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Retinal Arterial Occlusion in a Child With Factor V Leiden and Thermolabile Methylene Tetrahydrofolate Reductase Mutations
Activated protein C is a serine protease with anticoagulant properties.4 Activated protein C limits clot formation during normal hemostasis by inactivat ing factors V and VIII. Activated protein C resistance may be caused by a single point mutation in the factor V gene that codes for a factor V molecule that is not appropriately inactivated by activated protein C.5 An association between activated protein C resistance and central retinal vein occlusion in young adults has been described.2 Our case documents acute branch and central retinal venous occlusions along with chronic periph eral retinal vascular occlusions, severe capillary nonperfusion, and peripheral retinal neovascularization. Acute visual loss developed when macular involve ment occurred. We do not advocate screening for activated protein C resistance or factor V Leiden in typical unilateral cases of branch venous occlusion in older adults. However, activated protein C resistance should be considered in cases of peripheral capillary nonperfusion with retinal neovascularization. REFERENCES 1. Svensson P], Dahlback B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994;330: 517-522. 2. Williamson TH, Rumley A, Lowe GDO. Blood viscosity, coagulation, and activated protein C resistance in central retinal vein occlusion: a population controlled study. Br J Ophthalmol 1996;80:203-208. 3. Larsson J, Olafsdottir E, Bauer B. Activated protein C resis tance in young adults with central retinal vein occlusion. Br ] Ophthalmol 1996;80:200-202. 4. Dahlback B, Hildebrand B. Inherited resistance to activated protein C is corrected by anticoagulant cofactor activity found to be a property of factor V. Proc Natl Acad Sci U S A 1994;91:1396-1400. 5. Bertina RM, Koeleman BPC, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369:64-67.
Retinal Arterial Occlusion in a Child With Factor V Leiden and Thermolabile Methylene Tetrahydrofolate Reductase Mutations T. Talmon, MD, J. Scharf, MD, E. Mayer, MD, N. Lanir, PhD, B. Miller, MD, and B. Brenner, MD VOL.124, No. 5
PURPOSE: To analyze the potential cause of reti nal arterial occlusion in a 9-year-old child. METHODS: Case report. Antithrombin III, pro tein C, free protein S, activated protein C resis tance, and antiphospholipid antibodies in plasma were determined. Determination of factor V R506Q (Leiden mutation), thermolabile methy lene tetrahydrofolate reductase by polymerase chain reaction, and restriction enzyme analysis were performed. RESULTS: The patient was found to be heterozy gous for factor V R506Q (Leiden mutation) and homozygous for thermolabile methylene tetrahy drofolate reductase. CONCLUSION: Coexistence of two mild heredi tary thrombophilic states may result in severe thrombotic manifestations in young people.
R
ETINAL ARTERIAL OCCLUSION IS RARE IN CHILDREN
and young adults. Although atheroma in the carotid artery is the main cause of retinal arterial occlusion in older patients, other etiologic factors should be considered in young patients. Previous published studies12 consider migraine, valvular disor ders, and hypercoagulability as main factors involved in retinal vascular occlusions in children. We treated a girl with branch occlusion of the central retinal artery caused by two hereditary thrombophilic states: factor V R506Q (Leiden mutation) and thermolabile methylene tetrahydrofolate reductase. See also pp 673-676 and 687-689.
A 9-year-old otherwise healthy girl was examined for sudden blurred vision in her left eye that appeared after she watched a movie without performing physi cal activity. Medical history was unremarkable, and there was no family history of thrombosis or blood disorders. Examination disclosed a visual acuity of 20/20 in
Accepted for publication May 19, 1997. Department of Ophthalmology (T.T., J.S., E.M., B.M.) and Thrombo sis and Hemostasis Unit (N.L., B.B.), Rambam Medical Center, and Bruce Rappaport Faculty of Medicine (J.S., E.M., B.M., B.B.). Inquiries to B. Brenner, MD, Thrombosis and Hemostasis Unit, Department of Hematology, Rambam Medical Center, Haifa 31096, Israel; fax: 972 4 8542343. BRIEF REPORTS
689
FIGURE 1. Red free photograph of the left fundus showing upper temporal branch occlusion of central retinal artery with retinal ischemia.
FIGURE 2. Fluorescein angiography of the left eye showing delay in upper temporal branch artery filling and localized hyperfluorescence.
each eye. Both eyes had normal refractive media. The fundus of the right eye was normal. Fundus examina tion of the left eye disclosed occlusion of the upper temporal branch of the central retinal artery with retinal ischemia in the corresponding region, includ ing the upper part of the macular area (Figure 1). Visual field threshold central 10-2-III was normal in the right eye and showed a deep scotoma in the lower nasal quadrant of the left eye. Fluorescein angiography was typical for branch artery occlusion in the left eye (Figure 2). Physical examination was normal. Blood tests, including erythrocyte sedimentation rate, complete blood cell count, and blood chemistry, were all normal. No anti-DNA, antinuclear, or anticardiolipin antibodies were found. Cardiovascular evalua tion, including echo-Doppler of the heart and carotid arteries, was normal. Laboratory evaluation in search of thrombophilia disclosed normal activities of antithrombin III and protein C. Tests for lupus anticoagulant, Russel viper venom test, and thromboplastin titration index were negative. Free protein S was 29 U/dl (normal, 65 to 130 U/dl). Activated protein C sensitivity ratio was 1.78 (normal range, 2.07 to 3.50). Polymerase chain reaction and restriction enzyme analysis demon strated heterozygosity for factor V Leiden and homo-
zygosity for the thermolabile variant of methylene tetrahydrofolate reductase. The patient was treated with aspirin, 125 mg per day. Four weeks after the acute event, free protein S level was normal at 95 U/dl. The ischemia resolved slowly. The occlusion left some thickening of the arterial wall with full resolution of the blood flow. Protein S and protein C are vitamin K-dependent plasma glycoproteins that play a vital role in the downregulation of blood clotting.3 Protein C is acti vated by thrombin and thrombomodulin as an endothelial cell cofactor. Protein S is the cofactor of activated protein C. Sixty percent of this protein is in complex with the C 4b binding protein, a component of the complement system.4 Only the free circulating protein S acts as a cofactor of activated protein C. Activated protein C and protein S exert their antico agulant function by degradating the procoagulant factors Va and Villa. 56 Activated protein C resistance is defined as poor anticoagulant response of plasma to activated protein C.7 Most cases of resistance to activated protein C stem from a missense mutation in the gene coding for factor V, in which adenine replaces guanine at nucleotide 1691 (G1691 A). This change leads to the substitution of glutamine for arginine at position 506
690
AMERICAN JOURNAL OF OPHTHALMOLOGY
NOVEMBER 1997
(R506Q) thereby altering the first cleavage site in volved in the activation of factor V. This mutation, factor V Leiden, has been found in 30% to 40% of cases with familial thrombosis,8 and its prevalence in various ethnic white populations is 1% to 10%. The mutation is unique to white populations and results from a single origin.9 Many patients with this muta tion may be asymptomatic unless they have another genetic or acquired thrombophilic defect.10 Methylene tetrahydrofolate reductase is a key en zyme in the metabolism of homocysteine. The rare deficiency of this enzyme leads to severe hyperhomocysteinemia associated with arterial and venous thrombosis in the young.11 Recently, a point mutation that renders methylene tetrahydrofolate reductase thermolabile has been found to be highly prevalent (approximately 10%) in the general population, with higher prevalence in patients with arterial thrombo sis, including coronary, peripheral arterial, and cere bral vascular occlusion.12 Several recent studies have suggested that coexis tence of multiple genetic thrombophilic states in creases thrombotic risk.10,13 In particular, we have demonstrated that a combination of hereditary homocysteinuria and factor V Leiden leads to manifesta tion of thrombosis.14 Our report documents retinal arterial occlusion in a child caused by a combination of factor V Leiden and thermolabile methylene tetrahydrofolate reduc tase homozygosity. Although factor V Leiden has been associated clearly with venous thrombosis, most studies have failed to demonstrate a clear association between isolated factor V Leiden and arterial throm bosis. Potentially arterial thrombosis may become manifest when factor V Leiden is present in associa tion with another thrombophilic state.15 Our report may suggest that arterial thrombosis reported occasionally in patients with factor V Leiden can be partly explained by coexistence with the highly prevalent thermolabile methylene tetrahydro folate reductase homozygosity. Decreased free protein S levels may be found in patients with factor V Leiden and during an acute thrombotic event. Normal levels found 4 weeks after the acute event in our patient ruled out hereditary protein S deficiency. Retinal artery occlusion in children and young adults may result from multiple genetic thrombophilic VOL.124, No. 5
states, therefore requiring thorough evaluation of thrombophilia. REFERENCES 1. Brown GC, Magargal LE, Shields JA, Goldberg RE, Walsh RN. Retinal arterial obstruction in children and young adults. Ophthalmology 1981;88:18-25. 2. Greven CM, Slusher MM, Weaver RG. Retinal arterial occlusions in young adults. Am J Ophthalmol 1995; 120: 776-783. 3. Griffin JH, Evart B, Zimmerman TS, Kleiss AJ, Wideman C. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981;68:1370-1373. 4. Dahlback B, Stenflo J. High molecular weight complex in human plasma between vitamin K-dependent protein S and complement component C4b-binding protein. Proc Natl Acad Sci U S A 1981;78:2512-2516. 5. Suzuki K, Stenflo J, Dahlback B, Theodorsson B. Inactivation of human coagulation factor V by activated protein C. J Bid Chem 1983;258:1914-1920. 6. Fulcher CA, Gardiner JE, Griffin JH, Zimmerman TS. Proteolytic inactivation of human factor VIII procoagulant protein by activated human protein C and its analogy with factor V. Blood 1984;63:486-489. 7. Dahlback B, Carlsson M, Svensson PJ. Familial thrombo philia due to a previously unrecognized mechanism charac terized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci U S A 1993;90:1004-1008. 8. Svensson PJ, Dahlback B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994;330: 517-522. 9. Zivelin A, Griffin JH, Xu K, et al. A single genetic origin for a common Caucasian risk factor for venous thrombosis. Blood 1997;89:397-402. 10. Brenner B, Zivelin A, Lanir N, Greengard JS, Griffin JH, Seligsohn U. Venous thromboembolism associated with double heterozygosity for R506Q mutation of factor V and for T298M mutation of protein C in a large family of a previously described homozygous protein C-deficient newborn with massive thrombosis. Blood 1996;88:877-880. 11. Mudd SH, Levy HL, Skovby F. Disorders of transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle DL, editors. The metabolic and molecular bases of inherited disease. 7th ed. Volume 1. New York: McGraw-Hill, 1995:1279-1327. 12. Kluijtmans LAJ, van den Heuvel LPWJ, Boers GHJ, et al. Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reduc tase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet 1996;58:35-41. 13. Zoller B, Berntsdotter A, de Frutos PG, Dahlback B. Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S. Blood 1995;85: 3518-3523. 14. Mandel H, Brenner B, Berant M, et al. Coexistence of hereditary homocystinuria and factor V Leiden: effect on thrombosis. N Engl J Med 1996;334:763-768. 15. Brenner B, Vulfson SL, Lanir N, Nahir M. Coexistence of familial antiphospholipid syndrome and factor V Leiden: impact on thrombotic diathesis. Br J Haematol 1996;94: 166-167.
BRIEF REPORTS
691
Retinal Arterial Occlusion in a Child With Factor V Leiden and Thermolabile Methylene Tetrahydrofolate Reductase Mutations T. Talmon, MD, J. Scharf, MD, E. Mayer, MD, N. Lanir, PhD, B. Miller, MD, and B. Brenner, MD VOL.124, No. 5
PURPOSE: To analyze the potential cause of reti nal arterial occlusion in a 9-year-old child. METHODS: Case report. Antithrombin III, pro tein C, free protein S, activated protein C resis tance, and antiphospholipid antibodies in plasma were determined. Determination of factor V R506Q (Leiden mutation), thermolabile methy lene tetrahydrofolate reductase by polymerase chain reaction, and restriction enzyme analysis were performed. RESULTS: The patient was found to be heterozy gous for factor V R506Q (Leiden mutation) and homozygous for thermolabile methylene tetrahy drofolate reductase. CONCLUSION: Coexistence of two mild heredi tary thrombophilic states may result in severe thrombotic manifestations in young people.
R
ETINAL ARTERIAL OCCLUSION IS RARE IN CHILDREN
and young adults. Although atheroma in the carotid artery is the main cause of retinal arterial occlusion in older patients, other etiologic factors should be considered in young patients. Previous published studies12 consider migraine, valvular disor ders, and hypercoagulability as main factors involved in retinal vascular occlusions in children. We treated a girl with branch occlusion of the central retinal artery caused by two hereditary thrombophilic states: factor V R506Q (Leiden mutation) and thermolabile methylene tetrahydrofolate reductase. See also pp 673-676 and 687-689.
A 9-year-old otherwise healthy girl was examined for sudden blurred vision in her left eye that appeared after she watched a movie without performing physi cal activity. Medical history was unremarkable, and there was no family history of thrombosis or blood disorders. Examination disclosed a visual acuity of 20/20 in
Accepted for publication May 19, 1997. Department of Ophthalmology (T.T., J.S., E.M., B.M.) and Thrombo sis and Hemostasis Unit (N.L., B.B.), Rambam Medical Center, and Bruce Rappaport Faculty of Medicine (J.S., E.M., B.M., B.B.). Inquiries to B. Brenner, MD, Thrombosis and Hemostasis Unit, Department of Hematology, Rambam Medical Center, Haifa 31096, Israel; fax: 972 4 8542343. BRIEF REPORTS
689
FIGURE 1. Red free photograph of the left fundus showing upper temporal branch occlusion of central retinal artery with retinal ischemia.
FIGURE 2. Fluorescein angiography of the left eye showing delay in upper temporal branch artery filling and localized hyperfluorescence.
each eye. Both eyes had normal refractive media. The fundus of the right eye was normal. Fundus examina tion of the left eye disclosed occlusion of the upper temporal branch of the central retinal artery with retinal ischemia in the corresponding region, includ ing the upper part of the macular area (Figure 1). Visual field threshold central 10-2-III was normal in the right eye and showed a deep scotoma in the lower nasal quadrant of the left eye. Fluorescein angiography was typical for branch artery occlusion in the left eye (Figure 2). Physical examination was normal. Blood tests, including erythrocyte sedimentation rate, complete blood cell count, and blood chemistry, were all normal. No anti-DNA, antinuclear, or anticardiolipin antibodies were found. Cardiovascular evalua tion, including echo-Doppler of the heart and carotid arteries, was normal. Laboratory evaluation in search of thrombophilia disclosed normal activities of antithrombin III and protein C. Tests for lupus anticoagulant, Russel viper venom test, and thromboplastin titration index were negative. Free protein S was 29 U/dl (normal, 65 to 130 U/dl). Activated protein C sensitivity ratio was 1.78 (normal range, 2.07 to 3.50). Polymerase chain reaction and restriction enzyme analysis demon strated heterozygosity for factor V Leiden and homo-
zygosity for the thermolabile variant of methylene tetrahydrofolate reductase. The patient was treated with aspirin, 125 mg per day. Four weeks after the acute event, free protein S level was normal at 95 U/dl. The ischemia resolved slowly. The occlusion left some thickening of the arterial wall with full resolution of the blood flow. Protein S and protein C are vitamin K-dependent plasma glycoproteins that play a vital role in the downregulation of blood clotting.3 Protein C is acti vated by thrombin and thrombomodulin as an endothelial cell cofactor. Protein S is the cofactor of activated protein C. Sixty percent of this protein is in complex with the C 4b binding protein, a component of the complement system.4 Only the free circulating protein S acts as a cofactor of activated protein C. Activated protein C and protein S exert their antico agulant function by degradating the procoagulant factors Va and Villa. 56 Activated protein C resistance is defined as poor anticoagulant response of plasma to activated protein C.7 Most cases of resistance to activated protein C stem from a missense mutation in the gene coding for factor V, in which adenine replaces guanine at nucleotide 1691 (G1691 A). This change leads to the substitution of glutamine for arginine at position 506
690
AMERICAN JOURNAL OF OPHTHALMOLOGY
NOVEMBER 1997
(R506Q) thereby altering the first cleavage site in volved in the activation of factor V. This mutation, factor V Leiden, has been found in 30% to 40% of cases with familial thrombosis,8 and its prevalence in various ethnic white populations is 1% to 10%. The mutation is unique to white populations and results from a single origin.9 Many patients with this muta tion may be asymptomatic unless they have another genetic or acquired thrombophilic defect.10 Methylene tetrahydrofolate reductase is a key en zyme in the metabolism of homocysteine. The rare deficiency of this enzyme leads to severe hyperhomocysteinemia associated with arterial and venous thrombosis in the young.11 Recently, a point mutation that renders methylene tetrahydrofolate reductase thermolabile has been found to be highly prevalent (approximately 10%) in the general population, with higher prevalence in patients with arterial thrombo sis, including coronary, peripheral arterial, and cere bral vascular occlusion.12 Several recent studies have suggested that coexis tence of multiple genetic thrombophilic states in creases thrombotic risk.10,13 In particular, we have demonstrated that a combination of hereditary homocysteinuria and factor V Leiden leads to manifesta tion of thrombosis.14 Our report documents retinal arterial occlusion in a child caused by a combination of factor V Leiden and thermolabile methylene tetrahydrofolate reduc tase homozygosity. Although factor V Leiden has been associated clearly with venous thrombosis, most studies have failed to demonstrate a clear association between isolated factor V Leiden and arterial throm bosis. Potentially arterial thrombosis may become manifest when factor V Leiden is present in associa tion with another thrombophilic state.15 Our report may suggest that arterial thrombosis reported occasionally in patients with factor V Leiden can be partly explained by coexistence with the highly prevalent thermolabile methylene tetrahydro folate reductase homozygosity. Decreased free protein S levels may be found in patients with factor V Leiden and during an acute thrombotic event. Normal levels found 4 weeks after the acute event in our patient ruled out hereditary protein S deficiency. Retinal artery occlusion in children and young adults may result from multiple genetic thrombophilic VOL.124, No. 5
states, therefore requiring thorough evaluation of thrombophilia. REFERENCES 1. Brown GC, Magargal LE, Shields JA, Goldberg RE, Walsh RN. Retinal arterial obstruction in children and young adults. Ophthalmology 1981;88:18-25. 2. Greven CM, Slusher MM, Weaver RG. Retinal arterial occlusions in young adults. Am J Ophthalmol 1995; 120: 776-783. 3. Griffin JH, Evart B, Zimmerman TS, Kleiss AJ, Wideman C. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981;68:1370-1373. 4. Dahlback B, Stenflo J. High molecular weight complex in human plasma between vitamin K-dependent protein S and complement component C4b-binding protein. Proc Natl Acad Sci U S A 1981;78:2512-2516. 5. Suzuki K, Stenflo J, Dahlback B, Theodorsson B. Inactivation of human coagulation factor V by activated protein C. J Bid Chem 1983;258:1914-1920. 6. Fulcher CA, Gardiner JE, Griffin JH, Zimmerman TS. Proteolytic inactivation of human factor VIII procoagulant protein by activated human protein C and its analogy with factor V. Blood 1984;63:486-489. 7. Dahlback B, Carlsson M, Svensson PJ. Familial thrombo philia due to a previously unrecognized mechanism charac terized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci U S A 1993;90:1004-1008. 8. Svensson PJ, Dahlback B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994;330: 517-522. 9. Zivelin A, Griffin JH, Xu K, et al. A single genetic origin for a common Caucasian risk factor for venous thrombosis. Blood 1997;89:397-402. 10. Brenner B, Zivelin A, Lanir N, Greengard JS, Griffin JH, Seligsohn U. Venous thromboembolism associated with double heterozygosity for R506Q mutation of factor V and for T298M mutation of protein C in a large family of a previously described homozygous protein C-deficient newborn with massive thrombosis. Blood 1996;88:877-880. 11. Mudd SH, Levy HL, Skovby F. Disorders of transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle DL, editors. The metabolic and molecular bases of inherited disease. 7th ed. Volume 1. New York: McGraw-Hill, 1995:1279-1327. 12. Kluijtmans LAJ, van den Heuvel LPWJ, Boers GHJ, et al. Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reduc tase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet 1996;58:35-41. 13. Zoller B, Berntsdotter A, de Frutos PG, Dahlback B. Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S. Blood 1995;85: 3518-3523. 14. Mandel H, Brenner B, Berant M, et al. Coexistence of hereditary homocystinuria and factor V Leiden: effect on thrombosis. N Engl J Med 1996;334:763-768. 15. Brenner B, Vulfson SL, Lanir N, Nahir M. Coexistence of familial antiphospholipid syndrome and factor V Leiden: impact on thrombotic diathesis. Br J Haematol 1996;94: 166-167.
BRIEF REPORTS
691