Interaction of heritable and estrogen-induced thrombophilia: Possible etiologies for ischemic optic neuropathy and ischemic stroke

Our specific aim was to assess how thrombophilic exogenous estrogens intera cted with heritable thrombophilias leading to nonarteritic ischemic optic n europathy (NAION) and ischemic stroke. Coagulation measures were performed in a 74 year old patient and her immediate family. The proband had a 47 yea r 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 gen e, 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 broth er, sister, nephew, daughter, and two granddaughters were homozygous for th e C677T MTHFR mutation. The proband's brother was heterozygous for the G202 10A 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 ac tivator inhibitor-1 (PAI-1) gene, and heterozygous for the platelet glycopr otein IIIa PlA1/A2 polymorphism. Of 238 normal controls, none had the niece 's combination of 3 gene mutations. When ERT-mediated thrombophilia was sup erimposed on the proband's heritable thrombophilias, unilateral ischemic op tic neuropathy developed, her tenth thrombotic event over a 5 decade period . When estrogen-progestin oral contraceptives were given to the proband's n iece, she had an ischemic stroke at age 22. Exogenous estrogen-mediated thr ombophilia superimposed on heritable thrombophilia and hypofibrinolysis is associated with arterial and venous thrombi, and appears to be a preventabl e, and potentially reversible etiology for ischemic optic nt uropathy and i schemic stroke.