Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

On the basis of growing clinical evidence, it is well known that elevated plasma homocysteine (Hcy) levels are associated with higher risk of venous and arterial thrombosis. Several experimental studies have been carried out in order to elucidate the mechanisms involved that still remain unclear. The aim of our study was to evaluate the homocysteine effects on formation and structure of plasmatic fibrin network. We also assayed homocystine and cysteine to determinate possible participation of thiol group in the tested activity. Aliquots of a pool of plasma incubated separately with sulfur compounds were clotting with thrombin. Fibringeneration and fibrin networks were evaluated by kinetic studies and scanning electronic microscopy, respectively. No significant differences were observed on fibrin generation of the substances assayed in comparison to control. The scanning electronic microscopy showed that Hcy-associated networks were different from control, with shorter, thicker and more branched fibers, resulting in a more compact structure and probably more resistant to fibrinolysis. The thiol group would be involved in this effect. Our findings would be a new contribution to elucidate the mechanisms involved in harmful effects associated to hyperhomocysteinemia.
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PMID:Effects of homocysteine thiol group on fibrin networks: another possible mechanism of harm. 1241 93

Although hyperhomocysteinemia (HH) appears to be an independent risk factor for thrombosis, the pathophysiologic mechanisms seen in thrombus formation are largely unresolved. The aim of the present study was to investigate whether HH is accompanied by thrombogenic alterations as assessed by whole blood thromboelastographic profiles. Severe (111 micro mol/L) and intermediate (42 micro mol/L) HH were induced in two series of rats by feeding them a folate-depleted diet. Each group was compared with a separate control group. In rats suffering severe HH (n = 30), initiation of the coagulation was protracted, with a clotting time of 79.7 s (95% CI, 76.2-83.4) compared with 70.4 s (95% CI, 66.5-74.6) in controls (P = 0.001). The velocity of the propagation of coagulation was increased, reaching 0.119 mm/s (95% CI, 0.111-0.127) in HH rats compared with 0.104 mm/s (95% CI, 0.099-0.108) in controls (P < 0.001). The maximum clot firmness also was increased, i.e., 41.9 mm (95% CI, 40.5-43.4) in HH rats compared with 37.6 mm (95% CI, 36.5-38.7) in controls (P < 0.001). The resting thrombin-antithrombin complex concentration in plasma tended to be lower in HH rats [5.60 micro g/L (95% CI, 3.76-8.34) than in controls [8.56 micro g/L (95% CI, 6.44-11.37)] (P = 0.074). In the series of rats with intermediate HH (n = 16), the changes in the whole blood coagulation profile (WBCP) were similar to those in rats with severe HH although only the prolongation of the initiation phase was significant. In conclusion, our study revealed that the WBCP was influenced by high plasma homocysteine by 1) prolonging the initiation phase, 2) increasing the velocity of the coagulation propagation and 3) increasing the maximum clot firmness. These changes in WBCP may contribute to the increased risk of thrombosis in hyperhomocysteinemic individuals.
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PMID:Hyperhomocysteinemia due to folate deficiency is thrombogenic in rats. 1284 Jan 88

Elevated plasma homocysteine is associated with an increased risk of atherosclerosis and thrombosis. However, the mechanisms by which homocysteine might cause these events are not understood. We hypothesized that hyperhomocysteinemia might lead to modification of fibrinogen in vivo, thereby causing altered fibrin clot structure. New Zealand White rabbits were injected intraperitoneally (i.p.) every 12 h through an indwelling catheter with homocysteine or buffer for 8 weeks. This treatment raised the plasma homocysteine levels to about 30 micro mol L(-1) compared with 13.5 micro mol L(-1) in control rabbits by the end of the treatment period. The fibrinogen levels were 3.2 +/- 0.6 in homocysteine-treated and 2.5 +/- 1.1 mg mL(-1) in control rabbits. The reptilase time was prolonged to 363 +/- 88 for plasma from homocysteine-treated rabbits compared with 194 +/- 48 s for controls (P < 0.01). The thrombin clotting time (TCT) for the homocysteine-treated rabbits was significantly shorter, 7.5 +/- 1.7 compared with 28.6 +/- 18 s for the controls (P < 0.05). The calcium dependence of the thrombin clotting time was also different in homocysteinemic and control plasmas. Clots from plasma or fibrinogen of homocysteinemic rabbits were composed of thinner fibers than control clots. The clots formed from purified fibrinogen from homocysteine-treated rabbits were lyzed more slowly by plasmin than comparable clots from control fibrinogen. Congenital dysfibrinogenemias have been described that are associated with fibrin clots composed of thin, tightly packed fibers that are abnormally resistant to fibrinolysis, and recurrent thrombosis. Our results suggest that elevated plasma homocysteine leads to a similar acquired dysfibrinogenemia. The formation of clots that are abnormally resistant to fibrinolysis could directly contribute to the increased risk of thrombosis in hyperhomocysteinemia.
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PMID:Elevated plasma homocysteine leads to alterations in fibrin clot structure and stability: implications for the mechanism of thrombosis in hyperhomocysteinemia. 1287 4

Hyperhomocysteinemia is a risk factor for cardiovascular diseases that induces endothelial dysfunction. Here, we examine the participation of endothelial NO synthase (eNOS) in the homocysteine-induced alterations of NO/O(2)(-) balance in endothelial cells from human umbilical cord vein. When cells were treated for 24 h, homocysteine dose-dependently inhibited thrombin-activated NO release without altering eNOS phosphorylation and independently of the endogenous NOS inhibitor, asymmetric dimethylarginine. The inhibitory effect of homocysteine on NO release was associated with increased production of reactive nitrogen and oxygen species (RNS/ROS) independent of extracellular superoxide anion (O(2)(-)) and was suppressed by the NOS inhibitor L-NAME. In unstimulated cells, L-NAME markedly decreased RNS/ROS formation and the ethidium red fluorescence induced by homocysteine. This eNOS-dependent O(2)(-) synthesis was associated with reduced intracellular levels of both total biopterins (-45%) and tetrahydrobiopterin (-80%) and increased release of 7,8-dihydrobiopterin and biopterin in the extracellular medium (+40%). In addition, homocysteine suppressed the activating effect of sepiapterin on NO release, but not that of ascorbate. The results show that the oxidative stress and inhibition of NO release induced by homocysteine depend on eNOS uncoupling due to reduction of intracellular tetrahydrobiopterin availability.
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PMID:Homocysteine induces oxidative stress by uncoupling of NO synthase activity through reduction of tetrahydrobiopterin. 1518 55

Elevated plasma concentrations of the sulphur-containing amino acid homocysteine (Hcy) is associated with increased risk of atherosclerosis and arterial thrombosis. The mechanism by which Hcy exerts these effects has yet to be fully elucidated, although a variety of possible mechanisms have been proposed, including endothelial dysfunction or haemostatic abnormalities. However, the influence of Hcy on platelets, cells central to the atherothrombotic process, has never been addressed directly in patient studies. Here, the influence of mild hyperhomocysteinaemia (hHcy) on platelet function was explored in patients with peripheral occlusive arterial disease as evidence by intermittent claudication. Claudicants (n = 39) were assigned to one of two subgroups depending on their plasma Hcy concentrations. hHcy claudicants had plasma Hcy concentrations of 18.9 +/- 1.0 microM (n = 24), compared to 11.3 +/- 0.5 microM for normohomocysteinemic (nHcy) claudicants (n = 15) and 12.6 +/- 0.7 microM for age-matched controls (n=15). Platelet function was evaluated ex vivo in both groups and compared to age-matched controls. Platelet activation and sensitivity to nitric oxide-mediated inhibition was assessed by platelet fibrinogen binding and P-selectin expression. At low concentrations of adenosine diphosphate (ADP; 0.1 microM) and thrombin (0.02 U/ml), platelets from hHcy claudicants were more reactive than those from age-matched controls, but not nHcy claudicants. Agonist-induced P-selectin expression was significantly raised in hHcy claudicants compared to all other groups. Interestingly no differences were observed between nHcy claudicants and age-matched controls, indicating that claudication per se did not affect platelet function. Since platelet activity in vivo is determined by the exposure to both agonists and antagonists, we subsequently tested the sensitivity of platelets to inhibition by nitric oxide (NO), using the same platelet markers. Platelets from hHcy claudicants were significantly less sensitive to GSNO (1-100 microM)-mediated inhibition than all other groups. GSNO (1microM) induced 42.6 +/- 10 and 39 +/- 11.5% inhibition of ADP-induced fibrinogen binding for the nHcy claudicants and age-matched controls, respectively. However, in hHcy claudicants only 16.4 +/- 9.7% inhibition was observed, significantly less than the other groups (P < 0.01). Again no differences between nHCy claudicants and controls were observed. These results suggest the presence of claudication alone does not influence platelet function but if complicated with mild hyperhomocysteinemia, the sensitivity to agonists is increased, and more importantly, their sensitivity to inhibition is greatly reduced. The overall effect would be an increased propensity for platelet activation. The presence of even mildly elevated plasma Hcy could dramatically increase thrombotic risk.
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PMID:Altered platelet reactivity in peripheral vascular disease complicated with elevated plasma homocysteine levels. 1518 48

Homocysteine is a sulfhydryl-containing amino acid formed during the metabolism of methionine. Rapidly accumulating evidence links elevated homocysteine levels to thrombosis via several mechanisms such as increased tissue factor expression, attenuated anticoagulant processes, enhanced platelet reactivity, increased thrombin generation, augmented factor V activity, impaired fibrinolytic potential, and vascular injury, including endothelial dysfunction. Molecular mechanisms underlying prothrombotic actions of homocysteine are incompletely understood and involve oxidative stress, DNA hypomethylation, and proinflammatory effects. Current evidence from retrospective and prospective studies supports the concept that higher total plasma homocysteine concentration is associated with increased risk of coronary artery disease, stroke, and venous thromboembolism. Hyperhomocysteinemia is currently considered a relatively weak prothrombotic factor. It is still unclear whether administration of vitamins, that reduce homocysteine levels acting as cofactors of the enzymes involved in the methionine metabolism, may decrease the risk of arterial and/or venous thromboembolic events. Ongoing clinical trials might help clarify this issue.
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PMID:Homocysteine and thrombosis: from basic science to clinical evidence. 1636 30

Cerebral venous thrombosis (CVT) is rare compared to arterial causes of stroke. It is often encountered in young patients and may occur in children and neonates. Predisposition to CVT also has a genetic basis and inherited thrombophilias are known to cause 22.4% of the CVT cases. Inherited thrombophilias should be suspected if a patient has recurrent CVT, is less than 45 years age, has a family history of venous thrombosis or has no apparent acquired risk factor. Factor V Leiden (FVL) is the most common genetic risk factor, followed by the prothrombin gene mutation G20210A. Other less common inherited venous thrombophilias include deficiencies of Protein S, Protein C and antithrombin III. FVL, the G20210A prothrombin gene mutation and a deficiency of protein S and C, cause a reduction in the control of thrombin generation. Deficiency of antithrombin causes a decreased neutralization of thrombin. Both these mechanisms are responsible for venous thrombosis. Inherited thrombophilias with concomitant acquired risk factors like surgery, trauma, prolonged immobilization, pregnancy and puerperium, oral contraceptives, antiphospholipid antibodies and hyperhomocysteinemia may increase the risk of CVT manifold. Similarly the co-inheritance of two or more known mutations also increases the risk markedly. FVL, prothrombin G20210A mutation, increased factor VIIIc, protein C & S deficiency and antithrombin III deficiency have all been reported to cause neonatal stroke due to CVT. Maternal and foetal testing is suggested when CVT occurs in neonates.
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PMID:Genetics of cerebral venous thrombosis. 1718 72

Hyperhomocysteinemia is an independent risk factor for the development of atherosclerosis, as well as for arterial and venous thrombosis. However, the mechanisms through which elevated circulating levels of homocysteine cause vascular injury and promote thrombosis remain unclear. Here, we tested the hypothesis that homocysteine (Hcy) sensitizes endothelial cells to the effect of inflammatory mediators. Human umbilical vein endothelial cells (HUVEC) were incubated with Hcy 1.0 mM for varying time points, and then treated in the absence or presence of 1.5 U/ml thrombin or 10 mg/ml lipopolysaccharide (LPS). Hcy alone had no effect on the expression of vascular cell adhesion molecule (VCAM)-1. However, Hcy enhanced thrombin- and LPS-mediated induction of VCAM-1 mRNA and protein levels. Consistent with these results, pretreatment of HUVEC with Hcy resulted in a two-fold increase in LSP-mediated induction of leukocyte adhesion. The latter effect was significantly inhibited by anti-VCAM-1 antibodies. Together, these findings suggest that Hcy sensitizes HUVEC to the effect of inflammatory mediators thrombin and LPS, at least in part through VCAM-1 expression and function.
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PMID:Priming effect of homocysteine on inducible vascular cell adhesion molecule-1 expression in endothelial cells. 1840 66

Hyperhomocysteinemia is a pathological condition that increases cardiovascular risk due to prothrombotic behaviour in the patient. This case report concerns a 61-year-old man undergoing surgical coronary revascularization for early thrombosis of the venous graft. The postoperative antithrombin activity was extremely low (33%), despite normal preoperative values (79%) and a short cardiopulmonary bypass. At a subsequent screening, the patient was diagnosed with hyperhomocysteinemia (18.4 mmol/L) due to a heterozygous C677T mutation of the enzyme methylenetetrahydrofolate reductase associated with a folate deficiency. Hyperhomocysteinemia and cardiac operation are both factors that induce increased thrombin formation, which may induce antithrombin consumption and a consequent thrombotic event. Further studies are needed to define hyperhomocysteinemia as an independent risk factor for thrombotic events after cardiac surgery.
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PMID:Hyperhomocysteinemia, antithrombin consumption, and early venous graft closure in surgical coronary revascularization. 1861 69

Homocysteine (Hcy), an intermediate formed during the catabolism of the essential dietary amino acid methionine, and its cyclic thioester, homocysteine thiolactone (TL) formed from Hcy in plasma, may be implicated in pathological haemostasis and atherosclerosis. The mechanism by which TL exerts the prothrombotic effect and influences blood platelets remains unclear. Activation of blood platelets plays an important role in prothrombotic events. The aim of our study was to establish and compare the influence of a reduced form of homocysteine (at final doses of 10-100 microM) and its cyclic thioester, homocysteine thiolactone (0.1-1 microM), on platelet activation induced by thrombin (platelet aggregation), on platelet protein modifications (determined by parameters such as level of protein carbonyl groups, 3-nitrotyrosine residues in proteins) and on superoxide anion radicals ( O2-*) generation using the model system in vitro. We have observed that TL, like its precursor, Hcy, stimulates the generation of O2* in platelets and causes an augmentation of platelet aggregation induced by thrombin. Our present results in vitro also demonstrate that Hcy (10-100 microM) and TL at lower doses than Hcy (0.1-1 microM) cause modification of platelet proteins: diminished formation of carbonyl groups and distinctly decreased tyrosine nitration in platelet proteins after thrombin stimulation, but increased platelet aggregation induced by thrombin. TL like Hcy (at concentrations corresponding to concentrations in blood during hyperhomocysteinemia) modifies platelet responses to an important physiological agonist--thrombin.
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PMID:Comparative studies on homocysteine and its metabolite-homocysteine thiolactone action in blood platelets in vitro. 1897 64


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