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)

A model of Protein C (PC) activation in vivo was used to investigate the complexing of activated PC (APC) with its plasma inhibitors, PC inhibitor (PCI) and alpha 1-antitrypsin (alpha 1AT). Chimpanzees were infused with a bolus of activated factor X (F.Xa) together with vesicles of phosphatidylcholine and phosphatidylserine (PCPS). Pre- and post-infusion plasma samples were analyzed using enzyme linked immunosorbent based assays (ELISA) for PC and APC complexes, and immunoblotting of PC from nondenaturing polyacrylamide gel electrophoresis. Within 2 minutes of infusion, a 60% decrease in nonactivated PC zymogen (PCz) levels was observed. This coincided with a precipitous drop in plasma activities of cofactors VIIIa and Va. In contrast, total PC antigen (PCt) levels decreased by only 1%, indicating APC generation. Complexes of APC with both PCI and alpha 1AT were observed on immunoblots, and further identified and quantified using a sandwich ELISA employing antibodies to both PC and these inhibitors. The distribution of APC between these two inhibitors varied with the dose of F.Xa/PCPS infused. At a dose of F.Xa/PCPS of 24.05 pmol and 37.70 nmol/kg, respectively, an initial spike of APC generation, associated with decreases in the levels of factors VIIIa and Va, was noted but dissipated over the next 30 minutes. During this period, APC/inhibitor complexes appeared with the levels of APC-PCI and APC-alpha 1AT reaching 8.5 nmol/L and 2.2 nmol/L by 30 minutes, respectively. In contrast, at a higher dose of F.Xa/PCPS of 36.60 pmol and 56.30 nmol/Kg respectively, complexes of APC-alpha 1AT appeared rapidly and reached a level of 6 nmol/L by 30 minutes postinfusion, whereas APC-PCI complexes were only present at a concentration of 3.4 nmol/L by this time. Additional experiments with lower doses of F.Xa/PCPS suggest that PCI is the preferred inhibitor of APC, but as the availability of this inhibitor becomes limiting, alpha 1AT plays an increasingly crucial role as a secondary inhibitor of endogenously generated APC. Moreover, evidence is presented suggesting the existence of additional inhibitor(s) of APC that may have a role similar to alpha 1AT.
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PMID:A qualitative and quantitative analysis of the activation and inactivation of protein C in vivo in a primate model. 234 80

The purpose of this study was to evaluate the behavior of the hemostatic system during treatment with gestodene-containing oral contraceptives in monophasic (SHD 356, n = 15) and triphasic (SHD 415, n = 15) formulations. No changes in platelet (beta-thromboglobulin, platelet aggregate ratio, and megathrombocyte) and routine clotting assays were observed. Factor VIIc/factor VIIag ratio and fibrinopeptide A values showed a significant (p less than 0.005) increase after three cycles of both treatments. A slight, significant increase (p less than 0.01) in antithrombin III activity was observed during triphasic treatment. Protein C was unchanged. Fibrinolytic activity and plasminogen levels were significantly increased (p less than 0.05 and p less than 0.001). After 6 and 9 months, the factor VIIc/factor VIIag ratio was still significantly enhanced, whereas fibrinopeptide A values significantly (p less than 0.05) decreased, even if they were higher (p less than 0.05) than basal values. The persistence of factor VII activation without enhanced thrombin formation after long-term use of oral contraceptives suggests that at that time the activity of antithrombotic mechanisms counteracts the prothrombotic tendency, thus helping to minimize unwanted side effects on hemostasis during long-term drug administration.
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PMID:Effects of long-term gestodene-containing oral contraceptive administration on hemostasis. 237 36

An antigenic assay was developed for determination of protein C in horses. Protein C, a natural, vitamin K-dependent anticoagulant component in blood, was isolated from equine plasma, a specific antibody was produced in goats, and a rocket electroimmunophoresis assay was established. Tests were performed to verify the identity of the isolated protein C and to determine the purity of the antibody. Protein C antigen was measured in plasma from 34 clinically normal horses, and values were compared with amidolytic function values. The mean (+/- SD) values for the 2 test methods were similar (antigen content, 104.5 +/- 13.8%; amidolytic activity, 104.6 +/- 17.5%), but the correlation coefficient was 0.1. Four horses given Na coumarin had markedly decreased plasma protein C amidolytic activity and minimal decrease in protein C antigen content.
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PMID:Antigenic assay for protein C determination in horses. 238 86

To determine whether children treated with chronic peritoneal dialysis have a hypercoagulable state, various coagulation and fibrinolytic factor concentrations or activities were measured in 17 children undergoing chronic peritoneal dialysis. The patients had significantly increased activities of factors VII and VIII, and increased concentrations of von Willebrand factor (vWF), fibrinogen, factor XIIIA and factor XIIIS compared to reference values (P less than 0.001 in each case). The activated partial thromboplastin time was prolonged (P less than 0.001) and the thrombin clotting time was decreased (P less than 0.05) in these children. The prothrombin time and activities of factors XII, XI, IX, X, V and II were not significantly different from control values. Protein C concentrations were similar to normal, but antithrombin III concentrations were increased (P less than 0.05). Within the fibrinolytic pathway, decreased concentrations of plasminogen were found (P less than 0.001) and the concentrations of alpha-2-antiplasmin were increased (P less than 0.001). The plasma albumin concentration was below 33 g/l in 13 of the 17 children. The duration of treatment with peritoneal dialysis was directly correlated with vWF concentrations (P less than 0.001) and inversely correlated with factor VII concentrations (P less than 0.01). Of these patients 2 have since had clinical thrombotic episodes. The coagulation abnormalities found may have a role in the occurrence of thrombosis complicating renal transplantation.
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PMID:Coagulation abnormalities in chronic peritoneal dialysis. 239 81

Protein C (PC) deficiency is among the increasing number of recognized causes of hereditary thrombotic disease. Two types of PC deficiency have been described: 1) Type I, which is characterized by a concomitant decrease in PC activity and antigen, and 2) Type II, characterized by disproportionately low activity compared to antigen (i.e. a dysfunctional molecule). To date, only a small number of Type II patients have been described. This study was undertaken to evaluate a number of dysfunctional PC molecules by comparing PC clotting and amidolytic activities with antigen levels. For these studies, an automated PTT-based clotting PC assay was developed. This assay was sensitive to 1% of a normal plasma pool, specific, accurate, and reproducible (+/- 12%). A good correlation (r = 0.918) of the clotting activity to antigen was found in normal individuals and Type I heterozygous and homozygous patients. To classify Type II PC deficient patients, the antigen, amidolytic and clotting PC levels were compared in ten affected families. The clotting activities were decreased in all affected members, whereas the antigen levels were within the normal limits. In four of the 10 families, the amidolytic activity was normal and similar to the antigen levels. This suggests that in certain families, defects in the PC molecule occur in regions not associated with amidolytic functions. From these studies, the molecular basis of Type II PC deficiency is varied and complex, involving different functional domains of the PC molecule. Therefore, we have suggested a nomenclature algorithm for Type II PC deficiency based on the location of the defect within the specific domains of the PC molecule.
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PMID:Hereditary dysfunctional protein C molecules (type II): assay characterization and proposed classification. 240 41

The efficacy of three different protein C activity assays and of protein C antigen determination for the diagnosis of protein C deficiency was studied in 13 protein C deficient patients (11 with type I, 2 with type II deficiency) and in 51 presumably non-deficient patients (control group), both groups being on oral anticoagulant (OAC) treatment. For protein C activity measurement (1) the assay according to Francis (slightly modified) with thrombin activation and measurement of activated protein C in the aPTT system, (2) an assay using Protac activation and chromogenic substrate (Protac-CS) and (3) an assay using Protac activation and the aPTT system (Protac-PTT) were used. Protein C antigen was determined by Laurell immunoelectrophoresis. The three activity assays gave different results, with the highest values obtained by the Protac-CS assay and the lowest values by the Protac-PTT assay. The Francis assay gave intermediate results. Protein C activity and antigen values were significantly lower in protein C deficient patients compared to the control group. Protein C activity tests had a higher discriminative power than the antigen determination. After taking into account the intensity of treatment, by the Francis assay all deficient and non-deficient patients were correctly classified, by the Protac-CS and the Protac-PTT assay 2 and 4 patients, respectively, were misclassified and by the antigen assay 8 patients were misclassified. Calculation of the ratios of protein C activity to factor II activity was of high discriminative power. We conclude that for diagnosis of protein C deficiency protein C activity tests are superior to antigen determination not only in type II but also in type I deficient patients.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Diagnosis of protein C deficiency in patients on oral anticoagulant treatment: comparison of three different functional protein C assays. 240 42

Severe rejection crises occurred in 13 out of 20 cadaver kidney recipients; removal of the graft was inevitable in 10 cases. The plasminogen levels were found to be lower (76.5 +/- 2.9%) in the 13 patients with impaired graft acceptance (group B) than in the 7 patients experiencing only moderate rejection (group A, 93.7 +/- 5.2%, p less than 0.01) or the 41 patients with chronic renal disease (group C, 88.2 +/- 2.3%, p less than 0.01). Since alpha 2-antiplasmin was found to be enhanced, the alpha 2-antiplasmin/plasminogen ratio was high (1.56 +/- 0.07) in group B as compared with group A (1.19 +/- 0.05, p less than 0.002) and group C (1.11 +/- 0.04, p less than 0.001). The fibrinolytic capacity, which was assessed by a "reversed fibrin plate" assay, declined significantly after transplantation, and was lower in group B greater than 20 days after grafting. The neoantigen alpha 2-antiplasmin-plasmin complex was not detected in any patient; thus hyperfibrinolysis is unlikely to be responsible for the plasminogen decrease. Protein C rose above preoperative values (group A 117.1 +/- 8.7%; group B 133.7 +/- 9.0%) and reached higher levels in group A (221 +/- 24.1%) than in group B (157.4 +/- 14.8%, p less than 0.05) between days 11 and 20 after transplantation. No constant alterations were found with respect to antithrombin III and fibrinogen. Fibrin deposits, which reduce perfusion, can be found in the vessels of rejected kidney grafts. An impaired fibrinolytic capacity and a subsequent inability to remove these clots may be significant for the outcome of transplantation.
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PMID:Impaired fibrinolysis and protein C increase after cadaver kidney transplantation. 242 20

Thrombotic thrombocytopenic purpura (TTP) is characterized by widespread occluding and persistent microthrombotic lesions. Evidence for both endothelial damage and primary platelet aggregation as possible pathogenetic mechanisms has been produced. Persistence of microthrombi has not been explained satisfactorily. In patients with TTP we studied plasma fibrinolysis and protein C. Tissue plasminogen activator (t-PA) activity levels, measured functionally, were low or unmeasurable in 11 of 12 patients; t-PA antigen levels, measured immunochemically, were normal in all six observed. The level of potent inhibitor of plasminogen activation directed against both t-PA and urokinase was elevated significantly in all 12, whereas the alpha 2-antiplasmin level was elevated in only two. Protein C antigen levels were low in three of six patients observed. Fibrinolysis levels in patients in remission did not differ from those in patients with acute disease. Plasma exchange resulted in temporary reversal of the abnormalities, but achievement of clinical remission was not associated with permanent normalization of fibrinolysis. Inasmuch as all 12 patients had severely depressed fibrinolytic mechanisms it is possible that a defect in the fibrin-clearing system permits thrombus formation to occur and proceed in an unchallenged fashion, thereby contributing to the complex events leading to arterial ischemia in vital organs.
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PMID:Fibrinolysis in health and disease: abnormal levels of plasminogen activator, plasminogen activator inhibitor, and protein C in thrombotic thrombocytopenic purpura. 243 36

Protein C, like the other vitamin K-dependent plasma proteins that participate in blood coagulation, except prothrombin, has at least one high affinity calcium-binding site that is independent of gamma-carboxyglutamic acid. Calcium binding to this site is required for activation of protein C by the thrombin-thrombomodulin complex. In an attempt to localize this calcium-binding site, we subjected protein C to limited tryptic digestion. A monoclonal antibody that recognizes a calcium-dependent epitope both in intact protein C, in gamma-carboxyglutamic acid-domainless protein C, and in activated protein C, was used to isolate a fragment from the tryptic digest. The fragment was derived from the light chain of protein C and consisted of the two domains that are homologous to the epidermal growth factor precursor. Half-maximal binding of the intact protein and of the isolated fragment by the antibody occurred at 100-200 microM Ca2+. The results suggest the presence of a Ca2+-binding site in the epidermal growth factor homology region of protein C.
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PMID:Calcium-dependent interaction between the epidermal growth factor precursor-like region of human protein C and a monoclonal antibody. 244 97

We report a functional assay of Protein C on whole plasma using a snake venom called Protac-C. This method is simple, avoids absorption-elution techniques. Also this method can be adopted to a microtitre plate system testing of large number of samples. Functional levels by this test correlated well with the antigenic levels (r = .8) measured by ELISA. Protein C functional and antigenic values in 58 healthy volunteers were 82% and 95.5% respectively. The warfarinized samples showed a lower mean.
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PMID:Protein C functional assay using snake venom activator. 244 97


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