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ORIGINAL ARTICLE
Year : 2003  |  Volume : 51  |  Issue : 1  |  Page : 67-70

Intravitreal low molecular weight heparin in PVR surgery.


Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All Institute of Medical Sciences, New Delhi, India

Correspondence Address:
A Kumar
Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All Institute of Medical Sciences, New Delhi
India
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Source of Support: None, Conflict of Interest: None


PMID: 12701865

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  Abstract 

Purpose: To evaluate the efficacy of low molecular weight heparin (LMWH) in prevention of postoperative fibrin formation following vitreoretinal surgery with proliferative vitreoretinopathy (PVR).
Material and Methods: Thirty consecutive patients of retinal detachment with advanced PVR were enrolled in the study. They were randomised to study and control groups (n = 15 each). Study group patients received vitreoretinal surgery with 5 IU/cc of LMWH in vitrectomy infusion fluid. The control group patients received vitroretinal surgery without heparin in the infusion fluid. Patients were followed up at 1 week, 1 month and 3 months after surgery. Postoperative bleeding, media clarity, best-corrected visual acuity and success of the surgery at the end of 3 months were compared between the two groups.
Results: At each follow-up visit, the study group showed a better media clarity, which was statistically significant ( P = 0.0042). The study group had a 50% better chance of retinal reattachment compared to the control group. Five patients had intraoperative bleeding in the study group (33%) compared to 3 patients in the control group (20%).
Conclusion: Use of intravitreal LMWH prevents postoperative fibrin formation and is beneficial in repair of retinal detachments with PVR.

Keywords: Heparin, proliferative vitreoretinopathy, PVR surgery


How to cite this article:
Kumar A, Nainiwal S, Sreenivas B. Intravitreal low molecular weight heparin in PVR surgery. Indian J Ophthalmol 2003;51:67-70

How to cite this URL:
Kumar A, Nainiwal S, Sreenivas B. Intravitreal low molecular weight heparin in PVR surgery. Indian J Ophthalmol [serial online] 2003 [cited 2019 Sep 20];51:67-70. Available from: http://www.ijo.in/text.asp?2003/51/1/67/14735



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Proliferative vitreoretinopathy is defined as the growth and contraction of cellular membranes within the vitreous cavity and on both sides of the retinal surfaces. It is an anomalous scarring process in retinal detachments, and is the most common cause of failed surgery for rhegmatogenous retinal detachment.[1],[2]

The surgery for retinal detachment with advanced proliferative vitreoretinopathy (PVR) stage D 1 -D 3 is usually followed by an exuberant intraocular fibrinous reaction.[1] Surgical manipulation creates direct tissue injury and disrupts the blood-ocular barrier. Fibrin, which is formed as an end product of the coagulation cascade stimulates the migration of retinal pigment epithelial (RPE) cells and induces a morphological change in the fibroblast cells. Fibrin also provides a scaffold for cellular attachment and subsequent proliferation.[3]

Low molecular weight heparin (LMWH, Fragmin) acts by binding to fibronectin which is the most potent stimulator for RPE cell migration, and prevents hypocellular gel contraction. Animal and human studies using heparin as an intraocular infusion have demonstrated a reduction of fibrin exudation. In our previous experimental study the use of intraoperative daunorubicin (5 mg at the end of surgery) showed significant reduction of PVR after retinal detachment surgery.[4]

Asaria et al recently reported a significant reduction in the incidence of postoperative PVR in patients receiving the 5-FU and LMWH therapy and in the reoperation rate resulting from PVR.[5] However, increased bleeding during actual clinical application offsets this benefit. We undertook a clinical trial to assess the efficacy of intraoperative LMWH in prevention of fibrin formation after vitreoretinal surgery.


  Material and Methods Top


Thirty eyes of 30 patients of retinal detachment with advanced PVR D 1 -D 3 were enrolled in this study. They were randomly divided into two groups with 15 patients in the study group and 15 in the control group. Informed consent was obtained from all patients before entering the study.

Inclusion criteria

Only patients in the age group >18 years of primary rhegmatogenous retinal detachment with PVR D 1 -D 3 were included. Grading of PVR was done according the Retina Society classification.[6]

Exclusion criteria

Patients with a known history of bleeding diathesis, diabetic patients with proliferative retinopathy, patients with hepatic and renal failure, age < 18 years, failed retinal detachment surgeries, and traumatic retinal detachments were excluded from the study.

A complete preoperative work-up was done including visual acuity, refractive status, and indirect ophthalmo-scopy for grading of PVR [Table - 1] and fundus photographs were taken.

Surgery protocol in the study group

Five IU/cc of Fragmin LMWH was added to 500 ml of vitrectomy infusion fluid. A standard 3-port pars plana vitrectomy was performed in all eyes. The retinal folds were mobilised and the epiretinal membrane peeled. Endodrainage, air fluid exchange, and 360° endophoto-coagulation were performed. At the conclusion of surgery, silicone oil was injected in all patients as a vitreous substitute. The control group underwent a similar surgical procedure except that the infusion fluid did not contain Fragmin. Statistical analysis was performed using the Wilcoxon Rank sum method.

We used the Johnson and Blankenship grading system:[7]

Grade 0 No bleeding or minimal ooze that ceased without intervention.

Grade 1 More extensive bleeding and haemostasis that required elevation of the infusion bottle.

Grade 2 Bleeding that required elevation of the bottle and diathermy.

Grade 3 Bleeding that required elevation of the bottle and repeated diathermy.

Grade 4 Bleeding that produced significant accumula-tion of blood despite the above maneuvers, but did not prevent the completion of the surgery.

Grade 5 Extensive bleeding that prevented completion of the surgery.

Postoperatively patients were followed up at 1 week,

1 month and 3 months. At these visits media clarity, visual acuity and success of surgery, i.e., retinal reattachment at the end of 3 months were noted.

Media clarity was graded according to the Nussenblatt classification.[8]

Optic nerve head obscured 4+

Optic nerve head visible but border blurred 3+

Better visualisation of the retinal blood vessels 2+

Better definition of optic nerve head

and retinal blood vessel 1+

Blurring the retinal nerve fibre striations +

Nerve fibre structure well defined 0


  Results Top


The mean age of the patients was 44 ± 19.5 years in the study group and 51.27 ± 18.85 years in the control group. The study group included 12 males and 3 females (age 21 - 72 years). The control group had 11 male patients and 4 female patients (age 24 - 70 years). All patients had a visual acuity of light projection (LP). Four patients in the study group and 3 in the control group had a high myopia >6D.

The mean duration of retinal detachment in the study group was 19.2 ± 5.3 weeks and in the control group, 20.8 ± 4.9 weeks. The average surgical time was 90 ± 9.63 minutes and 85 ± 5.97 minutes in the study and the control group respectively. There was no statistically significant difference between the two groups with respect to the age, gender, preoperative visual acuity and the grades of the proliferative vitreoretinopathy.

Five patients in the study group had intraoperative bleeding; 3 patients had grade 1 bleeding (controlled after raising the infusion bottle), and two patients had grade 2 bleeding (requiring elevation of the infusion bottle and diathermy at the bleeding site). In the control group, 3 patients had intraoperative bleeding during membrane peeling. In two patients the bleeding was grade 1 and in one patient it was grade 2. The difference was not statistically significant.

Postoperative bleeding was noted in 3 patients in the study group and one patient in the control group. Redetachment occurred in one case from the study group and 4 cases in the control group, which required resurgery. None of the eyes from either group required silicone oil removal till the end of study protocol.

The postoperative visual acuity in both groups was similar at the end of first week. The study group had better visual acuity at the end of 3 months, but this was not statistically significant (P = 0.376; [Table - 2]). The media clarity (using Nussenblatt's classification) was significantly better in the study group throughout the study period [Table - 3].


  Discussion Top


Many low molecular weight heparins have been isolated and their pharmacologic properties investigated.[9] Initial studies using animal models of thrombus formation have demonstrated that LMWH can successfully inhibit thrombus formation.[10] Bleeding studies in animals also showed less haemorrhagic tendency with low molecular weight derivatives than with native heparin.[11],[12] Human pharmacological studies have demonstrated that intravenous administration of a heparin fragment of 4000-5000 da molecular weight could produce a high degree of factor Xa inhibition and lowered partial thromboplastin time.[10],[13] The drug also demonstrates first order elimination kinetics.[14]

Human clinical trials have assessed the actual therapeutic efficacy of LMWH for systemic problems like deep vein thrombosis, but not for ocular therapeutics.[15] These derivatives have proved equal to their parent compound in the prophylaxis and treatment of deep vein thrombosis. It has been hypothesised that LMWH would be a potentially effective inhibitor of intraocular fibrin formation following vitreoretinal surgeries.[16] To test this hypothesis, we chose patients with retinal detachment with PVR D 1 -D 3 .

Inclusion of Fragmin, an LMWH, in our intraocular infusion substantially reduced the amount of fibrin clot in this series. Patients who received LMWH had a negligible fibrin production that did not increase in severity, cleared rapidly and did not interfere with posterior segment visualisation as was shown by the better grade of media clarity. LMWH acts by inhibiting factors like fibronectin and other growth factors and has an inhibitory effect on the proliferation of RPE cells, glial cells and hence fibroblastic cells.

Visual recovery in both the groups was identical at one week after surgery. But at one month following surgery the LMWH group showed better recovery of vision than the control group, which continued into the third month. However, the difference in the visual acuity between the groups was not statistically significant. Since both groups were evenly matched with respect to the severity of PVR and duration, the difference in visual recovery cannot be attributed to preoperative factors. It may be hypothesised that the eyes in the study group showed a better and earlier visual recovery, because the LMWH inhibited all cells with proliferative or contractile potential.

The rate of redetachment was less in the study group as compared to the control group. This can be explained by the fact that the heparin inhibited factors like fibronectin, Plalelet Derived Growth Factor (PDGF), Epidermal Growth Factor (EFG) and Fibroblast Growth Factor (FGF), which are stimulators for the Retinal Pigment Epithelium (RPE) cell migration and proliferation, thereby decreasing the infiltration of fibrin clot and the synthesis of extracellular matrix, and maturation of the contractile deforming scar tissue. We also observed that the LMWH group of patients did not bleed intraoperatively or postoperatively.

Our randomised clinical trial demonstrated a trend towards a better rate of complete retinal attachment, media clarity and visual acuity at the end of the 3 months after vitreoretinal surgery with the use of LMWH. To conclude, LMWH in vitrectomy infusion could be a useful adjunct in retinal detachment with advanced PVR.

 
  References Top

1.
Rachel WF, Burton TC. Changing concepts of failure after retinal detachment surgery. Arch Ophthalmol 1970;97:480.   Back to cited text no. 1
    
2.
The Silicone Study Group. Vitrectomy with silicone oil or sulfur hexaflouride gas in eyes with severe proliferative vitreoretinopathy results of a randomized clinical trial Arch Ophtahlmol 1992;110:70.  Back to cited text no. 2
    
3.
Vidaurri-Leal JS, Glaser BM. Effect of fibrin on morphologic characteristics of retinal pigment epithelial cell. Arch Ophthalmol 1984;102:1376-79.  Back to cited text no. 3
    
4.
Kumar A, Tewari HK, Bathwal DP, Khosla PK. Experimental inhibition of PVR in retinal detachment using daunorubicin. Indian J Ophthalmol 1994;42:32-35.  Back to cited text no. 4
    
5.
Asaria RHY, Kon CH, Bunce C, Charteris DG, Wong D, Khaw PT, et al. Adjuvant 5-fluorouracil and Heparin Prevents Proliferative Vitreoretinopathy: Results from a Randomized, Double-blind, Controlled Clinical Trial. Ophthalmology 2001;108:1179-83.   Back to cited text no. 5
    
6.
The Retina Society Terminology Committee. The classification of retinal detachment with proliferative vitreoretinopathy. Ophthalmology 1983;90:121.  Back to cited text no. 6
    
7.
Johnson RN, Blankenship G. A prospective randomized clinical trial of heparin therapy for postoperative intraocular fibrin. Ophthalmology 1988;95:312-17.  Back to cited text no. 7
    
8.
Nussenblatt R, Smith RA. Nozik, 2nd ed. editors. Uveitis - A Clinical Approach to Diagnosis and Management. New York: Williams & Wilkins 1989. p 19.  Back to cited text no. 8
    
9.
Fareed J, Walenga JM, Hoppensteadt D, Racanelli A, Coyne E. Chemical and biological heterogeneity in low molecular weight heparins: Implications for clinical use and standardization. Semin Thromb Hemost 1989;15:440-63.  Back to cited text no. 9
    
10.
Thomas DP, Morton RE, Gray E, Banowcliffe TW. The relative antithrombotic effectiveness of heparin, a low molecular weight heparin, and a pentasaccharide fragment in an animal mode. Thromb Haemost 1989;61:204-7.  Back to cited text no. 10
    
11.
Cade JF, Buchanan MR, Boneu B, Ockelford P, Cater CJ, Cerskus AL, et al. A comparison of antithrombotic and haemorrhagic effects of low molecular weight heparin fractions: The influence of the method of preparation. Thromb Res 1984;35;613-25.  Back to cited text no. 11
    
12.
Breddin HK. Low molecular weight heparins and bleeding. Semin Thromb Hemost 1989;15:401-4.  Back to cited text no. 12
    
13.
Esquivel CO, Bergqvist D, Bjorck CG, Nilsson B. Comparison between commerical heparin, low molecular weight heparin and pentosan polysulfate on hemostasis and platelets in vivo. Thromb Res 1982;28:389-99.  Back to cited text no. 13
    
14.
Bratt G, Tornebohm E, Lockner D, Bergstrom K. A human pharmacologic study comparing conventional heparin and a low molecular weight fragment. Thromb Haemost 1985;53:208-11.  Back to cited text no. 14
    
15.
Hirsh J, Ofosu FA, Levine M. The development of low molecular weight heparins for clinical use. In: Verstraete M, Vermylen J, Lijnen HR, Arnout J, editors. Thrombosis and Haemostasis . Leuven, Belgium: Leuven University Press; 1987. pp 325-48.  Back to cited text no. 15
    
16.
Johnson RN, Balyeat E. Stern WH. Heparin prophylaxis for intraocular fibrin. Ophthalmology 1987;94:597-601.  Back to cited text no. 16
    



 
 
    Tables

  [Table - 1], [Table - 2], [Table - 3]


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