Intravitreal Tissue Plasminogen Activator Research Articles

Intravitreal Tissue Plasminogen Activator and Pneumatic Displacement of Submacular Hemorrhage Secondary to Retinal Artery Macroaneurysm

To assess the efficacy of treating submacular hemorrhages secondary to retinal arterial macroaneurysm with intravitreous tissue plasminogen activator (tPA) and gas. Six consecutive patients (6 eyes) with submacular hemorrhage secondary to retinal arterial macroaneurysm were included in this study. Tissue plasminogen activator, at a dose of 50 microg/0.1 mL, was injected through the pars plana into the vitreous cavity. Gas (0.3-0.5 mL of perfluoropropane) instillation followed tPA injection, either immediately after injection or sometime during the next day. Best postoperative visual acuity improved in 5 of 6 eyes (83%) and was unchanged in 1 of 6 (17%) eyes. In 5 of 6 (83%) eyes, the procedure resulted in complete or partial displacement of submacular hemorrhage out of the foveal area. Intravitreous injection of tPA and gas, followed by prone positioning of the patient, is an effective and simple treatment of submacular hemorrhage secondary to retinal arterial macroaneurysm. No complication occurred in this series.

Results of intravitreal tissue plasminogen activator and expansile gas injection for submacular haemorrhage in Thais

To study the results of intravitreal tissue plasminogen activator (tPA) and expansile gas injection for submacular haemorrhage in Thai patients. The medical records of Thai patients who presented with submacular haemorrhage between January 1998 and December 2002 were reviewed. The inclusion criteria were acute onset of bleeding (<1 month), treatment with intravitreal injection of tPA solution (50-100 mug in 0.1 ml) and expansile gas (0.3-0.4 ml of 100% perfluoropropane or sulphur hexafluoride), and at least 6 months of follow-up. Our main outcome measures were best final postoperative visual acuity and surgical complications. A total of 19 eyes of 19 patients completed the inclusion criteria with a mean duration of 13.1 days. The causes of haemorrhage were age-related macular degeneration in 15 eyes (78.9%), idiopathic choroidal neovascularization in two eyes (10.5%), and traumatic, and valsalva retinopathy in one eye each (5.2%). After a mean follow-up of 13 months (range 6-39 months), postoperative visual acuity improved two lines or greater in 12 eyes (63.2%), stabilized in six eyes (31.6%) and worsened in one (5.2%). The final visual acuity measured 20/63 or better in 10 eyes (52.6%). The surgical complications were breakthrough vitreous haemorrhage (three eyes) and cataracts (three eyes), and two had retinal detachments. The treatment of submacular haemorrhage with intravitreal injection of tPA and expansile gas improved visual acuity in more than half of the patients. In all, 10 in 19 eyes demonstrated final visual acuity at a functional level.

Intravitreous Recombinant Tissue Plasminogen Activator and Gas to Treat Submacular Hemorrhage in Age-Related Macular Degeneration

We evaluated the safety and efficacy of intravitreous recombinant tissue plasminogen activator (rTPA) and gas for the treatment of submacular hemorrhage in age-related macular degeneration (ARMD). From January 2000 to April 2002, we enrolled 15 patients with submacular hemorrhage secondary to ARMD. All patients received 100 microg rTPA and 0.3 mL perfluoropropane intravitreously. Postoperatively, all patients were kept in a supine position for 4 hours followed by a face-down position for 4 days. Anatomic and functional results were evaluated during a follow-up period of 6 to 19 months. Submacular blood was completely displaced in 12 patients (80%) and partially in three (20%). Best postoperative visual acuity improved in all 15 eyes; in seven eyes (47%), the improvement was two or more lines. Final visual acuity improved in 12 eyes, remained stable in two eyes, and worsened in one eye. Onset of hemorrhage within 21 days was associated with better gains of lines in best postoperative (p = 0.0256) and final visual acuity (p = 0.044). Although two patients developed mild breakthrough vitreous hemorrhage within 1 day after treatment, no rTPA-related retinal toxicity was observed. Intravitreous injections of rTPA and gas are safe and effective in improving visual acuity in patients with submacular hemorrhage secondary to ARMD. Although the final visual outcome is often limited by the progression of the disease, significant and stable visual recovery over an extended follow-up period is possible using this easy and convenient technique.

Intravitreal tissue plasminogen activator in the management of central retinal vein occlusion.

To evaluate the role of intravitreal tissue plasminogen activator (tPA) in the management of central retinal vein occlusion (CRVO) in patients with symptoms for <3 days. We evaluated the visual outcome of a consecutive series of patients with CRVO following intravitreal tPA injection. All patients presented with visual acuity worse than 20/50 within 3 days from the onset of symptoms. Main outcome measures included percentage of patients whose final vision improved to 20/50 or better and change in percentage of patients with vision of 20/200 or worse before and after treatment. Twelve patients received intravitreal tPA for CRVO. Nine patients (75%) had best-corrected visual acuity of 20/200 or worse at presentation compared with 4 patients (33%) at the last follow-up after treatment. Five (55%) of these 9 patients had final visual acuity that improved to 20/50 or better. The remaining four patients did not have improvement or their vision continued to worsen. All 4 patients had fluorescein angiographic evidence of >10 disk areas of capillary nonperfusion at presentation. Overall, 8 (67%) of 12 patients had final visual acuity of 20/50 or better. No side effects related to tPA injection were observed. Our data suggest that intravitreal tPA injection may have a beneficial role in the management of CRVO when used within a few days of the onset of symptoms in patients with no angiographic evidence of severe capillary nonperfusion even if initial visual acuity is 20/200 or worse.

Intravitreal Tissue Plasminogen Activator for the Treatment of Central Retinal Vein Occlusion

A 58-year-old hypertensive man with a perfused central retinal vein occlusion of 21 days' duration received 50 µg of intravitreal recombinant tissue plasminogen activator in 0.1 cc. Best-corrected visual acuity improved 2 weeks after the injection. Optical coherence tomography and fluorescein angiography demonstrated resolution of cystoid macular edema and improvement of venous outflow. Intravitreal tissue plasminogen activator may be a useful treatment for central retinal vein occlusion with a duration of 21 days or less. [Ophthalmic Surg Lasers Imaging 2003; 34:350–352.]

Retinal toxicity of intravitreal tissue plasminogen activator: Case report and literature review

Objective To present the clinical picture of retinal toxicity of commercial tissue plasminogen activator (tPA). Design Case report and literature review. Methods Two successive intravitreal injections of tPA (50 μg) 3 days apart with gas tamponade were given to treat a 49-year-old man with submacular hemorrhage. The adverse consequences of this treatment were monitored. A literature review of retinal toxicity of commercial tPA in animals was also done. Main outcome measures Retinal findings, electroretinograph (ERG) and visual acuity testing. Results Diffuse pigmentary alterations sparing the posterior pole, poor visual acuity after the absorption of submacular hemorrhage, reduced scotopic and photopic ERG A- and B-waves were noted. Conclusions This is the first reported case of retinal toxicity of commercial tPA in humans that resembles the descriptions of tPA-mediated retinal toxicity in animal models. The dosage of intravitreal tPA (between 50 and 100 μg) may be toxic to the human retina.

Intravitreous injection of tissue plasminogen activator and gas in the treatment of submacular hemorrhage under various conditions.

To investigate the efficacy and safety of treating submacular hemorrhages secondary to age-related macular degeneration (ARMD) with intravitreous recombinant tissue plasminogen activator (rt-PA) and gas under various conditions. Prospective, noncomparative case series. Forty-three consecutive eyes of 42 patients with recent (range, 2-28 days) subfoveal hemorrhage secondary to ARMD were included in this study. The size of subretinal hemorrhage ranged from 0.25 to 30 disc areas. All patients were treated with intravitreous injections of rt-PA (50 microg) and sulfur hexafluoride (0.5 ml). Postoperative prone positioning was maintained for 24 to 72 hours. Patient follow-up ranged from 4 to 18 months (mean, 6 months). Best and final postoperative visual acuity in relation to size and onset of hemorrhage, displacement of subretinal blood, and surgical complications. Best postoperative visual acuity compared with preoperative visual acuity was improved two or more Snellen lines in 19 eyes (44%) and stable in 24 eyes (56%). Final visual acuity was improved two or more lines in 13 eyes (30%), stable in 26 (61%), and two or more lines worse in 4 eyes (9%). Duration of hemorrhage <or=14 days was associated with a better gain of lines of vision (P = 0.0058). Best postoperative acuity was maintained for an average of 4.2 months (range, 0.5-12 months). Overall, complete displacement of blood from under the fovea was achieved in 35 eyes (81%). Nine eyes (21%) developed recurrent hemorrhage, which required repeat treatment. In three patients (7%), a mild breakthrough vitreous hemorrhage was observed. Our findings suggest that intravitreous injections of rt-PA and gas are of value for an improved and accelerated visual recovery in ARMD patients with submacular hemorrhage, although final visual outcome is often limited by the progression of the underlying ARMD. Patients with retinal hemorrhages of recent onset (<or=14 days) seem to have the most favorable results. A rapid displacement of submacular blood may reveal discrete choroidal neovascular membranes amenable to further treatment. The complication rate of this minimally invasive technique seems to be low.

Treatment of Submacular Hemorrhage with Low-Dose Intravitreal Tissue Plasminogen Activator Injection and Pneumatic Displacement

Treatment of Submacular Hemorrhage with Low-Dose Intravitreal Tissue Plasminogen Activator Injection and Pneumatic Displacement

Short and long term effect of intravitreal tissue plasminogen activator in eyes with submacular hemorrhage

Objective To determine the effect and side effects of intravitreal rTPA in eyes with submacular hemorrhage.

Treatment of recent onset central retinal vein occlusion with intravitreal tissue plasminogen activator: a pilot study

AIMSTo study the effects of intravitreal tissue plasminogen activator (tPA) in recent onset central retinal vein occlusion (CRVO).METHODS15 patients with recent onset CRVO (from 1–21 days' duration, mean 8 days)...

Pneumatic displacement of submacular hemorrhage.

Patients with thick submacular hemorrhage complicating age-related macular degeneration and other disorders typically have a poor visual prognosis. A new outpatient procedure, consisting of intravitreal injection of tissue plasminogen activator and gas followed by brief prone positioning, is effective in displacing thick submacular blood and facilitating visual improvement in most patients. Injection of gas alone also appears to be effective in many eyes. The procedure is technically simple and the rate of serious complications appears to be acceptably low. Although the final visual outcome is often limited by progression of age-related macular degeneration, significant and stable visual recovery is possible in selected eyes. Prospective clinical trials are needed to clarify the role for intravitreal tissue plasminogen activator and to provide definitive outcome comparisons with other management approaches.

Retinal toxicity of commercial intravitreal tissue plasminogen activator solution in cat eyes.

We previously reported retinal toxic reactions in rabbit eyes receiving intravitreal injections of commercial tissue plasminogen activator (tPA) in concentrations greater than or equal to 50 microg/0.1 mL, and recent clinical experience suggests that intravitreal tPA solution may produce toxic effects in human eyes. We therefore investigated the dose-dependent retinal toxicity of intravitreal commercial recombinant tPA solution in cat eyes, which have a vascularized inner retina and vitreous volume similar to that of human eyes. Commercial tPA in L-arginine solution was injected into the mid vitreous cavity of normal cat eyes in doses of 25, 50, 75, and 100 microg/0.1 mL and 200 microg/0.2 mL. Control (fellow) eyes received an equal volume of sterile saline solution. After injection, eyes were evaluated by ophthalmoscopy and electroretinography for 14 days and then enucleated for histopathological evaluation. Fundus pigmentary alterations were observed in eyes receiving doses greater than or equal to 50 microg/0.1 mL. Changes were centered in the area around the injection site, and the area's size increased in proportion to the dosage. Mean electroretinography B-wave amplitude measured at 14 days was significantly reduced in eyes receiving greater than or equal to 50 microg of tPA in a dose-dependent fashion. Light microscopy of the involved areas showed loss of photoreceptor elements with necrosis and proliferation of the retinal pigment epithelium. Intravitreal injection of commercial tPA solution results in dose-dependent retinal toxicity in cat eyes. Because cat eyes are similar to human eyes regarding retinal vascularity and vitreous volume, intravitreal injections of commercial tPA (with L-arginine vehicle) in concentrations greater than 25 microg/0.1 mL are potentially unsafe in human eyes.

Vitreous hemorrhage after intravitreal tissue plasminogen activator (t-PA) and pneumatic displacement of submacular hemorrhage

PURPOSE: To report the immediate complication of dense vitreous hemorrhage after intravitreal injection of tissue plasminogen activator and gas for treatment of two cases of sudden submacular hemorrhage associated with retinal arterial macroaneurysm. METHODS: Case reports. RESULTS: Two patients, a 67-year-old woman and a 92-year-old man, presented with sudden vision loss related to submacular hemorrhage from a retinal macroaneurysm. Tissue plasminogen activator at a dose of 50 μg to 75 μg and a sulfur hexafluoride (SF 6) gas bubble were injected intravitreally under local anesthesia. Dense vitreous hemorrhage was noted on the first postoperative day in both cases, which subsequently required pars plana vitrectomy removal. CONCLUSION: Sudden severe vitreous hemorrhage may be an immediate complication after intravitreal injection of tissue plasminogen activator and gas for treatment of submacular hemorrhage associated with retinal arterial macroaneurysm.

Induction of Posterior Vitreous Detachment in Rabbits by Intravitreal Injection of Tissue Plasminogen Activator Following Cryopexy

The purpose of this study was to generate intravitreal plasmin after intravitreal injection of tissue plasminogen activator (TPA) and cryopexy, and to assess its proteolytic effect on the vitreoretinal border region.Twenty-four hr after a mild cryopexy, 25 μg recombinant tissue plasminogen activator (TPA) was injected into the vitreous cavity, the fellow eye received an intravitreal injection of the same volume of buffered salt solution. Light, scanning and transmission electron microscopy was performed in 24 eyes that underwent vitrectomy 1 week later. Plasmin was measured prior and 2 hr after intravitreal TPA injection (4 eyes). Hyaluronic acid (8 eyes) and vitronectin (4 eyes) were measured 1 week after TPA- or BSS-injection and compared to untreated controls.In all eyes treated with TPA, histopathologic examination by scanning and transmission electron microscopy demonstrated a complete detachment of the vitreous from the surface of the retina as well as from the posterior surface of the lens. After BSS-injection, vitreous cortex attachment to the retina was demonstrated in all eyes. Two hr after TPA-injection, plasmin increased to 9.75 mU ml-1(s.d.±2.3). Neither a decrease of hyaluronic acid nor an increase of transglutaminase, that might alter the vitreous structure leading to a collapse of the vitreous, were detected in treated eyes. There was no increase of vitronectin indicating proliferative activity.A temporary breakdown of the blood–retinal barrier by cryopexy combined with intravitreal injection of TPA is a sufficient technique to induce a posterior vitreous detachment enzymatically. The method may be useful prior to mechanical vitrectomy.

A study of the ability of tissue plasminogen activator to diffuse into the subretinal space after intravitreal injection in rabbits

PURPOSE: Intravitreal injections of tissue plasminogen activator have been used to lyse fibrin from blood in the subretinal space, despite the lack of proof that tissue plasminogen activator can diffuse across the retina. We tested whether tissue plasminogen activator injected into the vitreous could penetrate the neural retina and enter the subretinal space. METHODS: We injected a mixture of 50 μg of tissue plasminogen activator (70 kD) labeled with fluorescein isothiocyanate and rhodamine B isothiocyanate–labeled dextran, which has a lower molecular weight (20 kD), into the midvitreous cavity of one eye in each of 18 rabbits. The eyes were enucleated after 3, 6, and 24 hours, and cryosections were examined with epifluorescent microscopy to determine the distribution of the labeled molecules. We also evaluated tissue plasminogen activator pharmacokinetics in one eye each of 18 rabbits in which a subretinal clot was induced by injecting autologous blood (50 μL) into the subretinal space through the sclera. Fluorescein isothiocyanate–labeled tissue plasminogen activator was injected into the vitreous 2 days after induction of the subretinal clot. RESULTS: Fluorescein isothiocyanate–labeled tissue plasminogen activator was present at the vitreal surface of the retina in a linear array in all 36 eyes studied, whereas the rhodamine B isothiocyanate–labeled dextran had diffused throughout the neural retina in the same sections. No fluorescein isothiocyanate signal was observed in the neural retina or in the subretinal clot. Vitreous hemorrhage caused by retinal perforation was observed in all eyes with intraretinal hemorrhage in which fluorescein isothiocyanate fluorescence was seen in the neural retina and inside the clot. CONCLUSION: Intravitreal tissue plasminogen activator did not diffuse through the intact neural retina to reach a subretinal clot. This study demonstrates no scientific rationale for the intravitreal tissue plasminogen activator treatment of submacular hemorrhage without vitreous hemorrhage presumably caused by an overlying retinal break.

Management of submacular hemorrhage with intravitreous tissue plasminogen activator injection and pneumatic displacement

Objective To investigate the efficacy and safety of treating thick submacular hemorrhages with intravitreous tissue plasminogen activator (tPA) and pneumatic displacement. Design Retrospective, noncomparative case series. Participants From 5 participating centers, 15 eligible patients had acute (<3 weeks) thick subretinal hemorrhage involving the center of the macula in eyes with pre-existing good visual acuity. Hemorrhages were secondary to age-related macular degeneration in 13 eyes and macroaneurysm and trauma in 1 eye each. Methods The authors reviewed the medical records of 15 consecutive patients who received intravitreous injection of commercial tPA solution (25–100 μg in 0.1–0.2 ml) and expansile gas (0.3–0.4 ml of perfluoropropane or sulfur hexafluoride) for thrombolysis and displacement of submacular hemorrhage. After surgery, patients maintained prone positioning for 1 to 5 days (typically, 24 hours). Main outcome measures Degree of blood displacement from under the fovea, best postoperative visual acuity, final postoperative visual acuity, and surgical complications. Results In 15 (100%) of 15 eyes, the procedure resulted in complete displacement of thick submacular hemorrhage out of the foveal area. Best postprocedure visual acuity improved by 2 lines or greater in 14 (93%) of 15 eyes. After a mean follow-up of 10.5 months (range, 4–19 months), final visual acuity improved by 2 lines or greater in 10 (67%) of 15 eyes and measured 20/80 or better in 6 (40%) of 15 eyes. Complications included breakthrough vitreous hemorrhage in three eyes and endophthalmitis in one eye. Four eyes developed recurrent hemorrhage 1 to 3 months after treatment, three of which were retreated with the same procedure. Conclusions Intravitreous injection of tPA and gas followed by brief prone positioning is effective in displacing thick submacular blood and facilitating visual improvement in most patients. The rate of serious complications appears low. Final visual outcomes are limited by progression of the underlying macular disease in many patients.

Intravitreal tPA and SF 6 Promote Clearing of Premacular Subhyaloid Hemorrhages in Shaken and Battered Baby Syndrome

Child abuse is a serious problem in many cultures. The ocular signs of shaken baby include intraretinal, subretinal, and preretinal hemorrhages. The hemorrhages may be unilateral or bilateral and are seen in 50% to 80% of patients. Previous treatment was limited to observation or vitrectomy, but some observed eyes develop amblyopia, and pediatric vitrectomy has many complications. We report 4 eyes in 2 children with shaken baby syndrome in whom we administered intravitreal tissue plasminogen activator (tPA) in an attempt to resolve preretinal hemorrhages earlier than observation alone without the complications of vitrectomy. The tPA dose ranged from 12.5-25 microg per injection. Eyes were injected once weekly for 3 consecutive weeks. Each time 0.25 cc of sulfur hexafluoride gas was also injected. Within 1 week following the last tPA administration, complete resolution of the preretinal hemorrhage was seen. There were no associated ophthalmic complications. Intravitreal tPA with an expansive gas is an alternative method to observation or vitrectomy for resolution of preretinal hemorrhages in battered babies and may allow faster resolution of hemorrhages without the complications of vitrectomy.

Intravitreal Tissue Plasminogen Activator for Acute Central Retinal Vein Occlusion

We investigated the efficacy of intravitreal tissue plasminogen activator (tPA) for the treatment of acute central retinal vein occlusion. Twenty-six eyes with central retinal vein occlusion (CRVO, n=23) and hemi-retinal vein occlusion (n=3) with recent onset of visual symptoms (< or = 21 days) were identified and given an intravitreal injection of 65 -110 microg of tPA. Among eyes with CRVO, visual acuity improved to > or = 20/40 in 7 of 23 patients (30.4%) at 6 weeks, and 8 of 23 patients (34.8%) at 6 months. Visual acuity improved or stabilized in 69.6% (16 of 23 patients) at the 6 week visit and persisted with longer follow-up. Four patients developed doubling of the visual angle. No patients developed rhegmatogenous retinal detachment, infection or neovascular glaucoma. One patient developed a small vitreous hemorrhage and 2 developed an increase in the size of pre-existing macular hemorrhage. Intravitreal tPA administered early in the course of central retinal vein occlusion did not lead to catastrophic hemorrhagic events. Intravitreal tPA may cause worsening of vision in some patients. While some eyes appear to have benefited from the therapy, no conclusions can be reached because there was not a concurrent control group. A randomized clinical trial is necessary to determine its efficacy. Intravitreal tPA administered early in the course of central retinal vein occlusion did not lead to catastrophic hemorrhagic events. A randomized clinical trial is necessary to determine its efficacy.

The use of intravitreal tissue plasminogen activator in the treatment of experimental subretinal hemorrhage in the pig model.

To clinically and surgically evaluate clot lysis in an animal model of subretinal hemorrhage after intravitreal injection of tissue plasminogen activator. Autologous subretinal hemorrhages were created via a transvitreal approach in 18 pigs. The next day (day 1) animals were randomly selected to receive either an intravitreal injection of 0.1 mL balanced salt solution or 0.1 mL tissue plasminogen activator (25 micrograms) followed by observation or vitrectomy a day later. On day 2, six pigs (all treated with tissue plasminogen activator) underwent a vitrectomy in which aspiration of the subretinal hemorrhage was attempted. The other eyes were evaluated for clot lysis by ophthalmoscopy at days 3, 10, and 30. All eyes were examined histopathologically. The eyes that had been treated with tissue plasminogen activator demonstrated a color change at the peripheral margin, which suggested that clot lysis had occurred. At the time of the vitrectomy, the clots were liquefied partially; removal by aspiration alone, however, was not possible. Photoreceptor damage was moderate to severe by day 10 in all eyes, whether they were treated with tissue plasminogen activator or balanced salt solution. All eyes that underwent vitrectomy had moderate to severe photoreceptor damage. In this animal model, intravitreal tissue plasminogen activator was associated with features that suggested partial clot lysis; tissue plasminogen activator did not produce sufficient lysis to allow surgical removal by aspiration alone, however.

Intravitreal recombinant tissue plasminogen activator in the treatment of experimentally induced bacterial endophthalmitis

Intravitreal injection of antibiotics has been shown to be effective in the treatment of bacterial endophthalmitis, but does not prevent the formation of fibrin. Recombinant tissue plasminogen activator (rTPA), a fibrinolytic agent, was evaluated in experimentally induced Staphylococcus aureus endophthalmitis in an animal model. Significant fibrinous reaction in the vitreous was present in three of six eyes treated with intravitreal injection of clindamycin and rTPA (50%) and in one of five eyes treated with clindamycin only (20%). Fibrin clot formation in the anterior chamber was present in two of six eyes treated with clindamycin and rTPA (33%) and not observed in the clindamycin treated eyes (0%). These findings suggest that rTPA does not play a beneficial role in the treatment of bacterial endophthalmitis in the presence of the vitreous.