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)

Thirty-seven young patients (less than 42 years of age) presenting with sudden onset of idiopathic nonembolic cerebrovascular disease were evaluated for underlying prothrombotic factors. Activated protein C resistance (APC-R) was measured by Dahlback's method and the modified method using factor V-deficient plasma. Activities of antithrombin (AT) III, protein C and S were measured. Anticardiolipin antibody was estimated by ELISA and lupus anticoagulant by kaolin clotting tests. APC-R was the most common defect (21.62%) followed by AT III deficiency and presence of anticardiolipin antibodies (5.6% each). The latter two were present together in one case. It is thus concluded that APC-R is the most common defect underlying idiopathic nonembolic cerebrovascular infarction in young individuals.
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PMID:Risk factors for thrombosis in nonembolic cerebrovascular disease. 1007 19

The molecular links between inflammation and coagulation are unquestioned. Inflammation promotes coagulation by leading to intravascular tissue factor expression, eliciting the expression of leukocyte adhesion molecules on the intravascular cell surfaces, and down regulating the fibrinolytic and protein C anticoagulant pathways. Thrombin, in turn, can promote inflammatory responses. This creates a cycle that logically progresses to vascular injury as occurs in septic shock. Most complex systems are regulated by product inhibition. This inflammation-coagulation cycle seems to follow this same principle with the protein C pathway serving as the regulatory mechanism. The molecular basis by which the protein C pathway functions as an anticoagulant is relatively well established compared to the mechanisms involved in regulating inflammation. As one approach to identifying the mechanisms involved in regulating inflammation, we set out to identify novel receptors that could modulate the specificity of APC in a manner analogous to the mechanisms by which thrombomodulin modulates thrombin specificity. This approach led to the identification of an endothelial cell protein C receptor (EPCR). To understand the mechanism, we obtained a crystal structure of APC (lacking the Gla domain). The crystal structure reveals a deep groove in a location analogous to anion binding exosite 1 of thrombin, the location of interaction for thrombomodulin, platelet thrombin receptor and fibrinogen. Thrombomodulin blocks the activation of platelets and fibrinogen without blocking reactivity with chromogenic substrates or inhibitors. Similarly, in solution, EPCR blocks factor Va inactivation without modulating reactivity with protease inhibitors. Thus, these endothelial cell receptors for the protein C system share many properties in common including the ability to be modulated by inflammatory cytokines. Current studies seek to identify the substrate for the APC-EPCR complex as the next step in elucidating the mechanisms by which the protein C pathway modulates the response to injury and inflammation.
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PMID:Inflammation, sepsis, and coagulation. 1018 92

Thrombophilia is defined as an increased tendency to thrombosis and can be inherited or acquired. The thrombotic events in patients with inherited thrombophilia tend to occur at a young age, are often idiopathic, recurrent and may occur at unusual sites (e.g. mesenteric, portal and cerebral veins and in inferior vena cava). The most common of the hereditary defects appear to be antithrombin, protein C, protein S deficiency, which account for 10% of individuals presenting with venous thromboembolism, resistance to anticoagulant effect of activated protein C (APC-R), which is present in 17 to 64% of patients with thrombosis and prothrombin 20210 G-->A variant with 6% prevalence in patients with thrombosis. APC-R is due in 90% to the presence of factor V Leiden. Rarer defects include heparin cofactor II (HC II), plasminogen or tissue plasminogen activator deficiency (TPA), elevated plasminogen activator inhibitor-1 (PAI-1) and dysfibrinogenemia. The most common acquired defects are antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies). Hyperhemocystinemia is responsible as well for arterial as venous thrombosis. A substantial proportion of venous thrombotic events occurs spontaneously, i.e. without a precipitating event. Risk factors for thrombosis include surgery, trauma, immobility, congestive heart failure, pregnancy including puerperium and oral contraceptive usage. The thrombotic risk is increased in patients who are homozygous for factor V Leiden and markedly increased in patients with combined defects.
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PMID:[Thrombophilic states]. 1035 55

The role of hereditary antithrombotic protein defects in juvenile deep vein thrombosis (DVT) was evaluated. Fifty six young patients (age <45 yr) with doppler-proven DVT were investigated for the presence of resistance to activated protein C (APC-R), lupus anticoagulant (LA), anticardiolipin antibodies and deficiencies of protein C, protein S, ATIII activities. Fifty nine normal healthy individuals served as controls. APC-R was observed to be the commonest defect underlying the Indian DVT as seen in 39.2% of patients followed by elevated ACA (5.3%), PAI (2.8%), presence of LA (2.8%) and reduced ATIII levels (2.8%). None of the subjects had protein C or S deficiency. APC-R was associated with ATIII deficiency in one case, and elevated ACA in two cases. In two subjects, APC-R was associated with elevated PAI levels. Patients with more than one prothrombotic factor had a higher prevalence of pulmonary thromboembolism, suggesting that the thrombogenic potential of APC-R is enhanced by the presence of coexisting hereditary or acquired prothrombotic defect.
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PMID:Pathogenetic factors underlying juvenile deep vein thrombosis (DVT) in Indians. 1041 51

Changes of hemostatic parameters during percutaneous transluminal coronary angioplasty (PTCA) in 75 patients with chronic coronary artery disease were evaluated. Plasma levels of D-dimer, soluble fibrin monomer, plasmin-alpha2 antiplasmin inhibitor complex, and tissue factor (TF) were significantly increased in all patients with chronic coronary artery disease. The activity of antithrombin and protein C and the levels of protein C antigen were significantly decreased 1 hr after PTCA, but they returned to normal range 1 day after PTCA. There was no significant difference in the level of plasma APC-PCI complex before and 1 hr after PTCA. The plasma levels of D-dimer, soluble fibrin monomer, thrombomodulin, TF and PPIC were significantly decreased 1 hr, and the plasma levels of plasmin-alpha2 antiplasmin inhibitor complex 1 day after PTCA. These findings suggest that the decrease of protein C and antithrombin resulted in activation of the coagulation system. One hour after PTCA, the plasma levels of (total-free) TF pathway inhibitor (TFPI) were significantly decreased, but the plasma levels of total and free-TFPI were significantly increased, suggesting that consumption of (total-free) TFPI occurs during PTCA. Overall, these findings suggest that the hypercoagulable state improves during PTCA and that transient decrease of antithrombin, protein C, (total-free) TFPI or plasmin-alpha2 antiplasmin inhibitor complex may cause restenosis of coronary artery.
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PMID:Changes of plasma hemostatic markers during percutaneous transluminal coronary angioplasty in patients with chronic coronary artery disease. 1044 Sep 9

Within the last few years, the knowledge of hereditary and acquired risk factors for venous thromboembolism has increased. Antithrombin-, protein C- and protein S-deficiency have been known since a long time as hereditary risk factors. Since 1993, three hitherto unknown risk factors have been described, the APC (activated protein C) resistance, hyperhomocysteinemia and a polymorphism in the 3-UT region of the prothrombin gene. These risk factors are relatively common in the normal population (in total 10-15%) and are found in 30-50% of patients with venous thromboembolism. The most important acquired risk factor for thromboembolism is the antiphospholipid antibody syndrome (APLS). The APLS is found in around 3% of patients with thromboembolism, patients with these abnormalities have a high risk for recurrency. The upper mentioned risk factors for thromboembolism do not only increase the risk for spontaneous thrombosis, but also the risk for thrombosis during typical high risk situations, such as surgery, trauma of the lower extremities, pregnancy and delivery. APC resistance and antithrombin deficiency increase the risk for development of thrombosis during oral contraceptive intake. Patients, in whom one of the upper mentioned risk factors have been diagnosed, should receive thrombosis prophylaxis during high risk situations. Not all patients with one thromboembolic event and a known risk factor are candidates for long-term oral anticoagulant treatment. Long-term oral anticoagulant treatment should be introduced after exclusion of major contraindications in patients with recurrent events, patients with a combination of risk factors and a life threatening event.
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PMID:[Thromboembolism--genetic and acquired risk factors]. 1047 76

Human anticoagulant activated protein C (hAPC) is less potent than the bovine APC (bAPC) molecule and our aims were to elucidate the molecular background for this difference and to create an APC with enhanced anticoagulant activity. In the protease domain of human protein C (hPC), the loop 148 (GWGYHSSREKEAKRN) is four residues longer than the corresponding loop in bovine APC (GWGY RDETKRN). To investigate whether this caused the species difference, the loop in hPC was replaced by the shorter bovine loop, whereas the longer human loop was introduced in bovine protein C. The mutation in hAPC yielded enhanced catalytic activity against chromogenic (4-fold) as well as natural (factors Va and VIIIa) substrates and 2-3-fold increased anticoagulant activity. The opposite effects were obtained with the bovine mutant. As compared to wild-type hAPC, the mutant hAPC was inhibited slightly faster by the protein C inhibitor, whereas the inhibition by alpha1-antitrypsin was unaffected by the mutation. A computer model of bAPC was developed in order to analyse further our data. Collectively, our results demonstrate enhanced catalytic efficiency to result from mutagenesis in the loop 148 and show that APC mutant with increased anticoagulant activity can be created.
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PMID:Interspecies loop grafting in the protease domain of human protein C yielding enhanced catalytic and anticoagulant activity. 1049 67

Many hemostatic and fibrinolytic parameters have been evaluated following hormone replacement therapy (HRT) but little is known about its influence on the anticoagulant response to activated protein C (APC-sensitivity). For this purpose, we studied the effect of transdermal 17-beta-estradiol (50 microg/24 h) by a continuous regimen on the APC-sensitivity, in 28 postmenopausal hysterectomized women (mean age, 47 years; range, 44-65 years). We also measured the plasma proteins directly involved in the protein C anticoagulant pathway, such as activities of factor VIII (VIII:C), factor V and free protein S. Von Willebrand factor (vWF) antigen, the carrier protein of factor VIII, was also determined. Blood sampling was done at baseline and after 16-week therapy. A significant increase in the normalized APC-sensitivity ratio (n-APC-SR) values (mean +/- SD: pre-trial, 0.88 +/- 0.14; post-trial, 1.01 +/- 0.12; P < 0.001) and a significant decrease of factor VIII:C plasma levels (pre-trial, 1.13 +/- 0.29 IU/ml; post-trial, 0.98 +/- 0.20 IU/ ml; P = 0.001) were found. No difference was observed in factor V, protein S and vWF plasma levels. Correlation studies demonstrated only a significant negative correlation between the percent change in n-APC-SR and the percent change in factor VIII:C (r = -0.574; P = 0.001). Our findings clearly show that HRT with transdermal estradiol improves the anticoagulant response to APC, probably as a result of a decreased factor VIII:C. We also suggest that a similar but opposite mechanism may occur for perorally administered estrogens used in the HRT. These results may have some clinical implications about the reported increase of the risk for venous thromboembolism following HRT.
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PMID:Beneficial effects of postmenopausal hormone replacement therapy with transdermal estradiol on sensitivity to activated protein C. 1075 11

These results, obtained in a small series of patients, suggest that both the ProC Global assay and the PCP Test would be suitable, using well-defined cut-off levels, to identify all the carriers of the Factor V Leiden mutation and all the patients with a protein C deficiency or with combined defects of the protein C pathway. For both assays, however, the sensitivity for protein S deficiency was below 60%. These results in selected patients are congruent with those previously reported in the literature about the ProC Global assay, the PCP Test, and other assays evaluating the functionality of the protein C anticoagulant pathway. All demonstrated a weak sensitivity to protein S deficiency, suggesting that protein S plays only a minor role as an APC cofactor in such global assays. A major discrepancy between the two evaluated assays was obtained in the group of patients without abnormality of the protein C pathway. Actually, using the ProC Global assay, more than 40% of the patients had a decreased PCAT-NR while presenting with none of the three tested abnormalities, whereas none of the studied patients had a ratio below 1.80, and only 5 of 143 (3.5%) had a ratio below 2.00 when using the PCP Test. The observation that around 40% of the control patients had a decreased PCAT-NR could suggest the influence of currently unknown defects of the protein C/protein S pathway on the ProC Global assay. It could also be hypothesized that the higher factor VIII levels already reported in patients with a history of thrombosis than in controls had a significant role in the low responsiveness, but this parameter was not tested in the authors' series. In that connection, it is also well established that elevated factor VIII levels both shorten the APTT and reduce the anticoagulant effect of heparin when evaluated using APTT. Actually, some of the samples investigated in this study were obtained during the acute phase of thrombosis. It is not possible to draw out the hypothesis of an association of biologically undetectable minor changes in various factors involved in the protein C anticoagulant pathway; all the individual factors would remain within their normal ranges. Finally, because 40% of the patients without abnormalities of the protein C pathway had a decreased PCAT-NR, the question arises whether the ProC Global assay might in itself be a biologic marker of thrombophilia, independent of its sensitivity for abnormalities of the protein C anticoagulant pathway. In that connection, the correlation between the result of the ProC Global assay and the risk for thromboembolism was recently evaluated by two different groups. In both cases, the preliminary results suggested that a decreased response to the ProC Global assay might be an independent risk factor for venous thrombosis. The two global assays could therefore have distinctly different applications. If the global assays are used in the hemostasis laboratory to screen for abnormalities of the protein C pathway, and thus to rationalize the use of specific assays, the PCP Test should be chosen, because of its high specificity. Because only 3.5% of the control patients had a ratio below 2.00 (and none had a ratio below 1.80), the PCP Test could be accurately used as a first-step assay in the laboratory screening for these abnormalities of the protein C anticoagulant pathway. Using such a flow chart, the specific assays for APC resistance or the identification of the factor V Leiden mutation and protein C would be performed only in case of a ratio below a cut-off defined using receiver operating characteristic (ROC)-analysis in unselected patients. Because of the weak sensitivity of this assay to both constitutional and acquired protein S deficiencies (below 15% using 1.80 as the cut-off level, or 60% using 2.00), the measurement of this parameter had to be performed in all cases. If, on the other hand, the assay is used to screen for risk factors for thrombosis, the ProC Global assay could b
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PMID:Screening for risk factors for thrombosis using a new generation of assays developed to evaluate the functionality of the protein C anticoagulant pathway. 1080 61

To search for evidence of coagulation activation ex vivo, the levels of human prothrombin fragment 1+2 (F1+2) were examined in 69 beta-thalassemia/Hb E patients. Levels of protein C inhibitor (PCI) and activated protein C - PCI (APC:PCI) complex were also determined in 9 of the above patients in conjunction with protein C (PC) antigen and activity, in an attempt to detect increased consumption of PC. In mean level of F1+2, there was a statistically significant difference between normal control and post-splenectomized patients (p < 0.05) but not between normal control and non-splenectomized patients (p > 0.05). The mean levels of PC activity and PC antigen in the patients were much lower than in normal controls. However, the mean levels of PCI and the mean level of APC:PCI complex in the patients were not significantly different from those in normal controls (p > 0.05). The high level of F1+2 in post-splenectomized patients found in this study agreed well with clinical and other laboratory findings. The normal level of PC inhibitor and APC:PCI complex found in this study provided no evidence of increased consumption of protein C in thalassemia patients.
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PMID:Hemostatic alterations in beta-thalassemia/hemoglobin E patients. 1092 66


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