The cleaving of vitreous from the retinal surface is an obvious surgical goal for many indications. It is likely desired for an improved natural history of diabetic and other macular edemas, proliferative diabetic disease, and maybe even neovascular age-related macular degeneration.
Plasmin is a fibrinolytic serum protease enzyme with dose-dependent activity that degrades the matrix proteins fibronectin and laminin, the major adhesives between the vitreous and the internal limiting membrane (ILM); activates matrix metalloproteinase 2; and breaks down vitreous macromolecules, thereby leading to the cleavage of the vitreous from the retinal surface and vitreous liquification.
AUTOLOGOUS PLASMIN
In its clinically useful forms, we have autologous plasmin enzyme, which is extracted from a patient several days prior to intravitreal injection, and microplasmin, a 29-kD human recombinant form of the protease active site of plasmin from ThromboGenics (Leuven, Belgium), which is currently in phase 2 trials (see main article). Autologous plasmin has been successfully used as an adjunct to vitrectomy for diabetic retinopathy, macular holes, proliferative vitreoretinopathy, and retinopathy of prematurity.
In our study,1 we sought to determine the efficacy of autologous plasmin, injected intravitreally in the office setting, to obtain a pharmacologic posterior vitreous detachment (PVD), which could then enhance the ability of intravitreally injected bevacizumab (Avastin; Genentech, South San Francisco, California) or triamcinolone to treat eyes with clinically significant macular edema due to diabetic retinopathy and cystoid macular edema due to central retinal vein occlusion (CRVO) that were refractory prior to treatment with these intravitreal agents.
Our goal was to create a safe, atraumatic nonsurgical PVD which could allow patients to potentially avoid the operating room when combined with currently known therapies to improve vision and reduce anatomic abnormalities. We looked at eyes that were unresponsive to other current therapies, had refractory macular edema, no clinical PVD, and had failed prior intravitreal steroid or bevacizumab injections. We defined failure as no significant improvement during their postinjection and laser course. Patients had no clinically discernible vitreoretinal traction, no active neovascular disease, and at least 6 months follow-up.
INCLUDED EYES
For our investigation, we ended up with five eyes that had appropriate follow-upÑthree with macular edema from diabetes and two from CRVO; all had a number of prior interventions. We drew blood from the patients 5 to 7 days before its use and separated out the plasmin using an infinity chromatography process. We then measured the activity of the plasmin and tested it for bacterial contamination.
We injected 1.6- to 2-IU of plasmin in a volume of 0.09 to 0.1 mL using a standard intravitreal procedure. The patients were given a combination of steroid-antibiotic drops for 1 week following injection and before the injection of intravitreal triamcinolone or bevacizumab. The mean visual acuity continued to improve in all eyes, although three of the eyes required an additional intravitreal steroid injection. All five of the eyes developed what appeared to be a clinically visible PVD, seen at an average of 5 weeks following plasmin injection. Statistically significant improvement in the mean foveal thickness was noted early by ocular coherence tomography and remained stable throughout follow-up.
SHORTCOMINGS, IMPLICATIONS FOR THE FUTURE
This was small series of eyes that was not controlled or randomized. We need longer follow-up in these patients and we also still have many unanswered questions: Are we really creating true PVDs (not vitreoschisis) with plasmin enzyme and no vitrectomy? From one of the surgical examples, it appears we are not likely doing that in all eyes. We do not know the optimal dose of autologous plasmin or if there is a potential for repeated use. It may be that treating these eyes earlier in the disease process will give better results, and perhaps plasmin can be combined with other treatments. The new recombinant microplasmin may have different properties, and perhaps we can potentially combine this concept with an in-office vitrectomy procedure.
We showed that this office procedure can lead to reduction or resolution of refractory macular edema and give some visual improvement in eyes able to respond to the same therapies that previously failed to show efficacy. Something about the action of plasmin enzyme on the vitreomacular interface has likely had an impact on the outcomes in these patients. Clearly, we are at the tip of the iceberg of a paradigm shift in which we will learn to manipulate the vitreous pharmacologically. In the future, I think we will learn much more about disease prophylaxis and the alteration of the natural history of a number of vitreoretinal diseases.
Tarek S. Hassan, MD, is a partner with Associated Retinal Consultants, P.C., and the Beaumont Eye Institute, William Beaumont Hospital, Royal Oak, Michigan. Dr. Hassan states that he has no financial interest in the products or companies mentioned. He is a member of the Retina Today Editorial Board, and may be reached at tsahassan@yahoo.com.
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