Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:EXPT03052 (THF)
 8,150 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The link between vascular disease and elevated homocysteine levels has been recognized for more than 30 years, and association with moderately elevated levels has been suspected for 20 years. Homocysteine is a sulfhydryl-containing amino acid that is formed by the demethylation of methionine. It is normally catalysed to cystathionine by cystathionine beta-synthase a pyridoxal phosphate-dependent enzyme. Homocysteine is also remethylated to methionine by methionine synthase, a vitamin B12 dependent enzyme and by methylenetetrahydrofolate reductase. Environmental factors such as folate, or vitamin B12, or vitamin B6 deficiencies and genetic defects such as cystathionine beta-synthase or abnormality of methylene-tetrahydrofolate reductase or some vitamin B12 metabolism defects may contribute to increasing plasma homocysteine levels. Normal fasting levels of homocysteine lie within the range 6-16 mumol/l. Apart from differences in assay methods, age, sex and nutritional status may affect the plasma levels. Though it is now well known that homocysteine is an independent risk factor for premature vascular disease, the pathogenesis of homocysteine-induced vascular damage is, for the most part, unknown. It may be multifactorial, including direct homocysteine damage to the endothelium, an enhanced low-density lipoprotein peroxidation, an increase of platelet thromboxane A2, or a decrease of protein C activation.
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PMID:[Deregulation of homocysteine metabolism and consequences for the vascular system]. 923 30

According to a recent hypothesis, venous thrombosis results from the concurrence of several factors. This hypothesis was assessed in patients with portal or hepatic venous thrombosis by simultaneously investigating most of the currently identified prothrombotic disorders, local precipitating factors, and other risk factors such as oral contraceptive use. Patients with a tumorous obstruction and patients with cirrhosis with portal vein thrombosis were excluded. The prothrombotic disorders that were investigated included classical and occult myeloproliferative disorders; antiphospholipid syndrome; protein C; protein S and antithrombin deficiency; factor V Leiden; factor II; and methylene-tetrahydrofolate-reductase gene mutations. We found 1 or several prothrombotic disorders and a local precipitating factor in 26 and 10 of the 36 patients with portal vein thrombosis, respectively; and in 28 and none of the 32 patients with hepatic vein thrombosis, respectively. We found a combination of prothrombotic disorders in 5 and 9 patients with portal and hepatic vein thrombosis, respectively, whereas such a combination is expected in less than 1% of asymptomatic subjects. Of the 10 patients with a local precipitating factor, 8 had a prothrombotic disorder. Of the 13 patients who use oral contraceptives, 10 had a prothrombotic disorder. We conclude that portal or hepatic venous thrombosis should be regarded as an index for 1 or several prothrombotic disorders, whether or not local precipitating factors or oral contraceptive use are found. Concurrence of prothrombotic disorders is more common than expected. Extensive investigation of prothrombotic disorders and anticoagulation should be considered in patients with portal or hepatic venous thrombosis.
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PMID:Cause of portal or hepatic venous thrombosis in adults: the role of multiple concurrent factors. 1070 47

Evaluation of inherited thrombophilia in patients with venous thromboembolism includes testing for functional activity of antithrombin, protein C and protein S, and resistance to activated protein C (factor V Leiden), which can be assessed with plasma and DNA-based assays. The antiphospholipid syndrome is an acquired disorder related to the development of antibodies against phospholipid-protein complexes. Testing for the antiphospholipid syndrome includes measurement of antibodies to phospholipid-protein complexes by immunoassay or by detecting interference of anti-phospholipid antibodies in sensitive phospholipid-based assays. Other genetic risk factors have been listed, including a common polymorphism in prothrombin gene (3'-untranslated region) related to an increase of prothrombin level (> 115%) and a common polymorphism in the methylene tetrahydrofolate reductase (enzyme involved in homocysteine metabolism) gene related to a mild increase of homocysteine blood level. More recently high plasmatic levels of factor VIII (> 150%) or factor XI (> 120%), not related so far to a molecular defect, have been identified as risk factors for deep vein thrombosis. As a candidate gene, factor XIII gene polymorphisms are under investigation. Beside the acquired or genetic risk factors involved in thrombophilia, the gene-environment interactions are of importance in the onset of thrombosis.
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PMID:[Laboratory testing for venous thromboembolism]. 1120 40

Congenital and acquired thrombophilia are associated with an increased risk of pregnancy-associated venous thrombosis and fetal loss. Two hundred eighty-nine patients with a history of recurrent spontaneous abortion were subjected to screening examinations for the etiology of these abortions. Endocrine abnormality (28.0%), uterine abnormality (10.4%), autoimmune diseases (1.4%), antiphospholipid antibody syndrome (4.5%), and balanced type chromosome translocation (4.2%) were found as underlying causes of recurrent abortions, and the remaining 55.0% of the 289 patients were classified as having an unexplained etiology. Congenital thrombophilia such as protein C (PC) deficiency, protein S (PS) deficiency, antithrombin deficiency, and factor V Leiden mutation was not frequently detected; only one patient had PS deficiency. A reduced factor XII activity was found at a frequency of 4.2%. The frequency of methylene tetrahydrofolate reductase gene C677T mutation in recurrent aborters (0.38) was the same as that found in a fertile control group. Although the prevalence of anti-beta2-glycoprotein I antibody (abeta2-GPI) syndrome was very low (1.7%), patients with a high titer of immunoglobulin G (IgG) class abeta2-GPI, despite anticoagulation therapy, experienced severe fetomaternal complications in subsequent pregnancies. The rate (13.8%) of positive tests for serum IgA class abeta2-GPI in patients with unexplained etiology was higher than that in the controls (0%) (P < .05). We conclude that congenital thrombophilia is rare in Japanese patients who had experienced consecutive spontaneous abortions.
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PMID:Recurrent pregnancy loss: etiology of thrombophilia. 1137 65

A subgroup of children with arterial ischemic stroke in the pre- or perinatal period present with delayed diagnosis. We identified 22 children who met the following criteria: (1) normal neonatal neurological history, (2) hemiparesis and/or seizures first recognized after two months of age, and (3) computed tomography or magnetic resonance imaging showing remote cerebral infarct. Laboratory evaluations included protein C, protein S, antithrombin, activated protein C resistance screen (APCR), Factor V Leiden (FVL), prothrombin gene defect, methylene tetrahydrofolate reductase variant (MTHFR), anticardiolipin antibody (ACLA), and lupus anticoagulant. Not all children received all tests. Age at last visit ranged from 8 months to 16.5 years (median 4 years). Twelve were boys. Fourteen had left hemisphere infarcts. Median age at presentation was 6 months. Eighteen had gestational complications. Fourteen children had at least transient coagulation abnormalities (ACLA = 11, ACLA + APCR = 1, APCR = 2 with FVL + MTHFR = 1); six of these children had family histories suggestive of thrombosis. Cardiac echocardiogram was unremarkable in the 15 tested. Outcomes included persistent hemiparesis in 22; speech, behavior, or learning problems in 12; and persistent seizures in five, with no evidence of further stroke in any patient. The persistence and importance of coagulation abnormalities in this group need further study.
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PMID:Presumed pre- or perinatal arterial ischemic stroke: risk factors and outcomes. 1150 98

During an 18-month period, 10 consecutive Mexican mestizos with a dinical marker associated with a primary hypercoagulable state were studied. The assessment of the sticky platelet syndrome (SPS) was done by the method described by Mammen. In addition, the activated protein C resistance phenotype, coagulation protein C activity and antigen, coagulation protein S, antithrombin III, plasminogen, tissue-type plasminogen activator activity, plasminogen activator inhibitor activity, plasminogen activator inhibitor type 1, IgG and IgM isotypes of anti-phospholipid antibodies, homocysteine levels, the factor V gene Leiden mutation, the 677 C->T mutation in the 5,10-methylen-tetrahydrofolate-reductase (MTHFR), and the G20210A polymorphism in the 3'-untranslated region of the prothrombin gene were studied. Six patients with the SPS were identified: only one displayed this as the single thrombophilic abnormality; in five others, additional thrombosis-prone conditions were found: heterozygosity for the MTHFR 677 gene mutation in five cases; and, in one case each, heterozygosity for the factor V Leiden mutation, heterozygosity for the factor II G20210A mutation, and antiphospholipid antibodies in another. Four of the six patients had a family history of thrombophilia. All patients were treated with aspirin and no new vasoocclusive episodes have been recorded. SPS in not an infrequent finding in Mexican mestizo thrombophilic patients and may contribute to thrombophilia.
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PMID:Primary thrombophilia in Mexico III: A prospective study of the sticky platelet syndrome. 1236 Dec 6

Long-distance air travel is increasing and cases of venous thromboembolism (VTE) following air travel have attracted both considerable public attention and legal claims against airlines. VTE is a common disorder worldwide with a notably high incidence in older individuals. Many biochemical factors that lead to, or accentuate, thrombus formation are associated with increased risk of VTE. These factors include thrombophilia, activated protein C resistance and factor V Leiden, prothrombin gene mutation, antiphospholipid antibodies, protein S and protein C deficiencies, and methylene tetrahydrofolate reductase polymorphism and homocysteinemia. Individual physical characteristics including age, weight and height are significant for personal risk of VTE as are other factors such as use of oral contraceptives in women. In the case of air travel-related venous thrombosis, superimposed upon these individual factors are the environmental factors directly related to air travel. Travel-related factors include stasis associated with prolonged periods of immobility, physiological stresses resulting from exposure to the cabin environment (low humidity and hypoxia) in long-haul flight and other in-flight factors. It is suggested that passenger behavior (movement, avoidance of dehydration and of alcohol) and appropriate pharmacological prophylaxis for high-risk travelers can reduce the likelihood of VTE. Physical prophylaxis (use of compression stockings or in-flight exercise devices) may also be of general benefit to passengers. It is recommended that airlines become more proactive in educating passengers concerning the dangers of VTE and in promoting passenger actions that can reduce risk. Airlines should also work to avoid cramped seating conditions (seat size and pitch) that contribute to prolonged immobility. Governments and regulatory authorities should mandate the provision of adequate seating conditions and a good cabin environment and should support studies that will define risks and determine the efficacy of protocols to minimize dangers of VTE. Increased long-haul air traffic and an aging population suggest that travel-related VTE may present a growing healthcare threat and has highlighted a need for additional biomedical research into the causes and potential solutions to this problem.
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PMID:Air travel-associated venous thromboembolism. 1263 60

Paediatric patients with systemic lupus erythematosus (SLE) and antiphospholipid antibodies (aPL), specifically lupus anticoagulants (LAC) are at high risk of developing thromboembolic events (TE). Our objectives were to determine the prevalence of TE in paediatric SLE patients with LAC and to determine if anticoagulation was effective to decrease morbidity, and prevent recurrent TE. We reviewed data on 149 paediatric SLE patients treated over 10 years. In all, 24 patients (16%) were LAC positive, and 21 TE occurred in 13 of these LAC positive patients (54% incidence of TE in LAC positive patients). The events were cerebral venous thrombosis (9), arterial stroke (3), deep venous thrombosis (4), pulmonary embolism (2), other venous event (1) and other arterial events (2). The median duration between SLE diagnosis and first TE was 15.2 months (range 0-62), and the median age at first TE was 15.1 years (range 11.4-18.4). Long-term anticoagulation was prescribed, and eight patients (62%) were transferred to adult care on lifelong oral warfarin; four (31%) remain under our care on lifelong warfarin, and one patient died of causes unrelated to her TE. No patient has been identified with deficiencies of protein C, protein S or antithrombin III. One patient is heterozygous for Factor V Leiden, and one is heterozygous for both the Prothrombin 20210A mutation and the MTHFR (methylene tetrahydrofolate reductase) mutation. Four patients had recurrent TE (31%), and three were not anticoagulated at the time of their second event. One patient had two recurrences on therapeutic anticoagulation. Thromboembolic events are prevalent in the LAC positive paediatric SLE population, and consideration for lifelong anticoagulation must occur after an initial TE.
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PMID:Thromboembolism in paediatric lupus patients. 1459 22

Catastrophic antiphospholipid syndrome (CAPS) is a severe and rare variant of antiphospholipid syndrome (APS) characterized by acute multiorgan failure due to small vessel thrombi in patients with positive antiphospholipid antibodies. We report a fatal case of catastrophic antiphospholipid syndrome in a young woman with a history of polymyositis and Hodgkin lymphoma. The patient was admitted to hospital because of severe foot pain following several weeks of skin ulcerations. Doppler ultrasonography showed evidence of arterial ischemia of the both lower extremities. Despite anticoagulation, immunosuppression, plasmapheresis and antibiotic therapy, she developed cutaneous gangrene, retroperitoneal hematoma, ileus, and acute respiratory and renal failure that resulted in death. Autopsy showed multifocal vascular injury and microthrombi with associated hemorrhages and infarcts in multiple organs. The patient had normal levels of functional protein C and protein S and a normal level of plasma homocysteine. Tests for common thromophilic gene mutations including prothrombin 20210, factor V Leiden 1691, and methylene tetrahydrofolate reductase 677 were negative. To our knowledge, this is the first CAPS patient with molecular studies for genetic prothrombotic mutations. Our report showed that there was no association between the development of CAPS and inherited thromophilia.
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PMID:Catastrophic antiphospholipid syndrome: a rare cause of disseminated microvascular thrombotic injury - a case report with pathological and molecular correlative studies. 1574 23


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