Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study, a new functional test for the detection of increased resistance of coagulation factor V to degradation by activated protein C (factor V Leiden mutation) was evaluated. The STA-STACLOT APC-R Test (Diagnostica Stago, Asnieres, France) is based on the specific activation of factor X by Crotalus viridis helleri snake venom. The results are given as clotting time in seconds of the patient's plasma in the presence of venom and activated protein C. The intra-assay coefficient of variation was 2.17% (n=20) for samples within the normal range, and 1.70% and 1.42% (n=20) for the plasma of a heterozygous or a homozygous carrier of the factor V Leiden mutation, respectively. The inter-assay coefficient of variation (n=10) was 7.75% for the plasma of a healthy donor, 5.05% for the plasma of a heterozygous carrier and 3.38% for the plasma of a homozygous individual. The normal range (5th-95th percentile) of 136.4 s-174.7 s was derived from the clotting time of the plasma of 38 healthy controls. Values below 136 s were found in every sample from patients carrying the factor V Leiden mutation (n=52), whereas no patient with protein C (n=11) or protein S deficiency (n=10) had reduced clotting times. Homozygous carriers of the factor V Leiden mutation had clotting times shorter than 66.0 s and heterozygous carriers had clotting times longer than 80.0 s. Thus, based upon the individual clotting time, patients homozygous for factor V Leiden mutation could easily be distinguished from normals or heterozygous individuals. The influence of coagulation factor X, V, or II deficiency on the STACLOT APC-R Test was evaluated and revealed prolonged clotting times at factor V activities below 50%. In the presence of lupus anticoagulant the specificity of the STA-STACLOT APC-R Test was clearly decreased. In the present study, we clearly show that the STA-STACLOT APC-R Test is able to discriminate carriers of the factor V Leiden mutation from healthy controls or patients with protein C or protein S deficiency.
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PMID:Evaluation of a highly specific functional test for the detection of factor V Leiden. 1119 68

Placental abruption is due to the rupture of the uterine spiral artery. The placenta separates totally or partially from the uterine wall during pregnancy. This serious syndrome has a great risk for the mother (shock and disseminated intravascular coagulation) and her child (mortality or morbidity). To the known risk factors like hypertension, the use of cocaine and smoking, homocysteine is recognized as an independent risk factor for vascular disease and endothelial dysfunction. In contrast to normal pregnancy where the spiral artery endothelium is replaced by trophoblast, the endothelium persists in case of placental abruption. In 165 women with placental vasculopathy and 139 matched controls hyperhomocysteinemia resulted in an odds ratio of 4.7 (95% CI: 1.6-14.0). The C677T mutation gave a risk of 2.5 (95% CI: 1.0-6.0). Even up to 2 or 3 years post-partum evidence could be found of endothelial dysfunction. The combination of hyperhomocysteinemia and thrombotic factors like APC resistance, Protein-C, Protein-S, antithrombin and factor V Leiden increases the risk of placental abruption 3-7 times. The common denominator of the effect of homocysteine on blood vessels could be sited in the process of proliferation of cells that need proper methyl groups for proper function (DNA synthesis and expression). These methyl groups are delivered by D-adenosylmethionine formed from methionine after remethylation of homocysteine. The coagulation factors and plasma homocysteine values can be modulated by vitamins, folic acid and folates in particular. To prove the clinical value of folate supplementation placebo-randomized trials are urgently needed: for placebo to be started after the period of neural tube closure.
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PMID:Clotting disorders and placental abruption: homocysteine--a new risk factor. 1130 Nov 73

Abnormalities of the protein C anticoagulant pathway i.e. protein C and protein S deficiencies and factor V Leiden-related activated protein C resistance are among the most frequent risk factors for thrombosis in the Caucasian population. Until now, their screening is based upon the use of individual assays for each component. However, normal results are found in more than 70% of the tested patients. So, there was a rational behind the development of global assays to evaluate the functionality of the protein C pathway, as this would rationalize the use of costly specific assays. Such global assays are based on the ability of endogenous activated protein C generated by activation of protein C by a snake venom extract to prolong a clotting time. Up to now, two assays are commercially available, the ProC Global assay (Dade Behring) and the Protein C Pathway Test (Gradipore). Both were found to be highly sensitive for the factor V Leiden and for protein C deficiency, as confirmed by different studies in patients with a history of venous thrombosis. However, sensitivity of both global assays for protein S deficiency was found to be only moderate and highly variable depending of the cut-off level used. So, these global assays can be validly used for the screening of the factor V Leiden-related APC resistance and for protein C deficiency, but protein S have to be measured in all the cases. The overall sensitivity of these assays for abnormalities of the protein C pathway was dramatically different, since 40% of the patients without any known abnormality have a decreased response to the ProC Global assay versus less than 13% for the Protein C Pathway Test. These characteristics suggest that the clinical usefulness of these two global assays might be different.
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PMID:[Clinical usefulness of global assays of the anticoagulant pathway of protein C]. 1160 84

Venous thromboembolism (VTE) is one of the common manifestations in the anti-phospholipid (aPL) syndrome. We examined the levels of IgG antibodies (Abs) to beta2-glycoprotein I (beta2-GP I) and prothrombin, lupus anticoagulant (LA) activity, activated protein C resistance (APC-R), and factor V Leiden in 96 patients with systemic lupus erythematosus (SLE); 19 with VTE and 77 without VTE. Acquired APC-R, which was not found in any patient with the factor V Leiden mutation, was present in 33 (34.4%) out of the 96 patients with SLE. The presence of acquired APC-R was a strong risk factor for VTE. The SLE patients were divided into four groups according to the results of enzyme-linked immunosorbent assay (ELISA) and LA activity for each aPL Abs: ELISA+, LA+; ELISA+, LA-; ELISA-, LA+; and ELISA-, LA-. A significant association was observed between APC-R and the co-existence of anti-beta2-GP I Abs and LA activity or of anti-prothrombin Abs and LA activity. There was no association between APC-R and the presence of anti-beta2-GP I Abs, anti-prothrombin Abs, or LA activity alone. However, when multivariate logistical regression analysis was performed, it was clear that only the co-existence of anti-prothrombin and LA activity was a significant risk factor for APC-R. These findings indicate that the co-existence of anti-prothrombin Abs and LA activity may be an important factor in the pathogenesis of acquired APC-R in patients with SLE.
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PMID:Acquired activated protein C resistance is associated with the co-existence of anti-prothrombin antibodies and lupus anticoagulant activity in patients with systemic lupus erythematosus. 1271 80

Since the majority of thrombophilic defects in women with pregnancy loss are in the protein C pathway, we have prospectively determined the diagnostic value of a protein C global assay in 60 consecutive women with pregnancy loss compared to 61 controls. Protein C activation time normalized ratio (PCAT-NR) in pregnancy loss women was significantly lower than controls (0.74 +/- 0.16 vs. 0.99 +/- 0.2; P < 0.0001). PCAT-NR lower than cut off level of 0.8 were found in 42/60 (70%) of PL women compared to 7/61 (11%) of controls (OR = 18.0, 95% CI: 6.3-53.4, P < 0.0001). Cut-off level of 0.8 successfully identified all pregnancy loss women with abnormality in the protein C pathway (12 factor V Leiden, 7 APC-Resistance without factor V Leiden, 15 low levels of protein S and 1 of protein C). Moreover, PCAT-NR below 0.8 was documented in 15/29 (52%) of PL women without thrombophilic risk factor compared to 3/55 (5%) of controls (OR = 18.6, 95% CI: 4.2-95.2, P < 0.0001). These results suggest that ProC Global may be useful as a screening test for protein C pathway abnormalities and may serve as a new thrombophilic risk factor in women with pregnancy loss.
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PMID:Protein C global assay in the evaluation of women with idiopathic pregnancy loss. 1215 73

Anti-phospholipid (aPL) antibodies (Abs) are well known to be associated with thromboembolic events in patients with systemic lupus erythematosus (SLE). However, the clinical relevance of a PL Abs in patients without SLE (non-SLE) who have venous thromboembolism remains unclear. We evaluated 143 non-SLE patients with a first episode of clinically suspected deep vein thrombosis (DVT) by using objective tests for diagnosing DVT and laboratory tests including the activated protein C resistance (APC-R) test, the factor V Leiden test, and various aPL Abs. The prevalence of acquired APC-R, in which case there was no factor V Leiden mutation, was significantly higher in patients with DVT (15/58 cases, 25.9%, p < 0.0001) than in those without DVT (3/80 cases, 3.7%), and confirmed that acquired APC-R was a strong risk factor for DVT (odds ratio [OR], 8.95; 95% confidence intervals [CI], 2.45-32.7; p < 0.001). Multivariate logistic analysis revealed that the presence of LA, aCL, anti-beta2-glycoprotein I, anti-prothrombin and anti-protein C Abs was not reliable as a risk factor for DVT in non-SLE patients, and that the presence of anti-protein S Abs was the most significant risk factor for DVT (OR, 5.88; 95% CI, 1.96-17.7; p < 0.002). Furthermore, the presence of anti-protein S Abs was strongly associated with acquired APC-R (OR, 57.8; 95% CI, 8.53-391; p < 0.0001). These results suggest that acquired APC-R may reflect functional interference by anti-protein S Abs of the protein C pathway, which action may represent an important mechanism for the development DVT in non-SLE patients.
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PMID:Acquired activated protein C resistance associated with anti-protein S antibody as a strong risk factor for DVT in non-SLE patients. 1242 83

Recently, discussions have focused on the question of whether acquired APC resistance (APCsr) is a clue to the observed association between risk of venous thromboembolism (VTE) and OC use especially with the so-called third-generation OCs. It seems plausible that abnormalities in an extrinsic-based APCsr reflect an increased risk of VTE in women, but this has not yet been properly studied. The objective of our study was to determine whether there was an association of extrinsic APC resistance with VTE risk in a case-control study. Sixty-seven women with confirmed VTE diagnosis were consecutively recruited in primary health care settings, interviewed and blood samples were taken at least 6 months after VTE. Cases were age-matched to 290 population controls. Extrinsic APC resistance was measured as normalized APC ratio (APCsr). The effect of APC on tissue factor-initiated thrombin generation was measured in plasma using alpha2-macroglobulin attached thrombin activity as an endpoint. The extrinsic APCsr was significantly associated with factor V Leiden (FVL) mutation, both in the cases and in the controls. Also, in the women using OC, significantly higher values of APCsr were observed, which confirms the results of other studies. We did not identify a significant association between the extrinsic APCsr and VTE in women not using OC who are non-carriers of factor V Leiden using different approaches: comparison of medians, analyses with unconditional logistic regression using various cut-points of the APCsr distribution, and the comparison between the highest and the lowest quartile of APCsr. With all attempts, the risk estimates were close to unity. In conclusion, we were not able to find evidence for any association of extrinsic APCsr with VTE in women who were not using OCs and non-carriers of FVL.
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PMID:The association between extrinsic activated protein C resistance and venous thromboembolism in women. 1244 58

The role played by a hypercoagulable state, either inherited or acquired, in the pathogenesis of upper-extremity deep vein thrombosis (UEDVT) remains a question of debate. We performed a case-control study including 79 patients with a first objectively confirmed episode of UEDVT, 31 secondary and 48 primary, and 165 healthy controls. Nine patients (11.4%) with UEDVT were carriers of the prothrombin G20210A mutation vs. six (3.7%) in controls; P = 0.025, OR: 3.39 (95% CI 1.16 to 9.88). No statistical difference was observed between cases and controls for the factor V Leiden mutation, AT, protein C or protein S deficiency and anticardiolipin antibodies (ACAs). Thirteen (35.1%) UEDVT patients were oral contraceptive (OC) users vs. 12 (16%) controls; P = 0.020, OR: 2.89 (95% CI 1.16-7.21). When secondary UEDVT patients were compared with controls, no differences were observed in any of the risk factors analysed. On the other hand, when primary UEDVT was considered, six (12.5%) patients were carriers of the prothrombin G20210A mutation vs. six (3.7%) controls; P = 0.031, OR: 3.76 (95% CI 1.15-12.26). Regarding ACAs, a borderline statistical significance was observed when primary UEDVT was compared with controls, P = 0.048; OR: 4.88 (95% CI 1.05-22.61). In primary UEDVT, 52% of the fertile women were OC users vs. 16% of controls; P = 0.001, OR: 5.78 (95% CI 2.13-15.67). When the interaction of both factors, i.e. prothrombin G20210A mutation and OC intake, were considered, the risk increased markedly, indicating a synergistic effect as observed with other thrombotic locations. In patients with primary UEDVT screening for antithrombin, protein C and protein S deficiency and APC resistance would not be justified, although it might be reasonable to determine the carrier status of the prothrombin G20210A mutation only in OC users.
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PMID:Prothrombin G20210A mutation and oral contraceptive use increase upper-extremity deep vein thrombotic risk. 1262 27

Hereditary thrombophilia is caused by various inherited disorders. Most lead to a familial tendency to recurrent venous, not arterial, thrombosis, usually at a young age, and with spontaneous onset. Most of the genetic defects known today affect the function of natural anticoagulant pathways, in particular, the protein C system. In this study, 602 (265 female, 337 male) patients with suspected thrombosis, arterial or venous, were referred to King Hussein Medical Center in Amman, Jordan. The prevalence of hereditary deficiencies of antithrombin (AT), protein S (PS), and protein C (PC) were studied over a seven-year period (1993-2000). Activated protein C (APC-R) resistance subjects were studied over four years (1996-2000). The mean age was 30 years in females and 42 years in males. A diagnosis was established in 22.4% (n = 135) of the subjects (20.3% venous, 2.1% arterial). Protein C deficiency was found in 3.8%, protein S deficiency in 2.3% and antithrombin deficiency in 1.4% of our sample group. An APC-R problem was seen in 23.0% (n = 89) of the surveyed population. Out of the APC-R patients, 75.0% had the DNA analysis of a factor V Leiden mutation present. Of the subjects found to have the mutation 87.0% were heterozygous and 13.0% were homozygous. These results confirm that APC-R, as a result of factor V Leiden mutation, is the most prevalent cause of thrombosis, and thrombophilia is related to venous, not arterial, thrombosis.
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PMID:Hereditary deficiencies of antithrombin III, protein S, and the protein C pathway in Jordanian thrombosis patients. 1277 77

Resistance to activated protein C (APC-R) is the leading cause of deep vein thrombosis (DVT). Deficiencies of protein C (PC) or its cofactor protein S (PS) are less frequent. Resistance usually results from nucleotide substitution (1691 GA) in the factor V gene (Leiden mutation). We searched for APC-R and the Leiden mutation (FVL) and measured the activities of PC, PS, antithrombin III (AT III) and Fb levels in patients with DVT. The results were analyzed against a history of thrombosis (idiopathic, risk factor related). We enrolled 29 patients aged 50 years or younger, with first symptoms of thrombosis detected before the age of 40 years. The control group consisted of 25 healthy volunteers of similar age. APC-R was established using Accelerimat (bioMerieux) assays. APC-R was diagnosed when the normalized sensitivity coefficient "r" was < 0.9. FVL was detected with the SSP-PCR (sequence specific primers-polymerase chain reaction) method. Abnormal APC-R "r" values were found in seven DVT patients (24%). Heterozygous (G/A genotype) form of the Leiden mutation was confirmed in six of them (all had a history of recurrent thrombosis). FVL carriers demonstrated lower PC levels in comparison with controls and DVT without FVL. Eight patients (27%) had PS activities below the cut-off point (60%). The deficiency in six of them was not associated with other abnormalities. Patients with recurrent thrombosis had markedly higher concentrations of Fb (usually without FVL) and reduced AT III activities. The study has shown that the APC-R test is useful for FVL screening. The Leiden mutation, elevated levels of Fb and reduced activities of PC are the main factors predisposing to DVT and its recurrence. Reduced activity of PS is usually an isolated abnormality tending to predispose to a single DVT episode.
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PMID:[Activated protein C resistance, Leiden mutation, anticoagulant proteins and fibrinogen levels in patients with deep venous thrombosis]. 1456 90


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