Clinical significance of determining plasma homocysteine: case-control study on arterial and venous thrombotic patients.

Nowadays, thrombosis is a leading cause of morbidity and mortality in most countries (1). The ensuing complications, the most serious of which is myocardial infarction, stroke, and pulmonary thromboembolism may cause long-term and severe disability. They increasingly affect younger populations and generate a great social and economic burden. There are hence continuing efforts to discover biochemical markers that would enable more reliable risk stratification (2). Considering that it is not uncommon that none of the five major risk factors for thrombosis is recognized in a patient presenting with complications of thrombosis, the last few years have witnessed intensified research on new risk factors and unveiling their effects on the pathogenesis of the thrombotic process (3). According to the data for the last ten years reported by the American Heart Association, the most convincing results have been obtained in studies on C-reactive protein (CRP), Lp(a) lipoprotein, apolipoprotein apo(a), fibrinogen, and homocysteine (4). Homocysteine is an aminothiol compound, which is the main metabolite of an essential amino acid, methionine. Homocysteine metabolism involves either remethylation to methionine or its irreversible metabolism to produce cysteine (5). The so-called homocysteine hypothesis of atherosclerosis, according to which even moderately elevated homocysteine levels may cause progression of atherosclerosis, was first postulated by McCully in 1969 (6), whereas the first evidence on the relation between pathological homocysteine metabolism and coronary disease in general population was provided by Wilcken and Wilcken in 1976 (7). The interest in homocysteine as a risk factor for development of thrombosis has been dramatically increasing since 1990, and it is still in the focus of attention of the scientific community. Hyperhomocysteinemia may result from a number of dietary and lifestyle factors, genetic factors, nutritional deficiencies, and other etiological factors (8-11). The most common form of genetically determined hyperhomocysteinemia is caused by the occurrence of a thermo-liable variant of methylenetetrahydrofolate reductase (tMTHFR), an enzyme involved in homocysteine metabolism, whose enzymatic activity is significantly reduced in hyperhomocysteinemia. The most frequent mutation leading to the manifestation of thermo liability of this enzyme is mutation of the MTHFR 677 gene, caused by alanine to valine substitution (12). The incidence of this mutation is relatively high, although it varies in different ethnic groups (13). It has still not been elucidated whether the degree of hyperhomocysteinemia is significantly higher in homozygous than in heterozygous carriers, however, it has been shown that hyperhomocysteinemia in the presence of this genetic mutation manifests only in the case of low folate levels, making folate deficiency a likely explanation for the expression of the MTHFR thermo liable genotype (14-16). The importance of clear understanding of the role of hyperhomocysteinemia in the etiopathogenesis of thrombosis is underlined by the fact that it can be corrected easily by simple dietary supplementation with group B vitamins and folic acid. If hyperhomocysteinemia is definitely confirmed to be an independent risk factor for thrombosis, this could be an efficient, safe, simple, and cost-effective means of preventing one of the major risk factors for this disease. Efficient recognition and management of risk factors for thrombosis are very important, and cost-effective methods for detecting risk factors are necessary for routine clinical treatment and prevention of this disease. The aim of our study was to determine the differences in plasma homocysteine levels between three MTHFR 677 genotype subgroups in patients with thrombosis and controls, as well as between patients with thrombosis and controls with same MTHFR 677 genotype.