Thrombophilia: genetic polymorphisms and their association with retinal vascular occlusive disease.

Venous thrombosis aVects one in 1000 individuals per year 2 causing significant morbidity and mortality. Inherited thrombophilia is a genetically determined tendency to thrombosis. Dominant abnormalities or combinations of mutations of varying penetrance giving rise to less severe defects may be suspected clinically from evidence of early age of onset, frequent recurrence, or family history. Milder traits may be discovered only by laboratory investigation. In most patients, however, thrombosis is episodic, separated by long asymptomatic periods. This episodic nature indicates that there is a trigger for each event and that the inherited trait requires interaction with other factors before a clinical disorder becomes apparent. Vascular occlusions of the eye encompass thrombosis of retinal veins, arteries, and anterior ischaemic optic neuropathy. The Eye Disease Case Control Study Group identified a number of risk factors for branch, central, and hemiretinal vein occlusions including hypertension, diabetes, a history of cardiovascular disease, an increased body mass index at 20 years of age, and patients with open angle glaucoma. Branch retinal vein occlusions were particularly linked with hypertension. This echoed the findings of earlier smaller studies. 8 In addition, hyperviscosity syndromes including a raised haematocrit and elevated erythrocyte aggregation rate, as well as other prothrombotic states (for example, hypofibrinolysis, increased levels of tissue factor), induced by increased levels of lipoprotein (a), malignancy, pregnancy, oestrogen therapy, and paroxysmal nocturnal haemoglobulinuria have all been associated with retinal vein occlusion. 9–12 In addition to the factors described above, there are associations between retinal vein occlusions and inherited defects in the proteins of the coagulation pathways. Hypercoagulability can be the result of deficiencies in particular elements of the coagulation cascade such as protein C, protein S, or antithrombin III. Abnormal levels of the components of the fibrinolysis pathway also occur including tissue plasminogen activator, urokinase, or increases in plasminogen activator inhibitor which inhibit resolution of a thrombus. Risk factors for retinal artery occlusions include hypertension, diabetes, hyperlipidaemia, and smoking which all increase the likelihood of carotid artery atherosclerosis. Embolic occlusions can occur with cardiac valvular disease, long bone fractures, use of intravenous drugs, following angioplasty, and with amniotic fluid emboli. In addition, as with retinal vein occlusions, there is an association with hypercoagulability, oral contraceptive use, pregnancy, and sickle cell disease. Non-arteritic anterior ischaemic optic neuropathy (NAION) is most probably caused by local factors which compromise the short posterior ciliary arteries, the pial circulation, and the retinal circulation at the optic nerve head and are most significant in the crowded disc. It may also, however, be associated with systemic factors which increase the likelihood of occlusion of these arteries. Such factors include diabetes (odds ratio, OR=5), increased body mass index (OR=1.07), ischaemic heart disease (OR=2.6), hypercholesterolaemia (OR=2.3), and acute events such as systemic hypotension. 16 Recently, polymorphisms in genes encoding proteins which are involved in the coagulation cascade or which can enhance coagulation have been described. This review will summarise recent literature on the role of these genetic polymorphisms as risk factors for each type of retinal vascular occlusion.