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Figure 1.
Biomicroscopy and optical coherence tomography (OCT) showing a complete posterior detachment in an eye treated with autologous plasmin enzyme (APE). A and B, Fundus photograph and fluorescein angiogram showing the branch retinal vein occlusion. C, OCT profile illustrating macular edema improvement. The first image shows the macula before injection of APE and 3 months after the third injection of bevacizumab. The middle image reflects a partial posterior hyaloid detachment after 4 days. The bottom image is the OCT scan 10 days after treatment, in which a significant improvement of the macular edema and the complete posterior vitreous detachment can be observed. This image corresponds to patient 6; the best-corrected visual acuity improved to 0.1 after 6 months of follow-up (Table 2).

Biomicroscopy and optical coherence tomography (OCT) showing a complete posterior detachment in an eye treated with autologous plasmin enzyme (APE). A and B, Fundus photograph and fluorescein angiogram showing the branch retinal vein occlusion. C, OCT profile illustrating macular edema improvement. The first image shows the macula before injection of APE and 3 months after the third injection of bevacizumab. The middle image reflects a partial posterior hyaloid detachment after 4 days. The bottom image is the OCT scan 10 days after treatment, in which a significant improvement of the macular edema and the complete posterior vitreous detachment can be observed. This image corresponds to patient 6; the best-corrected visual acuity improved to 0.1 after 6 months of follow-up (Table 2).

Figure 2.
Macular edema in patient 1. A and B, Fundus photograph and fluorescein angiogram show macular edema and an important degree of ischemia despite the laser photocoagulation treatment. C, Optical coherence tomography shows an important decrease in macular thickness 1 month after autologous plasmin enzyme injection.

Macular edema in patient 1. A and B, Fundus photograph and fluorescein angiogram show macular edema and an important degree of ischemia despite the laser photocoagulation treatment. C, Optical coherence tomography shows an important decrease in macular thickness 1 month after autologous plasmin enzyme injection.

Figure 3.
Improvement in fluorescein leakage and vitreous detachment in patient 3. A and B, Fluorescein angiogram images before and 1 month after intravitreal injection of plasmin; the improvement in the fluorescein leakage is clear. C-F, Optical coherence tomographic images showing the vitreous attached where the thickness has decreased to a more important degree and displaying improvement after the vitreous detachment.

Improvement in fluorescein leakage and vitreous detachment in patient 3. A and B, Fluorescein angiogram images before and 1 month after intravitreal injection of plasmin; the improvement in the fluorescein leakage is clear. C-F, Optical coherence tomographic images showing the vitreous attached where the thickness has decreased to a more important degree and displaying improvement after the vitreous detachment.

Table 1. 
Baseline Clinical Characteristics of Patients With Macular Edema Due to Branch Retinal Vein Occlusion Before Injection of the Autologous Plasmin Enzyme
Baseline Clinical Characteristics of Patients With Macular Edema Due to Branch Retinal Vein Occlusion Before Injection of the Autologous Plasmin Enzyme
Table 2. 
CMT Measured by Optical Coherence Tomography and Best-Corrected Visual Acuity Before APE Injection and at 1 and 6 Months After Injection
CMT Measured by Optical Coherence Tomography and Best-Corrected Visual Acuity Before APE Injection and at 1 and 6 Months After Injection
1.
Gutman  FA Macular edema in branch retinal vein occlusion: prognosis and management. Trans Sect Ophthalmol Am Acad Ophthalmol Otolaryngol 1977;83 (3, pt 1) 488- 495
PubMed
2.
Rehak  JRehak  M Branch retinal vein occlusion: pathogenesis, visual prognosis, and treatment modalities. Curr Eye Res 2008;33 (2) 111- 131
PubMedArticle
3.
The Branch Vein Occlusion Study Group, Argon laser photocoagulation for macular edema in branch vein occlusion. Am J Ophthalmol 1984;98 (3) 271- 282
PubMed
4.
Cekiç  OChang  STseng  JJ  et al.  Intravitreal triamcinolone injection for treatment of macular edema secondary to branch retinal vein occlusion. Retina 2005;25 (7) 851- 855
PubMedArticle
5.
Özkiris  AEvereklioglu  CErkilic  KDogan  H Intravitreal triamcinolone acetonide for treatment of persistent macular oedema in branch retinal vein occlusion. Eye (Lond) 2006;20 (1) 13- 17
PubMedArticle
6.
Rabena  MDPieramici  DJCastellarin  AANasir  MAAvery  RL Intravitreal bevacizumab (Avastin) in the treatment of macular edema secondary to branch retinal vein occlusion. Retina 2007;27 (4) 419- 425
PubMedArticle
7.
Mason  J  IIIFeist  RWhite  M  JrSwanner  J McGwin  G  JrEmond  T Sheathotomy to decompress branch retinal vein occlusion: a matched control study. Ophthalmology 2004;111 (3) 540- 545
PubMedArticle
8.
Saika  STanaka  TMiyamoto  TOhnishi  Y Surgical posterior vitreous detachment combined with gas/air tamponade for treating macular edema associated with branch retinal vein occlusion: retinal tomography and visual outcome. Graefes Arch Clin Exp Ophthalmol 2001;239 (10) 729- 732
PubMedArticle
9.
Charbonnel  JGlacet-Bernard  AKorobelnik  JF  et al.  Management of branch retinal vein occlusion with vitrectomy and arteriovenous adventitial sheathotomy, the possible role of surgical posterior vitreous detachment. Graefes Arch Clin Exp Ophthalmol 2004;242 (3) 223- 228
PubMedArticle
10.
Hvarfner  CLarsson  J Vitrectomy for non-ischaemic macular oedema in retinal vein occlusion. Acta Ophthalmol Scand 2006;84 (6) 812- 814
PubMedArticle
11.
Mandelcorn  MSMandelcorn  EGuan  KAdatia  FA Surgical macular decompression for macular edema in retinal vein occlusion. Can J Ophthalmol 2007;42 (1) 116- 122
PubMedArticle
12.
Murakami  TTakagi  HOhashi  H  et al.  Role of posterior vitreous detachment induced by intravitreal tissue plasminogen activator in macular edema with central retinal vein occlusion. Retina 2007;27 (8) 1031- 1037
PubMedArticle
13.
Takahashi  MKHikichi  TAkiba  JYoshida  ATrempe  CL Role of the vitreous and macular edema in branch retinal vein occlusion. Ophthalmic Surg Lasers 1997;28 (4) 294- 299
PubMed
14.
Ikeda  TSato  KKatano  THayashi  Y Attached posterior hyaloid membrane and the pathogenesis of honeycombed cystoid macular edema in patients with diabetes. Am J Ophthalmol 1999;127 (4) 478- 479
PubMedArticle
15.
Sebag  J Pharmacologic vitreolysis. Retina 1998;18 (1) 1- 3
PubMedArticle
16.
Gandorfer  APutz  EWelge-Lüssen  UGrüterich  MUlbig  MKampik  A Ultrastructure of the vitreoretinal interface following plasmin assisted vitrectomy. Br J Ophthalmol 2001;85 (1) 6- 10
PubMedArticle
17.
Díaz-Llopis  MUdaondo  PSalom  DGarcía-Delpech  SRomero  FJ Intravitreal autologous plasmin without associated-vitrectomy: pharmacological vitreolysis, a perfeccionated method using urokinase. Arch Soc Esp Oftalmol 2008;83 (5) 291- 292
PubMedArticle
18.
Díaz-Llopis  MUdaondo  PGarcía-Delpech  SCervera  ESalom  DQuijada  A Enzymatic vitrectomy by intravitreal autologous plasmin injection, as initial treatment for diffuse diabetic macular edema. Arch Soc Esp Oftalmol 2008;83 (2) 77- 84
PubMedArticle
19.
Scott  IUIp  MSVanVeldhuisen  PC  et al. SCORE Study Research Group, A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol 2009;127 (9) 1115- 1128
PubMedArticle
20.
Rizzo  SPellegrini  GBenocci  FBelting  CBaicchi  UVispi  M Autologous plasmin for pharmacologic vitreolysis prepared 1 hour before surgery. Retina 2006;26 (7) 792- 796
PubMedArticle
21.
Williams  JGTrese  MTWilliams  GAHartzer  MK Autologous plasmin enzyme in the surgical management of diabetic retinopathy. Ophthalmology 2001;108 (10) 1902- 1905
PubMedArticle
22.
Margherio  ARMargherio  RRHartzer  MTrese  MTWilliams  GAFerrone  PJ Plasmin enzyme-assisted vitrectomy in traumatic pediatric macular holes. Ophthalmology 1998;105 (9) 1617- 1620
PubMedArticle
Clinical Sciences
March 14, 2011

Intravitreal Plasmin Without Vitrectomy for Macular Edema Secondary to Branch Retinal Vein Occlusion

Author Affiliations

Author Affiliations: Retina and Uveitis (Drs Díaz-Llopis, Salom, and Udaondo) and Anterior Segment (Dr García-Delpech) Units, Department of Ophthalmology, Hospital La Fe de Valencia and Department of Ophthalmology, Universidad de Valencia (Dr Díaz-Llopis), Department of Physiology, Pharmacology, and Toxicology, Universidad Cardenal Herrera Orio (Dr Romero) and Departments of Ophthalmology (Drs García-Delpech and Salom) and Health Science (Dr Udaondo), Universidad Católica de Valencia San Vicente Mártir, Valencia, Spain.

Arch Ophthalmol. 2011;129(3):283-287. doi:10.1001/archophthalmol.2011.8
Abstract

Objectives  To evaluate the effects and safety of intravitreal injections of autologous plasmin enzyme (APE), without vitrectomy, as a treatment for macular edema secondary to branch retinal vein occlusion.

Design  Prospective, comparative, interventional case series.

Methods  Patients were recruited and enrolled consecutively from February 1 through October 31, 2008, at the Retina Unit of the Hospital General Universitario, Valencia, Spain. An eye from 8 patients diagnosed as having macular edema due to branch retinal vein occlusion received an injection, after having received topical anesthesia, of 0.2 mL of APE, which had been obtained using a simplified method. Best-corrected visual acuity and central macular thickness measured by optical coherence tomography constitute the main outcome measures of the study.

Results  The mean (SD) central macular thickness decreased from 494.875 (68.82) to 226.375 (28.67) μm 1 month after APE injection and to 228.570 (21.53) μm after 6 months (P < .001). The best-corrected visual acuity (logarithm of the minimal angle of resolution) improved from a preoperative value of 0.552 (0.17) to 0.217 (0.087) (mean, 20/80-20/32, Snellen equivalent) at the end of follow-up (P < .01). No secondary effects were observed during 6 months of follow-up.

Conclusion  This pilot study suggests that intravitreal injection of APE as a treatment for macular edema secondary to branch retinal vein occlusion improves central macular thickness and best-corrected visual acuity and may be a safe and effective alternative therapy for this condition if confirmed in controlled trials compared with standard care with longer follow-up.

Macular edema (ME) is the most common eye complication and a major cause of loss of visual acuity in patients with branch retinal vein occlusion (BRVO).1,2 Because of deterioration of vision caused by ME secondary to BRVO, different medical and surgical therapies have been tested and the results reported. Laser photocoagulation was superior to no treatment by 6 months after treatment in selected case individuals evaluated in the Branch Vein Occlusion Study.1,3 Intravitreal injections of triamcinolone acetate and bevacizumab as a treatment for ME due to BRVO currently are being evaluated.46 Surgical options, including cannulation of branch retinal veins, pars plana vitrectomy with or without adjunctive sheathotomy of the retinal vein adventitia, and pars plana vitrectomy with or without removal of internal limiting membrane,7,8 have not been shown definitively to yield more favorable results than standard care (grid photocoagulation in cases of BRVO1,2).

The incidence of ME has been suggested to be lower in cases of spontaneous posterior vitreous detachment, and traction of the vitreous cortex at the macula can play a role in exacerbating ME.912 In the presence of posterior vitreous detachment, intravitreal treatments using triamcinolone or antivascular endothelial growth factors theoretically could be less effective.13,14

It has been hypothesized that pharmacologic vitreolysis by intravitreal injection of autologous plasmin enzyme (APE) may allow better results to be obtained with vitreous surgery in cases in which a macular hole or diabetic ME is present.15,16 Recently, APE injection without associated vitrectomy was shown to be associated with decreased edema and improved visual acuity, at least for a few months, in the treatment of diabetic ME involving the center of the macula.17,18 This prospective controlled study, which has an interventional case series design, aimed to evaluate the effects and safety of APE intravitreal injections in the absence of an associated vitrectomy as a treatment for ME secondary to BRVO, using optical coherence tomography (OCT) to evaluate anatomical results.

METHODS

Patients were recruited and enrolled consecutively from February 1 through October 31, 2008, at the Retina Unit of the Hospital General Universitario, Valencia, Spain. The protocol was approved by the institutional review board of the hospital. An eye from 8 patients with ME due to BRVO was studied.

All patients were diagnosed by means of fluorescein angiography as having ME secondary to BRVO. Central macular thickness (CMT) was measured using OCT (Stratus OCT-3; Carl Zeiss Meditec AG, Jena, Germany). Treatment with intravitreal APE was offered to those who showed poor outcomes in visual acuity or macular thickness after grid laser, triamcinolone, or bevacizumab therapy or a combination of these treatments. Inclusion criteria consisted of the following: ME (perfused or nonperfused) secondary to BRVO, defined as fluorescein leakage as measured by fluorescein angiography and macular thickness greater than 300 μm as measured by OCT; patients with ME who had proven to be unresponsive to laser photocoagulation or other intravitreal treatments (<20% reduction and persistence of macular thickness >300 μm); and best-corrected visual acuity (BCVA) converted into logarithm of the minimal angle of resolution (logMAR) of 1.0 or greater (20/200).

Exclusion criteria consisted of the following: uncontrolled blood pressure (systolic and diastolic blood pressure greater than 150 and 90 mm Hg, respectively), renal insufficiency, intraocular surgery or any intravitreal treatment during the previous 3 months, and history of ocular hypertension and/or glaucoma. The nature of off-label use of autologous plasmin and its potential adverse effects, including endophthalmitis, retinal detachment, and uveitis, were discussed in depth with patients before obtaining their consent to participate in the study.

PREOPERATIVE EXAMINATION

Before receiving an injection of APE, all patients underwent a complete ophthalmologic examination consisting of BCVA measurement converted to logMAR, slitlamp examination, applanation tonometry, indirect ophthalmoscopy, macular mapping using OCT, fundus photography, and fluorescein angiography. The previous presence of posterior vitreous detachment was excluded by OCT and biomicroscopy in all cases.

PREPARATION OF APE AND INJECTION TECHNIQUE

The APE was prepared in the operating room approximately 45 minutes before injection, as previously described.15 Topical anesthesia was induced by applying 1% tetracaine eye drops on at least 3 occasions. The conjunctiva bulbi and fornices were rinsed repeatedly with povidone-iodine solution. An anterior chamber paracentesis was performed in all cases before injection. Patients then received a unilateral intravitreal injection of 0.2 mL of APE, sterilized through a 0.22-μm pore filter, via a 30-gauge needle. After the injection, intraocular pressure and retinal artery perfusion were assessed. Antibiotic eye drops (ofloxacin) and topical prednisone were applied 4 times a day for 10 days.

OUTCOME MEASURES AND STATISTICAL ANALYSIS

After the injection, BCVA measurement converted to logMAR and OCT were performed on each patient before treatment and at 1 and 6 months after treatment. Demographic characteristics of the patients were summarized with descriptive statistics via SPSS statistical software, version 13.0 for Windows (SPSS Inc, Chicago, Illinois). The Wilcoxon signed rank test for paired samples was used to compare the BCVA and CMT between baseline and at 1 and 6 months. P < .05 was accepted as significant.

RESULTS

Of the 8 patients (8 eyes) with ME associated with BRVO, 5 were women and 3 were men. Six had a history of hypertension (requiring treatment) or hypercholesterolemia. Mean age was 65 years (age range, 58-73 years). All showed a limited or nonexistent response to previous treatment with laser photocoagulation, intravitreal triamcinolone, bevacizumab injections, or a combination of those treatments, which had resulted in a less than 20% reduction of macular thickness. Patients 1, 2, and 7 showed nonperfused edema (ischemic area involving the macula) in the angiographic image before the plasmin treatment. Patients had received no treatment for 3 months before the APE injection. Pretreatment characteristics of the patients are summarized in Table 1. Patients were observed during a mean of 6 months of follow-up. Major adverse effects, such as uveitis, endophthalmitis, ocular toxicity, glaucoma, retinal tears, vitreous hemorrhage, or any systemic adverse events, were not observed in any of the cases. Biomicroscopy and OCT confirmed a complete posterior detachment in all the eyes treated with APE (Figure 1).

CENTRAL MACULAR THICKNESS

All patients displayed an important decrease in retinal thickness within 1 month of APE injection (Table 2, Figure 2, and Figure 3). At baseline, the mean (SD) CMT was 494.875 (68.82) μm. The mean CMT was 226.375 (28.67) μm 1 month after APE injection and 228.570 (21.53) μm after 6 months (Wilcoxon signed rank test, P < .001).

BEST-CORRECTED VISUAL ACUITY

Improvement of visual acuity was evident within the first month of intravitreal injection of APE (Table 2). The mean (SD) BCVA at baseline was 0.552 (0.17) (20/80-20/63). The BCVA was 0.197 (0.087) (20/25-20/32) at 1 month and 0.217 (0.087) after 6 months of follow-up (mean of 20/32, Snellen equivalent) (Wilcoxon signed rank test; P < .001 at 6 months compared with baseline). All patients displayed an improvement (>10 letters) in visual acuity at the last follow-up visit.

COMMENT

The preliminary results of this prospective controlled study suggest a beneficial effect, at least for several months, on ME due to BRVO of intravitreal injection of APE prepared by a simplified method, at least in cases of an associated attachment of the vitreous cortex to the macula. Results appeared to persist at least 6 months after only 1 intravitreal injection of APE. The pharmacologic vitreolysis and posterior detachment of the vitreous cortex produced by this method may be equivalent to performing a pars plana vitrectomy while minimizing the adverse effects associated with a surgical procedure.

The BRVO study group showed a benefit with grid photocoagulation in some patients with ME but also identified a subset of patients with limited benefit from it.3 Vascular endothelial growth factor and inflammation may also play an important role in the pathology of BRVO and could constitute the reason why photocoagulation has yielded limited benefits. Recently, new results from the Standard Care vs Corticosteroid for Retinal Vein Occlusion study have been published, and grid laser photocoagulation remains the standard method of treatment for patients with vision loss secondary to ME associated with BRVO.19 Because of the limited results with laser treatment, it is important to find new strategies to treat ME, which is an important cause of retinal vascular disorder and loss of visual acuity. Six months after treatment we observed no cataract progression, intraocular pressure elevation, or any other major complications (retinal detachment, vitreous hemorrhage, or endophthalmitis) associated with intravitreal APE injection.

Until now, one of the limitations of the use of APE was the relatively time-consuming and expensive preparation of the enzyme. The advantage of the simplified technique is that the APE can be prepared 1 hour before injection, which accelerates and simplifies the procedure, lowers its cost,17,18,20 and, perhaps most important, could make it accessible to most retina practices. The concentrations of APE obtained by this simplified method are substantially lower than those obtained by an alternative method described by several authors.17,21,22 Nevertheless, it appears to be effective enough to induce a complete vitreous detachment.

The current study has several limitations, the most important being its relatively small number of patients evaluated in a condition with a variable response (limiting the treatment to those with substantial loss of visual acuity) and the absence of control individuals (making it impossible to determine how these patients would have fared with no treatment or with grid laser photocoagulation if indicated). More studies with a larger number of patients enrolled are needed because this study's findings are not substantial enough to confirm the efficacy of this new treatment.

In conclusion, intravitreal injection of APE appeared to have substantial effects on ME due to BRVO associated with improvement in visual acuity, at least during a 6-month period. Further controlled studies are warranted to assess the long-term efficacy and safety of this approach.

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Article Information

Correspondence: Patricia Udaondo, MD, Department of Ophthalmology, Hospital La Fe de Valencia, C San Francisco de Borja 9, pta 10, Valencia 46007, Spain (patyudaondo@hotmail.com).

Submitted for Publication: September 10, 2009; final revision received April 28, 2010; accepted May 1, 2010.

Financial Disclosure: None reported.

References
1.
Gutman  FA Macular edema in branch retinal vein occlusion: prognosis and management. Trans Sect Ophthalmol Am Acad Ophthalmol Otolaryngol 1977;83 (3, pt 1) 488- 495
PubMed
2.
Rehak  JRehak  M Branch retinal vein occlusion: pathogenesis, visual prognosis, and treatment modalities. Curr Eye Res 2008;33 (2) 111- 131
PubMedArticle
3.
The Branch Vein Occlusion Study Group, Argon laser photocoagulation for macular edema in branch vein occlusion. Am J Ophthalmol 1984;98 (3) 271- 282
PubMed
4.
Cekiç  OChang  STseng  JJ  et al.  Intravitreal triamcinolone injection for treatment of macular edema secondary to branch retinal vein occlusion. Retina 2005;25 (7) 851- 855
PubMedArticle
5.
Özkiris  AEvereklioglu  CErkilic  KDogan  H Intravitreal triamcinolone acetonide for treatment of persistent macular oedema in branch retinal vein occlusion. Eye (Lond) 2006;20 (1) 13- 17
PubMedArticle
6.
Rabena  MDPieramici  DJCastellarin  AANasir  MAAvery  RL Intravitreal bevacizumab (Avastin) in the treatment of macular edema secondary to branch retinal vein occlusion. Retina 2007;27 (4) 419- 425
PubMedArticle
7.
Mason  J  IIIFeist  RWhite  M  JrSwanner  J McGwin  G  JrEmond  T Sheathotomy to decompress branch retinal vein occlusion: a matched control study. Ophthalmology 2004;111 (3) 540- 545
PubMedArticle
8.
Saika  STanaka  TMiyamoto  TOhnishi  Y Surgical posterior vitreous detachment combined with gas/air tamponade for treating macular edema associated with branch retinal vein occlusion: retinal tomography and visual outcome. Graefes Arch Clin Exp Ophthalmol 2001;239 (10) 729- 732
PubMedArticle
9.
Charbonnel  JGlacet-Bernard  AKorobelnik  JF  et al.  Management of branch retinal vein occlusion with vitrectomy and arteriovenous adventitial sheathotomy, the possible role of surgical posterior vitreous detachment. Graefes Arch Clin Exp Ophthalmol 2004;242 (3) 223- 228
PubMedArticle
10.
Hvarfner  CLarsson  J Vitrectomy for non-ischaemic macular oedema in retinal vein occlusion. Acta Ophthalmol Scand 2006;84 (6) 812- 814
PubMedArticle
11.
Mandelcorn  MSMandelcorn  EGuan  KAdatia  FA Surgical macular decompression for macular edema in retinal vein occlusion. Can J Ophthalmol 2007;42 (1) 116- 122
PubMedArticle
12.
Murakami  TTakagi  HOhashi  H  et al.  Role of posterior vitreous detachment induced by intravitreal tissue plasminogen activator in macular edema with central retinal vein occlusion. Retina 2007;27 (8) 1031- 1037
PubMedArticle
13.
Takahashi  MKHikichi  TAkiba  JYoshida  ATrempe  CL Role of the vitreous and macular edema in branch retinal vein occlusion. Ophthalmic Surg Lasers 1997;28 (4) 294- 299
PubMed
14.
Ikeda  TSato  KKatano  THayashi  Y Attached posterior hyaloid membrane and the pathogenesis of honeycombed cystoid macular edema in patients with diabetes. Am J Ophthalmol 1999;127 (4) 478- 479
PubMedArticle
15.
Sebag  J Pharmacologic vitreolysis. Retina 1998;18 (1) 1- 3
PubMedArticle
16.
Gandorfer  APutz  EWelge-Lüssen  UGrüterich  MUlbig  MKampik  A Ultrastructure of the vitreoretinal interface following plasmin assisted vitrectomy. Br J Ophthalmol 2001;85 (1) 6- 10
PubMedArticle
17.
Díaz-Llopis  MUdaondo  PSalom  DGarcía-Delpech  SRomero  FJ Intravitreal autologous plasmin without associated-vitrectomy: pharmacological vitreolysis, a perfeccionated method using urokinase. Arch Soc Esp Oftalmol 2008;83 (5) 291- 292
PubMedArticle
18.
Díaz-Llopis  MUdaondo  PGarcía-Delpech  SCervera  ESalom  DQuijada  A Enzymatic vitrectomy by intravitreal autologous plasmin injection, as initial treatment for diffuse diabetic macular edema. Arch Soc Esp Oftalmol 2008;83 (2) 77- 84
PubMedArticle
19.
Scott  IUIp  MSVanVeldhuisen  PC  et al. SCORE Study Research Group, A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol 2009;127 (9) 1115- 1128
PubMedArticle
20.
Rizzo  SPellegrini  GBenocci  FBelting  CBaicchi  UVispi  M Autologous plasmin for pharmacologic vitreolysis prepared 1 hour before surgery. Retina 2006;26 (7) 792- 796
PubMedArticle
21.
Williams  JGTrese  MTWilliams  GAHartzer  MK Autologous plasmin enzyme in the surgical management of diabetic retinopathy. Ophthalmology 2001;108 (10) 1902- 1905
PubMedArticle
22.
Margherio  ARMargherio  RRHartzer  MTrese  MTWilliams  GAFerrone  PJ Plasmin enzyme-assisted vitrectomy in traumatic pediatric macular holes. Ophthalmology 1998;105 (9) 1617- 1620
PubMedArticle
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