Interaction of Heritable and Estrogen-induced Thrombophilia: Possible Etiologies for Ischemic Optic Neuropathy and Ischemic Stroke

Summary

Our specific aim was to assess how thrombophilic exogenous estrogens interacted with heritable thrombophilias leading to nonarteritic ischemic optic neuropathy (NAION) and ischemic stroke. Coagulation measures were performed in a 74 year old patient and her immediate family. The proband had a 47 year history of 9 previous thrombotic episodes, and developed unilateral NAION 4 years after starting estrogen replacement therapy (ERT). The proband was heterozygous for two thrombophilic gene mutations (G20210A prothrombin gene, platelet glycoprotein IIIa PlA1/A2 polymorphism), and homozygous for the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene. Of 238 normal controls, none had these 3 gene mutations together. The proband’s mother and brother had deep venous thrombosis (DVT). The proband’s brother, sister, nephew, daughter, and two granddaughters were homozygous for the C677T MTHFR mutation. The proband’s brother was heterozygous for the G20210A prothrombin gene mutation. The proband’s niece was heterozygous for the G20210A prothrombin gene mutation, homozygous for the C677T MTHFR mutation, homozygous for the hypofibrinolytic 4G polymorphism of the plasminogen activator inhibitor-1 (PAI-1) gene, and heterozygous for the platelet glycoprotein IIIa PlA1/A2 polymorphism. Of 238 normal controls, none had the niece’s combination of 4 gene mutations. When ERT-mediated thrombophilia was superimposed on the proband’s heritable thrombophilias, unilateral ischemic optic neuropathy developed, her tenth thrombotic event over a 5 decade period. When estrogenprogestin oral contraceptives were given to the proband’s niece, she had an ischemic stroke at age 22. Exogenous estrogen-mediated thrombophilia superimposed on heritable thrombophilia and hypofibrinolysis is associated with arterial and venous thrombi, and appears to be a preventable, and potentially reversible etiology for ischemic optic neuropathy and ischemic stroke.

Keywords

Thrombophilia - G20210A prothrombin gene mutation - non-arteritic ischemic optic neuropathy - ischemic stroke - estrogen

• References

• 1 Salomon O, Huna-Baron R, Kurtz S, Steinberg DM, Moisseiev J, Rosenberg N, Yassur I, Vidne O, Zivelin A, Gitel S, Davidson J. Ravid, Seligsohn U. Analysis of prothrombotic and vascular risk factors in patients with nonarteritic anterior ischemic optic neuropathy. Ophthalmology 1999; 106: 739-42.
• 2 Glueck CJ, Bell H, Vadlamani L, Gupta A, Fontaine RN, Wang P, Tracy T, Stroop D, Gruppo D. Heritable thrombophilia and hypofibrinolysis. Arch Ophthalmol 1999; 117: 43-9.
• 3 Glueck CJ, Wang P, Fontaine R, Tracy T, Sieve-Smith L, Lang JE. The thrombophilic factor V Leiden mutation (Resistance to Activated Protein C) and estrogen therapy as risk factors for atherothrombotic cardiovascular disease in 423 hyperlipidemic women. Am J Cardiology 1999; 84: 549-54.
• 4 Glueck CJ, McMahon RE, Bouquot J, Triplett D, Gruppo R, Wang P. Heterozygosity for the Leiden mutation of the factor V gene, a common pathoetiology for osteonecrosis of the jaw, with thrombophilia augmented by exogenous estrogens. J Lab Clin Med 1997; 130: 540-3.
• 5 Glueck CJ, McMahon RE, Bouquot JE, Triplett D. Exogenous estrogen may exacerbate thrombophilia, impair bone healing, and contribute to development of chronic facial pain. Cranio, Craniomandibular Practice 1998; 16: 143-53.
• 6 Balasa VV, Gruppo R, Glueck CJ, Stroop D, Becker A, Pillow A, Wang P. The relationship of mutations in the MTHFR, Prothrombin, and PAI-1 Genes to plasma levels of Homocysteine, Prothrombin, and PAI-1 levels in Children and Adults. Thromb Haemost 1999; 81: 739-44.
• 7 Glueck CJ, Crawford A, Roy D, Freiberg R, Glueck H, Stroop D. Association of antithrombotic factor deficiencies and hypofibrinolysis with LeggPerthes Disease. J Bone Joint Surg 1996; 78A: 3-13.
• 8 Glueck CJ, Glueck HI, Tracy T, Speirs J, McCray C, Stroop D. Relationship between Lp(a), lipids, apolipoproteins, and fibrinolytic activity in 191 hyperlipidemic patients. Metabolism 42: 236-46 1993;
• 9 Glueck CJ, Shaw P, Lang J, Tracy T, Sieve-Smith L, Wang Y. Evidence that homocysteine is an independent risk factor for atherosclerosis in hyperlipidemic patients. Am J Cardiology 1995; 75: 132-6.
• 10 Glueck CJ, Fontaine RN, Gruppo R, Stroop D, Sieve-Smith L, Tracy T, Wang P. The 4G/4G polymorphism of the plasminogen activator inhibitor-1 gene, hypofibrinolysis, and osteonecrosis. Clinical Orthopedics 1999; 366: 133-46.
• 11 Gruppo R, Glueck CJ, McMahon RE, Bouquot J, Becker A, Tracy T, Wang P. Anticardiolipin antibodies, thrombophilia, and hypofibrinolysis. Pathophysiology of osteonecrosis of the jaw. J Lab Clin Med 1996; 127: 481-9.
• 12 Brandt G, Gruppo R, Glueck CJ, Stroop D, Becker A, Pillow A, Wang P. Sensitivity, specificity, and predictive value of modified assays for activated protein C resistance in children. Thromb Haemost 1998; 79: 567-70.
• 13 Weiss EJ, Bray PF, Tayback M, Schulman SP, Kickler Ts, Becker LC, Weiss JL, Gerstenblith G, Goldschmidt-Clermont PJ. A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. N Engl J Med 1996; 334: 1090-4.
• 14 Rosendaal FR, Siscovick DS, Schwartz SM, Beverly RK, Psaty BM, Longstreth Jr. WT, Raghunathan TE, Koepsell TD, Reitsma PH, Factor V. Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women. Blood 1997; 89: 2817-21.
• 15 Bontempo FA, Hasett AC, Faruki H, Steed DL, Webster MW, Makaroun MS, The Factor V. Leiden mutation: spectrum of thrombotic events and laboratory evaluation. J Vasc Surg 1997; 25: 271-6.
• 16 Eskandari MK, Bontempo FA, Hassett AC, Faruki H, Makaroun MS. Arterial thromboembolic events in women with the factor V Leiden mutation. Am J Surg 1998; 176: 122-5.
• 17 Henkens CM, Bom VJ, Seinen AJ, Van der Meer J. Sensitivity to activated protein C; influence of oral contraceptives and sex. Thromb Haemost 1996; 73: 402-4.
• 18 Price DT, Ridker PM. Factor V Leiden mutation and the risks for thromboembolic disease: a clinical perspective. Ann Intern Med 1997; 127: 895-903.
• 19 Rosendaal FR. Thrombosis in the young; epidemiology and risk factors. A focus on venous thrombosis. Thromb Haemost 1997; 78: 1-615.
• 20 Glacet-Bernard A, Kuhn D, Soubrane G. Ocular complications of hormonal treatments: oral contraception and menopausal replacement therapy. Contracept Fertil Sex 1999; 27: 285-90.
• 21 Martinelli I, Sacchi E, Landi G, Taioli E, Duca F, Mannucci PM. High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives. N Engl J Med 1998; 338: 1793-7.
• 22 DeStefano V, Chiusolo P, Paciaroni K, Casorelli I, Rossi E, Molinari M, Servidei S, Tonali PA, Leone G. Prothrombin G20210A mutant genotype is a risk factor for cerebrovascular ischemic disease in young patients. Blood 1998; 91: 3562-5.
• 23 Salomon O, Moisseiev J, Rosenberg N, Vidne O, Yassur I, Zivelin A, Treister G, Steinberg DM, Seligsohn U. Analysis of genetic polymorphisms related to thrombosis and other risk factors in patients with retinal vein occlusion. Blood Coag Fibrinolysis 1998; 9: 617-22.
• 24 Margaglione M, D’Andrea G, d’Addedda M, Giuliani N, Capucci G, Iannaccone L, Vecchione G, Grandone E, Brancaccio V, Di Minno G. The methylenetetrahydrofolate reductase TT677 genotype is associated with venous thrombosis independently of the coexistence of the FV Leiden and prothrombin A 20210 mutation. Thromb Haemost 1998; 79: 907-11.
• 25 Loewenstein A, Winder A, Goldstein M, Lazar M, Eldor A. Bilateral retinal vein occlusion associated with 5,10-methylenetetrahydrofolate reductase mutation. Am J Ophthalmol 1997; 124: 840-1.
• 26 Gardeman A, Humme J, Stricker J, Nguyen QD, Katz N, Phillip M, Tillmanns H, Hehrlein FW, Rau M, Haberbosch W. Association of the platelet glycoprotein IIIa PlA1/A2 gene polymorphism to coronary artery disease but not to nonfatal myocardial infarction in low risk patients. Thromb Haemost 1998; 80: 214-7.
• 27 Anderson JL, King GJ, Bair TL, Elmer SP, Muhlesteon JB, Habashi J, Carlquist JF. Associations between polymorphism in the gene encoding glycoprotein IIIa and myocardial infarction or coronary artery disease. J Am Coll Cardiol 1999; 33: 727-33.
• 28 Feldon SB. Anterior ischemic optic neuropathy: trouble waiting to happen. Arch Ophth 1999; 106: 651-2.