Childhood Rubeosis Iridis and Retinal Ischemia Secondary to
SARWAT SALIM, MD DAVID
There are many etiologies of vascular occlusive disease
of the retina and choroid. In the older population, it usually occurs secondary
to systemic vascular diseases, such as diabetes and hypertension.1
Additional risk factors which can predispose these individuals to thrombosis include
hyperlipidemia, malignancy, and immobility.2
In younger patients, inherited coagulation abnormalities are more frequently responsible.2,6
There is very limited ophthalmic literature on retinal vascular occlusions (RVO)
in the pediatric population.
We report a case of a young child with protein C, protein S, and
5,10-methylene tetrahydrofolate reductase deficiencies who developed neovascular
glaucoma secondary to vascular occlusion. An understanding of the common causes
of inherited thrombophilia and knowledge of the available therapeutic options are
essential to lessen the risk of recurrent episodes in an affected individual, and
to protect other family members.
The patient was born premature at 34 weeks of gestation by C-section
due to poor fetal growth secondary to unknown etiology. At birth, she weighed 3
pounds and 13 ounces.
Ocular examination at birth was remarkable for microcorneas of
8.5 mm in both eyes and congenital cataracts. Extensive evaluation was performed
to identify potential infectious and metabolic etiologies for the cataracts, but
none were found. She underwent uncomplicated cataract extraction on the right side
at 8 weeks of age and on the left side at 9 weeks of age, and was fitted with contact
lenses, which have been well tolerated. Subsequently, she had multiple examinations
under general anesthesia to monitor intraocular pressure (IOP). Normal IOP measurements
were obtained until 3 years of age. At approximately 4 years of age, she required
capsulectomy and aspiration of the regenerated lens material in the left eye. She
eventually developed glaucoma associated with a vitreous hemorrhage in the left
eye requiring medical therapy and eventually surgical intervention with Ahmed glaucoma
implant at 8 years of age. A month after placement of the drainage implant, the
patient was treated for an unresolved hyphema. On examination, she was noted to
have iris neovascularization in the left eye, but the details of the optic nerve
and retina could not be discerned due to vitreous hemorrhage. An ultrasound showed
that peripheral retina was attached. An isolated blot hemorrhage was noted near
the fovea in the right eye with normal appearance of the optic nerve and normal
IOP. Despite full efforts, the left eye continued to deteriorate with elevated pressures,
intractable pain, and reduction in visual acuity to normal light perception, necessitating
enucleation. Pathological specimen revealed retinal detachment and vitreous hemorrhage.
The trabecular meshwork appeared normal microscopically, but the angle was closed.
Ectropion uveae was noted pathologically with presence of an acellular membrane
lining the anterior and posterior surface of the iris.
The patient's infancy was remarkable for transient hemolytic anemia
associated with increased osmotic fragility of red blood cells with a negative Coombs'
test, suggesting diagnosis of hereditary spherocytosis. At 6 months of age, she
suffered a left internal capsule cerebral vascular accident with resultant right
hemiplegia. This mandated a work up of the coagulation system, and she was found
to have decreased levels of protein C and S consistent with a heterozygous deficiency,
and was found to be homozygous for the 5,10-methylene tetrahydrofolate reductase
gene mutation as well. Furthermore, evidence of a PlA2 (platelet allo-antigen) genetic
mutation consistent with a heterozygous state was found. Lupus anticoagulant and
homcysteine levels were found to be within the normal range. Both parents were subsequently
tested and were found to be protein S deficient. Because of the CVA and multiple
risk factors for future thrombotic events, she was started on aspirin initially
and later switched to coumadin, which has been continued to the present.
1. Inherited Thrombotic Disorder
Antithrombin III Deficiency
Prothrombin Gene Mutation
factor V deficient plasma dilution
anti lla and anti Xa
assay; chromogenic assay
S antigen assay; functional protein S assay
analysis-polymorphism of factor II gene
1691 of factor V gene
free antigenic assay
mutation (A G at position 506)
mutation (G A at position 20210)
Inherited causes of thrombophilia, listed in Table 1, can
result from disturbances in either the coagulation or anticoagulation pathways involved
in natural hemostasis. The main genetic disorders, which can lead to thromboembolic
disease in children and young adults include resistance to activated protein C (APC-R)
due to factor V Leiden (FV R506Q) mutation, prothrombin gene mutation, protein C
(PC) deficiency, protein S (PS) deficiency, and antithrombin (AT III) deficiency.3,4
In addition, screening for hyperhomocysteinemia has been recommended in the evaluation
of inherited thrombophilia.2
order to understand how these defects induce a hypercoagulable state, it is essential
to review the normal clotting cascade briefly,5,6
depicted in Figure 1. At the time of vascular injury, 2 processes, including blood
coagulation and formation of platelet plug, occur rapidly. In the presence of blood,
tissue factor (TF) complexes with factor VII (FVII) to form activated FVIIa, which
then activates factors IX and X to FIXa and FXa. The joining of FXa and FVa on an
anionic phospholipid surface forms a prothrombin activator complex, which converts
prothrombin to thrombin. Thrombin enhances platelet aggregation and coagulation
by exerting its action on protease activated receptors. Thrombin also forms fibrin
from fibrinogen. Platelet activation by thrombin serves as a positive feedback loop
facilitating more thrombin generation by augmenting the interaction of coagulation
factors, FVa and FVIIIa, with the appropriate receptors. Excessive platelet activation
is kept in balance by prostacyclin and nitric oxide, both of which are secreted
by the healthy endothelium around the site of injury.
Uncontrolled coagulation is regulated by natural anticoagulant
mechanisms. Protein C is a main physiologic anticoagulant that shifts thrombin's
procoagulant role into an anticoagulant one. Thrombomodulin, secreted by activated
endothelium, platelets, neutrophils, serves as an endothelial receptor for thrombin.
This resultant complex then converts inactivated PC to its active moiety, activated
PC (APC). The APC with its cofactor PS (free active form not bound to complement
protein) assembles on the endothelium cell PC receptor (EPCR), inactivating factors
FVa and FVIIIa , and inhibiting the conversion of factor X to factor Xa and of prothrombin
to thrombin. Activated PC also reduces thrombin's induced activation of platelets
and stimulates fibrinolysis by inactivation of plasminogen activator inhibitor-1
Inherited defects in these physiologic coagulation inhibitors
can predispose patients to thrombosis. Activated PC resistance associated with factor
V Leiden mutation is the most common cause of inherited hypercoagulation.3,4
This mutation involves an amino acid substitution where arginine is converted to
glutamine at position 506. This point mutation results in production of abnormal
factor V, which is resistant to cleavage by APC, leading to elevated levels of factor
V and thrombin. This mutation has been reported to affect at least 3% of the population
worldwide. It is important to note from a clinical perspective that certain populations,
such as Asians and African Americans, are spared from these mutations.1
Another inherited defect that involves the procoagulant pathway is prothrombin gene
mutation. Here, a point mutation in the promoter region of prothrombin gene, converting
G to A at position 20210 (G20210A), increases the risk of thrombosis.4
Our patient was found to be negative for these 2 mutations.
1. Physiological coagulation and anticoagulation pathways maintaining hemostasis.
Less commonly, inherited defects involving the anticoagulant
pathways, including PC, PS, and antithrombin can predispose patients to thrombotic
III is an alpha, 2-globulin, which inactivates thrombin and other serine proteases,
including factors Xa, IXa, XIIa, APC. Antithrombin III deficiency is an autosomal
dominant disorder with most affected individuals being heterozygous. Protein C and
S are both vitamin K dependent proteins synthesized by the liver. Deficiencies of
PC and PS are inherited as autosomal dominant disorders and produce identical clinical
syndrome of recurrent thromboembolic disease. Deficient states in these 2 proteins
can be either due to quantitative or functional activity of these proteins. A small
group of patients who are homozygous or compound heterozygous for the PC or PS deficient
gene suffer severe thrombotic complications early in life. These individuals usually
are a product of consanguineous union. The majority of patients with these deficiencies,
being heterozygous, usually remain asymptomatic until young adulthood. Our patient,
although being heterozygous, was affected at such an early age, most likely due
to concomitant presence of both deficiencies.
Our patient was also found to be homozygous for the 5,10-methylene
tetrahydrofolate reductase (MTHFR) gene mutation and heterozygous for the PlA2 genetic
mutation. The MTHFR gene plays a role in the conversion of methylenetetrahydrofolate
into methyltetrahydrofolate, which is a necessary step in remethylation of homocysteine
to methionine.7 Mutation
involving the MTHFR enzyme can result in up to 50% reduction in its activity with
resultant hyperhomocysteinemia. Although elevated levels of homocysteine have been
reported in patients with cardiovascular disease and peripheral vascular disease,
its role in retinal vascular occlusion remains controversial.2,7
There is no clear consensus if hyperhomocysteinemia presents an independent risk
factor or is just a marker for thrombosis. There also have been conflicting reports
on the role of MTHFR mutation in vascular occlusions. In one study, RVO was found
to be statistically associated with MTHFR mutation.8
In this study; however, homocysteine levels were not assessed. In our patient, the
homocysteine level was reported to be normal. This actually is not surprising given
the fact that only one third of the patients with MTHFR reductase mutation develop
hyperhomocysteinemia. Another plausible explanation is that homocysteine level may
have been normalized since it was measured long after the onset of the thrombotic
event. The PlA2 phenotype was evaluated because some studies have suggested it as
a genetic risk factor for coronary artery disease and stroke. While some studies
have indicated a strong association between the PlA2 polymorphism of the glycoprotein
IIIa gene and acute thrombosis, others remain inconclusive.18-20
Inherited thrombophilic disorders can affect virtually any major
organ system. Systemic involvement has been reported to involve cranial, renal,
pulmonary, and deep vein thrombosis. Ophthalmic involvement may be seen concurrently
with any of the above or may be a presenting feature. The most common ophthalmic
manifestation in all age groups is vaso-occlusive disease of the retina and choroid.
In the pediatric population, retinal hemorrhages and vitreous hemorrhage should
alert an ophthalmologist to a possible underlying thrombophilic state. Although
the literature in the younger population is limited to mostly case reports, a wide
spectrum of ophthalmic manifestations has been reported in addition to arterial
and venous retinal occlusion, including ischemic optic neuropathy,13
leukocoria from retinal detachment or persistent hyperplastic primary vitreous,3
amaurosis fugax,12 and vertebrobasilar
In our patient, it is reasonable to speculate that vaso-occlusive
retinopathy occurred in the left eye, predisposing the patient to anterior-segment
neovascularization and vitreous hemorrhage, and eventually leading to intractable
neovascular glaucoma. As mentioned earlier, inherited heterozygous defects in the
coagulation system usually do not become symptomatic until the second or the third
decade. Our patient had multiple-gene mutations leading to PC, PS, and MTHFR deficiencies.
This may have been the reason for the early onset of disease.
Treatment modalities for patients with inherited coagulation disorders
are still evolving. At present, recommendations include antiplatelet agents such
as aspirin, which reduce thromboxane production without affecting prostacyclin synthesis
and anticoagulation with heparin, followed by coumadin.5
Our patient was initially started on aspirin after the CVA, but was later commenced
on coumadin after PC and PS deficiencies were discovered. In the pediatric population,
therapy with these agents presents many challenges, and it is still not clear whether
all patients should go on lifelong anticoagulation. The use of warfarin can result
not only in severe bleeding, but may induce necrosis of the skin and adipose tissues
at higher doses. Also, the possibility of Reye Syndrome with the use of aspirin
should be carefully addressed.15
In general, individual patients are assessed separately depending on their risk
factors.4 Patients with AT
III deficiency are usually at increased risk of recurrence and are placed on lifelong
anticoagulation. Patients heterozygous for PC or PS deficiency usually have fewer
recurrences and in these individuals, anticoagulation is reserved after their second
episode of thromboembolism. Patients who are homozygous for the factor V Leiden
mutation are usually started on long-term anticoagulation. In cases of hyperhomocysteinemia,
patients should be supplemented with the appropriate vitamins, including folic acid,
vitamin B6, and vitamin B12.4,8
Patients should be cautioned in the setting of risk factors for increased thrombotic
activity, such as pregnancy, surgery, oral contraceptives, and appropriate measures
should be taken.6 Plasma
transfusions of fresh frozen plasma, prothrombin complex concentrate, and protein
C concentrate have also been tried.4,6,16
Recently, there has been an interest in statins, lipid lowering agents, which may
have antithrombotic actions.5
Asymptomatic family members should be screened and should receive appropriate prophylaxis.
Knowledge of inherited thrombophilia and its role in vascular
occlusive disease of the retina and choroid by an ophthalmologist is essential to
prevent potentially blinding and lethal complications. Prompt diagnosis by the ophthalmologist
can lead to early medical evaluation of the infant or child and initiation of proper
treatment. Individuals with early signs of ischemia in the contralateral eye should
be monitored very closely and may require pan-retinal photocoagulation to prevent
devastating sequelae. RP
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vein thrombosis. Acta Ophthalmologica Scandinavica. 1999;619-621.
2. Lahey JM, Tunc M, et al. Laboratory evaluation of hypercoagulable
states in patients with central retinal vein occlusion who are less than 56 years
of age. Ophthalmology. 2002;109:126-131.
3. Mintz-Hittner H, Miyashiro M, et al. Vitreoretinal findings
similar to retinopathy of prematurity in infants with compound heterozygous protein
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5. Durrani OM, Gordon C, Murray P. Primary anti-phospholipid
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of age affected by central retinal vein occlusion. Ophthalmology. 2004;111:940-945.
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associated with methylenetetrahydrofolate reductase mutation. Ophthalmology.
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14. Golub BM, Sibony PA, Coller BS. Protein S deficiency associated
with central retinal artery occlusion. Arch Ophthalmology. 1990;108:918.
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Syndrome in a six-year old female patient. AJO. 2003;135:542-544.
16. Dreyfus M, Masterson M, et al. Semin Thromb Hemos.1995;21:371-381.
17. Carraro,Paolo. Guidelines for the laboratory investigation
of inherited thrombophilias. Recommendations for the first level clinical laboratories.
Clin Chem Lab Med. 2003;41:382-391.
18. Goodall AH, et al. Increased binding of fibrinogen to glycoprotein
IIIa-proline 33 (HPA-1b, PlA2, Zwb) positive platelets in patients with cardiovascular
disease. Eur Heart J. 1999;20:742-747.
19. Corral J, et al. HPA-1 genotype in arterial thrombosisrole
of HPA-1b polymorphism in platelet function. Blood Coagul Fibrinolysis.1997;8:284-290.
20. Zotz RB, et al. Polymorphism of platelet membrane glycoprotein
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myocardial infarction in coronary artery disease. Thromb Haemost. 1998;79:731-735.
Sarwat Salim, MD, and David Walton, MD, are
glaucoma specialists at Massachusetts Eye and Ear Infirmary/Harvard Medical School.
Neither author has financial interest in any of the information contained in this
article. Dr. Salim can be contacted by e-mail at
Dr. Walton can be contacted by e-mail at
Retinal Physician, Issue: January 2006