anassociationwithRVOswaspresent(P = 0.02).158 Because lipoprotein a levels are primarily genetically determined and are little inßuenced by interventions designed to treat hyperlipidemia such as diet changes, bile salt, or Þsh oil supplements, as well as the use of chelating resins, statins, or Þbrates, there is little incentive to determine the status of a patient with RVO with respect to this variable.158

6.2.6.5 Von Willebrand Factor

Higher levels of von Willebrand factor are prothrombotic. However, the results of studies seeking any association of VWF and CRVO are inconsistent. There was a statistically signiÞcantly higher mean factor von Willebrand Factor level in patients with CRVO compared to population-based controls in a study from England.200 In a case-control study of 63 cases and 63 controls, the median VWF was not statistically different in the two groups.19

6.2.6.6 Other Coagulation Factors

Table 6.3 lists several other coagulation factors that have been examined for association with RVO. Although some factors have associations, the evidence is not sufÞciently strong to indicate that these factors need to be checked in clinical care.

6.2.7 Hyperhomocysteinemia

Increased plasma homocysteine concentration is atherogenic and prothrombotic through many mechanisms, including induction of a secondary increase in factor V; activation of factors V, X, and XII; reduction in protein C activation, plasminogen activator binding; reduced nitric oxide bioavailability; reduced prostacyclin synthesis; inhibition of thrombomodulin and heparin sulfate expression; increased oxidative stress; a mitogenic effect on arterial smooth muscle cells; increased expression of stress-related genes; and endothelial damage.22,37,65,137,154,194 The biochemistry of the metabolic pathway in which homocysteine is an intermediary amino acid was covered in Chap. 1. Plasma homocysteine concentrations are affected by genetic inßuences and by behavioral and dietary inßuences. The genetic inßuences are covered in Chap. 3. This chapter covers studies of association of the presence of RVO and hyperhomocysteinemia from whatever cause. In these studies, no attempt has been made to isolate the genetic effect, and therefore they sample patients with both primary and acquired hyperhomocysteinemia.

Among the nongenetic conditions that elevate plasma homocysteine concentrations are renal

insufÞciency, diabetes mellitus, hypothyroidism, organ transplantation, psoriasis, and cancer; low intake of vitamins B6, B12, and folate; use of exogenous estrogens, carbamazepine, phenytoin, antifolates, and tricyclic antidepressants; smoking; and consumption of alcohol and caffeine.22,54,137,193 Mean plasma homocysteine shows variation across countries because of genetic variation, variation in diet and vitamin use, and differences in prevalence of clinical conditions inßuencing homocysteine concentrations.133,137,194 Moreover, normal values depend on gender with values in males elevated 25% on average compared to premenopausal females.22,111 Mean plasma homocysteine concentration varies from 6 mmol/l in Japan to 14.7 mmol/l in South Asian Indians.133,137 The deÞnitions of hyperhomocysteinemia vary across studies as well. They are typically based on the principle that a value is classiÞed as high if it exceeds the 95th percentile for the population, which varies.193

The relationship of plasma homocysteine to RVO has been inconsistent across studies. The inconsistency may result from the control groups chosen in the many case-control studies. Various studies have chosen controls from the general population, from healthy adults, blood donors, and clinic or hospital patients matched on one or more factors.146 Failure to match cases and controls for age, gender, and atherosclerotic risk factors introduces confounding, as homocysteine depends on these characteristics.37,146 Plasma homocysteine should be tested on fasting samples; nonfasting samples could be confounded by this pitfall.38,189 One study reported an inverse correlation of plasma homocysteine concentration and time that the sample was drawn after the acute event, introducing yet another source of variation across studies.193 The stronger studies examine plasma homocysteine within a week of the acute event.37

A latent tendency to develop elevated plasma homocysteine can be detected in patients with a normal fasting plasma homocysteine by use of a methionine loading test. In this test performed in a fasting state, 0.1 g/kg body weight of oral methionine is given followed by plasma concentration testing 8 h later.111 This provocative test may

detect latent hyperhomocysteinemia in up to 28% of patients with normal plasma homocysteine.18

6.2.7.1 Pooled Retinal Vein Occlusion

The evidence regarding a relationship of plasma homocysteine and pooled RVO is generally consistent across studies. In a meta-analysis of ten case-control studies, nine suggested an association between elevated serum homocysteine and RVO.22,183 The one that did not was limited to patients of less than 50 years of age.22,109 Since that meta-analysis, more recent studies have supported an association of plasma homocysteine and pooled RVO.172

The BMES examined the relationship of total plasma homocysteine to prevalence of pooled RVO. In a multivariate analysis controlling for age, sex, hypertension, and an interaction of age and smoking, an elevated total plasma homocysteine (greater than 15 mmol/l) was not associated with prevalence of RVO among persons older than 70 years (OR 1.51, 95% CI 0.71Ð 3.22). In patients less than 70 years of age, an association was noted (OR 3.76, 95% CI 1.06Ð 13.40).29 The absence of an association in the older cohort may have been an artifact of a low prevalence.29

6.2.7.2 Branch Retinal Vein Occlusion

The evidence regarding an association of hyperhomocysteinemia and BRVO is inconsistent. In a meta-analysis of three case-control studies through 2003, all showed an association.22 Since that meta-analysis, two other studies have not conÞrmed the association, although small sample sizes could have prevented the detection of any true, small difference.144,204

6.2.7.3Central and Hemicentral Retinal Vein Occlusion

Case reports and uncontrolled case series have linked CRVO and hyperhomocysteinemia.16 Case-control studies associating raised plasma homocysteine and CRVO have been inconsistent.22 Vine found hyperhomocysteinemia to be twice as prevalent in patients with bilateral CRVO