Letters to the Editor

Treatment of acute central retinal artery occlusion with the platelet glycoprotein IIb/IIIa receptor inhibitor tirofiban
Dear Sir, Central retinal artery occlusion (CRAO), not an infrequent presentation to the emergency department, is usually a blinding event for which we have no effective treatment. A spontaneous remission and recovery of visual function is rare. Without treatment the probability of a significant visual improvement (improvement of more than two lines) is reported with up to 8 % (1, 2). Conventional CRAO management is directed to improve retinal artery perfusion by lowering intraocular pressure (by means of ocular massage, anterior chamber paracentesis, or antiglaucomatous medication) and by altering blood rheology by administering anti-platelet agents. Carbogen and hyperbaric oxygen therapy are further treatment forms that aim to produce retinal vasodilation and increase oxygen delivery to the hypoxic retina. Despite these diverse efforts most patients continue to experience severe vision loss: a significant visual improvement by conventional minimally invasive management is reported to occur in 15 to 21% of patients (35). Local intraarterial fibrinolysis by catheter-assisted administration of urokinase or tissue plasminogen activtor (tPA) in the ophthalmic artery has been applied with favourable clinical results (visual improvement in up to 35% of patients) in the CRAO management (2, 3, 6). However, because of the risk of systemic, life-threatening side effects of superselective fibrinolyis and possible local complications of the invasive procedure, it is a subject of much controversy. To date, no randomised controlled trial has been conducted to evaluate the risks and benefits of local intra-arterial fibrinolysis for CRAO. Due to this uncertainity, treatment of CRAO still remains an unsolved ophthalmologic problem and a challenge for the attending practitioner. Most cases of CRAO have been reported to be of either thrombotic or embolic origin, and platelet activation and aggregation, with resultant arterial thrombus formation, are pivotal in its pathophysiology (4). The development of inhibitors of fibrinogen binding to the platelet glycoprotein IIb/IIIa receptor has expanded the therapeutic options for treating thrombotic arterial disorders. In several controlled and randomised studies, glycoprotein IIb/IIIa inhibitors have been proven to be safe and effective in patients with acute ischemic events in other organs and to improve prognosis of cerebrovascular insults or acute coronary syndromes. This prompted us to conduct a pilot, non-controlled phase 1 study investigating tirofiban, an intravenously administered short-acting, nonpeptide inhibitor of the platelet glycoprotein IIb/IIIa receptor in the treatment of acute central retinal artery occlusion. Eighteen consecutive patients (3 females; average age 67, range 4678 years) who had acute CRAO with symptom onset (acute, painless monocular loss of vision) less than 12 hours were assigned to treatment with tirofiban (0.4 g/kg/min for 30 min; followed by an infusion of 0.1 g/kg/min over 48h) plus full-dose heparin (administered as an intravenous bolus of 5000 units, followed by an infusion of 1000 U per hour, adjusted to two times the control value for the activated partial-thromboplastin time) and aspirin (500 mg intravenous bolus). Patients' baseline characteristics are summarized in Table 1. All patients were checked for exclusion criteria indicated in Table 2. The study was approved by the local ethics committee. Informed consent was obtained from all patients. Visual loss and the effect of treatment for 48 hours after tirofiban administration were recorded by determining best-corrected distance visual acuity in a standard clinical setting. In brief, this employs a target recognition task that requires patients to accurately name letters of the alphabet that are projected in descending size at 6 m distance. A patients visual acuity is specified by the smallest line of letters that can be correctly identified, and given in decimal notation. Poorer vision was determined by reducing the testing distance or recording counting fingers at 25 cm (CF), hand movements (HM), perception of light (PL) or no perception of light (NLP). Normal visual acuity on this scale is 1.0. Visual acuity before treatment ranged from NLP to 0.05 (Fig. 1). The median duration of visual loss up to commencing tirofiban treatment was 7 hours with a mean SD of 8.5 4.5 hours.

Correspondence to: PD Dr. Hans Hlschermann Dept. of Internal Medicine, Div. of Cardiology University of Giessen Klinikstr. 36, D-35392 Giessen, Germany Tel.: +49 641 9942101, Fax.:+49 641 9942109 E-mail: hoelschermann@.uni-giessen.de Received February 28, 2005 Accepted after resubmission June 26, 2005

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Figure 1: Scattergram shows visual acuities in 18 eyes with CRAO before and after treatment with tirofiban. Visual acuity is given in a logarithmic scale. Vision less than 0,025 is recorded as counting fingers (CF), perception of hand movements (HM), perception of light (PL) and no perception of light (NPL). Points lying above the diagonal line represent improvement in visual acuity.

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There was no detectable correlation of the delay between symptom onset and treatment initiation and visual outcome. With tirofiban treatment, a significant visual improvement (more than 2 lines) was observed in 8 of 18 patients (44%), an additional 4 patients improved slightly (1 step improvement) (22%). Two patients recovered completely and regained a visual acuity of 1.0. In 6 patients (33%), tirofiban treatment had no detectable effect. No patient had an intracranial haemorrhage or other bleeding complications related to the study regimen. Initial visual acuity had no predictive value for visual improvement. This is the first study evaluating the use of a glycoprotein IIb/ IIIa receptor antagonist in the treatment of CRAO. When compared to published data, our initial results suggest that tirofiban might be superior to both the natural course and the conservative management of disease and appears to be an at least equivalent therapeutic alternative to fibrinolysis, so far the only therapy proven to improve visual outcome in CRAO patients (7). Only about 150 treatments of local intra-arterial administrations are published to date. The success rate in these studies (significant visual improvement) is up to 35% (2, 3, 6). The success rate in the present study with tirofiban was 44%. Local intraarterial administration of fibrinolytic agents, however, is not without danger, requires complete angiography by an experienced neuroradiologist, has limited availability, requires additional personnel, and still remains at least as emergency procedure a logistic challenging. Furthermore, CRAO patients must be selected carefully for both systemic and local fibrinolysis and a substantial portion of patients have to be excluded from fibrinolysis to decrease the risk of cerebrovascular accidents. Consequently, in two metaanalyses the recommendation was given to choose the riskless possible therapy for CRAO as long as there is no sufficient evidence to justify fibrinolytic therapy (2, 3, 6). The rationale for the use of GP IIb/IIIa inhibitors in acute ischemic arterial events is to facilitate the restoration of blood flow. While GPIIb/IIIa has to date become a primary therapeutic target in other vascular beds and GPIIb/IIIa inhibitors have been setting a new standard of care in acute ischemic arterial events, this is the first report on the treatment of CRAO with a GP IIb/ IIIa inhibitor. The present attempt to treat CRAO with the GP IIb/ IIIa receptor antagonist tirofiban seems to be promising in terms of efficacy and safety. We found, that 44% of patients showed a significant visual amelioration under intravenously administered tirofiban. With this, the clinical benefit obtained by tirofiban treatment is in the same range or even extends the reported results for intra-arterial fibrinolytic therapy and is superior to the published outcome of conventional therapy (4). Furthermore, no major bleeding complications, and particularly no cerebrovascular hemorrhage, were observed under combined tirofiban, heparin and acetylsalicylic acid. Thus, treatment of CRAO with this combined antithrombotic therapy appears to be safe as already suggested by the safety data of several large clinical trials in pa-

Table 1: Baseline characteristics of patients.

Baseline characteristics Hyperlipidemia Hyperuricemia Diabetes mellitus Arterial Hypertension Adipositas Cigarette smoking Coronary artery disease Peripheral artery disease Cerebrocascular disease Number of patients 14 6 3 17 7 5 3 2 5 % 70 30 15 85 35 25 15 10 25

Table 2: Exclusion criteria for tirofiban.

Exclusion Criteria

Uncontrolled arterial hypertension (> 180/110 mmHg) Intracerebral bleeding during the last 12 months Recent bleeding of clinical relevance Hematochezia or hematuria Active peptic ulcer (during the last 3 months) Thrombocytopenia (< 90.000/mm3) Anticoagulant therapy by coumarines (INR > 1,5) Pericarditis, vasculitis, suspicion of aortic dissection Severe injury or surgery during the last six weeks

tients with acute coronary syndromes. Tirofiban therapy, nevertheless, obviously was not appropriate for all patients with CRAO. Similary to failures with other invasive treatments, patients may not have improved under tirofiban because of nonthrombotic CRAO or an individual extended latency period (delay from visual loss to beginning of treatment). In conclusion, inhibition of platelet GP IIb/IIIa appears to be a safe, efficient, easily practicable and available emergency procedure which extends the reported results of commonly used minimally invasive treatments of CRAO that probably even do not improve the natural course of the disease (3). The results of this pilot study are promising, however, they should be interpreted with full appreciation of the small number of patients involved in a non-controlled fashion. We now need and should support a randomised controlled multi-center trial of GP-IIb/IIIa-inhibitors for treatment of CRAO. Hans Hlschermann1, Cathrin Krombach1, Anette Jung2, Felix Jacobi2, Harald Tillmanns1, Frank Weinand2 1Department of Internal Medicine, and 2Department of Ophthalomology, Justus Liebig University, Giessen, Germany

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References
1. Feltgen N, Schmidt D, Hansen L. Occlusion of the retinal artery. Ophthalmologe 2003; 100: 6667. 2. Schmidt D, Schumacher M, Wakhloo AK. Microcatheter urokinase infusion in central retinal artery occlusion. Am J Ophthalmol 1992; 113: 42934. 3. Arnold M, Koerner U, Remonda L et al. Comparison of intra-arterial thrombolysis with conventional treatment in patients with acute central retinal artery occlusion. J Neurol Neurosurg Psychiatry 2005; 76: 1969. 4. Beatty S, Au Eong KG. Local intra-arterial fibrinolysis for acute occlusion of the central retinal artery: a meta-analysis of the published data. Br J Ophthalmol 2000; 84: 9146. 5. Mueller AJ, Neubauer AS, Schaller U et al. Evaluation of minimally invasive therapies and rationale for a prospective randomized trial to evaluate selective intra-arterial lysis for clinically complete central retinal artery occlusion. Arch Ophthalmol 2003; 121: 137781. 6. Weber J, Remonda L, Mattle HP et al. Selective intra-arterial fibrinolysis of acute central retinal artery occlusion. Stroke 1998; 29: 20769. 7. Beatty S, Au Eong KG. Acute occlusion of the retinal arteries: current concepts and recent advances in diagnosis and management. J Accid Emerg Med 2000; 17: 3249.

The thrombomodulin-1208/-1209delTT gene promoter polymorphism does not affect basal or LPSdependent monocyte TM mRNA transcription in healthy volunteers
Dear Sir, Thrombomodulin (TM), a glycoprotein receptor expressed on the surface of endothelial cells and monocytes, is required to activate the protein C anticoagulant pathway (1) and may therefore modulate monocyte procoagulant activity. There are few data on monocytic TM expression (2, 3), and the possible contribution of TM to the whole-blood coagulation balance is unknown. The TM gene Ala455Val polymorphism, associated with coronary heart disease in some populations (4), is in strong linkage disequilibrium (=0.98) with a two-nucleotide deletion at position 1209 (-1208/-1209delTT) that was linked to varicose vein disease in a group of 327 patients with venous thromboembolic disease.(5) The relation between this promoter polymorphism and monocyte TM mRNA levels has not been studied and it is not known whether or not the polymorphism alters TM transcription. We postulated that the 1208/-1209delTT polymorphism might be associated with basal or lipopolysaccharide (LPS)modulated TM mRNA expression in monocytes and/or with the whole-blood clotting time (WBCT). We measured monocyte TM mRNA content by real-time quantitative reverse-transcription PCR (sense primer: 5'-CGGTGCGAGGACGTGGATGACT-3'; antisense primer: 5'-ACTCGCCGTCCACCAGGTCGT-3'; expected PCR product 121 bp). TM being an intronless gene, primers could not be positioned at the junction between two exons or in different exons, potentially leading to non specific signal generation due to contaminating genomic DNA. In our experimental conditions, this contaminating DNA accounted for less than 2% of the TM-specific cDNA Ct values. WBCT was a modified recalcification assay. We performed the monocyte TM mRNA quantification and the WBCT assay together with plasma FVIIIc and prothrombin fragment (F1+2) assays, to study 100 healthy young men, as previously described.(6) LPS repressed 77% of baseline TM gene expression (p<0.0001) and halved the WBCT (table). These quantitative results confirm the effect of LPS on human monocyte TM mRNA expression.(2) In basal conditions, the WBCT did not correlate with monocyte TM mRNA expression (R=0.16, p=0.1). These results do not rule out a weak effect of monocyte TM expression on the coagulation balance in vivo, as the WBCT is less reliable in basal than in LPS conditions.(6) However, we found no correlation between basal monocyte TM mRNA expression and F1+2 plasma levels (R=0.02, p=0.8). The WBCT did not correlate with TM mRNA expression in LPS conditions either (R=0.07, p=0.5). This is not surprising, as monocyte tissue factor expression is a major determinant of the WBCT in LPS conditions.(6, 7) The results were not affected by adjustment for the FVIIIc level. As shown in the table, the 1208/-1209delTT TM gene polymorphism was not associated with TM expression or with the ex vivo WBCT in
Table 1: Means and standard deviations are given for TM mRNA and WBCT.
TM 1208/-1209delTT Genotype Wild-type homozygotes n=83 Basal TM mRNA (arbitrary units) Basal WBCT (s) LPS TM mRNA (arbitrary units) LPS WBCT (s) 99.965.2 205.428.5 22.918.0 131.018.5 1208/-1209delTT heterozygotes n=17 100.547.3 208.630.2 26.316.1 136.712.8 p value

Correspondence to: Prof. Pascale Gaussem Service dHmatologie Biologique A Hpital Europen Georges Pompidou 2040, rue Leblanc, F-75908 Paris cedex 15, France Tel.: +33156093901, Fax: +33156093913 E-mail: pascale.gaussem@egp.aphp.fr Received March 23, 2005 Accepted after revision June 17, 2005 Financial support: This work was partially funded by grants from Programme Hospitalier de Recherche Clinique (Ministre charg de la Sant, PHRC-AOR01023, sponsor: Inserm), Association Claude Bernard, and Ministre de lEnseignement et de la Recherche.

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