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.
A, Fundus photograph of the right
eye, showing a central retinal vein occlusion with venous tortuosity, disc
edema, cotton-wool spots, and hemorrhages in all quadrants. B, Fundus angiogram
of the right eye (292 seconds of fluorescein injection). C, Fundus photograph
of the same right eye, showing a central retinal vein occlusion 1 week later.
Disc swelling, venous engorgement with flame-shaped hemorrhages on the disc
and the surrounding retinal tissue.
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.
Fundus photograph of the left
eye (male sibling) showing a less severe disc edema, hyperemia, and venous
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.
Fundus photograph of the right
eye (female sibling) 10 months later, with a reduction of retinal edema and
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: firstname.lastname@example.org).
MM Screening for resistance to activated protein C and the mutant gene
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RM A common genetic variation in the 3N untranslated region of the prothrombin
gene is associated with elevated plasma prothrombin levels and an increase
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A Branch retinal vein occlusion associated with the 20210 G to a prothrombin
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PM Plasma total homocysteine and retinal vascular disease. Eye.
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