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Past, present, and future
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.
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Past, present, and future