Hyperhomocysteinemia and Hypofibrinolysis in Young Adults With Ischemic Stroke

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Abstract
Data from epidemiological and case-control studies suggest that increased total homocysteine (tHcy) levels are associated with increased risk for thromboembolic disease. The mechanisms by which hyperhomocysteinemia contributes to thrombogenesis are incompletely understood. The main objectives of this study of young ischemic stroke patients were (1) to examine fasting and post-methionine load levels of tHcy, (2) to ascertain the genotype frequency of the C677CT mutation in the methylenetetrahydrofolate reductase gene (TT genotype), and (3) to study the possible interaction between plasma tHcy levels and fibrinolytic factors. This case-control study was based on 80 consecutive patients aged 18 to 44 years admitted between January 1992 and May 1996 as a result of a first-ever ischemic stroke. Forty-one healthy control subjects were recruited. Measurement of fasting tHcy and post-methionine load levels and evaluation of the fibrinolytic system were undertaken at least 3 months (mean, 5.1+/-1. 9 months) after admission. Genotyping of the methylenetetrahydrofolate reductase gene was performed. Although the increase after methionine loading (ie, postload tHcy minus fasting-level tHcy) was significantly higher among patients, there was no difference in fasting and postload tHcy levels. After adjustment for conventional risk factors, elevated postload increase tHcy levels were associated with a 4.8-fold increased risk of ischemic stroke. There was no difference between patients and control subjects in either TT genotype frequency or T allele frequency. Abnormal response to methionine loading was associated with higher tissue plasminogen activator (tPA) mass concentration, higher plasminogen activator inhibitor-1 levels, and lower tPA activity. After adjustment for age, sex, body mass index, serum cholesterol, and triglycerides, an abnormal increase in postload tHcy levels remained significantly associated with tPA mass concentration levels (P=0.03). 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 and controls. A moderately elevated increase in tHcy after methionine loading may provide a additional thrombogenic risk mediated in part by interactions with the fibrinolytic system. In young stroke patients, a methionine loading test to detect hyperhomocysteinemia should always be considered in the convalescent phase of the disease.