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

To assess the prevalence of impaired homocysteine metabolism in young adults with arterial occlusive disease, 80 consecutive patients under 45 years old were screened. Various laboratory blood investigations and a standardized methionine loading test were performed. In the first 52 patients plasma levels of free homocysteine were determined; thereafter the levels of total homocysteine (a more sensitive measure of impaired homocysteine metabolism) were measured. The methionine loading test was abnormal in 15 patients (19 per cent) who did not differ from the other 65 with respect to prevalence of other risk factors, clinical characteristics, and electrocardiographic and angiographic findings. Blood levels of glucose, vitamins B6 and B12, folate, protein C and protein S, fibrinogen and low-density lipoprotein cholesterol did not differ significantly between the two groups. The prevalence of impaired homocysteine metabolism in young patients with arterial occlusive disease is greater than the 1-2 per cent found in the normal population.
 ...
PMID:Impaired homocysteine metabolism: a risk factor in young adults with atherosclerotic arterial occlusive disease of the leg. 795 34

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.
 ...
PMID:Hyperhomocysteinemia and thrombosis: acquired conditions. 919 9

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.
 ...
PMID:[Deregulation of homocysteine metabolism and consequences for the vascular system]. 923 30

Hyperhomocysteinemia is a condition which, in the absence of kidney disease, indicates a disrupted sulfur amino acid metabolism, either because of vitamin deficiency (folate, B12 and B6) or a genetic defect. Epidemiologic 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 two to 13. This association was enhanced by including a methionine loading test. There is some evidence which suggests that hyperhomocysteinemia and activated protein C resistance have synergistic effect on the onset of thrombotic disease. Recent studies with animal models for mild hyperhomocysteinemia provided encouraging results in the understanding of the mechanism that underlies this relationship between mild elevations of plasma homocysteine and vascular disease. These animal models pointed to the possibility that the effect of elevated homocysteine is multifactorial, affecting both the vascular wall structure and the blood coagulation system.
 ...
PMID:Relationship between homocysteine and thrombotic disease. 970 66

The effect of homocysteine-lowering treatment on thrombin generation was investigated in 17 subjects with hyperhomocysteinemia (aged 22-60 years), 11 of whom had symptomatic atherosclerotic vascular disease. All subjects had fasting total homocysteine levels above 16 micromol/L. The formation of thrombin was assessed by measuring thrombin-antithrombin III complexes and prothrombin fragment 1+2 in peripheral venous blood and in the bleeding time blood collected at 30-second intervals from skin incisions on a forearm. All the tests were performed before and after an 8-week treatment with folic acid p.o. 5 mg/day, vitamin B6 p.o. 300 mg/day, and vitamin B12 i.m. 1000 microg given on a weekly basis. Following the 8-week therapy, the median plasma homocysteine concentration became significantly reduced from 20 to 10 micromol/L, while plasma levels of fibrinogen, prothrombin, and antithrombin III as well as activity of protein C, S, and factor VII showed no changes. Vitamin treatment was associated with a significant fall in thrombin-antithrombin III complexes and prothrombin fragment 1+2 concentrations in peripheral venous blood. Bleeding time became prolonged by about 60 seconds. At sites of hemostatic plug formation, plasma concentrations of both thrombin markers significantly decreased. Compared with pretreatment values, significantly less thrombin was produced during the first 3 minutes of bleeding after homocysteine-lowering therapy. In subjects with hyperhomocysteinemia a reduction of plasma fasting homocysteine concentration by folic acid and vitamins B12 and B6 administration is associated with attenuation of thrombin generation both in peripheral blood and at sites of hemostatic plug formation.
 ...
PMID:Treatment of hyperhomocysteinemia with folic acid and vitamins B12 and B6 attenuates thrombin generation. 1052 5

The frequency of the heterozygous 844ins68 mutation of the cystathionine beta-synthase (CBS) gene and of its association with the homozygous C677T transition of the methylenetetrahydrofolate reductase (MTHFR) gene, plasma fasting tHcy, folate and vitamin B12 levels were evaluated in 309 consecutive patients with objectively diagnosed early-onset venous (n = 200) or arterial thromboembolic disease (n = 109) recruited over 25 months in Milan (North Italy) and Naples (South Italy). The above gene polymorphisms were also evaluated in a population of 787 unmatched controls, 204 of whom--similar to patients for age- and sex-distribution--had fasting tHcy, vitamins and activated protein C resistance measured in their plasma. Moderate fasting hyperhomocysteinemia was detected in 15.5% of patients and in 5.9% of 204 controls (Mantel-Haenszel OR after stratification for type of occlusive disease and gender: 2.88; 1.48-5.32). The frequencies of the 677TT mutation of the MTHFR gene and of the heterozygous 844ins68 insertion of the CBS gene were not significantly different in the patient (19.4% and 6.9%) and the control population (16.5% and 7.8%), but the association of the two gene polymorphisms found in 3.9% of patients and in 1.1% of controls - was significantly associated with an increased risk of venous or arterial occlusive diseases (RR = 3.63; 1.48-8.91). The MTHFR 677TT mutation (RR: 6.92; 3.86-12.4) and its association with the 844ins68 insertion (RR: 21.9; 8.35-57.4), but not the isolated insertion (RR: 0.71), were more frequent in patients and controls with fasting hyperhomocysteinemia than in normohomocysteinemic subjects, irrespective of the type of occlusive disease (venous or arterial). When adjusted for determinants of hyperhomocysteinemia in the patient and the control populations (generalized linear model), fasting tHcy levels were significantly higher in subjects with association of the two gene abnormalities (24.2+/-3.8 micromol/L) than in subjects with the MTHFR 677TT mutation only (14.0+/-5.8 micromol/L, p = 0.004). Activated protein C resistance was significantly more prevalent in venous patients (9.9%) than in controls (3.9%, OR = 2.69; 1.08-6.88). Six of 21 venous patients with APC-resistance also had hyperhomocysteinemia (RR = 5.04; 0.68-37.6), but isolated fasting hyperhomocysteinemia retained statistical significance for the association with venous occlusive disease (RR = 2.84; 1.34-6.01). Heterozygosity for the 844ins68 mutation of the CBS gene is not per se a risk factor for premature arterial and/or venous occlusive diseases. However, when detected in combination with thermolabile MTHFR, it increases by almost 4-fold the risk of occlusive diseases (arterial and/or venous), by increasing the risk and the degree of fasting hyperhomocysteinemia.
 ...
PMID:Contribution of the cystathionine beta-synthase gene (844ins68) polymorphism to the risk of early-onset venous and arterial occlusive disease and of fasting hyperhomocysteinemia. 1105 53

Homocysteine is an amino acid that is capable of disturbing the proper growth of cells. Hyperhomocysteinemia can lead to a non-closure of the neural tube. The underlying basis is a derangement of homocysteine metabolism due to a missense mutation of the MTHFR enzyme that has to catalyze the folate metabolic cycle furnishing sufficient methyl groups for DNA and tRNA synthesis. Folate can overcome the dysfunction of the mutation and the decreased activity of the thermolabile MTHFR. Homocysteine is also recognized as an independent risk factor for obstetrical vascular disease that can manifest itself in maternal veins (thrombosis), arteries (preeclampsia) or spiral arteries supplying the placenta (placental abruption). Low vitamin status (folic acid, vitamin B6 and B12), hyperhomocysteinemia, the MTHFR gene mutation C677T, and thrombotic factors like Protein C, Protein S. antithrombin III, factor V Leiden and Activated Protein C, are alone or in combination high risk factors for obstetrical vascular disease. Their values can be modulated by B-vitamin status and could be able to prevent disease from occurring or recurring. Placebo-randomized trials have been done in neural tube defects but are urgently needed in the vascular area. The common denominator of the effect of homocysteine on the embryo and the blood vessels (endothelium) could be sited in the process of proliferation of cells that need proper methyl groups for proper function.
 ...
PMID:Homocysteine and human reproduction. 1121 39

Elevated plasma homocysteine is a new risk factor for atherosclerotic vascular disease resulting in progressive atherogenesis in the arteries of the limbs, the coronary arteries and the cerebrovascular system. Hyperhomocysteinemia may be induced by failure or decreased enzyme activity of the cystathionine-beta-synthase and methylenetetrahydrofolate reductase due to genetic mutation or deficiency of folic acid, vitamin B12 and vitamin B6. Oxidation of homocysteine to homocystine is accompanied with production of hydrogen peroxide inducing damage of endothelium through oxidative stress. The injury of the endothelium by homocysteine can be shown by measuring flow-induced vasodilation in men. The abnormalities of coagulation found in hyperhomocysteinemia is related to the impairment of the function of endothelial cells and inhibition of the thrombomodulin-protein C and glycosaminoglycan-antithrombin-III anticoagulant system. Homocysteine decreases the level of glutathione peroxidase in the endothelial cells, and inhibits its activation leading to the impairment of oxidative defensive mechanism, and to the free radical-induced NO-inactivation. In decreasing of plasma homocysteine level and preventing its influence on endothelium, moreover in improving of endothelial function the folic acid has cardinal importance, however the vitamin B12 and vitamin B6 also play role in the maintenance of normal homocysteine level of blood.
 ...
PMID:[Homocysteine--a risk factor for atherosclerosis]. 1148 6

A 54-year-old man of Persian origin presented to our department with a 1-year history of ulcers on the right leg that had been unresponsive to numerous topical treatments, accompanied by lymphedema of the right leg. Medical history included hypergonadotropic hypogonadism, which had not been further investigated. He was treated for 20 years with testosterone IM once monthly, which he stopped a year before the current hospitalization for unclear reasons. The patient reported no congenital lymphedema. Physical examination revealed two deep skin ulcers (Figure 1) on the right leg measuring 10 cm in diameter with raised irregular inflammatory borders and a boggy, necrotic base discharging a purulent hemorrhagic exudate. Bilateral leg pitting edema and right lymphangitis with lymphadenitis were noted. He had low head hair implantment, sparse hair on the body and head, hyperpigmentation on both legs, onychodystrophia of the toenails (mainly the large toe and less prominent on the other toes), which was atrophic lichen-planus-like in appearance and needed no trimming (Figure 2), normal hand nails, oral thrush, and angular cheilitis. Other physical findings were gynecomastia, pectus excavatum, small and firm testicles, long extremities, asymmetrical goiter, systolic murmur 2/6 in left sternal border, and slow and inappropriate behavior. The patient's temperature on admission was 39 degrees C. Blood cultures were negative for bacterial growth. Results of laboratory investigations included hemoglobin (11.2 g/dL), hematocrit (26.8%), normal mean corpuscular volume and mean corpuscular hemoglobin volume, and red blood cell distribution width (16%). Blood smear showed spherocytes, slight hypochromia, anisocytosis, macrocytosis, and microcytosis. Blood chemistry values were taken for iron (4 micro g/dL [normal range 40-150 micro g/dL]), transferrin (193 mg/dL [normal range 220-400 mg/dL]), ferritin (1128 ng/mL [normal range 14-160 ng/mL]), transferrin saturation (1.5% [normal range 20%-55%]), serum folate (within normal limits), and vitamin B12 (within normal limits). Direct Coombs' test equaled positive 2 + IgG. All these values indicated anemia of chronic diseases combined with hemolytic anemia. Further blood work-up tested antinuclear antibody (positive <1:80 homogeneous pattern), rheumatoid factors (143 IU/mL [positive >8.5 IU/mL]), C-reactive protein (286 mg/L [normal range 0-5 mg/L]), anticardiolipin IgM antibody (9.0 monophosphoryl lipid U/mL [normal range 0-7.00 MPL U/mL]) and antithrombin III activity (135% [normal range 74%-114%]). Results of other blood tests were within normal limits or negative, including lupus anticoagulant, beta2 glycoprotein, anticardiolipin IgG Ab, anti-ss DNA Ab, C3, C4, anti-RO, anti-LA, anti-SC-70, anti-SM Ab, P-ANCA, C-ANCA, TSH, FT4, anti-T microsomal, antithyroglobulin, protein C activity, protein S free, cryoglobulins, serum immunoelectrophoresis, VDRL, hepatitis C antibodies, hepatitis B antigen, and human immunodeficiency virus. Endocrinological work-up examined luteinizing hormone (22.9 mIU/mL [normal range for adult men 0.8-6 mIU/mL]), follicle stimulating hormone (49.7 mIU/mL [normal range for adult men 1-11 mIU/mL]), testosterone (0.24 ng/mL [normal range for adult men 2.5-8.0 ng/mL]), bioavailable testosterone (0.02 ng/mL [normal range for adult men >0.6 ng/mL]), and percent bioavailable test (8.1% [normal value >20%]). These results indicate hypergonadotropic hypogonadism. Plasminogen activator inhibitor 1 was 6 U (normal value 5-20 U/mL). Karyotyping performed by G-banding technique revealed a 47 XXY karyotype, which is diagnostic of Klinefelter's syndrome. Doppler ultrasound of the leg ulcers disclosed partial thrombus in the distal right femoral vein. X-rays and bone scan displayed osteomyelitis along the right tibia. Histological examination of a 4-mm punch biopsy from the ulcer border revealed hyperkeratosis, acanthosis, hypergranulosis, and mixed inflammatory infiltrate containing eosinophils compatible with chronic ulcer. Multiple vessels were seen, compatible with a healing process. Direct immunofluorescence of the biopsy revealed granular IgM in the dermo-epidermal junction. Indirect immunofluorescence was negative. Thyroid function tests showed normal thyroid stimulating hormone and free throxine4. Multinodular goiter was seen on thyroid scan and ultrasound. Thyroid fine needle aspiration was compatible with multinodular goiter (normal follicular cells, free colloid, macrophages with pigment). IV treatment with amoxicillin-clavulanic acid 1 g t.i.d. was administered for 2 weeks, with a decrease in temperature and normalization of the leukocyte level. Oral antibiotic treatment with amoxicillin-clavulanic acid was continued for 10 more days, followed by 25 days of ciprofloxacin for the osteomyelitis. Local treatment included saline soakings followed by application of Promogran (Johnson & Johnson, New Brunswick, NJ) and Kaltostat (ConvaTec Ltd., a Bristol-Myers Squibb Company, New York, NY) with slight improvement. At the same time, the patient was treated with warfarin sodium due to deep vein thrombosis under international normalized ratio 2-3. The patient was treated with IM testosterone once monthly for 1 year, which resulted in a reduction in the diameter and depth of the leg ulcers (Figure 3). Blood tests were not performed for follow-up of the immune state.
 ...
PMID:Klinefelter's syndrome presenting with leg ulcers. 1536 65

The identification of constitutional and/or acquired risk factor is of major importance in the treatment of thromboembolic disease in young people; it contributes to evaluate the risk of recurrence and to define the period of oral prophylactic anticoagulant treatment. Several congenital or acquired abnormalities of haemostasis are actually defined. In this paper, we report the case of a 34-year-old man who developed a deep venous thrombosis, five months before the diagnosis of megaloblastic anemia, probably due to pernicious anemia. The thrombosis was partially explained by the acquired hyperhomocysteinemia induced by vitamin B12 deficiency. Moreover, activated protein C resistance due to factor V Leiden, was revealed in our patient. This latter improved under anticoagulant treatment combined with vitamin B12. Combination in one individual, of different risk factors predisposing to inherited and/or acquired thrombophilia, results in increased risk for thrombo-embolic disease, suggesting synergic interaction between these factors.
 ...
PMID:[Association of tow thrombotic risk factors: factor V Leiden and hyperhomocysteinemia. A case report]. 1670 35


1 2 Next >>