Antithrombotic Effect of Ticlopidine in an Experimental Model of Retinal Vein Occlusion

Abstract

Purpose: Ticlopidine inhibits adenosine diphosphate (ADP)-induced platelet aggregation and may be effective in patients with retinal vein occlusions (RVO). This study tests the efficacy of ticlopidine in an animal model of RVO.

Methods: Rose bengal-mediated argon laser photothrombosis of retinal veins was created in rabbits pretreated with oral ticlopidine, aspirin, or saline. The number of laser spots necessary to produce a partial or complete RVO was recorded and tabulated.

Results: Pretreatment with ticlopidine significantly increased the number of laser spots needed to produce a partial (P = .02), or a complete (P = .002) RVO as compared to the control group. Pretreatment with ticlopidine significantly increased the number of laser spots needed to produce a partial RVO (P = .02). Pretreatment with aspirin significantly increased the number of laser spots needed to produce a complete RVO (P = .002).

Conclusion: Ticlopidine may be a useful antiplatelet agent for the treatment of patients with RVO. Patients treated with ticlopidine should be monitored for the possible development of hematologic disorders.

Introduction

Central retinal vein occlusion (CRVO) is a relatively common, often blinding, ocular thrombotic disorder for which there is no effective treatment.1, 2, 3 Histopathology of acute CRVO and branch retinal vein occlusions (BRVO) demonstrate disrupted endothelium and platelet/fibrin thrombosis within an often-narrowed vascular lumen. The fresh clot is usually found at the level of or behind the lamina cribrosa in CRVO or at an arteriovenous crossing in BRVO.4, 5 The platelet/fibrin thrombus with time becomes stabilized and may become recanalized. Many treatments have been attempted to combat this disorder with little or no success; these treatments include systemic fibrinolytics⁶ and anticoagulants,⁷ isovolemic hemodilution,⁸ panretinal,⁹ grid,¹⁰ and chorioretinal photocoagulation,¹¹ hyperbaric oxygen,¹² and treatment with such antiplatelet drugs as bifemlane¹³ and troxerutin.¹⁴

Ticlopidine is a thienopyridine derivative that inhibits adenosine diphosphate (ADP)-induced platelet aggregation (Figure 1). The mechanism of action of ticlopidine is via indirect inhibition of fibrinogen binding to the glycoprotein IIb/IIIa complex.¹⁵ Ex vivo studies in rabbits have shown that ticlopidine significantly reduces the amount of platelet aggregation to extracellular matrix.¹⁶ In addition, ex vivo studies on human volunteers revealed a significant inhibition of ADP-induced platelet aggregation in the ticlopidine group versus placebo.¹⁷ A large multicenter clinical trial, the Canadian-American Ticlopidine Study, has demonstrated that ticlopidine in patients who have had a recent stroke reduced the incidence of another stroke, myocardial infarction, or vascular death by 30.2% compared with placebo.¹⁸ Furthermore, ticlopidine has also been found to reduce complications due to platelet aggregation in patients undergoing hemodialysis, coronary artery bypass surgery, carotid endarterectomy, and extracorporeal circulation.¹⁹ However, oral ticlopidine is associated with diarrhea, rashes, hemorrhages, and hematologic disorders. Hematologic disorders such as leukopenia, thrombocytopenia, and pancytopenia are rare and resolve upon discontinuation of the drug, but close monitoring of the patients taking this drug is required.

We hypothesized that ticlopidine may be useful for prophylaxis, and also for possible treatment of a fresh platelet/fibrin thrombus in acute retinal vein occlusion (RVO). We tested this hypothesis in a platelet-rich model of RVO²⁰ in the albino rabbit by investigating whether pretreatment with ticlopidine or aspirin would increase the number of laser applications needed to produce a partial or complete occlusion of a retinal vein by photoactivation of intravenous rose bengal.