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)

Levels of protein C functional activity were studied in twenty-nine full-term infants with symptomatic congenital heart disease, who presented in the neonatal period. Protein C levels on admission ranged from < 10% to 61% (mean 37.7% S. D. 14.1%). Eight of the twenty-nine babies had protein C levels between 1.5 and > 3.0 S. D. below the normal neonatal mean with no parental evidence of familial deficiency. Of these infants with low protein C two developed thrombotic complications and four had evidence of coagulation factor consumption. Critically ill infants were over-represented in the group with low protein C. Severely ill newborn infants with protein C at or below the lower limit of the normal neonatal range may be at increased risk of either a consumptive coagulopathy or major thrombosis.
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PMID:Protein C activity in severely ill newborns with congenital heart disease. 129 67

To investigate the status of the protein C-protein S anticoagulant pathway in thalassemic patients, we measured protein C and protein S levels of plasma of 30 adults and 18 children with beta-thalassemia/HbE disease, beta-thalassemia major and HbE disease. Mean +/- 1 SD values of protein C, protein S and other coagulant proteins produced by the liver were as follows: protein C 50.4 +/- 17.2%; protein S 58.8 +/- 25.5%; antithrombin III 78.1 +/- 12.8%; PLG 86.4 +/- 18.4%; prothrombin 71.0 +/- 13.1%; factor VII 72.7 +/- 21.5%; and factor X 79.2 +/- 15.6%. Protein C and protein S levels of thalassemic patients were significantly lower than those of other coagulant proteins produced by the liver. Decrease in protein C level was stronger than that of proteins S. gamma-Carboxylated protein C levels of splenectomized patients were significantly lower than those of nonsplenectomized patients. Severe decrease of protein C and protein S may be responsible for occurrence of thrombosis in thalassemic patients.
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PMID:Protein C and protein S deficiency in thalassemic patients. 129 96

The study was aimed at an evaluation of individualized indications for antithrombotic therapy for secondary prevention in a group of 40 young survivors (aged 30-40 years) of myocardial infarction, presenting a stable phase of coronary disease. The control group consisted of 19 healthy men, of approximately similar age distribution. The determinations concerned the following: in vitro ADP and collagen induced platelet aggregation, plasma fibrinogen concentration, factor VII, VIII and antithrombin III activity, protein C concentration, spontaneous fibrinolytic activity and fibrinolytic activity after venostasis, plasminogen and alpha-2 antiplasmin activity. Moreover, to determine correlations with hemostatic parameters lipids, apolipoproteins, glucose, uric acid plasma concentration as well as percentages of lipoproteins and glycolyzed hemoglobin were also studied. In the study group various hemostasis disturbances were found: an increased platelet aggregation induced by low concentrations of ADP, increased plasma fibrinogen concentration and factor VII activity, decreased protein C concentration and impaired plasma fibrinolytic activity after venostasis. Some correlations between hemostatic and lipids parameters were also observed. Results of the study have suggested necessity for the individualized antithrombotic prevention in young survivors of myocardial infarction with antiplatelet and/or anticoagulant drugs.
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PMID:[Evaluation of thrombotic risk in young men after myocardial infarction during a period of clinical stability]. 130 May 61

We have applied single-strand conformation polymorphism (SSCP) to the analysis of exon 7 of the anticoagulant protein C (PC) gene, in 13 PC-deficient Spanish families. Abnormal patterns were visualized in three samples from type I or quantitative PC deficient proposita. A previously undescribed mutation due to a TT insertion after nucleotide 6139, between codons Gly-142 and Arg-143 was found in one family. The mutation (6139,ins TT) should result in a frameshift with a stop at codon 156, which agrees with the presence of a type I or quantitative PC deficiency in the affected members of the family. The second mutation identified was a C to T transition at nucleotide 6274, 9 base pairs into intron G. This mutation (6274,C-->T), found for the first time in a Spanish family, is identical to the previously characterized PC Sant Louis. The third mutation was a G to A transition that replaces arginine 178 with glutamine (178,R-->Q). This is the third case of 178,R-->Q mutation in 17 apparently unrelated Spanish families with type I PC deficiency. Furthermore, SSCP analysis allowed the detection of another previously described mutation in a PC-deficient Spanish family (178,R-->W).
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PMID:Protein C deficiency: identification of a novel two-base pair insertion and two point mutations in exon 7 of the protein C gene in Spanish families. 130 54

Hereditary protein C (PC) deficiency is usually associated with a high risk of thrombosis. We report the results of a study undertaken to screen for molecular defects in families with hereditary quantitative PC deficiency. Using a strategy combining polymerase chain reaction amplification of selected gene fragments, denaturing gradient gel electrophoresis of the amplification products, and direct sequencing of fragments with altered melting behavior, we studied the PC gene exons and exon/intron junctions of subjects with hereditary type I PC deficiency. Computer simulation of DNA melting was used to design several sets of primers, each containing a GC-clamp, permitting the complete analysis of each amplified exon sequence. Using this procedure, we identified two previously undescribed mutations located in exon VII: a C-to-T substitution generating a nonsense codon in place of Arg 157 in the mature PC and a G-to-A substitution converting Arg 178 to GIn. The two mutations were detected in, respectively, 3 and 2 apparently independent families. This strategy is therefore a valuable tool for screening patients, and the results emphasize its advantages over plasma assays in individuals with a family history of thrombosis.
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PMID:Two novel mutations responsible for hereditary type I protein C deficiency: characterization by denaturing gradient gel electrophoresis. 130 59

The objective of this study was to clarify the specificity of anticardiolipin antibodies (aCL). Eighteen monoclonal hybridoma aCL from systemic lupus erythematosus (SLE)-prone MRL/Mp-lpr/lpr mice were established, and the reactivity of monoclonal aCL to phospholipids, DNA, nuclei of human epithelial cells, platelets, vascular endothelial cells, heparin, protein C and thrombomodulin was examined. All the 18 monoclonal aCL reacted with phosphatidylserine and some showed reactivity to phosphatidylinositol and phosphatidylcholine. Six of 16 monoclonal aCL were demonstrated to have the property of lupus anticoagulant. Monoclonal aCL were classified into three categories, in terms of DNA-binding specificity. Ten of 18 aCL had characteristics of antinuclear antibodies. Six of 11 aCL reacted with platelets. Three of 18 aCL were bound to vascular endothelial cells and to heparin. No monoclonal aCL reacted with protein C or thrombomodulin. Therefore, the conclusion was made that monoclonal aCL from SLE mice showed a polyspecific nature.
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PMID:Monoclonal autoantibodies to cardiolipin derived from SLE mice. 130 87

The structural domains of protein C involved in its interaction with thrombin-thrombomodulin on the endothelial cell surface have been investigated using isolated intact domains of bovine protein C produced from controlled proteolytic digests of the protein. The fragments investigated include the gamma-carboxyglutamic acid (Gla)-rich module, the two epidermal growth factor (EGF)-like modules, and a fragment consisting of the Gla and the two EGF-like modules. The effects of these fragments on the catalytic efficiency (Km and Vmax) of activation of protein C by the endothelial cell surface thrombin-thrombomodulin complex (IIa-TM) have been evaluated in vitro using a stirred microcarrier cell culture of bovine aortic endothelial cells and purified proteins. Neither the Gla nor the two EGF-like modules alone had any discernible effect on protein C activation. The intact Gla-EGF fragment, however, inhibited protein C activation. The results are consistent with a rapid equilibrium competitive inhibition model, in which the Gla-EGF fragment competes with protein C for binding to IIa-TM, and indicate that the Gla-EGF fragment alone accounts for most of the binding energy of intact protein C for IIa-TM. In addition, a requirement for the Gla residues of protein C for binding is implied by the observation that heat-decarboxylated Gla-EGF fragment was not an inhibitor of protein C activation. In addition, chloromethyl ketone-inactivated activated protein C was found to bind to IIa-TM with the same affinity as protein C, suggesting that the changes which occur in protein C upon activation do not affect that part of the protein responsible for binding to IIa-TM, that is the Gla-EGF region. The Gla-EGF region from factor X also weakly inhibited the IIa-TM activation of protein C.
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PMID:Identification of structural domains in protein C involved in its interaction with thrombin-thrombomodulin on the surface of endothelial cells. 130 72

Fibrin deposition is a common accompaniment of renal allograft rejection, indicating disruption of the normal physiologic balance between procoagulant and anticoagulant pathways. In vitro, tumor necrosis factor (TNF) induces endothelial expression of the procoagulant, tissue factor, and downregulation of thrombomodulin, a key component of the thrombomodulin/protein C (PC)/protein S (PS) pathway, which normally maintains an anticoagulant state by inactivating thrombin, preventing further thrombin formation by degrading factors Va and VIIIa, and decreasing plasminogen activator inhibitor activity. Raised levels of TNF were recently demonstrated within the blood of patients during episodes of renal allograft injection, and may be an early and discriminatory marker of rejection. This led us to investigate prospectively whether monitoring of serum TNF levels was of value clinically, and was associated with effects on circulating PC and PS levels, or alterations in intragraft thrombomodulin expression. Plasma samples (n = 454) were collected three times/week from all patients (n = 25) undergoing renal transplantation during a 9-month consecutive period, and assayed by ELISA and functional assays for TNF, PC, and free PS (FPS). Portions of renal biopsies, taken to evaluate episodes of acute deterioration of renal function, were evaluated by immunoperoxidase labeling for the presence and distribution of TNF, thrombomodulin, PC, PS, thrombin, fibrin, and factors V and VIII. Comparison of 78 plasma samples collected during 26 episodes of biopsy-proven acute cellular rejection with samples collected during periods of stable renal function (n = 349) showed that TNF levels rose significantly (390 +/- 242 pg/ml, p less than 0.01) above background levels 3 days before rising serum creatinine concentrations, and peaked (2,426 +/- 978 pg/ml) on the day of clinical rejection. PC-antigen (Ag) concentrations also decreased 3 days before rejection (68 +/- 13%, p less than 0.05), and were maximally depressed (49% +/- 16%, p less than 0.001) on the day of rejection. FPS levels were normal until the day before rejection (63% +/- 8%, p less than 0.01) and, like PC, were maximally depressed (43 +/- 10%) at rejection. Plasma TNF levels were significantly and inversely correlated with PC-Ag (p less than 0.001) and FPS (p less than 0.005) levels during rejection, regardless of whether such rejection episodes were steroid responsive or required OKT3 monoclonal antibody therapy. TNF, PC, and FPS levels were normal during episodes of cyclosporine toxicity and viral infection.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Tumor necrosis factor production during human renal allograft rejection is associated with depression of plasma protein C and free protein S levels and decreased intragraft thrombomodulin expression. 130 55

The two-way and three-way interactions among active-site-blocked bovine thrombin, bovine protein C, and the elastase fragment of rabbit thrombomodulin (elTM) were examined by analytical ultracentrifugation at 23.3 degrees C in 100 mM NaCl, 50 mM Tris (pH 7.65), and 1 mM benzamidine, in the presence of 0 to 5 mM calcium chloride. Thrombin and elTM form a tight (Kd less than 10(-8) M) 1:1 complex in the absence of Ca2+ that weakens with the addition of Ca2+ (Kd approximately 4 microM in 5 mM Ca2+). Without Ca2+, thrombin and protein C form a 1:1 complex (Kd approximately 1 microM) and what appears to be a 1:2 thrombin-protein C complex. The Kd for the 1:1 complex weakens over 100-fold in 5 mM CaCl2. Protein C and elTM form a Ca(2+)-independent 1:1 complex (Kd approximately 80 microM). Nearly identical binding to thrombin and elTM is observed when active-site-blocked activated bovine protein C is substituted for protein C. Thrombin inhibited by diisopropyl fluorophosphate and thrombin inhibited by a tripeptide chloromethyl ketone exhibited identical behavior in binding experiments, suggesting that the accessibility of protein C to the substrate recognition cleft of these two forms of thrombin is nearly equal. Human protein C binds with lower affinity than bovine protein C. Ternary mixtures also were examined. Protein C, elTM, and thrombin form a 1:1:1 complex which dissociates with increasing [Ca2+]. In the absence of Ca2+, protein C binds to the elTM-thrombin complex with an apparent Kd approximately 1 microM.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ca2+ dependence of the interactions between protein C, thrombin, and the elastase fragment of thrombomodulin. Analysis by ultracentrifugation. 131 45

The APC gene is responsible for familial adenomatous polyposis and is considered to be a tumor suppressor gene associated with development of sporadic colorectal tumors. Here we report the disruption of the APC gene caused by somatic insertion of a long interspersed repetitive element (LINE-1 sequence) into the last exon of the APC gene in a colon cancer. The inserted sequence was composed of a 3' portion of the LINE-1 consensus sequence and nearly 180 base pairs of polyadenylate tract. Furthermore, since an 8-base pair target site duplication was observed, retrotranscriptional insertion of an active LINE-1 sequence is suspected as the cause of this insertion event. This is the first report of the disruption of a tumor suppressor gene caused by somatic insertion of a mobile genetic element.
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PMID:Disruption of the APC gene by a retrotransposal insertion of L1 sequence in a colon cancer. 131 68


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