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)

Some of the soluble factors that affect haemostasis produced in the course of hepatosplenic schistosomiasis, including endotoxins (Ex), interleukin-1 alpha (IL-1 alpha) and tumour necrosis factor-alpha (TNF-alpha) were studied. Forty-one patients with hepatosplenic schistosomiasis were studied and classified into early hepatosplenic schistosomiasis (n = 12), hepatocellular decompensation (n = 14), vascular decompensation (n = 15) as well as twelve healthy controls. Thrombin-antithrombin complex (TAT), protein C and free protein S antigen and activity, endotoxin, IL-1 alpha and TNF-alpha levels were measured in all cases. Evidence of enhanced thrombin generation (elevated TAT levels) with reduced anticoagulant potential (reduced protein C and free protein S antigen and activity levels) could be demonstrated, thus reflecting decreased production and increased consumption of both coagulant and anticoagulant proteins. The association of high Ex, IL-1 alpha and TNF-alpha levels may suggest their possible implication in the causation of intravascular coagulation in hepatosplenic schistosomiasis.
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PMID:Is the coagulopathy of hepatosplenic schistosomiasis immune-related? 786 86

Our laboratory recently found a novel mechanism for thrombophilia, which is characterized by an inherited resistance to activated protein C (APC). The APC-resistance test, which measures the anticoagulant response to APC in an activated partial thromboplasin time (APTT) reaction, was devised and used to screen a cohort of consecutive thrombosis patients. APC-resistance was found in approximately 40% of the cases. Other known causes for thrombosis, such as deficiencies of protein C, protein S or antithrombin, were found in another 5% of the patients. Our results, which have recently been confirmed from other laboratories, suggest APC-resistance to be highly prevalent in thrombosis patients. In a majority of cases, APC-resistance was demonstrated to be inherited and family studies revealed an autosomal dominant mode of inheritance. In the investigated families, APC-resistance was associated with thrombosis, which suggests a causal relationship between APC-resistance and thrombosis. An anticoagulant cofactor activity, which corrected APC-resistance, was found in normal plasma, whereas plasma from an individual with pronounced APC-resistance was devoid of this activity. Purification and characterization of the novel APC-cofactor suprisingly revealed that it was identical to coagulation factor V. Thus, factor V is not only an important procoagulant, but also expresses anticoagulant properties as a cofactor to APC. Our present data suggest the anticoagulant function to be a property of unactivated factor V, whereas the procoagulant activity is expressed after activation to Va. APC-resistant individuals have normal levels of procoagulant V-activity, it is now known that APC-resistance is caused by mutation in the factor V gene changing arginine 506 to a glutamine, thus affecting the APC-cleavage site.
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PMID:Inherited resistance to activated protein C, a major cause of venous thrombosis, is due to a mutation in the factor V gene. 795 62

Protein C inhibitor (PCI) is a plasma serine proteinase inhibitor (serpin) that is a major physiological regulator of activated protein C. Inhibition of its target proteinase is accelerated by heparin in a reaction that involves the binding of both inhibitor and proteinase to heparin to form a ternary complex. This study was undertaken to understand the role of the H helix region (residues 264-278) of PCI in heparin binding and used (i) a recombinant truncated PCI fusion protein of the first 294 residues, (ii) H helix synthetic peptides containing single Arg/Lys-->Glu substitutions, and (iii) site-directed Ala mutagenesis of 4 basic residues (Arg-269, Lys-270, Lys-276, and Lys-277) in the H helix region of full-length recombinant PCI (rPCI) expressed in Baculovirus. The PCI fusion protein interfered in heparin-accelerated PCI-proteinase inhibition reactions, and it bound to heparin-Sepharose. Compared to the wild-type PCI fusion protein, deletion of the H helix from the fusion protein resulted in a reduction of both heparin-Sepharose binding and the ability to compete for heparin during PCI-proteinase inhibition reactions. Competition assays with H helix synthetic peptides revealed that the R269E altered peptide was the least effective at blocking heparin-catalyzed PCI-proteinase inhibition reactions. Compared with full-length active wild-type rPCI, R269A: K270A and K276A:K277A rPCI both had reduced heparin-Sepharose binding, but only R269A:K270A rPCI showed a loss of heparin-accelerated proteinase inhibition for both activated protein C and thrombin. We conclude that a major heparin-binding site of PCI is the H helix, unlike its heparin-binding serpin homologues antithrombin and heparin cofactor II, which bind heparin primarily through the D helix.
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PMID:Role of the H helix in heparin binding to protein C inhibitor. 796 20

Protein S (PS) and protein C (PC) anticoagulant activities and thrombin-antithrombin complex (TAT) were measured in 20 patients with AIS, 25 patients with chronic stable angina (CSA) and a control group (C). Although plasma levels of TAT were significantly elevated in patients with CSA (p < 0.01 vs C), they were much higher in patients with AIS (p < 0.001 vs CSA). PC anticoagulant activity was similar in patients and controls. At variance, PS anticoagulant activity was lower in patients with AIS than in those with CSA and controls (p < 0.05), reflecting differences in total PS and C4B-binding protein (C4B-BP) antigen possibly resulting from involvement in the mechanisms of inflammation, complement activation and acute-phase response. The ratios of anticoagulant PS and PC to procoagulant vitamin K-dependent factors IX and II were reduced in AIS patients (0.05 > p > 0.005 vs C). In addition, the ratios of anticoagulant PC and PS to factor IX were lower in patients with AIS than in those with CSA (p < 0.05). These results indicate that in patients with acute ischemic cardiac syndromes the markedly increased in vivo thrombin generation is associated with an unbalance between coagulant and anticoagulant vitamin K-dependent factors.
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PMID:Protein S and protein C anticoagulant activity in acute and chronic cardiac ischemic syndromes. Relationship to inflammation, complement activation and in vivo thrombin activity. 797 87

An abnormal anticoagulant response in vitro to activated protein C (aPC) has been proposed as an aetiological factor in familial thrombophilia. It is postulated that this phenomenon is due to an inherited molecular defect of factor V resulting in poor inactivation by aPC. We conducted a family study when the proband presented in her second pregnancy with superficial phlebitis, a history of deep venous thrombosis and a family history of venous thromboembolic disease. No abnormality of antithrombin activity, protein C activity or deficiency of protein S were demonstrated in the family members tested. The proband had aPC ratios below the laboratory range on three consecutive occasions. In addition, her mother, who had a history of recurrent DVTs and a pulmonary embolus, and also an asymptomatic nulliparous sister, both had aPC resistance ratios below the laboratory range on consecutive samples. Further information about the combined risk of aPC resistance and pregnancy is needed before guidance on the management of affected women can be formulated.
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PMID:Familial thrombophilia and activated protein C resistance: thrombotic risk in pregnancy? 798 34

We attempted to determine if a hypercoagulability state exists in patients with polycythemia vera (PV) and essential thrombocythemia (ET). We studied the hematocrit level, platelet count, use of any antiaggregant drugs, thrombotic or bleeding accidents and plasma levels of antithrombin III, protein C, total protein S, free protein S, vWF:Ag (Von Willebrand's factor related antigen), thrombin-antithrombin complexes, D-dimer, fibrinolytic activity, tissue plasminogen activator, plasminogen and PAI-1 in 33 patients (19 with ET and 14 with PV). PAI-1 plasma concentration was significantly higher in, both ET and PV patients than in the control group, and were higher in those patients with previous thrombotic episodes than in asymptomatic patients or with previous bleeding episodes. Increasing age was associated to more thrombotic episodes while younger patients presented with more hemorrhagic complications. A linear correlation between platelet count and PAI-1 levels in PV patients (r = 0.44, p < 0.05) and ET patients (r = 0.30, p < 0.05) was found. Fibrinolytic activity in patients with ET was significantly decreased when compared to the control group. A hypofibrinolytic state could be an additional factor which could be used as a predictive index of the thrombotic or bleeding tendency in each patient.
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PMID:High plasma levels of plasminogen activator inhibitor 1 (PAI-1) in polycythemia vera and essential thrombocythemia are associated with thrombosis. 799 52

Several physiological antithrombotic proteins--including antithrombin, protein C, protein S, tissue factor pathway inhibitor, and components of the fibrinolytic system--act as inhibitors at strategic sites in the coagulation cascade to maintain normal blood fluidity under normal circumstances. The molecular basis of specific inherited hypercoagulable states has been recently elucidated. With the description of resistance to activated protein C, which is the commonest coagulation defect associated with thrombophilia, a specific primary hypercoagulable state can be identified in over 50% of patients with thrombophilia. Although the prevalence in the normal population of some "prothrombotic" mutations is remarkably high, most affected individuals do not have clinical thrombotic complications, so it is likely that clinically apparent hypercoagulable states result from multigene interactions, and that clinical episodes of thrombosis are precipitated by acquired prothrombotic insults in patients with an inherited predisposition to thrombosis.
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PMID:Hypercoagulable states: molecular genetics to clinical practice. 799 3

We studied 84 consecutive patients referred with the suspicion of pulmonary embolism (PE) to investigate the influence of clinical and hematological profiles on the diagnosis and severity of this disease and recovery. Diagnosis of PE was confirmed in 48 out of 84 patients by perfusion scintigraphy and/or pulmonary arteriography. Severity of PE and entity of recovery were investigated by measuring standard PaO2 on blood gas analysis and the number of unperfused lung segments ULS on perfusion scintigraphy. Most common clinical predisposing conditions were more frequent, though not significantly so, in embolic patients and a very low prevalence of PE was appreciable in patients without clear predisposing conditions. Among coagulation factors, only thrombin-antithrombin (TAT) complexes were twice as high in embolic as in nonembolic patients (14.0 +/- 13.6 vs. 7.0 +/- 4.2 ng/ml; p < 0.02), while there was no statistically significant difference between embolic and nonembolic patients for activated partial thromboplastin time, prothrombin time, antithrombin III, protein C, fibrinogen, plasminogen, alpha 2-plasmin inhibitor, and plasminogen activator inhibitor-1. Sensitivity and specificity of TAT complexes in diagnosis of PE were 95.8% and 30.5%, respectively. Therefore, normal values of TAT complexes may help exclude the diagnosis of PE, while abnormal values allow to reinforce the clinical suspicion of PE. No relation was found between coagulation parameters and the severity of PE. The follow-up of 48 patients with confirmed PE was favorable on the average; however, neither the presence of predisposing conditions nor abnormal coagulation parameters allow to predict the degree of functional and scintigraphic improvement during follow-up.
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PMID:Clinical, anamnestic and coagulation data in patients with suspected or confirmed pulmonary embolism. 800 95

In 30 consecutive children with congenital heart disease scheduled for pediatric cardiac operations, thrombomodulin, protein C, free protein S, and thrombin-antithrombin complex were measured by enzyme-linked immunosorbent assay after the induction of anesthesia (baseline value), and then before, during, and after cardiopulmonary bypass until the first postoperative day. The patients were divided prospectively into two groups: children weighing less than 10 kg (group 1; n = 15) and those weighing more than 10 kg (group 2; n = 15). At baseline, the plasma concentration of thrombomodulin was significantly higher in the children in group 1 than in those in group 2 (83.1 +/- 11.0 ng/mL versus 29.2 +/- 12.1 ng/mL). During cardiopulmonary bypass, the thrombomodulin level was reduced in both groups without showing any significant group differences. Five hours after cardiopulmonary bypass and on the first postoperative day, the thrombomodulin level exceeded normal values only in the children weighing less than 10 kg. In both groups, the protein C levels were already below normal at the beginning of the study. The baseline protein S concentration was higher in the smaller children (80% +/- 18%) than in the larger children (66% +/- 11%). It was reduced by cardiopulmonary bypass in both groups; however, postoperatively it did not return to normal in group 1 (45.1% +/- 10%). Plasma levels of the thrombin-antithrombin complex were similar in both groups, with a marked increase at the end of cardiopulmonary bypass, and returned to near-normal levels by 5 hours after bypass.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Thrombomodulin in pediatric cardiac surgery. 801 Aug 6

Proteoglycans play pivotal roles in the regulation of thrombin. Thrombomodulin (TM) binds thrombin through protein-protein contacts and a chondroitin sulfate moiety. The complex activates the anticoagulant zymogen, protein C. Thrombin and a thrombin mutant with Arg93, Arg97, and Arg101 changed to Ala bind soluble TM lacking the chondroitin sulfate with comparable affinities, but the mutant binds TM containing chondroitin sulfate 45-fold weaker than thrombin. A simple hyperbolic relationship describes the Ca2+ dependence of protein C activation with the thrombin mutant-TM complex whether or not the TM contains chondroitin sulfate. A similar Ca2+ dependence is observed with wild type thrombin only when the TM contains chondroitin sulfate. Thus, charge neutralization of Arg93, Arg97, and Arg101 mimics the functional effects of the chondroitin sulfate. The mutant and wild type thrombin are inhibited at comparable rates by antithrombin +/- the pentasaccharide capable of inducing the "active" antithrombin conformation, but heparin acceleration of antithrombin inhibition of the mutant is reduced by more than 95%. Binding studies revealed that the mutant has a > or = 20-fold decrease in heparin affinity. We conclude that heparin and chondroitin sulfate interact with one or more of these Arg residues. These basic residues appear to play a critical role in the regulation of thrombin activity.
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PMID:Glycosaminoglycan contributions to both protein C activation and thrombin inhibition involve a common arginine-rich site in thrombin that includes residues arginine 93, 97, and 101. 802 55


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