissue plasminogen activator. Ophthalmic Surg Lasers 1998;29:762–6.
Lambrou FH, Synder RW, Williams GA. Use of tissue plasminogen activator in experimental hypema. Arch Ophthalmol 1987;105:995–7.
Wollensak G, Meyer JH, Loffler KU, et al. Band-like keratopathy after treatment of postoperative fibrin reaction with tissue plasminogen activator. Klin Monatsbl Augenheilkd 1996;209:43–6.
Chen SN, Yang TC, Ho CL, et al. Retinal toxicity of intravitreal tissue plasminogen activator: case report and literature review. Ophthalmology 2003;110:704–8.
Lim JI, Fiscella R, Tessler H, et al. Intraocular penetration of topical tissue plasminogen activator. Arch Ophthalmol 1991;109:714–17.
Lim JI, Maguire AM, John G, et al. Intraocular tissue plasminogen activator concentrations after subconjunctival delivery. Ophthalmology 1993;100:373–6.
Cellini M, Baldi A, Possati GL. Topical treatment of postvitrectomy fibrin formation with tissue plasminogen activator. Int Ophthalmol 1994–95;18:351–3.
Zwaan J, Latimer WB. Topical tissue plasminogen activator appears ineffective for the clearance of intraocular fibrin. Ophthalmic Surg Lasers 1998;29:476–83.