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)

We determined the numbers, cellular origin and thrombin-generating properties of microparticles in healthy individuals (n = 15). Microparticles, isolated from fresh blood samples and identified by flow cytometry, originated from platelets [237 x 10(6)/L (median; range 116-565)], erythrocytes (28 x 10(6)/L; 13-46), granulocytes (46 x 10(6)/L; 16-94) and endothelial cells (64 x 10(6)/L; 16-136). They bound annexin V, indicating surface exposure of phosphatidylserine, and supported coagulation in vitro. Interestingly, coagulation occurred via tissue factor (TF)-independent pathways, because antibodies against TF or factor (F)VII were ineffective. In contrast, in our in vitro experiments coagulation was partially inhibited by antibodies against FXII (12%, p = 0.006), FXI (36%, p <0.001), FIX (28%, p <0.001) or FVIII (32%, p <0.001). Both the number of annexin V-positive microparticles present in plasma and the thrombin-generating capacity inversely correlated to the plasma concentrations of thrombin-antithrombin complex (r = -0.49, p = 0.072 and r = -0.77, p = 0.001, respectively), but did not correlate to prothrombin fragment F1+2 (r = -0.002, p = 0.99). The inverse correlations between the number of microparticles and their thrombin-forming capacity and the levels of thrombin-antithrombin complex in plasma may indicate that microparticles present in the circulation of healthy individuals have an anticoagulant function by promoting the generation of low amounts of thrombin that activate protein C. We conclude that microparticles in blood from healthy individuals support thrombin generation via TF- and FVII-independent pathways, and which may have an anticoagulant function.
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PMID:Cell-derived microparticles circulate in healthy humans and support low grade thrombin generation. 1134 98

Various heterologous reporter genes have been widely used for the functional characterization of gene promoters. Many such studies often found weak to very strong silencer activities to be associated with specific parts of the basal promoter or further upstream regions. In this study, we carried out a systematic study on human blood coagulation factor IX (hFIX) and anti-coagulant protein C (hPC) genes, previously shown to have silencer activities associated with their 5'-flanking regions containing promoter sequences. With newly constructed chloramphenicol acetyltransferase (CAT) reporter vectors carrying hFIX or hPC gene promoter sequences, we confirmed the strong silencer activities associated with the regions nt -1895 through nt -416 of the hFIX gene or with the region nt -802 through nt -82 of the hPC gene. However, no such silencer activities associated with the specific regions were found when autologous hFIX cDNA, hFIX minigenes, or hPC minigenes were used as reporters in the expression vector system. Relative levels of CAT, hFIX, and hPC proteins produced in the transient assays correlated well with their mRNA levels. Human FIX minigene constructs containing a simian virus 40 (SV40) 3'-untranslated region (UTR) taken from the CAT reporter gene showed no silencer activity, indicating that SV40 3'-UTR sequence of the CAT reporter gene does not contribute to the silencer activity. Expression vectors constructed with the beta-galactosidase gene under the control of hFIX gene promoter sequences also showed no silencer activity associated with the region nt -1895 through nt -416. These findings indicate that silencer activities associated with specific regions of promoter sequences as analyzed with CAT reporter genes may represent artifacts specific to the CAT reporter genes. Our findings strongly suggest a need for re-examination of promoter characterizations of many eukaryotic genes, which have been studied to date with CAT reporter genes.
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PMID:Limitation in use of heterologous reporter genes for gene promoter analysis. Silencer activity associated with the cloramphenicol acetyltransferase reporter gene. 1247 56

C-reactive protein (CRP) has been proposed as a risk factor for cardiovascular disease; however, this association is confounded by mutual relationships with both classical and haematological cardiovascular risk factors. We, therefore, measured CRP with a high-sensitivity assay in stored plasma samples from 414 men and 515 women in the north Glasgow MONICA (MONItoring trends in CArdiovascular diseases) survey, to study its correlation with haematological variables, classical risk factors and prevalent cardiovascular disease. CRP correlated with age, oral contraceptive use, menopause and most classical cardiovascular risk factors (except blood pressure). CRP also correlated with plasma levels of the pro-inflammatory cytokine interleukin 6, and haematocrit, viscosity, red cell aggregation, white cell count, and coagulation factors [fibrinogen, factor (F) VII in women, FVIII, FIX] and inhibitors (antithrombin and protein C in women; protein S) but not coagulation activation markers. CRP was significantly associated with prevalent cardiovascular disease in both men (P = 0.03) and women (P = 0.009), however, the association became non-significant after adjustment for firstly classical risk factors, then fibrinogen. We conclude that correlations with classical and haematological risk factors account for a substantial component of the association of CRP with prevalent cardiovascular disease, but there is evidence of a residual, independent effect among women.
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PMID:C-reactive protein: associations with haematological variables, cardiovascular risk factors and prevalent cardiovascular disease. 1282 55

In mammalian blood coagulation, five proteases (factor VII [FVII]; factor IX [FIX]; factor X [FX]; protein C [PC] and prothrombin [PT]) act with five cofactors (tissue factor [TF]; factor V [FV]; factor VIII [FVIII]; thrombomodulin and protein S) to control the generation of fibrin. Biochemical evidence, molecular cloning data and comparative sequence analysis support the existence of all components of this network in all jawed vertebrates, and strongly suggest that it evolved before the divergence of teleosts over 430 million years ago. Phylogenetic analysis of the amino acid sequences of the Gla-EGF1-EGF2-SP domain serine proteases (FVII, FIX, FX, PC) and the A domain-containing cofactors (FV and FVIII) strongly supports the evolution of the blood coagulation network through two rounds of gene duplication, and supports the hypothesis that vertebrate evolution benefited from two global genome duplications. The jawless vertebrates (hagfish and lamprey) that diverged over 450 million years ago have a blood coagulation network involving TF, PT and fibrinogen. Preliminary evidence indicates that they may have a smaller complement of Gla-EGF1-EGF2-SP domain proteins, suggesting the existence of a 'primitive' coagulation system in jawless vertebrates.
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PMID:450 million years of hemostasis. 1287 Dec 84

Hydroxyurea (HU) has been shown to reduce the frequency of vaso-occlusive manifestations in both adults and children with sickle cell disease (SCD), and the induction of hemoglobin F (HbF) is thought to be the underlying mechanism responsible for clinical improvement in some patients. However, there exists no good correlation between the amount of HbF increase and clinical response. Recent studies suggest that increased activity of the coagulation system may be important in the pathogenesis of vascular occlusion in sickle cell disease. To analyze the effect of HU on the coagulation system in children, the authors studied the levels of some coagulation factors and natural inhibitors. Eleven children who had been treated with HU because of SCD (5 patients), sickle-beta-thalassemia (3 patients), and beta-thalassemia intermedia (3 patients) were enrolled in the study. Levels of the coagulation factors II, V, VII, VIII, IX, X, XI, and XII, and of protein C and protein S, prothrombin times, activated partial thromboplastine times, thrombin times, and reptilase times were measured before the treatment and at the 5th or 6th months of HU therapy when the patients were in a steady-state condition. There was a decrease in all of the coagulation factors except for FIX and FXII and in inhibitors such as protein C and protein S. However, statistically significant decreases were observed only in factor VIII and protein C levels. The rates of decrease were 54.8 and 12.5% (p = .015 and p = .018) in FVIII and protein C, respectively. This result shows that HC has significant effects on the coagulation and natural inhibitory systems.
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PMID:The effect of hydroxyurea on the coagulation system in sickle cell anemia and beta-thalassemia intermedia patients: a preliminary study. 1463 15

The etiology of venous thromboembolic disease has been the subject of several recent discoveries, particularly on genetic predisposing factors. The laboratory investigation that may help to evaluate the risk for individual patients includes the measurements of coagulation inhibitors (antithrombin, protein C, and protein S) in plasma assays, the search for the factor V Leiden mutation by the plasma activated protein C resistance test (always to be confirmed by DNA analysis when abnormal), and the search for the prothrombin gene mutation by DNA analysis. Among acquired abnormalities, the most frequently involved are phospholipid-dependent autoantibodies associated or not with a subset of antibodies having an anticoagulant effect in vitro (lupus anticoagulant). Other coagulation abnormalities such as increased FVIII, FIX, or FXI levels or hyperhomocysteinemia have been suggested to be risk factors for thrombosis, although additional studies are required to definitively assess their role.
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PMID:Venous thromboembolic disease: risk factors and laboratory investigation. 1519 17

During tissue factor (TF)-induced coagulation, the factor (F)VIIa-TF complex activates factor (F)X and factor (F)IX. Through positive feedback, the generated FXa and FIXa activate FVII-TF. The first epidermal growth factor-like (EGF1) domains of FX and FIX serve as important TF-recognition motifs when FVIIa-TF activates FX or FIX. Here, we investigated the role of EGF1 domains of FXa and FIXa during the activation of FVII-TF and inhibition by tissue factor pathway inhibitor (TFPI). FXaPCEGF1 (EGF1 domain of FXa replaced with that of protein C), and FXaQ49P (EGF1 domain mutant with impaired calcium-binding), and the corresponding FIXa mutants were generated, and their abilities to activate FVII-TF were compared with the wild-type (WT) enzymes. In the absence of TF, the rates of FVII activation were similar between WT enzymes and mutant FXa and FIXa proteases. In the presence of either soluble TF (sTF) or relipidated TF, each mutant of FXa or FIXa activated FVII-TF at a slower rate than the corresponding WT enzyme. Kinetics of inhibition of the amidolytic activity of WT and the mutant FXa proteases by either two-domain or full-length TFPI were similar. However, compared with the complex of TFPI-FXaWT, the abilities of the complexes of TFPI-FXa mutants to inhibit FVIIa-TF were impaired. We conclude that the EGF1 domains of FXa and FIXa are important for the activation of FVII-TF and for the formation of FVIIa-TF-FXa-TFPI complex.
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PMID:The first epidermal growth factor-like domains of factor Xa and factor IXa are important for the activation of the factor VII--tissue factor complex. 1563 74

Autoimmune thrombocytopenic purpura (ITP) is a disease that presents with skin and mucous membrane bleeding due to thrombocytopenia. In the literature, there are a few studies about the effect of high-dose steroid therapy on coagulation tests in different diseases, but their results are still controversial. In this study, coagulation parameters were investigated that might have a role in hemostatic compensation in childhood acute ITP before and after high-dose methylprednisolone (HDMP) treatment. The study includes 21 children age 1.5 to 14 years with acute ITP and 21 healthy age-matched control subjects. All patients with acute ITP received HDMP for 7 days. Before and after HDMP treatment (0 and 8 days) prothrombin time, partial thromboplastin time, fibrinogen, Protein C, Protein S, antithrombin III, and the levels of factor II (FII), FV, FVII, FVIII, FIX, FX, FXI, and FXII were studied in all subjects. The results were compared with those of the control group. Pre-treatment Protein C and Protein S levels in the patient group were significantly lower than those in the control groups (p<0.05). Protein S and Protein C levels were significantly improved after HDMP treatment in patient group. There were lower FV, FVII, FX values in the patient group compared to the control groups on admission. There was no difference in AT III and fibrinogen levels before and after treatment. As a result, some changes in the coagulation system associated with thrombocytopenia were observed in patients with acute ITP. These changes may be accepted as compensatory mechanisms to maintain hemostasis.
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PMID:Effects of high-dose methylprednisolone therapy on coagulation factors in patients with acute immune thrombocytopenic purpura. 1624 77

Factor VIII (FVIII) inhibitors develop as either alloantibodies against exogenous FVIII in patients with congenital hemophilia A after FVIII-replacement therapy or as autoantibodies against endogenous FVIII in previously healthy, nonhemophilic individuals. The predominant immunoglobulin G (IgG) subclass of FVIII inhibitors is IgG(4). The main epitopic regions are known to be located, however, in the A2, A3, and C2 domains. The A2 and A3 epitopes have been identified between amino acid residues 484 and 509 and residues 558 and 565, respectively. Both of these regions are close to the binding sites for activated FIX (FIXa). Two regions have been identified in the C2 domain, one in the amino-terminal portion of the domain (residues 2181-2243) and the other in the carboxy-terminal portion of the domain (residues 2248-2312 and residues 2315-2330). In addition, a crystallographic analysis of a complex of the C2 domain and a human monoclonal IgG(4)(K) Fab revealed that this type of antibody is in direct contact with hydrophobic and basic residues of the membrane-binding surface. Inactivated FVIII is rapidly cleared from the circulation in the presence of inhibitors. The inhibitors also bind to essential FVIII ligand proteins, including von Willebrand factor, FIXa, FXa, and thrombin, and to surface membrane phospholipid. Some type 2 inhibitors interfere with binding to activated protein C.
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PMID:Characterization of factor VIII inhibitors. 1651 28

We have developed a cell-based model of thrombin generation using activated monocytes as a source of tissue factor (TF) and platelets serving as a surface for thrombin generation. Monocytes are activated by lipopolysaccharide and express cell-bound TF. To these are added physiologic (plasma) concentrations of all the plasma procoagulants as well as TF pathway inhibitor, antithrombin, and C1-esterase inhibitor. Coagulation takes place in microtiter wells and is initiated by factor VIIa (FVIIa) and calcium. At time intervals, aliquots are removed, platelet activation is measured by the expression of P-selectin, and thrombin generation is measured by chromogenic assay. In addition, one can measure the activation of FIX, FX, FVIII, FV, and FXI. Initial results reveal that the FVIIa-TF interaction results in the activation of FX to FXa and FIX to FIXa. FXa stays in the vicinity of the TF-bearing cell and, in the presence of FVa, converts a small amount of prothrombin to thrombin on the surface of the TF cell. This small amount of thrombin is not sufficient to clot fibrinogen, but is sufficient to activate platelets and FVIII, FV, and FXI. Following platelet activation, FVIIIa, FVa, and FXa occupy sites on the activated platelet surface. FIXa, activated by TF-FVIIa, does not remain on the TF cell, but converts FX to FXa on the platelet surface. FXIa acts to boost FIXa generation on the activated platelet, increasing FXa and subsequent thrombin generation. We have also shown that activated protein C does not inactivate Va on the platelet surface but rather on endothelial cell surfaces.
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PMID:A cell-based model of thrombin generation. 1667 64


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