Giant aortic arch thrombus, methylenetetrahydrofolate reductase (MTHFR) A1298C heterozygous gene mutation, smoking and hormonal replacement therapy

We report the case of a mobile aortic arch thrombus possibly induced by the combination of postmenopausal hormonal replacement therapy (HRT) and cigarette smoking in a woman with methylenetetrahydrofolate reductase (MTHFR) A1298C mutation. No other cause for her illness could be identified despite an extensive laboratory work-up for thrombophilic state. Surgical exploration showed the floating aortic arch thrombus attached on a histologically normal aortic wall. At an 8-year follow-up, she remained free of recurrence after discontinuation of HRT and counseling to quit smoking. The probable synergistic impact of tobacco smoking as an additional risk factor for thrombophilic events in women with MTHFR variant and using HRT has yet to be determined. Previous studies and case reports focusing on MTFHR variation and the incidence of thrombotic events have provided conflicting evidence of an association. With the understanding that this case does not yet ascribe cause-and-effect relationship between MTHFR variant and clot formation, important public health concerns are raised. The prevalence of MTHFR A1298C genotype is population-specific, implying that permissive geneenvironment interactions other than genetic mutation alone may also be relevant in establishing a clinically overt disease. Causality remains to be proven in prospective evaluation across diverse geographic areas taking into account interactions with dietary and other life-style risk factors. Furthermore, in such genetically predisposed patients, future genome-wide association studies to identify loci variants that determine the overall susceptibility to thrombosis may prove helpful to derive preventive interventions.