vitamin-b-12 and Thrombophilia

Topics: Administration, Oral; Anticoagulants; Blood Coagulation Tests; Cardiovascular Diseases; Double-Blind Method; Drug Therapy, Combination; Folic Acid; Homocysteine; Humans; Hyperhomocysteinemia; Marfan Syndrome; Multicenter Studies as Topic; Mutation; Polymorphism, Genetic; Randomized Controlled Trials as Topic; Risk Factors; Thrombophilia; Time Factors; Venous Thrombosis; Vitamin B 12; Vitamin B 6

Hyperhomocysteinaemia is often the result of inherited abnormalities of the enzymes involved in homocysteine metabolism or vitamin deficiencies (vitamins B12, B6 or folate) and is present in approximately 5% of the general population. High homocysteine levels in these individuals are associated with a significant increase in relative risk for both arterial and venous thromboembolic disease. Consequently, effective homocysteine-lowering therapeutic strategies have been extensively investigated. Folic acid represents the cornerstone of treatment. In daily doses of at least 0.4 mg, it effectively reduces homocysteine levels, even in non-folate-deficient patients. The addition of vitamins B12 and/or B6, to folic acid supplementation may provide a small further reduction in homocysteine levels in certain groups of patients. Renal impairment is an important cause of hyperhomocysteinaemia. Individuals with hyperhomocysteinaemia secondary to renal disease commonly require significantly higher doses of folic acid (5-40 mg) to achieve maximal therapeutic effect. The important question of whether effective homocysteine-lowering therapy translates into a reduction in vascular disease remains unknown but is being addressed in a series of ongoing prospective trials.

Topics: Folic Acid; Homocysteine; Humans; Hyperhomocysteinemia; Methionine; Pyridoxine; Renal Insufficiency; Thrombophilia; Vitamin B 12; Vitamins

Hyperhomocysteinemia refers to an elevated circulating level of the sulfur-containing amino acid homocysteine and has been shown to be a risk factor for vascular disease in the general population. In patients with renal failure, hyperhomocysteinemia is a common feature. The underlying pathophysiological mechanism for this phenomenon is unknown. Proposed mechanisms include reduced renal elimination of homocysteine and impaired nonrenal disposal, possibly because of inhibition of crucial enzymes in the methionine-homocysteine metabolism by the uremic milieu. Absolute or relative deficiencies of folate, vitamin B6, or vitamin B12 may also play a role. Several case-control and prospective studies have now indicated that hyperhomocystenemia is an independent risk factor for atherothrombotic disease in patients with predialysis and end-stage renal disease. In renal patients, plasma homocysteine concentration can be reduced by administration of folic acid in doses ranging from 1 to 15 mg per day. In more than 50% of the cases, however, the homocysteine concentration remains above 15 micromol/L. The effects of vitamin B12 or vitamin B6 are unclear. Large intervention trials are now needed to establish whether homocysteine-lowering therapy will reduce atherothrombotic events in patients with renal failure. These studies are now planned or are ongoing.

Topics: Adult; Arteriosclerosis; Cardiovascular Diseases; Case-Control Studies; Child; Endothelium, Vascular; Female; Folic Acid; Folic Acid Deficiency; Follow-Up Studies; Homocysteine; Humans; Hyperhomocysteinemia; Kidney Diseases; Kidney Failure, Chronic; Kidney Transplantation; Life Tables; Male; Methionine; Peritoneal Dialysis; Prospective Studies; Pyridoxine; Renal Dialysis; Survival Analysis; Thrombophilia; Vitamin B 12; Vitamin B 12 Deficiency; Vitamin B 6 Deficiency

Homocystinuria (HCU) due to cystathionine beta-synthase (CBS) deficiency leads to severe hyperhomocysteinemia (HHcy). Vascular events (VE) remain the major cause of morbidity and mortality in the untreated patients with HCU. The study on the natural history of untreated HCU disclosed that, at the time of maximal risk, in other words beyond 10 years old, there was one event per 25 years. Recent studies from Australia (n = 32), The Netherlands (n = 28), and Ireland (n = 24) have documented the effects of long-term treatment on the vascular outcome of a total of 84 patients with 1314 patient-years of treatment for HCU. The mean (range) age was 27.8 (2.5 to 70) years. Five VE were recorded during treatment; one pulmonary embolism, two myocardial infarctions, and two abdominal aneurysms. All five VE occurred in B6-responsive patients at a mean (range) age of 48.8 (30 to 60) years. In 1314 patient-years of treatment, 53 VE would have been expected if they remained untreated; instead only 5 were documented, relative risk = 0.091 (95% confidence interval [CI] 0.043 to 0.190; p < 0.001). Appropriate homocysteine-lowering therapy for severe HHcy significantly reduced the vascular risk in patients with HCU. VE were rare with treatment despite the fact that the post-treatment homocysteine levels were several times higher than the cutoff point for homocysteine in the normal population. The present findings may have relevance to the current concept of "mild HHcy" as a risk factor for vascular disease, with elevated plasma homocysteine levels considerably lower than that of the post-treatment levels in this group of reported patients.

Topics: Adolescent; Adult; Aged; Australia; Child; Child, Preschool; Cohort Studies; Cystine; Drug Resistance; Female; Folic Acid; Follow-Up Studies; Genetic Predisposition to Disease; Homocysteine; Homocystinuria; Humans; Hyperhomocysteinemia; Infant; Ireland; Male; Methionine; Middle Aged; Netherlands; Pyridoxine; Risk; Risk Factors; Thrombophilia; Vascular Diseases; Vitamin B 12

High plasma levels of homocysteine are the results of the interplay between congenital and environmental factors. In the last two decades, a growing amount of interest has focused on mild-to-moderate hyperhomocysteinemia as a risk factor of thromboembolic diseases. Case-control and cross-sectional studies clearly indicated that mild-to-moderate hyperhomocysteinemia is associated with heightened risk of both arterial and venous thrombosis. On the other hand, prospective studies did not unequivocally show that hyperhomocysteinemia is associated with a high thrombotic risk. Therefore, additional studies are needed to define whether hyperhomocysteinemia is a risk factor for thrombosis, especially of the venous circulation. Among these, prospective cohort studies will clarify better the temporal relationship between high homocysteine levels and the thrombotic event. Most importantly, however, randomized, placebo-controlled, double-blind trials of the effects of homocysteine-lowering vitamins on the thrombotic risk are urgently needed. Not only will they help in defining whether the relationship between hyperhomocysteinemia and thrombosis is causal, they will also have a potential dramatic impact in the prevention of thromboembolic events.

Topics: Adult; Aged; Animals; Arteriosclerosis; Avitaminosis; Case-Control Studies; Clinical Trials as Topic; Cohort Studies; Cross-Sectional Studies; Cystathionine beta-Synthase; Female; Folic Acid; Gene Frequency; Homocysteine; Homocystinuria; Hormone Replacement Therapy; Humans; Hyperhomocysteinemia; Male; Methionine; Methylation; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Muscle, Smooth, Vascular; Oxidoreductases Acting on CH-NH Group Donors; Prevalence; Primates; Prospective Studies; Pyridoxine; Risk Factors; Smoking; Tamoxifen; Thrombophilia; Thrombosis; Vitamin B 12

The Vitamins and Thrombosis (VITRO) study investigated the effect of homocysteine lowering by daily supplementation of B vitamins on the risk reduction of deep vein thrombosis (DVT) and pulmonary embolism (PE). Patients between 20 to 80 years old with a first objectively confirmed proximal DVT or PE in the absence of major risk factors and a homocysteine concentration above the 75th percentile of a reference group were asked to participate (hyperhomocysteinemic group). A similar study was conducted in a random sample of patients with a homocysteine below the 75th percentile of the reference group (normohomocysteinemic group). After informed consent was obtained, patients were randomized to daily multivitamin supplementation (5 mg folic acid, 50 mg pyridoxine, and 0.4 mg cyanocobalamin) or placebo and were followed for 2.5 years. End points were objectively diagnosed recurrent DVT or PE. A total of 701 patients were enrolled (360 in the hyperhomocysteinemic and 341 in the normohomocysteinemic group). The number of recurrent events of venous thrombosis was 43 of 353 in the vitamin group (54/1000 py) and 50 of 348 in the placebo group (64/1000 py). The hazard ratio associated with vitamin treatment was 0.84 (95% CI, 0.56-1.26): 1.14 (95% CI, 0.65-1.98) in the hyperhomocysteinemic group and 0.58 (95% CI, 0.31-1.07) in the normohomocysteinemic group. The results of our study do not show that homocysteine lowering by B vitamin supplementation prevents recurrent venous thrombosis.

Topics: Adolescent; Adult; Aged; Dose-Response Relationship, Drug; Double-Blind Method; Female; Folic Acid; Homocysteine; Humans; Hyperhomocysteinemia; Male; Middle Aged; Proportional Hazards Models; Pulmonary Embolism; Pyridoxine; Recurrence; Risk Factors; Thrombophilia; Treatment Failure; Venous Thrombosis; Vitamin B 12

Topics: Australia; Cohort Studies; Double-Blind Method; Edible Grain; Folic Acid; Food, Fortified; Humans; Hyperhomocysteinemia; Ischemic Attack, Transient; Randomized Controlled Trials as Topic; Sample Size; Secondary Prevention; Stroke; Thrombophilia; Treatment Outcome; Vitamin B 12; Vitamin B 6

In the past years several case-control studies established the association of an elevated plasma homocysteine concentration and the risk of venous thromboembolism. It is still unclear if elevated homocysteine concentrations can cause venous thrombosis. The VITRO (VItamins and ThROmbosis) trial is the first multicenter, randomized, double-blind and placebo-controlled study to evaluate the effect of homocysteine-lowering therapy by means of 5 mg folic acid, 0.4 mg vitamin B12 and 50 mg vitamin B6. The study is a secondary prevention trial in 600 patients who suffered from a first episode of idiopathic deep vein thrombosis (DVT) or pulmonary embolism (PE), or both. There will be 300 hyperhomocysteinemic and 300 normohomocysteinemic patients included, all with an objectivated venous thrombosis. The end point is recurrence of venous thrombosis.

Topics: Adult; Aged; Aged, 80 and over; Comorbidity; Double-Blind Method; Female; Folic Acid; Follow-Up Studies; Homocysteine; Humans; Hyperhomocysteinemia; Incidence; Male; Middle Aged; Netherlands; Prospective Studies; Pulmonary Embolism; Pyridoxine; Retrospective Studies; Secondary Prevention; Thrombophilia; Thrombophlebitis; Treatment Outcome; Ultrasonography; Venous Thrombosis; Vitamin B 12

Topics: Adult; Anticoagulants; Blood Coagulation; Gastrectomy; Humans; Hyperhomocysteinemia; Male; Obesity, Morbid; Recurrence; Thrombophilia; Treatment Outcome; Venous Thromboembolism; Vitamin B 12; Vitamin B 12 Deficiency; Vitamins

Topics: Adult; Aged; Aged, 80 and over; Aging; Atrial Fibrillation; Female; Homocysteine; Humans; Hyperhomocysteinemia; Male; Middle Aged; Thrombophilia; Vitamin B 12

Topics: Aging; Homocysteine; Humans; Hyperhomocysteinemia; Thrombophilia; Vitamin B 12

High plasma homocysteine (Hcy) ​​levels may be responsible for vaso-occlusive episodes and may have acquired and/or genetic causes. This cross-sectional study aimed to investigate the role of methylenetetrahydrofolate reductase (MTHFR; C677T; A1298C) and cystathionine-β-synthase (CBS; T833C/844ins68, G919A) polymorphisms in serum levels of folic acid, vitamin B12 and Hcy, and to verify a possible association between these polymorphisms and the clinical variability. Blood samples of Brazilian patients with a diagnosis of thrombosis were submitted to genotyping by PCR-based methods and serum dosages of folic acid, vitamin B12 and Hcy. Except for the CBS G919A polymorphism, all other genetic markers were in Hardy-Weinberg equilibrium. An increased risk for venous thrombosis was found for the MTHFR 1298CC carriers (OR = 1.688; 95%CI = 0.839-3.398, P = 0.018) and those homozygously mutant for the CBS haplotype 844ins68/T833C (OR = 2.488; 95%CI = 0.501-12.363, P = 0.031), while heterozygous for this CBS haplotype showed an increased risk for higher Hcy levels (OR = 5.900; 95%CI = 1.003-34.691, P = 0.030). Significant interactions were observed among the MTHFR C677T, MTHFR A1298C and CBS haplotype 844ins68/T833C polymorphisms in the results for Hcy levels (P = 0.000), where heterozygous had higher values. Interactions among these polymorphisms can affect serum Hcy levels, where multiple heterozygosis could be a risk factor for vaso-occlusive episodes.

Topics: Adolescent; Adult; Brazil; Cross-Sectional Studies; Cystathionine beta-Synthase; Epistasis, Genetic; Female; Folic Acid; Gene Frequency; Genetic Predisposition to Disease; Genotype; Heterozygote; Homocysteine; Homozygote; Humans; Linkage Disequilibrium; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Polymorphism, Single Nucleotide; Risk Factors; Thrombophilia; Thrombosis; Vitamin B 12; Young Adult

To examine the relationship of inherited thrombophilia and other thrombotic risk factors with preeclampsia (PE) in a population of pregnant Turkish women.. This was a case cross-sectional study in which 70 women with PE and 60 normal pregnant women were studied to find out the frequency of women with risk factors including inherited thrombophilia among preeclamptic cases.. Hemoglobin, platelet count, uric acid, vitamin B12, folic acid, copper, homocysteine, plasminogen activator inhibitor-1, fibrinogen, protein S, protein C, activated protein C resistance values show significant differences in women with PE in comparison to women with normal pregnancy.. There may be a link between inherited thrombophilia and PE, at least in a sample of Turkish pregnant women. We also propose that the association between thrombophilia and PE is stronger than suggested previously. Furthermore, copper is selectively elevated in women with PE as an independent marker.

Topics: Cross-Sectional Studies; Female; Folic Acid; Humans; Pre-Eclampsia; Pregnancy; Thrombophilia; Vitamin B 12

A 39-year-old man was admitted with a sudden visual loss in the left eye. Visual acuities were 10/10 on the right and 1/10 on the left. Fundus examination did not show any abnormalities. Visual acuity improved to 10/10 and visual field defect regressed in the following 2 weeks. Three years later, the patient returned with acute visual loss in the right eye. Visual acuities were 2/10 on the right and 10/10 on the left. Right optic disc had blurred margins with mild oedema. The tests revealed methylenetetrahydrofolate reductase A1298C mutation with positive lupus anticoagulant and hyperhomocysteinaemia. Enoxaparin was initialised with vitamin B12 supplementation. Complete visual recovery occurred in the following 3 weeks in both eyes. Thrombophilic screening seems to be important in the treatment and prevention of an attack in the second eye of patients with non-arteritic anterior ischaemic optic neuropathy.

Topics: Adult; Humans; Male; Optic Nerve Diseases; Thrombophilia; Visual Acuity; Vitamin B 12

Pregnancy losses must be categorised into biochemical loss, early embryonic loss, late foetal loss and stillbirth cases. No haemostasis-related investigations are necessary for biochemical losses. Antiphospholipid antibodies must be checked for three early losses or one late loss. A complete blood count will reveal the rare essential thrombocytemias, a functional fibrinogen assay the exceptional dysfibrinogenemia cases. Vitamin B12 and intracellular folates levels must be checked in case of clinical or biological suspicion. Constitutive thrombophilias must not be routinely assessed because a therapeutic option is not definitively demonstrated. Screening for constitutive thrombophilias should be only indicated for clinical research purposes, only for late foetal loss and stillbirth cases.

Topics: Abortion, Spontaneous; Antibodies, Antiphospholipid; Biomarkers; Blood Cell Count; Female; Folic Acid; Hemostasis; Humans; Pregnancy; Pregnancy Complications, Hematologic; Risk Factors; Thrombophilia; Vitamin B 12; Vitamin B Complex

Methylenetetrahydrofolate reductase (MTHFR) polymorphisms are associated with thrombophilia and vasculopathy that may result in cutaneous ulceration. Pyoderma gangrenosum (PG) is a clinical diagnosis that may be made following exclusion of alternate causes of ulceration, including vascular inflammatory or occlusive disease, infection, and malignant neoplasm.. We describe 2 patients with MTHFR polymorphisms discovered during hypercoagulable evaluation for cutaneous ulcerations on the lower extremities. Both patients showed a rapid improvement following treatment with oral vitamin supplementation and local wound care. One patient developed several subsequent ulcers when he decided to discontinue his therapy, and following reinitiation of therapy, the new ulcerations healed. The treatment was tolerated well without any adverse effects.. MTHFR polymorphisms should be part of a comprehensive laboratory evaluation during hypercoagulable workup. Vitamin supplementation with folic acid (B(9)), pyridoxine hydrochloride (B(6)), and cyanocobalamin (B(12)) may result in healing of cutaneous ulcerations in some patients with MTHFR mutations.

Topics: Adult; Child; Folic Acid; Humans; Male; Methylenetetrahydrofolate Reductase (NADPH2); Polymorphism, Genetic; Pyoderma Gangrenosum; Pyridoxine; Skin Ulcer; Thrombophilia; Treatment Outcome; Vitamin B 12; Vitamin B Complex

Genetic polymorphisms that are found among factors of the coagulation cascade are factor V leiden mutation (FVL), prothrombin (PT), and methylenetetrahydrofolate reductase (MTHFR), reported for thrombotic complications. We have investigated the associations of these gene polymorphisms in patients with end-stage renal disease (ESRD).. We genotyped 258 patients for FV G1691A, PT G20210A, and MTHFR (C677T, A1298C) gene by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis and were compared with 569 healthy controls. Serum folate, total homocysteine (tHcys), and vitamin B(12) were measured in both patients with ESRD and controls.. No homozygous individuals for the mutant AA genotype of FVL G1691A were observed in this study. The frequency of the heterozygous genotypes was (11.2%), which was nearly 3 times higher than that observed in controls (3.2%), with a odds ratio of 3.87 (P = .0001, 95% CI = 2.11-7.11). PT G20210A mutation was missing in both patients and the controls. At MTHFR locus, TT genotype of C677T was present in 9.6% among ESRD, while CC genotype of A1298C was present in 11.7% of the ESRD. In control group, it was significantly low that is, 4.2% and 3.2%, respectively (P = .0034; OR = 2.44, 95% CI = 1.36-4.36 and P < .0001; OR = 4.03; 95% CI = 2.2-7.37). The combined analysis of the 2 genotypes showed further increased risk in ESRD ~15 folds. Further, the carrier of TT and CC genotypes of C677T and A1298C had significantly higher total homocysteine (tHcys) level than those with CC and AA genotypes (P < .001).. The carrier of FVL, TT genotype of C677T, and CC genotype of A1298C polymorphisms may act as risk factors for ESRD.

Topics: 3' Untranslated Regions; Adult; Alleles; Amino Acid Substitution; Factor V; Female; Folic Acid; Genetic Predisposition to Disease; Genotype; Homocysteine; Humans; Hyperhomocysteinemia; Kidney Failure, Chronic; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Mutation, Missense; Point Mutation; Prothrombin; Risk Factors; Thrombophilia; Vitamin B 12; Young Adult

There is considerable evidence that elevated plasma homocysteine levels are associated with a prothrombotic milieu, whereas activation of the coagulation cascade is an important component of the pathogenesis of sepsis. The protein C pathway has been reported to play a central role both in the propagation of sepsis and a hyperhomocysteinemia-induced hypercoagulable state. Our primary aim was to measure plasma homocysteine levels in mechanically ventilated patients with severe sepsis/septic shock and to assess the association of these levels with relevant clinical outcomes.. The study cohort included 102 mechanically ventilated patients with severe sepsis or septic shock. Demographics, comorbidities, clinical data and severity scores were recorded. Plasma homocysteine, vitamin B12, folate, creatinine, and protein C levels were measured in all study subjects upon enrollment, and genotyping for the C677T and A1298C polymorphisisms of the methylenetetrahydrofolate reductase (MTHFR) gene and for factor V Leiden (FVL) mutations was performed as well. The primary outcomes were mortality at 28 and 90 days; secondary outcomes included the number of days without renal or cardiovascular failure and the ventilator-free days during the study period.. Homocysteine levels were not significantly associated with any primary or secondary outcomes in the multivariable analysis. In addition, a synergistic effect of homocysteine with protein C levels was not detected.. Our data suggest that plasma homocysteine levels may not inform the prognosis of mechanically ventilated patients with severe sepsis/septic shock.

Topics: Activated Protein C Resistance; Aged; Blood Coagulation Tests; Cohort Studies; Comorbidity; Factor V; Female; Folic Acid; Homocysteine; Homocystinuria; Hospital Mortality; Humans; Hyperhomocysteinemia; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Muscle Spasticity; Point Mutation; Protein C; Psychotic Disorders; Respiration, Artificial; Sepsis; Shock, Septic; Thrombophilia; Vitamin B 12

Non-arteritic anterior ischemic optic neuropathy (NAION) is a multifactorial disease that is caused by an infarction of the vessels that supply the optic nerve head. This study aims at evaluating the role of traditional and emerging cardiovascular risk factors on the development of NAION.. A total of 85 newly diagnosed NAION patients and 107 age- and gender-matched healthy controls were studied. All participants underwent blood testing for homocysteine and lipoprotein(a). Plasma levels of vitamin B6 and B12, and folic acid were also determined. Plasma values of all these parameters were evaluated as continuous variables, by a logarithmic transformation. In addition, traditional cardiovascular risk factors were considered.. With univariate analysis, higher values of homocysteine and Lp(a) (OR 4.24, 95% CI 2.01-8.94, p < 0.0001; OR 1.32, 95% CI 1.04-1.67, p = 0.03, respectively) and lower values of vitamin B6 (OR 0.44, 95% CI 0.25-0.76, p = 0.003) were significantly associated with NAION. At multivariate analysis, adjusted for age, gender, smoking habit, hypertension, dyslipidemia, diabetes, sleep apnea, and thrombophilic risk factors, the higher homocysteine and Lp(a) values (OR 5.74, 95% CI 2.41-13.67, p = 0.0001; OR 1.27, 95% CI 1.01-1.63, p = 0.04) and lower vitamin B6 values (OR 0.42, 95% CI 0.23-0.77, p = 0.005) maintained their significant relationship with NAION.. This study demonstrated that elevated plasma homocysteine and lipoprotein(a) levels, as well as low vitamin B6 levels, may increase the risk of developing NAION. A screening for these thrombophilic markers could be useful in subjects experiencing NAION.

Topics: Adult; Aged; Aged, 80 and over; Cardiovascular Diseases; Case-Control Studies; Dyslipidemias; Enzyme-Linked Immunosorbent Assay; Female; Folic Acid; Homocysteine; Humans; Hypertension; Lipoprotein(a); Male; Middle Aged; Optic Neuropathy, Ischemic; Risk Factors; Thrombophilia; 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

The aim of this study was to evaluate the effect of treatment in patients analyzed for recurrent spontaneous miscarriage with a diagnosis of a hereditary thrombophilia, the presence of antiphospholipid and/or autoimmune antibodies, and/or hyperhomocystinemia (HHC) with or without methylenetetrahydrofolate reductase (MTHFR) polymorphisms. In total, 76 women with 2 or more embryonic or fetal losses were analyzed. Of these, 49 (64.4%) women were found to have one or more thrombophilias and/or autoimmune antibodies, and 33 (43.4%) women were found to have a MTHFR polymorphism and/or HHC. Since completion of the recurrent miscarriage analysis, 39 women conceived again. All women with a thrombophilia were treated with low-dose aspirin plus low molecular weight heparin. All women with previously diagnosed HHC and/or MTHFR polymorphisms were treated with folate and vitamin B(6) and B(12) supplementation. In the thrombophilia group, 27 women conceived resulting in 20 successful pregnancies (74.1%) and 7 pregnancy losses (2 trisomy 16, 1 ectopic pregnancy and 4 unexplained miscarriages), i.e. an unexplained pregnancy loss rate of 14.8%. In the HHC/MTHFR group 22 women conceived, resulting in 17 successful pregnancies (77.3%) and 5 pregnancy losses (1 trisomy 16, 1 Turner syndrome and 3 unexplained miscarriages), i.e. an unexplained pregnancy loss rate of 13.6%.

Topics: Abortion, Habitual; Adult; Antibodies, Antiphospholipid; Aspirin; Female; Folic Acid; Heparin, Low-Molecular-Weight; Humans; Hyperhomocysteinemia; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Polymorphism, Genetic; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Outcome; Thrombophilia; Vitamin B 12; Vitamin B 6

High plasma levels of total homocysteine (tHcy) are a risk factor for deep vein thrombosis. Because no information on the relationship between cerebral vein thrombosis and hyperhomocysteinemia is available, a case-control study of 121 patients with a first episode of cerebral vein thrombosis and 242 healthy control subjects was carried out. Fasting plasma levels of tHcy and their postmethionine load (PML) increments, together with other laboratory markers of thrombophilia, were measured in plasma or DNA. Hyperhomocysteinemia (high fasting tHcy and/or PML increments) was diagnosed in 33 patients (27%) and 20 control subjects (8%) (odds ratio, 4.2; 95% confidence interval [CI], 2.3-7.6). Low levels of serum folate and the 677TT methylene tetrahydrofolate reductase were associated with hyperhomocysteinemia, but in a multivariate model hyperhomocysteinemia only was associated with an increased risk of cerebral vein thrombosis. Oral contraceptive intake was associated with the disease with an odds ratio of 6.1 (95% CI, 3.3-11.0). The combined presence of the latter and hyperhomocysteinemia increased the risk of the disease with an odds ratio of 19.5 (95% CI, 5.7-67.3). In conclusion, hyperhomocysteinemia is associated with a 4-fold increased risk of cerebral vein thrombosis; whether or not its correction with vitamins reduces the risk of the disease remains to be demonstrated.

Topics: Adolescent; Adult; Case-Control Studies; Child; Female; Folic Acid; Homocystine; Humans; Hyperhomocysteinemia; Intracranial Thrombosis; Male; Methionine; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Oxidoreductases Acting on CH-NH Group Donors; Risk Factors; Thrombophilia; Venous Thrombosis; Vitamin B 12

The GAIT (Genetic Analysis of Idiopathic Thrombophilia) Project is a family-based study dedicated to elucidating the genetic basis of hemostasis-related phenotypes and thrombosis risk. In this paper, we have examined several lesser-studied hemostasis-related phenotypes in the 21 GAIT families: levels of vitamin B 12, serum folate, whole blood folate, alpha2-antiplasmin, prekallikrein, beta2-glycoprotein I, soluble P-selectin, factor XIII A and B subunits and a new coagulation measurement based on thromboplastin time in the presence or absence of thrombomodulin. Using the variance component method, we estimated the relative contributions of genetic and environmental influences on these phenotypes. In addition, we calculated the genetic correlations between thrombosis risk and each of these phenotypes. All 12 phenotypes showed significant genetic contributions with genes accounting for 22% to 78% of the variance after correction for covariate effects. Four phenotypes (three traits involving thromboplastin-thrombomodulin mediated coagulation time and serum folate) exhibited significant genetic correlations with thrombosis. Thus, some of the genes that influence quantitative variation in these physiological phenotypes also influence the risk of thrombosis. The high heritabilities and significant genetic correlations between thrombosis and some risk factors suggest that joint consideration of correlated quantitative phenotypes will aid in identifying susceptibility genes.

Topics: Adult; alpha-2-Antiplasmin; beta 2-Glycoprotein I; Blood Coagulation Tests; Comorbidity; Contraceptives, Oral, Hormonal; Factor XIII; Female; Folic Acid; Genetic Predisposition to Disease; Glycoproteins; Humans; Male; Middle Aged; P-Selectin; Phenotype; Risk Factors; Smoking; Spain; Thrombomodulin; Thrombophilia; Thromboplastin; Vitamin B 12

The biological effects of age, sex and vitamin status on plasma total homocysteine (tHcy), and association of hyperhomocysteinaemia with venous thromboembolism in Taiwanese Chinese individuals, were investigated. Eighty patients (16-85 years) with venous thrombophilia and 123 healthy subjects (15-85 years) without history of vascular thrombosis were studied for plasma levels of tHcy, folate and vitamin B12. A multivariate analysis in healthy subjects revealed that plasma tHcy levels tended to increase with age (P < 0.001) and with decreasing plasma levels of folate (P=0.001) or vitamin B12 (P < 0.029); men tended to have higher plasma tHcy levels than women (P=0.006). Thrombotic risk assessment in a case-control study demonstrated that neither plasma level of tHcy [odds ratio (OR), 1.07; 95% confidence interval (CI), 0.96-1.18; P=0.210] nor hyperhomocysteinaemia (OR, 1.65; 95% CI, 0.50-5.49; P=0.415) was significantly associated with venous thrombophilia. The relationship between hyperhomocysteinaemia and recurrence of episode remained insignificant (P=0.560). We conclude that age, sex and vitamin status affect plasma tHcy but hyperhomocysteinaemia is possibly not an important risk factor for venous thrombophilia in Taiwanese Chinese.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Case-Control Studies; China; Female; Folic Acid; Humans; Hyperhomocysteinemia; Male; Middle Aged; Nutritional Status; Odds Ratio; Risk Factors; Sex Factors; Taiwan; Thrombophilia; Vitamin B 12

Elevated plasma total homocysteine (tHcy) is associated with a higher risk of thrombosis. Crohn's disease (CD) is associated with hypercoagulability of undefined etiology. We investigated tHcy in patients with CD and its relationship with vitamin status, disease activity, location, duration, and history of terminal ileum (TI) resection.. We examined fasting plasma tHcy, folate, serum vitamin B12 levels, and sedimentation rate in consecutive adult patients with CD. Harvey-Bradshaw index of CD activity and history of TI resection and thromboembolism were recorded.. Median plasma tHcy was 10.2 micromol/L in 125 patients with CD. Men (n = 60) had higher plasma tHcy than women (n = 65) (11.2 vs. 9.1 micromol/L; p = 0.004). Patients with a history of TI resection showed lower serum B12 levels (293 vs. 503 pg/mL; p < 0.001) and higher plasma tHcy levels (11.0 vs. 9.35 micromol/L; p = 0.027) than patients without such history. Multivariate analysis showed history of TI resection, serum B12, and creatinine levels to be significant predictors of elevated plasma tHcy. Fourteen patients with CD with a history of thrombosis had an elevated median plasma tHcy of 11.6 micromol/L.. Terminal ileum resection contributes to elevated plasma tHcy levels in CD cases. We recommend tHcy screening in patients with CD, especially in those with prior history of TI resection, and the initiation of vitamin supplementation when appropriate.

Topics: Adult; Blood Sedimentation; Creatinine; Crohn Disease; Female; Folic Acid; Follow-Up Studies; Homocysteine; Humans; Ileum; Male; Thrombophilia; Vitamin B 12

Total fasting plasma homocysteine (tHcy), homozygosity for the C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene and for the A2756G mutation of the methionine synthase (MS) gene, vitamin B12 and folate plasma levels were evaluated in 170 consecutive patients (89 M, 81 F; mean age 41 +/- 12 yrs) with documented early-onset thrombosis (89 venous, 69 arterial, 12 both; mean age at first episode 36 +/- 11 yrs), and in 182 age- and sex-matched healthy control subjects. Moderate hyperhomocysteinemia (HHcy, tHcy >19.5 microM in men and >15 microM in women) was detected in 45 patients (26.5%) and in 18 controls (9.9%, Mantel-Haenszel OR and 95% C.I. after stratification for arterial or venous thrombosis: 3.25, 1.78-5.91). The 677TT MTHFR genotype was not significantly more prevalent in patients (27.6%) than in controls (21.4%, RR = 1.42: 0.84-2.41), and markedly contributed to HHcy (Mantel-Haenszel RR after stratification for case/control status: 8.29, 4.61-14.9). The 2756GG MS genotype, observed in 4 patients (2.4%) and 8 controls (4.4%), was not associated to HHcy. tHcy was negatively correlated to folate and vitamin B12 levels, with better correlation found in subjects with the 677TT mutation (r = -0.42 and -0.25) than with the 677CC or CT MTHFR genotype (r = 0).37 and -0.11). However, folate was similar in patients and controls and vitamin B12 was higher in patients (460 +/- 206 vs. 408 +/-185 pg/ml, p = 0.011). In a generalized linear model, 44% of the variation in tHcy levels was explained by folate and vitamin B12 levels, the MTHFR genotype, gender, and by the interaction of the MTHFR genotype with folate (p < or =0.028); the interactions of vitamin B12 with the MTHFR genotype, gender and patient/control status also significantly contributed to the variation in tHcy levels (p < or =0.028). A 4-week administration of 5-methyltetrahydrofolate (15 mg/day) markedly lowered plasma tHcy in 24 patients with MTHFR 677TT genotype, but the response to treatment correlated with vitamin B,2 levels (p = 0.023). Subjects carrying the MTHFR 677TT genotype have higher folate and vitamin B12 requirements irrespective of the A2756G polymorphism of the MS gene. Yet unidentified abnormalities of MS or of any of the enzymes participating in the synthesis of methylated vitamin B12 may play an important role in the phenotypic expression of moderate hyperhomocysteinemia.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Adolescent; Adult; Age of Onset; Aged; Amino Acid Substitution; Case-Control Studies; Fasting; Female; Folic Acid; Gene Frequency; Genetic Heterogeneity; Homocysteine; Humans; Hyperhomocysteinemia; Italy; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Nutritional Requirements; Oxidoreductases Acting on CH-NH Group Donors; Point Mutation; Risk Factors; Sex Factors; Tetrahydrofolates; Thrombophilia; Thrombosis; Vitamin B 12; Vitamin B 12 Deficiency

To evaluate whether increased plasma homocysteine concentrations (hyperhomocysteinemia) are associated with thrombosis of arteriovenous (AV) grafts, we determined plasma homocysteine, plasma and erythrocyte folate, plasma vitamin B12, and vitamin B6 (pyridoxal-5'-phosphate [PLP]) in 48 patients (45 black patients and three white patients) with end-stage renal disease who received hemodialysis. 5,10-Methylenetetrahydrofolate reductase (MTHFR) genotypes were also analyzed. The patients were divided into two groups, including a thrombosis-prone group with frequent graft loss (n = 24) and a control group with prolonged graft survival who were matched by age and duration of dialysis (n = 24). Hyperhomocysteinemia (>15 micromol/L) was found in 42 patients. There were no significant differences in all values, including the concentrations of homocysteine and vitamins between the two groups. Based on plasma folate and PLP concentrations, over 70% of patients appeared to have inadequate folate and/or vitamin B6 nutriture. Plasma homocysteine concentrations showed significant negative correlations with plasma and erythrocyte folate, and plasma vitamin B12 in all patients combined, whereas no significant correlation was found between plasma PLP and homocysteine concentrations. Among 48 patients, the heterozygous mutation (Val/Ala) of MTHFR was found only in three patients, two of whom belonged to the thrombosis-prone group and one to the control group, and there were no individuals with homozygous thermolabile mutation (Val/Val). All three white patients had Ala/Ala genotype, and 3 in 45 black patients (6.7%) were heterozygotes (Val/Ala).

Topics: Adult; Aged; Aged, 80 and over; Arteriovenous Shunt, Surgical; Blood Vessel Prosthesis; Erythrocytes; Female; Folic Acid; Genotype; Graft Occlusion, Vascular; Homocysteine; Humans; Male; Methylenetetrahydrofolate Dehydrogenase (NADP); Middle Aged; Pyridoxine; Renal Dialysis; Risk Factors; Thrombophilia; Vitamin B 12