thromboplastin and Folic-Acid-Deficiency

Aims of our study were to evaluate the prevalence of high lipoprotein (a) [Lp(a)] and homocysteine levels - both in the fasting state (FHcy) and post-methionine (PMHcy) - in young coronary artery disease (CAD) patients, and to investigate the role of genetic and environmental factors for hyperhomocysteinaemia.. We studied 140 patients with angiographically documented CAD (24 women

Topics: Adult; Biomarkers; Blood Coagulation; Case-Control Studies; Chelating Agents; Coronary Disease; Fasting; Female; Folic Acid Deficiency; Homocysteine; Humans; Lipoprotein(a); Male; Methionine; Middle Aged; Risk; Statistics, Nonparametric; Thromboplastin; Vitamin B 12 Deficiency

A moderate elevation of plasma homocysteine is a risk factor for atherosclerosis and arterial and veinous thrombosis. However, the mechanisms leading to vascular disorders are poorly understood because studies that have investigated the potential atherothrombogenicity of hyperhomocysteinemia in vivo are scarce. Using a rat model, we were the first to show that dietary folic acid deficiency, a major cause of basal hyperhomocysteinemia, is associated with enhanced macrophage-derived tissue factor and platelet activities. We proposed that an homocysteine-induced oxidative stress may account for this hypercoagulable state. To determine the true thrombogenicity of moderate hyperhomocysteinemia and better understand its etiology, we have carried out an acute methionine load in control and folate-deficient animals. When rats were fed the control diet, a transient fourfold increase in plasma homocysteine levels was observed 2 h after the methionine administration. As with prolonged dietary folic acid deficiency, this methionine load potentiated the platelet aggregation in response to thrombin and ADP as well as the thrombin-induced thromboxane synthesis. It also stimulated the basal and lipopolysaccharide-induced tissue factor activity of peritoneal macrophages. These prothrombotic effects were associated with an increased lipid peroxidation characterized by an elevation of plasma conjugated dienes, lipid hydroperoxides, and thiobarbituric acid-reactive substances. When rats were fed a folic acid-deficient diet, the methionine load did not cause any further increase in plasma homocysteine concentration, platelet activation, macrophage tissue factor-dependent coagulation, or lipoperoxidation. Altogether, our data showed that the prethrombotic state due to both the altered remethylation and transsulfuration pathways resulted from the moderate elevation of circulating homocysteine. We conclude that moderate hyperhomocysteinemia plays a role in the development of a thrombogenic state that might be mediated by the occurrence of oxidative stress.

Topics: Adenosine Diphosphate; Amino Acids; Analysis of Variance; Animals; Blood Platelets; Diet; Folic Acid Deficiency; Glutathione; Homocysteine; Lipid Peroxidation; Macrophages, Peritoneal; Male; Malondialdehyde; Methionine; Platelet Aggregation; Rats; Rats, Sprague-Dawley; Regression Analysis; Thiobarbituric Acid Reactive Substances; Thrombin; Thromboplastin; Thromboxanes

Folic acid deficiency represents a vitamin deficiency that may be due either to an inadequacy of the dietary supply or to an increased requirement. It leads to a number of abnormalities including hematological, neurological and cardiovascular disorders. In this study, we investigated whether folic acid deficiency would influence platelet and macrophage activities. For 6 weeks, rats were fed a test diet containing a low amount of folic acid (250 mu g/kg) by comparison with a control diet (750 mu g/kg). We found 40 and 32 percent reductions (P < 0.05) of plasma and erythrocyte folates, respectively in the tested group. Peritoneal macrophages of the folic acid deficient animals exhibited greater (20 x) tissue factor (TF) activity than in the controls. We also found that folate depletion significantly enhanced the thrombin- and ADP-induced platelet aggregation (+64 and + 13 percent, respectively). Moreover, the results of incubations with radiolabeled arachidonic acid indicated that platelets of folic acid deficient animals incorporated more labeling than controls did. When stimulated with thrombin, the mobilization of arachidonate from platelet phospholipids and its subsequent formation of cyclooxygenase and lipoxygenase metabolites were enhanced in the deficient animals. In particular, thromboxane biosynthesis was markedly increased. The analysis of the plasma fatty acid composition showed a decrease in the plasma unsaturation index related to a marked fall of long chain (n-3) fatty acids which was also observed in platelets. These data suggested the occurrence of an oxidative stress in folic acid deficient animals which was confirmed by increases in plasma lipid peroxidation products (more than +20 percent) and an enhanced susceptibility of erythrocytes to free radicals (+23 percent). Altogether these data suggested that folic acid deficiency altered the circulating and cellular fatty acid composition and thus influenced the balance of the platelet eicosanoid synthesis. In addition, total homocysteine and glutathione concentrations were highly increased in plasma from folate-depleted rats. From these results, we conclude that folate deficiency can potentiate the coagulation pathway mediated by the macrophage TF as well as the platelet activation process. It is suggested that these dysfunctions might be related to the loss of (n-3) polyunsaturated fatty acids. The latter could result from an increased lipid peroxidation triggered by the folic acid deficienc

Topics: Animals; Blood Coagulation; Blood Platelets; Chromatography, Liquid; Diet; Eicosanoids; Erythrocytes; Fatty Acids, Omega-3; Folic Acid; Folic Acid Deficiency; Glutathione; Homocysteine; Lipid Peroxidation; Macrophages, Peritoneal; Oxidative Stress; Phospholipids; Platelet Aggregation; Rats; Rats, Sprague-Dawley; Thromboplastin; Thromboxanes