PEER REVIEWED
Childhood Rubeosis Iridis and Retinal Ischemia Secondary to Hereditary Thrombophilia
SARWAT SALIM, MD • DAVID WALTON, MD

INTRODUCTION

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.

CASE REPORT

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.

DISCUSSION

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

In 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 (PAI-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.

Less commonly, inherited defects involving the anticoagulant pathways, including PC, PS, and antithrombin can predispose patients to thrombotic events.^3,4,6 Antithrombin 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 insufficiency.^5,9

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.

CONCLUSION

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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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 sarwat_salim@meei.harvard.edu. Dr. Walton can be contacted by e-mail at blacki@att.net.