Heritable Thrombophilia and Hypofibrinolysis

Abstract

Objective: To determine whether heritable thrombophilia and hypofibrinolysis were risk factors for retinal vein occlusion. Design: Measures of thrombophilia (increased likelihood of thrombus formation) included anticardiolipin antibodies (IgG and IgM), the lupus anticoagulant (including dilute Russell viper venom clotting time), antigenic proteins C and S, and homocysteine. Polymerase chain reaction assays were performed for 3 thrombophilic gene mutations (factor V Leiden, methylenetetrahydrofolate reductase, and prothrombin gene). Measures of hypofibrinolysis (reduced ability to lyse thrombi) included lipoprotein Lp(a), plasminogen activator inhibitor activity, and polymerase chain reaction analysis of the hypofibrinolytic 4G/5G polymorphism of the PAI1 gene. These coagulation measures were performed in 17 patients with retinal vein occlusions with comparison with serologic coagulation measures and polymerase chain reaction assays in 40 and 234 healthy normal volunteers as controls, respectively. Results: Of 14 patients with retinal vein occlusion with measures of dilute Russell viper venom clotting time, a thrombophilic antiphospholipid antibody, 6 (43%) had abnormal results (Ͼ38.8 seconds) compared with 1 (3%) of 30 controls (P = .002). Of 17 patients with vein occlusion, 3 (18%) were heterozygous for the thrombophilic factor V Leiden G1691A mutation compared with 7 (3%) of 233 controls (P = .02). Of 17 patients with vein occlusion, 2 (12%) had normal alleles (5G/5G) for the plasminogen activator inhibitor gene promoter; the other 15 (88%) were heterozygous or homozygous for the 4G polymorphism, which is associated with hypofibrinolysis. Of 234 controls, 85 (36.3%) had the 5G/5G allele; 149 (63.7%) were heterozygous or homozygous for the 4G polymorphism (P = .03). Patients with vein occlusion were more likely to have high levels of the major determinant of hypofibrinolysis, plasminogen activator inhibitor activity. These levels were high (Ͼ22 U/L) in 6 (38%) of 16 patients with vein occlusion compared with 1 (2%) of 40 controls (2 = 12.8; P = .001). Patients with vein occlusion were more likely (8/16 [50%]) to have high levels of hypofibrinolytic Lp(a) (Ͼ35 mg/dL) than controls (5/40 [13%]; 2 = 9; P = .003). The median Lp(a) level in patients with vein occlusion who had the 4G/4G genotype was 62 mg/dL compared with 5.3 mg/dL in controls with the 4G/4G genotype (P = .05). Conclusion: Thrombophilia and hypofibrinolysis are possible causes of retinal vein occlusion.

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

“…However, it was pointed out by Vine30 that the patient group was highly selected, having being referred and hospitalised specifically for a thrombotic examination. This was also true of a study by Glueck et al 11 who found a positive correlation in a population of patients with retinal venous occlusions (mean age of 52 years) which included 24% with a history of thrombotic events. The only study not apparently biased and which found a positive correlation was a case controlled study by Albisinni et al 31 but this had a lower prevalence of the mutation (11.1% v 1% controls, compared to 18% v 3% controls by Glueck et al 11 and 29% v 9% controls by Greiner et al 29 in the affected population).…”

“…Likewise, a study of 102 patients found a positive correlation between MTHFR homozygosity and retinal vein occlusion (OR 1.9; 95% CI 0.95–3.81) 37. Conversely, Glueck et al 11 in a study of 14 patients with retinal venous occlusions could not confirm this association and a study of 116 Scandinavian patients did not find any difference in either the prevalence of the mutation or hyperhomocysteinaemia between controls and patients with central retinal vein occlusions, even if all patients over 50 were excluded 59. Furthermore, a recent retrospective case control study of 174 Irish patients found that a homozygous MTHFR genotype did not increase the risk of retinal or arterial vein occlusion 60.…”

“…However, a large study of 102 Israeli patients did not find an association between the polymorphism and retinal vein occlusion (2.9% patients compared to 5.7% of controls) 37. Likewise, both Backhouse et al 49 in 16 and Glueck et al in 14 patients with retinal vein occlusions11 failed to find any association. A retrospective case controlled study of 61 patients with NAION did not find any increased prevalence of the prothrombin mutation 16…”

Retinal vein occlusion: evaluation of “classic” and “emerging” risk factors and treatment

“…Lupus Anticoagulans (LAC), anti-cardiolipin antibodies (ACA) and anti-beta-2-glycoprotein I IgG/IgM are commonly considered risk factors for VTE and ATE. Coniglio et al [19] and Glueck et al [20] concluded that significant percentage of LAC and ACA were present in patients with RVO, but Marcucci et al [9] have found no differences between patients and controls. Currently the role played of LAC and ACA in the RVO is still contradictory.…”

Thrombophilia and retinal vascular occlusion

“…Most studies associating estrogen–progestin oral contraceptives with CRVO or CRAO are case reports of only one to three cases 18,21–23. Most reports of CRVO or CRAO associated with estrogens or estrogen agonists8–14,18–21 have not assessed interactions between pharmacologic thrombophilia conferred by estrogens or estrogen agonists and the inherited and acquired thrombophilia15,16,24–35 known to be causally associated with RVO.…”