Central retinal vein occlusion in sickle cell disease.

Abstract: Central retinal vein occlusion has not been reported previously in patients with sickle cell anemia. We describe the case of a 31-year-old man with sickle cell anemia who developed this complication. The search for risk factors for central retinal vein occlusion in this young patient revealed protein S deficiency and a history of iron deficiency. He was treated with anticoagulation therapy, and his vision improved gradually.

Key Words: central retinal vein occlusion, protein S deficiency, sickle cell disease 

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The levels of proteins C and S in sickle cell disease (SCD) patients are lower than in healthy individuals, (1), (2) although it is not known whether this abnormality plays a role in the thrombotic complications of SCD. Patients without SCD who have protein C or S deficiency are predisposed to central retinal vein occlusion (CRVO). (3), (4) We report here the first case of SCD with central retinal vein occlusion. This patient's protein S levels were abnormally low on different occasions in different laboratories. An additional risk factor could have been a history of iron deficiency, because this abnormality has also been associated with CRVO. (5-7) The patient's vision deteriorated gradually for 4 months after the start of anticoagulation.

Discussion

Central retinal vein occlusion is one of the most common retinal vascular disorders. It affects mostly older patients and is generally associated with atherosclerosis, hypertension, diabetes, glaucoma, and orbital compression. (9), (10) In younger patients, CRVO can be due to a congenital orbital anomaly or systemic disorders such as end-stage renal disease, hypercholesterolemia, [beta]-thalassemia, and various hypercoagulable states. (11-13) Activated protein C resistance (factor V Leiden mutation) is the most common cause of central retinal vein occlusion in young people. (12) Sickle cell patients as a group have lower levels of the naturally occurring anticoagulants protein S and protein C. (1), (2) This has been attributed to either hemostatic abnormalities or hepatic dysfunction. In normal individuals, the rheologic alterations affecting the retinal vasculature are an increase in the blood viscosity (14) and a reduced erythrocyte deformability. (5) These alterations lead to sluggish blood flow in the retinal vasculature and, with the morphologic changes in the vascular system, promote an occlusive event. Sickle cells also have decreased deformability. Tissue hypoxia in sickle cell patients may produce metabolic dysfunction of the capillary and venous endothelium. As a result, veins become distended and leakage of blood through the vessel wall may occur. The ocular circulation is unique in that the terminal branches of the vessels pass from an extraocular low-pressure system into an intraocular high-pressure system. Therefore, the relative perfusion pressure is low in the retinal vascular system. If the intraocular pressure rises further, as in chronic simple glaucoma, central retinal vein occlusion develops.

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In severe anemia due to causes other than sickle cell anemia, hypoxia is believed to induce venous endothelial incompetence and decreased erythrocyte deformability despite the presence of an adequate retinal perfusion pressure, leading to stasis and thrombosis. (5) A few case reports have been published suggesting that iron deficiency is a risk factor for CRVO even in the absence of other risk factors. (5-7) It was well known at the turn of the century that sudden blindness could ensue after severe blood loss. (15) The retinal changes noted in such cases included pallor of the disk, sometimes with disk edema, retinal hemorrhages, and exudates. These changes developed within 48 hours of the hemorrhage. Repeated blood loss rather than a single hemorrhagic episode was thought to be responsible for these visual disturbances. Pears and Pickering (16) postulated that transient impairment of retinal blood flow during episodes of hypotension was the most likely cause of the ocular changes in these cases. Holt and Gordon-Smith (17) described retinal hemorrhages and exudates in severe iron deficiency anemia. These changes generally were not severe and consisted of "cotton wool" exudates. The rarity of these reports suggests that central retinal vein occlusion is a most unusual complication of iron deficiency. This is particularly so when one considers that iron deficiency anemia is an extremely frequent medical problem in many developing countries; its highest prevalence is among young children and women of childbearing age. (18)

In our patient, the following factors could have played a role in the pathogenesis of his CRVO, in addition to protein S deficiency: sickle cell-related vaso-occlusion, anemia, and possibly prior iron-deficiency. He also had unexplained high glycine and glutamine serum concentrations. It is unclear, however, whether the high concentrations of these amino acids played a role in hypercoagulability.

Key Points

* Central retinal vein occlusion has not been reported previously in patients with sickle cell disease (SCD).

* The levels of proteins C and S in SCD patients are lower than in normal subjects, although it is not known whether this abnormality plays a role in the thrombotic complications of SCD.

* In our patient, various factors could have played a role in the pathogenesis of his central retinal vein occlusion, in addition to protein S deficiency: sickle cellrelated vaso-occlusion, anemia, and possibly prior iron deficiency.

Table 1. Laboratory studies in a sickle cell patient with central
retinal vein occlusion (a)

Test                                  Result     Normal
                                                  range

Hemoglobin (g/dl)                        7.3      12.7-16.7

Hematocrit (%)                          21        36.7-48.3

MCV (fl)                                85.4        79-98

WBC count (X 1,000/m[m.sup.3])          15.1       3.3-9.6

Platelet count (X 1,000/m[m.sup.3])    375         154-345

Sedimentation rate (mm/h)               75           0-25

Serum iron ([micro]g/dl)                60          50-150

Serum transferrin (mg/dl)              230         204-345

Serum ferritin ([micro]g/L)             67          18-370

Protein C (%)                          116          72-149

Protein S activity (%)                  48          72-118

Protein S free (%)                      43          72-128

Protein S total antigen                 12          20-25
([micro]g/ml)

Antithrombin III (%)                    96          75-127

Fibrinogen (mg/dl)                     380         168-458

Lupus anticoagulant                   Negative     Negative

Anticardiolipin antibody              Negative     Negative

Factor V Leiden mutation              Negative     Negative

Homocysteine ([mu]mol/L)                 6           4-17

Serum glycine ([mu]mol/L)              559         151-490

Serum glutamine ([mu]mol/L)            867         205-756

MCV, mean corpuscular volume; WBC, white blood cell.

Accepted July 16, 2003

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9702-0202

References

(1.) Bayazit AK, Kiline Y. Natural coagulation inhibitors (protein C, protein S, antithrombin) in patients with sickle cell anemia in a steady state. Pediatr Int 2001;43:592-596.

(2.) el-Hazmi MA, Warsy AS, Bahakim H. Blood proteins C and S in sickle cell disease. Acta Haematol 1993;90:114-119.

(3.) Greiner K, Hafner G, Dick B, et al. Retinal vascular occlusion and deficiencies in the protein C pathway. Am J Ophthalmol 1999;128:69-74.

(4.) Bertram B, Remky A, Arend O, et al. Protein C, protein S, and antithrombin III in acute ocular occlusive diseases. Ger J Ophthalmol 1995;4:332-335.

(5.) Kirkham TH, Wrigley PF, Holt JM. Central retinal vein occlusion complicating iron deficiency anaemia. Br J Ophthalmol 1971;55:777-780.

(6.) Tashiro T, Takahashi H, Masuda H, et al. Complication of central retinal vein occlusion in iron deficiency anemia [in Japanese]. Meikai Daigaku Shigaku Zasshi 1990;19:437-442.

(7.) Kacer B, Hattenbach LO, Horle S, et al. Central retinal vein occlusion and nonarteritic ischemic optic neuropathy in 2 patients with mild iron deficiency anemia. Ophthalmologica 2001;215:128-131.

(8.) Castro O, Poillon WN, Finke H, et al. Improvement of sickle cell anemia by iron-limited erythropoiesis. Am J Hematol 1994;47:74-81.

(9.) Appiah AP, Trempe CL. Risk factors associated with branch vs. central retinal vein occlusion. Ann Ophthalmol 1989;21:153-157.

(10.) Dodson PM, Kubicki AJ, Taylor KG, et al. Medical conditions underlying recurrence of retinal vein occlusion. Br J Ophthalmol 1985;69:493-496.

(11.) Gupta A, Agarwal A, Bansal RK, et al. Ischaemic central retinal vein occlusion in the young. Eye 1993;7:138-142.

(12.) Larsson J, Olafsdottir E, Bauer B. Activated protein C resistance in young adults with central retinal vein occlusion. Br J Ophthalmol 1996;80:200-202.

(13.) Walters RF, Spalton DJ. Central retinal vein occlusion in people aged 40 years or less: A review of 17 patients. Br J Ophthalmol 1990;74:30-35.

(14.) Williamson TH, Rumley A, Lowe GD. Blood viscosity, coagulation, and activated protein C resistance in central retinal vein occlusion: A population controlled study. Br J Ophthalmol 1996;80:203-208.

(15.) Gowers WR. Manual and Atlas of Medical Ophthalmoscopy. London, Churchill, 1904, ed 4, p. 227.

(16.) Pears MA, Pickering GW. Changes in the fundus oculi after haemorrhage. Q J Med 29:153, 1960.

(17.) Holt JM, Gordon-Smith EC. Retinal abnormalities in diseases of the blood. Br J Ophthalmol 1969;53:145-160.

(18.) Centers for Disease Control and Prevention. Recommendations to prevent and control iron deficiency in the United States. MMWR Recomm Rep 1998;47(RR-3):1-29.

RELATED ARTICLE: Case Report

A 31-year-old black man with sickle cell anemia (SS genotype) had frequent vaso-occlusive crises and for several years was enrolled in an institutional review board-approved phlebotomy program to reduce red cell mean corpuscular hemoglobin concentration and hemoglobin S polymerization by means of iron restriction. His clinical response was published previously (Patient 3 in Castro et al (8)). There was no family history of recurrent clots. Approximately 1 year after stopping the experimental phlebotomy program, he developed more frequent crises and also a chronic ulcer on his ankle. He also developed sudden (over 1 day) and severe deterioration in the vision of his left eye. Ophthalmic evaluation showed visual acuity to be 20/20 in the right eye, but he could only count fingers at 1 ft with the left eye. There were scattered retinal hemorrhages, dilated retinal veins, and significant optic disk edema and retinal edema on the left eye (Fig. 1). The findings in the left eye were consistent with a central retinal vein occlusion. In addition, however, there were multiple peripheral arteriolar and venous occlusions typical of sickle cell anemia. His impaired vision was primarily because of the significant optic nerve swelling and retinal edema. Laboratory findings are listed in Table 1 and show that, of the tests performed for hypercoagulability, only the protein S (total and free antigens and activity) deficiency results were abnormal in different laboratories on two different occasions. There was no evidence of iron deficiency. Treatment options that were considered included surgical interventions and anticoagulation. In addition, because he was at risk for neovascularization in the left eye, peripheral laser photocoagulation was considered but not carried out. He was treated with anticoagulation therapy initially with full doses of enoxaparin and subsequently placed on long-term warfarin. The visual acuity improved gradually over a period of 4 months, and repeat retinal examinations during this period showed resolution of central vein thrombosis (Figs. 2 and 3).

Syed Hasan, MD, Mamoon Elbedawi, MD, Oswaldo Castro, MD, Mark Gladwin, MD, and Alan Palestine, MD

From the Department of Medicine and Center for Sickle Cell Disease, Howard University, Metro Retina Consultants, P.C., Washington, DC, and Critical Care Medicine Section, Clinical Center, National Institutes of Health, Bethesda, MD.

Presented in abstract form at the 2002 meeting of the American Society of Hematology (Blood 2002;100[Suppl 1]:23b).

Reprint requests to Syed Hasan, MD, Center for Sickle Cell Disease, 2121 Georgia Avenue, N.W., Washington, DC 20059. Email: [e-mail]