Hyperhomocysteinemia and hypofibrinolysis in young adults with ischemic stroke

Background and Purpose-Data from epidemiological and case-control studies s uggest that increased total homocysteine (tHcy) levels are associated with increased risk for thromboembolic disease. The mechanisms by which hyperhom ocysteinemia contributes to thrombogenesis are incompletely understood. The main objectives of this study of young ischemic stroke patients were (1) t o examine fasting and post-methionine load levels of tHcy, (2) to ascertain the genotype frequency of the C677CT mutation in the methylenetetrahydrofo late reductase gene (TT genotype), and (3) to study the possible interactio n between plasma tHcy levels and fibrinolytic factors. Methods-This case-control study was based on 80 consecutive patients aged 1 8 to 44 years admitted between January 1992 and May 1996 as a result of a f irst-ever ischemic stroke. Forty-one healthy control subjects were recruite d. Measurement of fasting tHcy and post-methionine load levels and evaluati on of the fibrinolytic system were undertaken at least 3 months (mean, 5.1 +/- 1.9 months) after admission. Genotyping of the methylenetetrahydrofolat e reductase gene was performed. Results-Although the increase after methionine loading (ie, postload tHcy m inus fasting-level tHcy) was significantly higher among patients, there was no difference in fasting and postload tHcy levels. After adjustment for co nventional risk factors, elevated postload increase tHcy levels were associ ated with a 4.8-fold increased risk of ischemic stroke. There was no differ ence between patients and control subjects in either TT genotype frequency or T allele frequency, Abnormal response to methionine loading was associat ed with higher tissue plasminogen activator (tPA) mass concentration, highe r plasminogen activator inhibitor-1 levels, and lower tPA activity. After a djustment for age, sex, body mass index, serum cholesterol, and triglycerid es, an abnormal increase in postload tHcy levels remained significantly ass ociated with tPA mass concentration levels (P=0.03). Conclusions-A moderately elevated increase in tHcy levels after methionine loading was associated with an increased risk for ischemic stroke in young adults. In contrast, fasting tHcy levels did not differ between patients an d controls. A moderately elevated increase in tHcy after methionine loading may provide a additional thrombogenic risk mediated in part by interaction s with the fibrinolytic system. In young stroke patients, a methionine load ing test to detect hyperhomocysteinemia should always be considered in the convalescent phase of the disease.