Idiopathic Central Retinal Vein Occlusion in 2 Siblings With the 20210 G→A Prothrombin Variant

Genetic variations in clotting factor genes may be very important in both venous and arterial thrombosis. Inherited thrombophilia has been associated with a deficiency of anticoagulant proteins such as protein C, protein S, antithrombin III (AT III), and factor V Leiden mutation.¹

Another procoagulant mutation, located in the 3′-untranslated region of the prothrombin (PT) gene 20210 G→A PT mutation has recently been associated with an increased risk of venous thrombosis.² Franco et al³ thought the prevalence of the PT G→A mutation was found to be 2- to 7-fold higher among patients with atherosclerotic disease than in healthy controls. Heterozygosity for the 20210 A allele was reported to be associated with increased PT (factor II of coagulation) and venous thromboembolism.^2-4 We report 2 cases of retinal vein occlusion (RVO) in 2 siblings who tested positive for the clotting factor II 20210 A variant.

A 38-year-old white woman (patient 1) reported painless decrease in vision of 2 days' duration in her right eye. On admission, the patient's best-corrected visual acuity was 20/60 OD and 20/20 OS. She also had a right relative afferent pupillary defect. Slitlamp examination of both eyes was unremarkable. Applanation tonometry disclosed an intraocular pressure of 14 mm Hg OD and 18 mm Hg OS. Ophthalmoscopic examination of the patient's right eye showed the presence of a central RVO (Figure 1A), which was confirmed by fluorescein angiography (Figure 1B). Fundus examination of the left eye revealed a normal posterior pole. One week later, visual acuity in the right eye deteriorated to 20/200 as well as the fundus aspect (Figure 1C). Her family medical history had some remarkable points. At age 35 years, she suffered from deep-vein thrombosis in her right leg. Her father had an ischemic stroke at the age of 51 years and died at 56 years. Alcohol abuse and cigarette smoking were excluded as well.

Eleven months later, the patient's 41-year-old brother (patient 2) was admitted to our department with a diagnosis of papillophlebitis in his left eye (Figure 2). Best-corrected visual acuity was 20/30 OS and 20/20 OD. Slitlamp examination did not disclose any abnormality in the anterior segment of either eye.

Complete ophthalmic history and examination, as well as general medical history and physical examinations investigating factors associated with an increased risk of retinal vein occlusion, were obtained in both patients and were negative. Laboratory testing, including a complete blood cell count, serum chemistries, glucose tolerance, hemoglobin electrophoresis, erythrocyte sedimentation rate, serum lipids, quantitative immunoglobulins, antinuclear and anticardiolipin antibody titers, human immunodeficiency virus (HIV) serology, presence of lupus anticoagulant, and syphilis serology, had normal results. Common coagulation tests (PT, activated partial thromboplastin time, fibrinogen) and studies for congenital causes of hypercoagulability, including AT III, protein C, protein S, resistence to activated protein C deficiencies, and factor V Leiden mutation, were also within normal limits. Additionally, the 2 siblings were tested for the PT 20210 A variant. Only the latter test was positive for the heterozygous form of the PT 20210 A gene in both cases. The same heterozygous condition was demonstrated in one of their nieces, but she had no clinical manifestations. The 20210 A allele of the PT gene was detected by PCR amplification of a 142-bp (base pair) fragment, including nucleotide 20210, using a downstream mutagenic primer that introduced a recognition site for the restriction enzyme Hind III, where adenine was present at position 20210.

On the other hand, previous studies have documented that an elevated plasma homocysteine levels may be a risk factor for RVO.⁵ Homocysteinemia was investigated in this family too, but only the first case of RVO showed a higher plasma homocysteine level than the second case of RVO and in their niece (14.8 µmol/L vs 9.4 µmol/L and 9.3 µmol/L, respectively). Homocysteine levels were determined by high-performance liquid chromatography with electrochemical detection.

At a follow-up period of 10 months, patient 1's visual acuity was stablized (20/200 OD). Figure 3 shows a fundus photograph of the right eye. In contrast, her brother, patient 2, had improved visual acuity to 20/20 OS (4 months after his), with total spontaneous resolution of the retina lesions.

The mutation of PT G→A variant is linked to an increased thrombotic tendency,² and has been associated with both artery and venous disease.^3,4 This feature is probably mediated by various conditions. Firstly, the heterozygosity for the 20210 A allele is associated with a 25% increase in circulating PT levels.^2-4 Secondly, these elevated PT levels are associated with increased thrombin formation and activation of the coagulation.³ Franco et al³ detected plasma PT levels in carriers (1.26 ± 10 U/mL) were higher than in noncarriers (1.03 ± 1 U/mL, P = .02). A "prothrombic" interpretation is also in keeping with the fact that 20210 mutation was originally described as a risk factor for venous thrombosis, a fact that has been confirmed in other recent studies.^3,4

In our patients, this mutation leads to an increase in plasma PT rate of the order of 30% too. In these 2 cases, who tested positive for the 20210 A mutation, the plasma PT levels were 1.62 U/mL (normal plasma PT levels = 1.0 U/mL) and 1.51 U/mL, respectively. They were performed by a thromboplastin-based assay using factor II – deficient plasma (Instrumentation Laboratory UK, Warrington, England) on a Sysmex CA 6000 (Globe Scientific Inc, Paramus, NJ) coagulation analyser. Our patients represent a documented association between RVO and the 20210 G→A heterozygous genotype. Even if this correlation cannot be demonstrated solely by these patients, the history of deep-vein thrombosis at age 37 years further supports the presence of a specific thrombophilic disorder in one of these patients. Although we cannot conclude that the RVO was a direct result of the 20210 G→A mutation, this association was the only known risk factor for thromboembolism we found in these 2 patients. But this association, PT 20210 A variant and RVO, is strengthened in the first case by another relative to RVO. We have found higher plasma levels of homocysteina in the woman with RVO compared with the second case of RVO. A fact that is known as a possible new risk factor for RVO.⁵

A laboratory evaluation for coagulophaty, including the PT 20210 A variant and homocysteinemia, may be considered in young patients with RVO or in older patients with RVO, especially those without obvious venous thrombosis risk factors and coagulopathies. Thus, this PT gene sequence variation and the homocysteine plasma levels add to the list of recognized genetic risk factors for thrombophilia. Additional genetic investigations in a sufficiently large number of patients are needed to establish the presence of a significant correlation between mutations of the PT gene, homocysteinemia, and RVO.

Reprints: Cristina Peris-Martínez, MD, Avda, Autopista del Saler 12, 3a planta, Puerta 7, University Hospital "La Fe," Department of Ophthalmology, 46013 Valencia, Spain (e-mail: cperis@ctv.es).