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)

Acquired and inherited prothrombotic risk factors increase the risk of thrombosis in children. This review is based on "milestone" pediatric reports and new literature data (January 2001-February 2002) on the presence of acquired and inherited prothrombotic risk factors, imaging methods, and treatment modalities in pediatric thromboembolism. After confirming clinically suspected thromboembolism with suitable imaging methods, pediatric patients should be screened for common gene mutations (factor V G1691A, prothrombin G20210A and MTHFR C677T genotypes), rare genetic deficiencies (protein C, protein S, antithrombin, and plasminogen), and new candidates for genetic thrombophilia causing elevated levels of lipoprotein(a), and homocysteine, and probable genetic risk factors (elevations in fibrinogen, factor IX, and factor VIIIC, and decreases in factor XII). Data interpretation is based on age-dependent reference ranges or the identification of causative gene mutations/polymorphisms with respect to individual ethnic backgrounds. Pediatric treatment protocols for acute thromboembolism, including thrombolytic and anticoagulant therapy, are mainly adapted from adult patient protocols.
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PMID:Thromboembolism in children. 1217 65

Fasting plasma homocysteine level and the related clinical findings were analysed in 240 consecutive patients with venous thromboembolism. Hyperhomocysteinemia, defined as a plasma level above 20 micromol/l (corresponding to the percentile 95th in the controls), was present in 11.2% of the patients. Plasma homocysteine level was similar in patients presenting with either deep venous thrombosis, pulmonary embolism or both conditions. It was significantly higher in patients with primary (unprovoked) VTE than in patients with secondary disease (associated with at least one risk factor): 12.3 vs. 9.55 micromol/l (p < 0.005). Mean homocysteine was higher in male than in female patients (14.51 vs. 12.9 micromol/l, p < 0.05) and increased significantly with age. Hyperhomocysteinemia was more frequent in patients with relapsing disease (14 of 76, 18.4%) than in those presenting with a single episode (13 of 164, 7.9%) (p = 0.034). Furthermore, hyperhomocysteinemia was correlated with reduced protein C level (p = 0.013). In a multivariate analysis, two factors were significantly associated with hyperhomocysteinemia: older age (p < 0.0001) and idiopathic occurrence (p < 0.02). Since the frequency of homozygous MTHFR thermolabile variant was rather similar in patients and controls, testing for C677T mutation was not helpful in screening VTE patients. However, the homozygous mutation was significantly more prevalent among hyperhomocysteinemia patients, confirming its role in the genesis of hyperhomocysteinemia. According to its prevalence, to the putative role in venous and arterial disease and the availability of an effective and low-cost corrective therapy, hyperhomocysteinemia deserves interest, especially in the elderly and in the patients with idiopathic VTE disease.
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PMID:Hyperhomocysteinemia and venous thromboembolism: a risk factor more prevalent in the elderly and in idiopathic cases. 1218 10

Inherited and acquired thrombophilias have been associated with recurrent pregnancy loss. Over recent years our ability to detect protein and genetic abnormalities responsible for thrombotic tendency has improved. We are now left with the task of deciphering which of these thrombophilias carries an increased risk for recurrent pregnancy loss. Acquired thrombophilias including lupus anticoagulant and anticardiolipin antibodies have been linked to recurrent pregnancy loss. However the evidence for the role of inherited thrombophilias such as, heterozygosity for the factor V Leiden, prothrombin G20210A mutation, the methylenetetrahydrofolate reductase (C677T MTHFR) mutation, as well as deficiencies of antithrombin, protein C and protein S is less clear. The methods for diagnosis and the evidence for their associations are discussed in this paper. Treatment modalities independent of those needed to prevent thrombotic events in pregnancy have generally not been studied. Given the present available data, there is insufficient evidence to include inherited thrombophilias in the initial evaluation of RPL. It is important to look for other, more common, causes of recurrent miscarriage in the evaluation of these patients.
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PMID:Thrombophilias and recurrent miscarriage. 1236 98

The objective of this study is to evaluate the association between venous thromboembolism (VTE) in pregnancy with thrombophilic factors. Thirty pregnant women with VTE were compared with 30 pregnant women matched by age and race without VTE and evaluated for risk factors and thrombophilia. Statistical analysis used two-tailed Fisher's exact test. VTE distribution was 30% in first trimester, 9% in 2nd trimester, 26% in 3rd trimester and 35% postpartum. Seventeen (57%) of VTE cases versus 2 (7%) of control cases had specific thrombophilia diagnosis ( p <0.001). The results were: Factor V Leiden mutation (27 vs. 3%) p = 0.026, MTHFR homozygous 677 mutation (10 vs. 44%) p = 0.017, prothrombin gene mutation (11 vs. 0%), protein C deficiency (7 vs. 0%), antiphospholipid antibodies (27 vs. 3%) p = 0.026, mean lipoprotein levels 49 versus 23 mg/dL, p = 0.008, mean homocysteine levels 7.8 versus 7.1 umol/L. An association is suggested between thromboembolic events in pregnancy and thrombophilia, especially Factor V Leiden gene mutation and elevated antiphospholipid antibodies. A new finding is the association of elevated lipoprotein A levels with thromboembolic events in pregnancy.
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PMID:Association between inherited thrombophilias, antiphospholipid antibodies, and lipoprotein A levels and venous thromboembolism in pregnancy. 1263 77

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

Neonatal thrombosis is a serious event that can cause mortality or result in severe morbidity and disability. The most important risk factor for the development of thrombosis during the neonatal period is the presence of an indwelling central line and consequently the vessels involved tend to be those most frequently used for catheterization. Other documented risk factors for the development of neonatal thrombosis include asphyxia, septicemia, dehydration, maternal diabetes and cardiac disease. Main laboratory findings for the diagnosis of hypercoagulable states, include shortened aPTT, decreased levels of inhibitors (AT III, Protein C and Protein S), increased resistance to activated protein C, defective fibrinolysis (basal and after stimuli), increased levels of clotting factors (fibrinogen, factor VII, factor VIII, etc.), increased and/or hyperactive platelets, increased whole blood and/or plasma viscosity, Antiphospholipid antibodies and presence of prothrombotic molecular defects like FV Leiden, P20210 and MTHFR. Approximately 4% and 2% respectively of Caucasians are heterozygous for these gene defects. Their causative role in neonatal thrombosis is unknown but they may have a contributory role in the pathogenesis of thrombosis in neonates.
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PMID:Neonatal thrombosis. 1470 31

Inherited and acquired thrombophilia are associated with recurrent pregnancy loss. Recently, an increased risk for thromboembolic disease was described for patients with elevated coagulation factor VIII, but it is unknown whether there is also an association to early pregnancy loss. We therefore evaluated the relation between recurrent early pregnancy loss and levels of coagulation factor VIII. We enrolled 49 unrelated Caucasian women with a history of 2-6 early pregnancy losses and 48 healthy controls, who had delivered at least one term infant and had never experienced pregnancy loss. We determined factor V Leiden-, G20210A prothrombin-, MTHFR C677T- and A1298C-gene mutations, levels of antithrombin, protein C, protein S, factor VIII, C-reactive protein and antiphospholipid antibodies. There was a significantly higher rate of pregnancy losses in women with Antiphospholipid Syndrome (p = 0.043). Furthermore, plasma levels of coagulation factor VIII were significantly higher in cases than in controls (130.5 IU/dl +/- 25.4 vs 119.5 IU/dl +/- 24.1; p = 0.032) and appeared independent of C-reactive protein (R = 0.146, p = 0.323 in cases; R = -0.028, p = 0.850 in controls). The relative risk for recurrent pregnancy loss in women with factor VIII levels above 151 IU/dl (90(th) percentile of controls) was 2.5 (0.7 - 8.9, 95 percent confidence interval), for levels above 156 IU/dl (95(th) percentile of controls) 3.9 (0.8 - 20.0, 95 percent confidence interval). Elevated maternal plasma levels of coagulation factor VIII tend to be associated with an increased risk for recurrent early pregnancy loss.
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PMID:Elevated coagulation factor VIII and the risk for recurrent early pregnancy loss. 1504 30

The role of genetic susceptibility to coronary artery disease (CAD) seems to be quite important in young patients. In the last years the attention has been focused on polymorphisms influencing some biological functions (coagulation and fibrinolysis, platelets, vascular function, lipid metabolism, inflammation). The study of prothrombotic polymorphisms has kindled a deep interest. The role of atherosclerosis and thrombosis is different in the different ages. In all the studies we examined, the polymorphism G20210A in the prothrombin gene was associated with an increased risk of acute myocardial infarction (AMI) in young people, especially when other risk factors were present. Contradictory results have been found in the studies on Factor V Leiden: according to many authors the activated protein C resistance (APCR) is associated with an increased risk of AMI only in smokers, above all if women. On the other hand, some polymorphisms of the Factor VII gene seem to be protective. Young AMI could be also caused by a reduction of the fibrinolytic activity, as it was found when the allele 4G in the promoter of plasminogen activator inhibitor (PAI) gene is present. The attention has also been focused on the effects of variations in genes that influence platelet functions. According to a metanalysis of studies published up to 1999, there is no association between the polymorphism PlA1/A2 of the GP IIIa gene and young AMI, whereas there is doubt about the role of the polymorphism in the GP IIb e GP Ib genes. Moreover, it seems to be present an association with the polymorphisms in the thrombopoietin gene (C4830A and A5713G). Also the role of some genes coding for proteins influencing the vascular functions has been valued. Few studies were performed on genetics of the renin-angiotensin-aldosterone system and the results are insufficient and contradictory, such as those about the association between the polymorphism G894T in the eNOS gene or the polymorphism C677T in the MTHFR gene and young AMI. Genes coding for proteins involved in the lipid metabolism have been closely examined. Many polymorphisms were discovered in the Apo B gene: the variant C-516T was found to be associated with increased LDL levels, whereas the results about the association between this and other polymorphisms in the same gene (I/D of LAL sequence, PvuII, MspI, Asp4311Ser) and young AMI are discordant. On the other hand, the variant e4 of the ApoE gene was associated with an increased risk of AMI at young age in many works. In the last years, a particular interest has kindled the study of the relationship between inflammation, atherosclerosis and CAD. Even if the studies performed are few, it was found an association between young AMI and polymorphism C-260T in the CD14 gene, between coronarics atherosclerosis and polymorphism A516C in the E Selectin gene or polymorphisms Leu125Val and Ser563Asn in the PECAM1 gene.
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PMID:Genetic risk factors in myocardial infarction at young age. 1528 79

As ethnic variations are known to exist in inherited genetic defects, the clinico-haematological profile of Indian children with thrombophilia may be different from that of Caucasians. The aim of the study was to analyse the phenotypic and genotypic causes of thrombophilia in Indian children. Forty patients with arterial (21 patients) and venous (19 patients) thrombosis were the subjects of the study. Their age ranged from 6 days to 15 years. All of the patients were initially screened by Pro C Global assay. Activated protein C resistance (APCR) was measured. In cases with low Pro C Global values, protein C (PC), protein S (PS) and factor V G1691A, prothrombin G20210A and MTHFR C677T polymorphism were tested in all 40 cases. Of the 21 patients with arterial thrombosis, 4 (19%) had PC deficiency, 7 (33.3%) had PS deficiency and 1 (4.8%) had combined deficiency of PC and PS. Of the 19 patients with venous thrombosis, 5 (26.3%) each had PC and PS deficiency and 4 (21%) had combined PC and PS deficiency. Heterozygous factor V G1691A defect was seen in one (4.8%) patient with arterial thrombosis and three (15.8%) patients with venous thrombosis. Heterozygous MTHFR C677T polymorphism was seen in five (23.8%) patients with arterial thrombosis and in four (21%) patients with venous thrombosis. Prothrombin G20210A polymorphism was absent in all patients and controls. Protein C system defect is common in Indian children with thrombosis.
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PMID:Protein C system defects in Indian children with thrombosis. 1544 30

While genetic factors clearly play a key role in colorectal cancer (CRC) pathogenesis and in determining its phenotypic features, the precise genes that involved are largely unknown. To gain insight into these genes, consecutive Israeli CRC patients were genotyped using SNPs from within candidate genes: APC, beta-Catenin, K-RAS, DCC, P16, PTEN, RB1, P15, APOE, ERCC2, P53, MTHFR and hMSH2. Genotyping of consecutive, unselected colorectal cancer patients was done mostly by utilizing the MassARRAY technology (Sequenom) and to a lesser extent DGGE, ARMS and direct DNA sequencing. Correlation of genotypes with specific phenotypic features was carried out for all patients and separately for the Ashkenazim. Overall, 456 patients were analyzed, the majority (64.25%) being of Ashkenazi origin; mean age at diagnosis was 65.6 +/- 14 (range 25-90 years), and the mean follow-up was 4.7 +/- 0.28 (range 0-30 years). Statistically significant associations were noted between SNPs in beta-catenin and APOE and a positive family history of cancer (beta-catenin: p=0.034, APOE: p=0.033); tumor location and a DCC SNP (p=0.038) and the P53 R72P mutation and survival (p=0.0336). In Ashkenazi patients, ERCC2 and MTHFR genes' SNPs were associated with age at diagnosis (ERCC2: p=0.025, MTHFR: p=0.0005); a P53 polymorphism, APOE and Rb SNPs with a family history of cancer (P53 p=0.034;APOE p=0.04, Rb p= 0.022); DCC SNP with tumor location (p=0.014); and p15 SNP with tumor grade (p=0.032). This preliminary study shows that genetic factors play a role in determining CRC phenotypic features and that a larger cohort with longer follow-up is clearly needed.
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PMID:Genotype phenotype correlations in Israeli colorectal cancer patients. 1552 94


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