Ocular Vascular Thrombotic Events: A Diagnostic Window to Familial Thrombophilia (Compound Factor V Leiden and Prothrombin Gene Heterozygosity) and Thrombosis
Free accessOtherFirst published online February, 2009
Ocular Vascular Thrombotic Events: A Diagnostic Window to Familial Thrombophilia (Compound Factor V Leiden and Prothrombin Gene Heterozygosity) and Thrombosis
In a 12-member, 3-generation kindred with conjoint inheritance of G1691A factor V Leiden (FVL) and G20210A prothrombin gene (PTG) mutations, identified through a proband with amaurosis fugax and his father with nonarteritic ischemic optic neuropathy (NAION), the authors' hypothesis was that ocular thrombosis was a diagnostic window to familial thrombophilia—thrombosis. The authors used polymerase chain reaction (PCR) measures for thrombophilia (FVL, PTG, C677T-A1298C methylenetetrahydrofolate reductase [MTHFR], platelet glycoprotein PLA1A2) and hypofibrinolysis (plasminogen activator inhibitor-1 4G4G). The 39-year-old white male proband, with amaurosis fugax and transient ischemic attacks (TIA), was found to be a compound heterozygote for FVL and PTG mutations. His symptoms resolved only after coumadin. His 44-year-old brother (deep venous thrombosis [DVT]) and 46-year-old sister (DVT, pulmonary embolus [PE]) were compound FVL—PTG gene heterozygotes. Of 4 asymptomatic children born to these 3 siblings, 2 were FVL heterozygotes and 2 PTG heterozygotes. The proband's 69-year-old father, with NAION and ischemic stroke, had PTG heterozygosity, familial high factor VIII, and compound MTHFR C677T-A1298C mutation with homocysteinemia. The proband's 61-year-old aunt had PTG heterozygosity, recurrent DVT, and mesenteric artery thrombosis. The proband's 67-year-old mother, free of thrombotic events, was a FVL heterozygote, had high factor VIII, and PAI-1 4G4G homozygosity. In this extended kindred, ocular thrombotic events (amaurosis fugax, NAION) were associated with variegated thrombotic events, including TIA, ischemic stroke, DVT, PE, and mesenteric artery thrombosis, and opened a diagnostic window to family screening and treatment for complex thrombophilias, which had previously been undiagnosed.
Greiner K., Hafner G., Dick B., Peetz D., Prellwitz W., Pfeiffer N.Retinal vascular occlusion and deficiencies in the protein C pathway. Am J Ophthalmol. 1999;128: 69-74.
2.
Hansen L., Kristensen HL, Bek T., Ingerslev J.Markers of thrombophilia in retinal vein thrombosis. Acta Ophthalmol Scand. 2000;78:523-526.
3.
Larsson J., Hillarp A., Olafsdottir E., Bauer B.Activated protein C resistance and anticoagulant proteins in young adults with central retinal vein occlusion. Acta Ophthalmol Scand . 1999;77:634-637.
4.
Pianka P., Almog Y., Man O., Goldstein M., Sela BA, Loewenstein A.Hyperhomocysteinemia in patients with nonarteritic anterior ischemic optic neuropathy, central retinal artery occlusion, and central retinal vein occlusion . Ophthalmology. 2000;107:1588-1592.
5.
Klein R., Klein BE, Moss SE, Meuer SMThe epidemiology of retinal vein occlusion: the Beaver Dam Eye Study. Trans Am Ophthalmol Soc. 2000;98:133-141.
6.
Wenzler EM, Rademakers AJ, Boers GH, Cruysberg JR, Webers CA, Deutman AFHyperhomocysteinemia in retinal artery and retinal vein occlusion. Am J Ophthalmol. 1993;115:162-167.
7.
von Mach MA, Guz A., Wiechelt J., Pfeiffer N., Weilemann LSSystemic fibrinolytic therapy using urokinase in central retinal artery occlusion. A case study. Dtsch Med Wochenschr.2005;130:1002-1006.
8.
Ozdek S., Yulek F., Gurelik G., Aydin B., Hasanreisoglu B.Simultaneous central retinal vein and retinal artery branch occlusions in two patients with homocystinaemia. Eye. 2004 ;18:942-945.
9.
Ben-Ami R., Zeltser D., Leibowitz I., Berliner SARetinal artery occlusion in a patient with factor V Leiden and prothrombin G20210A mutations. Blood Coagul Fibrinolysis. 2002;13:57-59.
10.
Vielpeau I. , Le Hello C., Legris A., Salsou E., Lecoq PJRetinal vascular occlusion and primary antiphospholipid syndrome. Report of 2 cases. J Fr Ophtalmol.2001;24: 955-960.
11.
Salomon O., Huna-Baron R., Moisseiev J., et al. Thrombophilia as a cause for central and branch retinal artery occlusion in patients without an apparent embolic source. Eye. 2001;15:511-514.
12.
Greiner K., Peetz D., Winkgen A., Prellwitz W., Pfeiffer N., Hafner G.Genetic thrombophilia in patients with retinal vascular occlusion. Int Ophthalmol. 1999;23: 155-160.
13.
Bertram B., Remky A., Arend O., Wolf S., Reim M.Protein C, protein S, and antithrombin III in acute ocular occlusive diseases . Ger J Ophthalmol. 1995;4:332-335.
14.
Czerlanis C. , Jay WM, Nand S.Inherited thrombophilia and the eye. Semin Ophthalmol. 2008;23:111-119.
15.
Akar N., Gokce H.High levels of FVIII and FIX in a pediatric patient with retinal artery occlusion . Pediatr Hematol Oncol. 2002;19:593-595.
16.
Glueck CJ, Fontaine RN, Wang P.Interaction of heritable and estrogen-induced thrombophilia: possible etiologies for ischemic optic neuropathy and ischemic stroke. Thromb Haemost. 2001;85:256-259.
17.
Glueck CJ, Wang P., Bell H., Rangaraj V., Goldenberg N.Nonarteritic anterior ischemic optic neuropathy: associations with homozygosity for the C677T methylenetetrahydrofolate reductase mutation. J Lab Clin Med. 2004;143:184-192.
18.
Larsson J.Central retinal artery occlusion in a patient homozygous for factor V Leiden . Am J Ophthalmol. 2000;129:816-817.
19.
Leifert D., Auw-Hadrich C., Leifert JAArterial ocular occlusion associated with systemic venous thrombophilia-2 case reports. Klin Monatsbl Augenheilkd. 2006 ;223:908-913.
20.
Srinivasan S. , Fern A., Watson WH, McColl MDReversal of nonarteritic anterior ischemic optic neuropathy associated with coexisting primary antiphospholipid syndrome and factor V Leiden mutation. Am J Ophthalmol. 2001;131:671-673.
21.
Glueck CJ, Goldenberg N., Bell H., Golnik K., Wang P.Amaurosis fugax: associations with heritable thrombophilia. Clin Appl Thromb Hemost. 2005;11:235-241.
22.
Bick RL, Alfar H., Goedecke C.Thrombophilic causes of retinal vascular thrombosis: etiology and treatment outcomes. Clin Appl Thromb Hemost. 2002;8:315-318.
23.
Glueck CJ, Wang P., Hutchins R., Petersen MR, Golnik K.Ocular vascular thrombotic events: central retinal vein and central retinal artery occlusions [published online ahead of print December 26, 2007]. Clin Appl Thromb Hemost. doi:10.1177/1076029607304726.
24.
Glueck CJ, Golnik K., Ping W.Amaurosis fugax caused by heritable thrombophilia-hypofibrinolysis in cases without carotid atherosclerosis: thromboprophylaxis prevents subsequent transient monocular partial blindness. Clin Appl Thromb Hemost. 2007;13:124-129.
25.
Nagy V., Steiber Z., Takacs L., et al. Trombophilic screening for nonarteritic anterior ischemic optic neuropathy. Graefes Arch Clin Exp Ophthalmol. 2006;244:3-8.
26.
Randhawa S. , Van Stavern GPSticky platelet syndrome and anterior ischaemic optic neuropathy. Clin Exp Ophthalmol. 2007 ;35:779-781.
27.
Salomon O., Huna-Baron R., Kurtz S., et al. Analysis of pro-thrombotic and vascular risk factors in patients with nonarteritic anterior ischemic optic neuropathy. Ophthalmology . 1999;106:739-742.
28.
Glueck CJ, Bell H., Vadlamani L., et al. Heritable thrombophilia and hypofibrinolysis. Possible causes of retinal vein occlusion. Arch Ophthalmol. 1999;117:43-49.
29.
Glueck CJ, Wang P., Bell H., Rangaraj V., Goldenberg N.Associations of thrombophilia, hypofibrinolysis, and retinal vein occlusion . Clin Appl Thromb Hemost. 2005;11: 375-389.
30.
Arsene S., Delahousse B., Regina S., Le Lez ML, Pisella PJ, Gruel Y.Increased prevalence of factor V Leiden in patients with retinal vein occlusion and under 60 years of age. Thromb Haemost. 2005;94:101-106.
31.
Janssen MC, den Heijer M., Cruysberg JR, Wollersheim H., Bredie SJRetinal vein occlusion: a form of venous thrombosis or a complication of atherosclerosis? A meta-analysis of thrombophilic factors. Thromb Haemost. 2005;93:1021-1026.
32.
Incorvaia C. , Bandello F., Parmeggiani F., D'Angelo S., Costagliola C., Sebastiani A.Recurrent central retinal vein occlusion in a young thrombophilic patient with factor V Leiden mutation. Eur J Ophthalmol.2002;12: 131-134.
33.
Rodeghiero F., Tosetto A.Activated protein C resistance and factor V Leiden mutation are independent risk factors for venous thromboembolism . Ann Intern Med. 1999;130:643-650.
34.
Glueck CJ, Freiberg RA, Fontaine RN, Sieve-Smith L., Wang P.Anticoagulant therapy for osteonecrosis associated with heritable hypofibrinolysis and thrombophilia. Expert Opin Investig Drugs. 2001;10: 1309-1316.
35.
Balasa VV, Gruppo RA, Glueck CJ, et al. Legg-Calve-Perthes disease and thrombophilia. J Bone Joint Surg Am. 2004;86A:2642-2647.
36.
Glueck CJ, Pranikoff J., Aregawi D., et al. The factor V Leiden mutation, high factor VIII, and high plasminogen activator inhibitor activity: etiologies for sporadic miscarriage. Metabolism. 2005;54:1345-1349.
37.
Glueck CJ, Wang P., Bornovali S., Goldenberg N., Sieve L.Polycystic ovary syndrome, the G1691A factor V Leiden mutation, and plasminogen activator inhibitor activity: associations with recurrent pregnancy loss. Metabolism. 2003;52:1627-1632.
38.
Current management of amaurosis fugax. The Amaurosis Fugax Study Group. Stroke. 1990;21:201-208.
39.
McGwin G. Jr, Vaphiades MS, Hall TA, Owsley C.Nonarteritic anterior ischaemic optic neuropathy and the treatment of erectile dysfunction. Br J Ophthalmol. 2006;90:154-157.
40.
Balasa VV, Gruppo RA, Glueck CJ, et al. The relationship of mutations in the MTHFR, prothrombin, and PAI-1 genes to plasma levels of homocysteine, prothrombin, and PAI-1 in children and adults. Thromb Haemost. 1999;81: 739-744.
41.
Glueck CJ, Iyengar S., Goldenberg N., Smith LS, Wang P.Idiopathic intracranial hypertension: associations with coagulation disorders and polycystic-ovary syndrome. J Lab Clin Med. 2003;142:35-45.
42.
Glueck CJ, Aregawi D., Goldenberg N., Golnik KC, Sieve L., Wang P.Idiopathic intracranial hypertension, polycystic-ovary syndrome, and thrombophilia . J Lab Clin Med. 2005;145:72-82.
43.
Glueck CJ, Glueck HI, Tracy T., Speirs J., McCray C., Stroop D.Relationships between lipoprotein(a), lipids, apolipoproteins, basal and stimulated fibrinolytic regulators, and D-dimer. Metabolism. 1993;42: 236-246.
Vossen CY, Walker ID, Svensson P., et al. Recurrence rate after a first venous thrombosis in patients with familial thrombophilia. Arterioscler Thromb Vasc Biol . 2005;25:1992-1997.
46.
Makris M., Rosendaal FR, Preston FEFamilial thrombophilia: genetic risk factors and management. J Intern Med Suppl. 1997;740:9-15.
47.
Mainardi JR, Pelsma PM, Koning H., et al. Double-homozygosity for factor V Leiden and the prothrombin gene G20210A variant in a young patient with idiopathic venous thrombosis . Blood. 1999;94:1828-1829.
48.
Liu XY, Gabig TG, Bang NUCombined heterozygosity of factor V leiden and the G20210A prothrombin gene mutation in a patient with cerebral cortical vein thrombosis. Am J Hematol. 2000;64:226-228.
49.
Friedline JA, Ahmad E., Garcia D., et al. Combined factor V Leiden and prothrombin genotyping in patients presenting with thromboembolic episodes. Arch Pathol Lab Med . 2001;125:105-111.
50.
Ehrenforth S., von Depka Prondsinski M., Aygoren-Pursun E., Nowak-Gottl U., Scharrer I., Ganser A.Study of the prothrombin gene 20201 GA variant in FV:Q506 carriers in relationship to the presence or absence of juvenile venous thromboembolism. Arterioscler Thromb Vasc Biol.1999;19:276-280.
51.
Margaglione M., Brancaccio V., Giuliani N., et al. Increased risk for venous thrombosis in carriers of the prothrombin G→A20210 gene variant. Ann Intern Med. 1998;129:89-93.
52.
Incorvaia C. , Parmeggiani F., Costagliola C., et al. The heterozygous 20210 G/A genotype prevalence in patients affected by central and branch retinal vein occlusion: a pilot study. Graefes Arch Clin Exp Ophthalmol. 2001;239:251-256.
53.
Bombeli T., Basic A., Fehr J.Prevalence of hereditary thrombophilia in patients with thrombosis in different venous systems. Am J Hematol. 2002;70:126-132.
54.
Cheong JL, Bucknall R.Retinal vein thrombosis associated with a herbal phytoestrogen preparation in a susceptible patient. Postgrad Med J. 2005;81:266-267.
55.
Holak HM, Holak NH, Holak S., Holak S.A. Szymaniec S. Retinal vein branch occlusion and palsy of the N abducens in protein S deficiency. Ophthalmologe. 2005; 102:279-285.
56.
Incorvaia C. , Lamberti G., Parmeggiani F., et al. Idiopathic central retinal vein occlusion in a thrombophilic patient with the heterozygous 20210 G/A prothrombin genotype . Am J Ophthalmol. 1999;128:247-248.
57.
Martinelli I.Unusual forms of venous thrombosis and thrombophilia . Pathophysiol Haemost Thromb. 2002;32: 343-345.
58.
Backhouse O. , Parapia L., Mahomed I., Lee D.Familial thrombophilia and retinal vein occlusion . Eye. 2000;14 (pt 1):13-17.
