thromboplastin and Hyperhomocysteinemia

Behçet disease (BD) is a rare multisystem, inflammatory disease of unknown etiology with vascular involvement and associated thrombogenicity. This review aims to describe the involvement of various mediators in endothelial cell damage and in the hypercoagulable state of BD. The scenario of the chronic inflammation present in BD shows an increased oxidative condition that contributes to endothelial cell damage and induces platelet, leukocyte, and endothelial cell activation through the release of proinflammatory cytokines and chemokines. These factors, together with the increased levels of homocysteine observed in BD patients, induce the endothelial cell expression of adhesion molecules (VCAM-1 and ICAM-1) and tissue factor; the release of cytokines, soluble CD40L (sCD40L), matrix metalloproteinase-9, and blood coagulation factor V; the inhibition of fibrinolysis; the disruption of nitric oxide metabolism; and the increase in platelet reactivity and lipid peroxidation. Endothelial cell dysfunction leads to a prothrombotic and antifibrinolytic phenotype in BD patients. Increased levels of homocysteine, fibrinogen, and plasminogen activator inhibitor type 1 seem to be involved in the procoagulant condition of this pathology that has been verified by end-point tests as well as by global coagulation tests.

Topics: Autoantibodies; Behcet Syndrome; Blood Coagulation Tests; CD40 Antigens; CD40 Ligand; Cell Adhesion Molecules; Cytokines; Endothelium, Vascular; Fibrinolysis; Humans; Hyperhomocysteinemia; Inflammation; Leukocytes; Lipid Peroxidation; Matrix Metalloproteinase 9; Models, Biological; Nitric Oxide; Platelet Activation; Reactive Oxygen Species; Thromboembolism; Thrombophilia; Thromboplastin

A moderate increase in plasma total homocysteine (t-hcy) is considered to be an independent risk factor for cardiovascular disease (CVD) in general population. One of the mechanisms by which hyperhomocysteinemia contributes to cardiovascular risk has been explained to be the increased thrombotic potential. Elevated t-hcy levels were also reported in chronic renal failure patients because the renal function is a major determinant of serum t-hcy levels.. We measured serum hcy and ADP-induced platelet aggregation and plasma tissue factor as a major activator of the coagulation cascade in hemodialysis (HD), peritoneal dialysis (PD) and early stage chronic renal failure (early stage CRF) patients who are not receiving dialysis and compared with those of control. In addition, we also determined serum vitamin B12 and folat levels which are the important factors regulating the metabolism of t-hcy.. Hcy levels in all patient groups were significantly higher (HD: 20.42 +/- 1.91 micromol/l, PD: 35.47 +/- 6.30, early stage CRF: 24.39 +/- 3.06) than the normal levels (10.74 +/- 0.74) in spite of standard multivitamin supplementation. The highest t-hcy values were found in peritoneal dialysis patients. Vitamin B12 levels in hemodialysis/peritoneal dialysis patients and folat levels in hemodialysis/early stage CRF patients were also significantly above those of control. On the other hand, the significant elevations in plasma tissue factor concentration were found in all patient groups (HD: 331.4 +/- 31.3 pg/ml, PD: 306.0 +/- 30.0, early stage CRF: 277.2 +/- 25.5 and. 69.5 +/- 13.5). t-hcy levels were positively correlated with creatinine (r: 0.791 p < 0.002) and tissue factor levels (r: 0.526 p < 0.05) in only early stage CRF group. The association between t-hcy and tissue factor persisted after these two parameters were adjusted for creatinine (r: 0.649 p < 0.05). On the other hand the same correlations were not observed in dialysis patient groups. In spite of the high tissue factor levels, ADP-induced platelet aggregations were found to be lower in all patient groups (HD: 102.6 +/- 6.7, PD: 98.6 +/- 7.6 and Early stage CRF: 84.9 +/- 7.6) than controls (154.9 +/- 13.7).. These results suggest that hyperhomocysteinemia and increased tissue factor level are present in patients with renal failure, despite supplementation with vitamin B6 and B12 and folat. However, elevated levels of these thrombogenic factors are not linked with platelet aggregation.

Topics: Adult; Case-Control Studies; Chromatography, High Pressure Liquid; Enzyme-Linked Immunosorbent Assay; Female; Folic Acid; Homocysteine; Humans; Hyperhomocysteinemia; Kidney Failure, Chronic; Male; Platelet Aggregation; Renal Dialysis; Thromboplastin; Vitamin B 12; Vitamin B 6

To assess the hypercoagulability in PBC and its relationship with homocysteine (HCY) and various components of the haemostatic system.. We investigated 51 PBC patients (43F/8M; mean age: 63+/-13.9 yr) and 102 healthy subjects (86 women/16 men; 63+/-13 yr), and evaluated the haemostatic process in whole blood by the Sonoclot analysis and the platelet function by PFA-100 device. We then measured HCY (fasting and after methionine loading), tissue factor (TF), thrombin-antithrombin complexes (TAT), D-dimer (D-D), thrombomodulin (TM), folic acid, vitamin B6 and B12 plasma levels. C677T 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism was analyzed.. Sonoclot RATE values of patients were significantly (P<0.001) higher than those of controls. Sonoclot time to peak values and PFA-100 closure times were comparable in patients and controls. TAT, TF and HCY levels, both in the fasting and post-methionine loading, were significantly (P<0.001) higher in patients than in controls. Vitamin deficiencies were detected in 45/51 patients (88.2%). The prevalence of the homozygous TT677 MTHFR genotype was significantly higher in patients (31.4%) than in controls (17.5%) (P<0.05). Sonoclot RATE values correlated significantly with HCY levels and TF.. In PBC, hyper-HCY is related to hypovitaminosis and genetic predisposing factors. Increased TF and HCY levels and signs of endothelial activation are associated with hypercoagulability and may have an important role in blood clotting activation.

Topics: Adult; Aged; Antithrombin III; Female; Folic Acid; Hemostasis; Homocysteine; Humans; Hyperhomocysteinemia; Liver Cirrhosis, Biliary; Male; Middle Aged; Peptide Hydrolases; Platelet Function Tests; Thrombomodulin; Thrombophilia; Thromboplastin; Vitamin B 12; Vitamin B 6

Recently, our laboratory devised a dynamic whole blood (WB) thrombelastographic coagulation model employing activation with minute amounts of tissue factor. A series of studies were conducted to validate the feasibility of the model to illustrate hypocoagulation in various bleeding disorders and its usefulness in detecting the haemostatic effect of pro-coagulants by ex vivo titration experiments. In this context, the present study hypothesized that the thrombelastographic model also can reveal hypercoagulation. Hence, the objective of the present study was to record dynamic WB coagulation profiles in a series of patients (n=76) who had previously suffered from a venous (n=34) or arterial (n=42) thrombo-embolic event and to compare the results with those of a group of healthy reference subjects (n=60).. Patients receiving vitamin K antagonist treatment were not enrolled in the study. Forty-four of the patients had no known thrombophilia risk factor and 32 patients had at least one thrombophilia risk factor.. The most commonly found risk factors were mild hyperhomocysteinaemia and heterozygosity for the factor V Leiden polymorphism. The data showed that, as compared with the healthy controls, patients with a history of venous or arterial thromboembolism had a significantly greater hypercoagulant WB coagulation clot signature as defined by a shortened clotting time together with an accelerated maximum velocity of clot propagation.. In future studies with ex vivo dose titration assessment of pro-coagulant components mixed with blood from a patient suffering from compromised haemostasis, observation of a significantly shortened clot initiation concomitant with a distinctly accelerated clot propagation is likely to indicate an increased risk of thrombosis.

Topics: Adolescent; Adult; Aged; Factor V; Feasibility Studies; Female; Humans; Hyperhomocysteinemia; Male; Middle Aged; Risk Factors; Thrombelastography; Thromboembolism; Thrombophilia; Thromboplastin

Activated protein C resistance (APCR), high tissue factor (TF) expression, and hyper-homocysteinemia are associated with thromboembolic diseases. Thromboembolism is a frequent complication of systemic lupus erythematosus (SLE). In this study, we evaluated the prevalence of APCR, high TF, and homocysteine with correlation of the thrombotic tendency in SLE. Ninety-four SLE patients and 28 normal controls were included. APC ratio and TF antigen were measured using commercial kits. Plasma homocysteine level was measured using HPLC. The prevalence of APCR, high TF antigen level, and hyper-homocysteinemia in our SLE patients were 21.3%, 66.0%, and 23.4%, respectively. The median plasma level of TF antigen in SLE patients was 145.23 pg/mL (range, 31.00-778.50 pg/mL), which was significantly higher than the control value of 39.83 pg/mL (range, 1.55-168.50 pg/mL). The median APC ratio in SLE patients was 2.76 (range, 1.48-13.47), which was significantly lower than the control value of 3.59 (range, 0.26-5.66). The plasma level of homocysteine was not significantly different from that of control. A significant association was observed between the presence of APCR (OR = 8.59, P < 0.0001) but not with the presence of high plasma TF antigen level (OR = 1.24, P = 0.67) and thrombotic complications in SLE patients. In conclusion, APCR and high plasma TF levels are common in SLE, but a significant association was observed only between the presence of APCR and thrombosis in SLE patients.

Topics: Activated Protein C Resistance; Adolescent; Adult; Aged; Aged, 80 and over; Case-Control Studies; Female; Homocysteine; Humans; Hyperhomocysteinemia; Lupus Erythematosus, Systemic; Male; Middle Aged; Prevalence; Retrospective Studies; Thromboembolism; Thromboplastin; Thrombosis

Although hyperhomocysteinemia (HHcy) is a well-known risk factor for the development of cardiovascular disease, the underlying molecular mechanisms are not fully elucidated. Here we show that induction of HHcy in apoE-null mice by a diet enriched in methionine but depleted in folate and vitamins B6 and B12 increased atherosclerotic lesion area and complexity, and enhanced expression of receptor for advanced glycation end products (RAGE), VCAM-1, tissue factor, and MMP-9 in the vasculature. These homocysteine-mediated (HC-mediated) effects were significantly suppressed, in parallel with decreased levels of plasma HC, upon dietary supplementation with folate and vitamins B6/B12. These findings implicate HHcy in atherosclerotic plaque progression and stability, and they suggest that dietary enrichment in vitamins essential for the metabolism of HC may impart protective effects in the vasculature.

Topics: Animals; Apolipoproteins E; Arteriosclerosis; Cells, Cultured; Diet; Disease Models, Animal; Folic Acid; Humans; Hyperhomocysteinemia; Immunohistochemistry; Male; Matrix Metalloproteinase 9; Methionine; Mice; Mice, Inbred C57BL; Mice, Knockout; Pyridoxine; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Thromboplastin; Vascular Cell Adhesion Molecule-1; Vasculitis; Vitamin B 12

In ischemic heart disease (IHD) patients high plasma levels of Tissue Factor (TF), the trigger of coagulation cascade, are present. Homocysteine (Hcy) is a risk factor for coronary artery disease, and several different pathophysiological mechanisms by which Hcy may play a role in thrombus formation have been postulated in "in vitro" studies. We investigated the "in vivo" role of Hcy in affecting plasma levels of TF, its inhibitor Tissue Factor Pathway Inhibitor (TFPI) and hypercoagulability.. We investigated 119 IHD patients who underwent PTCA and compared them with 103 healthy subjects. TF, TFPI, Thrombin-Antithrombin complexes (TAT) and Hcy levels were significantly higher in the patients than in the controls. A positive correlation was found between Hcy and TF (r = 0.54; p < 0.0001), Hcy and TFPI (r = 0.26; p <0.05) as well as Hcy and TAT (r = 0.33; p <0.0001) levels. An inverse correlation existed between folate intake and Hcy levels (r = -0.28; p = 0.001). Hcy levels within the first quartile and in the highest quartile were associated with a lower (p < 0.001) and higher (p <0.0001) rate of clinical recurrences, respectively. Patients with TF values in the first quartile had a lower rate of angiographically documented clinical recurrences as compared to those in the fourth quartile (p <0.01); those in the highest quartile of TF showed a higher rate of recurrences (p = 0.001). Multivariate analysis confirmed these results (first quartile of Hcy: OR 0.02, C1 0.002-0.27; fourth quartile of Hcy: OR 36.5, C1 3.6-365/first quartile of TF: OR 0.006, C1 0.001-0.44; fourth quartile of TF: OR 16.4, C1 3.0 - 90.0), also after adjustment for risk factors and Hcy and TF respectively.. In this study we show that TF, TFPI and TAT levels are correlated with Hcy plasma levels in IHD patients, providing evidence of an "in vivo" pathophysiological mechanism of hyperhomocysteinemia. The observed association between angiographically documented clinical recurrences and TF and Hcy values awaits confirmation in studies designated to evaluate this issue on a larger number of patients.

Topics: Adult; Aged; Angina Pectoris; Angioplasty, Balloon, Coronary; Antithrombin III; Coronary Angiography; Female; Homocysteine; Humans; Hyperhomocysteinemia; Lipoproteins; Male; Middle Aged; Myocardial Ischemia; Peptide Hydrolases; Recurrence; Risk Factors; Thrombophilia; Thromboplastin; Vitamins