Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Homocystinuria is a rare inherited metabolic disease. Arterial and venous thromboembolic events represent frequent and life-threatening complications in homocystinuric patients. It has been suggested that mild homocysteinemia could be a risk factor for vascular disease. We have therefore measured total plasma homocysteine (HCy) concentrations by radioisotopic assay in 50 subjects with venous or arterial thrombosis and studied the relationship between HCy, coagulation and fibrinolytic parameters. Values were considered abnormal if they were higher than 2.7 standard deviations (SD) above the mean, i.e., 14.1 mmol/l. Thus, eighteen of the 50 patients with thrombosis were classified in the hyperhomocysteinemia group. Nine of these subjects had only this isolated risk factor. No correlations were found between HCy and antithrombin III, protein C, protein S and plasminogen levels, or plasma plasminogen activator inhibitor activity. Nevertheless, the correlation between tissue-plasminogen activator antigen and total plasma HCy was significant (r = 0.61, p < 0.001). Increased homocysteinemia seems to be a risk factor for thrombotic events especially knowing that HCy presents a direct cytotoxic effect. Vitamin therapy, already used in homozygote homocystinuric patients, might be beneficial in the prevention of thromboembolic disease in heterozygous patients.
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PMID:Elevated total plasma homocysteine, a risk factor for thrombosis. Relation to coagulation and fibrinolytic parameters. 832 83

Growing evidence suggests that moderately elevated levels of homocysteine are associated not only with arterial thrombosis and atherosclerosis but also with venous thrombosis as well. We have reviewed recent studies that indicate that homocysteine inhibits several different anticoagulant mechanisms that are mediated by the vascular endothelium. The protein C enzyme system appears to be one of the most important anticoagulant pathways in the blood. Homocysteine inhibits the expression and activity of endothelial cell surface thrombomodulin, the thrombin cofactor responsible for protein C activation. Homocysteine inhibits the antithrombin III binding activity of endothelial heparan sulfate proteoglycan, thereby suppressing the anticoagulant effect of antithrombin III. Homocysteine also inhibits the ecto-ADPase activity of human umbilical vein endothelial cells (HUVECS). Because ADP is a potent platelet aggregatory agent, this action of homocysteine is prothrombotic. Homocysteine also interferes with the fibrinolytic properties of the endothelial surface because it inhibits the binding of tissue plasminogen activator. Homocysteine stimulates HUVEC tissue factor activity. We have found that lipoprotein(a) [Lp(a)] also stimulates HUVEC tissue factor activity. The combination of Lp(a) plus homocysteine induced more tissue factor activity than either agent alone. These disruptions in several different vessel wall-related anticoagulant functions provide plausable mechanisms for the occurrence of thrombosis in hyperhomocysteinemia.
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PMID:Homocysteine and hemostasis: pathogenic mechanisms predisposing to thrombosis. 864 72

Mild hyperhomocysteinemia has been identified as a risk factor for arterial disease and for venous thrombosis. Individuals homozygous for the thermolabile variant of the methylene tetrahydrofolate reductase gene (MTHFR) which results from a common mutation Ala677-->Val and is found in 5-15% of the general population, have significantly elevated plasma homocysteine levels and may account for one of the genetic risk factors in vascular disease. We have analyzed the prevalence of MTHFR-T homozygotes in patients with arterial disease or venous thrombosis. We studied 191 patients with arterial disease and 127 individuals with venous thrombosis and compared with 296 unmatched controls. The results showed that there was a high prevalence of homozygotes for the mutated MTHFR-T allele among a group of patients with arterial disease (19%) in the absence of hyperlipoproteinemia, hypertension, and diabetes mellitus when compared to controls (4%), odds ratio of 5.52 (95% C.I., 2.27 to 13.51). The prevalence of homozygotes among patients with venous thrombosis was 11%, odds ratio of 2l93 (95% C.I., 1.23 to 7.01). The risk of venous thrombosis remained high, odds ratio of 2.63, even after we excluded 27 patients with hereditary thrombophilia (e.g. factor V Leiden, dysfibrinogenemia, deficiency of protein C, protein S, antithrombin III, or factor XII) from the 127 overall cases with venous thrombosis. These data support the hypothesis that being a homozygote for the MTHFR-T is a risk factor for the development of arterial disease and also for venous thrombosis.
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PMID:The mutation Ala677-->Val in the methylene tetrahydrofolate reductase gene: a risk factor for arterial disease and venous thrombosis. 918 84

Hyperhomocysteinemia is a condition which, in the absence of kidney disease, indicates a disrupted sulfur amino acid metabolism, either because of vitamin (folate, B12 and B6) deficiency or a genetic defect. Epidemiological evidence suggests that mild hyperhomocysteinemia is associated with increased risk of arteriosclerotic disease and stroke. The relationship between hyperhomocysteinemia and thrombosis has been investigated in 10 studies involving a total of 1200 patients and 1200 controls. Eight of these studies demonstrated positive association with odds ratios that ranged from 2 to 13. This association was enhanced by including a methionine loading test. There is some evidence which suggests that hyperhomocysteinemia and APC resistance have a synergistic effect on the onset of thrombotic disease. Studies on the mechanism that underlies the relationship between thrombosis and hyperhomocysteinemia used non-physiologically high levels of homocysteine, rendering the data doubtful as to their patho-physiological relevance.
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PMID:Hyperhomocysteinemia and thrombosis: acquired conditions. 919 9

Annually, 1 in 1,000 individuals is affected by venous thrombosis. Risk factors that are known to increase the risk of thrombosis may be either genetic or acquired, or have a combined origin. Many of these risk factors are very frequent, among which several have been recently identified, such as resistance to activated protein C by factor V Leiden, hyperhomocysteinemia, high levels of factors VIII, as well as the classical acquired risk factors, such as surgery and malignancies. When the prevalence of risk factors is high, it becomes likely that in some individuals two or more risk factors will be present simultaneously. The question "What happens to the risk in these circumstances?" is one involving interaction, also known as effect modification or synergy. In this article we review the prevalence and risk estimates for the various genetic and acquired risk factors for venous thrombosis, discuss the concept of interaction, and give an overview of the evidence for interaction of these risk factors.
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PMID:Risk factors for venous thrombosis: prevalence, risk, and interaction. 924 4

Recurrent fetal loss and other placental vascular pathologies of pregnancy have long been associated with antiphospholipid syndrome-an acquired autoimmune thrombophilic state. The number of known heritable thrombophilic disorders has grown rapidly in recent years with the identification of activated protein C resistance, factor V Leiden mutation and hyperhomocysteinemia as major causes of thrombosis. Data accumulated over the past two years suggest that heritable thrombophilia is associated with increased risk of fetal loss and pre-eclampsia. The present review discusses potential pathogenetic mechanisms for this association and evaluates reported therapeutic regimes for the prevention of fetal loss in women with thrombophilia.
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PMID:Thrombophilia and fetal loss. 924 90

Congenital homocysteinuria is a rare inherited metabolic disorder with early onset atherosclerosis and arterial and venous trombosis. Moderate hyperhomocysteinemia is more frequently encountered and is recognized as an independent cardiovascular risk factor. Several case-control studies demonstrate an association between venous thromboembolism and moderate hyperhomocysteinemia. A patient with moderate hyperhomocysteinemia has a 2-3 relative risk of developing an episode of venous thromboembolism. The occurrence of mild hyperhomocysteinemia in heterozygotes for the mutation of Leiden factor V involves a 10-fold increase in the risk of venous thromboembolism. The biochemical mechanism by which homocysteine may promote thrombosis is not fully recognized. Homocysteine inhibits the expression of thrombomodulin, the thrombin cofactor responsible for protein C activation, and inhibits antithrombin-III binding. Treatment with folic acid reduces the plasma level of homocysteinemia, but no study has demonstrated its efficacy in reducing the incidence of venous thromboembolism or atherosclerosis. Hyperhomocysteinemia should be included in the screening of abnormalities of hemostasis and thrombosis in patients with idiopathic thromboembolism, and mild hyperhomocysteinemia may justify a trial of folic acid.
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PMID:[Homocysteine and venous thromboembolism]. 930 44

Increased thrombin generation occurs in many individuals with inherited defects in the antithrombin or protein C anticoagulant pathways and is also seen in patients with thrombosis without a defined clotting abnormality. Hyperhomocysteinemia (H-HC) is an important risk factor of venous thromboembolism (VTE). We prospectively followed 48 patients with H-HC (median age 62 years, range 26-83; 18 males) and 183 patients (median age 50 years, range 18-85; 83 males) without H-HC for a period of up to one year. Prothrombin fragment F1+2 (F1+2) was determined in the patient's plasma as a measure of thrombin generation during and at several time points after discontinuation of secondary thromboprophylaxis with oral anticoagulants. While on anticoagulants, patients with H-HC had significantly higher F1+2 levels than patients without H-HC (mean 0.52 +/- 0.49 nmol/l, median 0.4, range 0.2-2.8, versus 0.36 +/- 0.2 nmol/l, median 0.3, range 0.1-2.1; p = 0.02). Three weeks and 3, 6, 9 and 12 months after discontinuation of oral anticoagulants, up to 20% of the patients with H-HC and 5 to 6% without H-HC had higher F1+2 levels than a corresponding age- and sex-matched control group. 16% of the patients with H-HC and 4% of the patients without H-HC had either F1+2 levels above the upper limit of normal controls at least at 2 occasions or (an) elevated F1+2 level(s) followed by recurrent VTE. No statistical significant difference in the F1+2 levels was seen between patients with and without H-HC. We conclude that a permanent hemostatic system activation is detectable in a proportion of patients with H-HC after discontinuation of oral anticoagulant therapy following VTE. Furthermore, secondary thromboprophylaxis with conventional doses of oral anticoagulants may not be sufficient to suppress hemostatic system activation in patients with H-HC.
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PMID:Levels of prothrombin fragment F1+2 in patients with hyperhomocysteinemia and a history of venous thromboembolism. 940 13

Inherited thrombophilia is associated with an increased risk of thrombosis. Classically it consists of protein C and protein S deficiency, activated protein C resistance and antithrombin III deficiency. In pregnancy, in addition to thrombosis, inherited thrombophilia is associated with poor obstetric outcome, including recurrent miscarriage, late fetal loss, abruption and pre-eclampsia. Hyperhomocysteinaemia is a newly recognized cause of familial thrombophilia. It is likely that further causes such as prothrombin gene mutations will be added to the rapidly expanding list. The diagnosis of some forms of genetic thrombophilia must, however, be approached with caution during pregnancy, particularly protein S deficiency and activated protein C resistance.
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PMID:Inherited thrombophilia and pregnancy. 955 9

Hypercoagulable states are a group of conditions associated with increased predisposition to thromboembolic events. Most of the inherited abnormalities recognized to date are associated with venous thromboembolism (VTE) rather than arterial thrombosis. The well-recognized inherited hypercoagulable states are the deficiencies of antithrombin, protein C and protein S, and the resistance to APC (factor V Leiden). These entities represent aberrations in the natural anticoagulant systems that exist in plasma. Other causes of inherited thrombophilia include abnormalities in the proteins of the fibrinolytic system, dysfibrinogenemias, deficiency of heparin cofactor II, abnormal thrombomodulin, elevated levels of histidine-rich glycoprotein, and the recently described variation in the prothrombin gene. One entity that has become firmly established as a predisposing factor for recurrent VTE is hyperhomocysteinemia. About half of VTE episodes in patients with inherited thrombophilias occur in relation to events that are generally recognized as predisposing states, such as surgery, pregnancy (particularly puerperium) and immobilization. In this review, the risks of VTE associated with inherited risk factors are discussed, and guidelines for the diagnosis and management are presented.
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PMID:Inherited hypercoagulable states. 957 5


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