blood cell count, red blood cell count, platelet count, or serum Þbrinogen.32 In the BDES, hematocrit, white blood cell count, and platelet count were not associated with prevalence, 5-year incidence of BRVO, or 15-year incidence of BRVO.95,96

6.2.6 Coagulation Abnormalities

Coagulation abnormalities are classiÞed as primary and secondary. Primary abnormalities represent genetic mutations that alter the normal coagulation pathways. These are covered in Chap. 3. Secondary abnormalities arise from acquired conditions such as malignancy, pregnancy, diabetes mellitus, or use of certain drugs.75 Many studies do not make a distinction between types of coagulation abnormalities and simply report coagulation protein levels and associations between levels and RVO. This chapter concentrates on these types of studies in which a genetic characteristic has not been isolated. In the future, when genetic studies of these factors and their relationships to RVO have been explored, several of the following sections will be better grouped in the chapter on genetics and RVO.

Some studies have not found differences in prevalences of hypercoagulability across categories of RVO and have therefore pooled patients with CRVO, HCRVO, and BRVO.1 The validity of these groupings has been questioned.183

6.2.6.1 Antiphospholipid Antibodies

Antiphospholipid antibodies (APLAs) are polyclonal immunoglobulins that bind to anionic

phospholipids in cell membranes and proteins of the coagulation cascade.97 They promote expression of adhesion molecules on the surface of endothelial cells potentially causing a state of hypercoagulability.30,50,190 They are found in 1Ð9.1% of the general population, usually in low titers, and in such instances may represent a marker of vascular injury without thrombogenic importance.190

APLAs prolong coagulation tests in vitro, yet paradoxically promote thrombosis in vivo, probably by inßuencing phospholipids of platelet and vascular endothelial cell walls and by interacting with coagulation factors.42,140,160 Their anticoagulant effects in vitro arise because they bind to the partial thromboplastin that is added to plasma to conduct the prothrombin (PT) or partial thromboplastin time (PTT) tests.97 A prolonged PTT is the most common abnormal clotting test in the presence of APLAs. The PT may be normal or slightly prolonged.97,113,197 To be considered as a factor in disease etiology, high titers of APLAs are required.160

APLAs include the lupus anticoagulant (LA), anticardiolipin antibody (ACA), and antibodies that produce a false positive VDRL test for syphilis. They can be directed against B2 glycoprotein I, phosphatidylserine, and double-stranded DNA, but the most important ones are IgG ACA, IgM ACA, and the LA.139 The antiphospholipid antibody syndrome is deÞned as arterial or venous thrombosis with a medium or high titer of an APLA on two occasions separated by 6 months, thrombocytopenia, or recurrent spontaneous abortions due to placental insufÞciency.13,182 The syndrome can be found in association with an

underlying autoimmune systemic diseases such as systemic lupus erythematosus. In the absence of an associated disease, it is called the primary antiphospholipid antibody syndrome.13,182 APLAs can be associated with neoplastic diseases, and certain drugs including chlorpromazine, hydralazine, phenytoin, procainamide, and quinidine.97

Although the rate of retinal abnormalities in patients with primary antiphospholipid syndrome is variable, ranging from 7% to 88% in different studies, the prevalence of antiphospholipid antibodies in patients with RVO is not well deÞned.25,55 Arterial thrombosis is more commonly associated with antiphospholipid syndrome than venous thrombosis, but isolated RVO and other venous thrombotic events in association with the syndrome can occur.113,197 The association of APLAs and RVO has been inconsistent in the literature.13,30,56,71,116,160,199 Laboratory testing for antiphospholipid antibodies is not standardized, and it is difÞcult to generalize from small case series. In a meta-analysis of 12 case-control studies of pooled RVO up to 2006, four showed an association with APLAs and eight did not.190 The same meta-analysis reviewed Þve studies of CRVO and APLAs, and an association was found in three.185

Although few would advocate the routine screening for APLAs in any age patient with RVO, one should probe the medical history for a pattern that might suggest the need to pursue this line of inquiry. SpeciÞcally, a previous personal or family history of spontaneous abortions or arterial or venous thrombotic events should prompt investigation for APLAs.149,183

6.2.6.2 Factor VII

Elevation of factor VII is procoagulant. Factor VII is present in plasma in inactivated and activated forms. The activated form is typically 1% of the total plasma factor VII. Some assays do not distinguish the two forms, which can confound the interpretation of results.87 In a pooled casecontrol study of 54 cases of CRVO and BRVO with 19 controls, median activated factor VII levels were signiÞcantly higher in patients with RVO compared to controls (74 and 90 mU/ml for

CRVO and BRVO, respectively, compared to 42 mU/ml for controls, P = 0.0004).87 There was no statistically signiÞcant difference in mean factor VII levels between patients with CRVO and population-based controls in a study from England.200 Too few studies have examined this factor to be able to reach a conclusion regarding its signiÞcance in RVO.

6.2.6.3 Factor VIII

Elevated factor VIII is thrombophilic.62 There was no statistically signiÞcant difference in mean factor VII levels between patients with CRVO and population-based controls in two studies from England.19,200 Likewise, in a case-control study of 42 chronic pooled RVOs, there was no difference in factor VIII activity between the groups.184 In a separate case-control study, elevated factor VIII was present in 3 of 30 patients with pooled CRVO/BRVO and none of 40 controls, P = 0.041.62

6.2.6.4 Lipoprotein a

Lipoprotein a (Lp(a)) inhibits the conversion of plasminogen to plasmin and therefore is procoagulant. Studies examining a possible association of Lp(a) with RVO are difÞcult to interpret because there is no accepted range of normal for this test. As a result, investigators must make an arbitrary decision about what to consider as the normal cutpoint.158 The choice of the cutpoint can change the conclusions of the study.158 In a casecontrol study of 262 patients with pooled RVO and 262 ageand gender-matched controls, Lp(a) levels greater than 300 mg/l were associated with RVOs in multivariate models that controlled for age, sex, and vascular risk factors (OR 2.15, 95% CI 1.39Ð3.32).171 In a case-control study of 40 patients with CRVO and no known risk factors, lipoprotein a was elevated in the patients with CRVO compared to the controls.11 In a case-con- trol study of 132 patients with pooled RVO and 52 controls matched for age, sex, and cardiovascular risk, Lp(a) levels greater than 300 mg/l were not associated with RVOs, but when the cutpoint for abnormality was changed to 100 mg/l,