UNIPROT:P00750 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of human activated protein C (APC) on fibrinolysis was studied in a cell-free system by continuously monitoring the thrombin-induced formation and subsequent tissue-type plasminogen activator-induced degradation of fibrin. In systems comprising dialyzed human plasma, APC shortens the time for lysis to occur in a concentration-dependent, saturable manner. Half-maximal activity occurs at an APC concentration of 10 nM. The effect is mediated by enhanced plasminogen activation and is dependent upon ionized calcium. The effect is lost when plasma adsorbed with barium citrate is utilized in place of unadsorbed plasma. The effect can be reconstituted, however, from components recovered from the barium citrate precipitate. Fractionation of the barium citrate adsorbable proteins with polyethylene glycol (PEG) provides two fractions, one of which is obtained by precipitation at 5% PEG, and the other of which is obtained from the 5% PEG supernatant by further precipitation at 40% PEG. The latter fraction contains Factor X and presumably the other vitamin K-dependent clotting factors. Both of these fractions together, but neither of them alone, fully reconstitute barium-adsorbed plasma, such that APC-enhanced fibrinolysis occurs as in non-adsorbed plasma. These fractions also are sufficient to provide for an APC effect in a system in which purified plasminogen and fibrinogen are used in place of barium citrate-adsorbed plasma. Thus, an effect of APC on tissue-type plasminogen activator-induced fibrinolysis exists which is Ca2(+)-dependent and requires two or more, as yet unidentified, components that can be precipitated from human plasma by barium citrate.
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PMID:The activated protein C-mediated enhancement of tissue-type plasminogen activator-induced fibrinolysis in a cell-free system. 212 Feb 9

Hemostatic abnormalities are present in a majority of patients with metastatic cancer. These abnormalities can be categorized as 1) increased platelet aggregation and activation, 2) abnormal activation of coagulation cascade, 3) release of plasminogen activator, and 4) decreased hepatic synthesis of anticoagulant proteins like Protein C and antithrombin III. The abnormal activation of coagulation cascade is mediated through release of Tissue Factor, Factor X activators, and other miscellaneous procoagulants from the plasma membrane vesicles of tumor cells. Macrophages of a tumor-bearing host also produce increased amounts of Tissue Factor. Production of Factor X activators and macrophage Tissue Factor is decreased by warfarin. The ability of the tumor cells to produce platelet-aggregating activity and plasminogen activator parallels their metastatic potential in animal and experimental systems. These studies also show that antiplatelet agents and antibodies against plasminogen activator can suppress the metastatic process. One or more laboratory abnormalities of hemostasis can be shown in up to 95% of patients with metastatic cancer. These abnormalities, however, are unable to predict subsequent development of thromboembolic or hemorrhagic complications. Clinical complications occur in 9-15% of the patients in the form of thrombotic or hemorrhagic disorders. The therapy of tumor-related coagulopathy should be guided by its clinical expression. Subclinical DIC should not be treated. Coumadin is generally ineffective for therapy of thrombosis in cancer patients. There is no consensus regarding the use of heparin in acute promyelocytic leukemia (APL). The defibrination in APL may be from disseminated intravascular coagulation as well as systemic fibrinolysis, as shown by decreased alpha 2 antiplasmin levels. In such cases, epsilon aminocaproic acid plus heparin therapy may be of benefit.
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PMID:Hemostasis in malignancy. 174 46

Alveolar fibrin deposition commonly accompanies acute lung injury, but the nature of the local abnormalities of coagulation and fibrinolysis that support pathologic fibrin deposition are not well understood. The trended abnormalities of procoagulant and fibrinolytic activities occurring in lung lavage fluids of Fischer 344 rats after lung injury induced by intravenous oleic acid (OA) or intratracheal bleomycin were studied. After injury by either agent, bronchoalveolar lavage (BAL) contained increased procoagulant activity and decreased fibrinolytic activity. Lavage procoagulant activity was mainly due to an activator of Factor X attributable to the extrinsic coagulation pathway, and fibrinolytic activity was almost completely plasminogen dependent. Major mechanisms of inhibition of fibrinolytic activity involved both the inhibition of the plasminogen activator (PA) and plasmin. These abnormalities were temporally associated with prominent alveolar fibrin deposition in both models. In OA-treated animals, lavage fibrinolytic activity was absent or profoundly decreased, and antiplasmin and procoagulant activities were increased within 4 hours after the induction of acute lung injury. By 24 hours after OA, lavage PA inhibitor (PAI) activity was elevated with sustained antiplasmin activity. By 3 days after OA, these abnormalities had resolved in association with almost complete resolution of alveolar fibrin deposits. Within 3 days after bleomycin-induced lung injury, lavage procoagulant activity was increased and fibrinolytic activity was depressed due to increased antiplasmin and PAI activities. These conditions persisted for 2 weeks, during which time alveolar fibrin deposition was associated with the development of pulmonary fibrosis. These data indicate that a disruption of the normal balance between procoagulant and fibrinolytic activities occurs in alveolar lining fluids of rats with alveolitis induced by either OA or bleomycin, and that concurrent abnormalities of pathways of fibrin turnover that occur in alveolar lining fluids promote the alveolar fibrin deposition associated with these lung injuries.
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PMID:Abnormalities of pathways of fibrin turnover in lung lavage of rats with oleic acid and bleomycin-induced lung injury support alveolar fibrin deposition. 247 34

To identify factors potentially influencing expression of type 1 plasminogen activator inhibitor (PAI-1), we characterized the human tissue-specific distribution of PAI-1 mRNA and the influence of epidermal growth factor (EGF) on expression of steady state levels of PAI-1 mRNA and secretion of PAI-1 by Hep G2 cells. Two species of PAI-1 mRNA (3.2 and 2.2 kilobases) were detected, and the ratio of the two varied among tissues (3 to 5:1) in contrast to the 1:1 ratio detected in Hep G2 cells. Expression of PAI-1 mRNA was inversely related to the distribution of tissue-type plasminogen activator mRNA (2.3 kilobases). Nu-Serum, a growth media supplement, increased steady state levels of PAI-1 mRNA 5-fold within 3 h. Factors responsible were found to be trypsin-sensitive and dialysis-resistant. Antisera to EGF attenuated Nu-Serum-induced increases of PAI-1 mRNA by 57%, suggesting that EGF or EGF homologous peptides contributed to the response. EGF elicited increases of PAI-1 mRNA levels in a dose-dependent manner. Induction was rapid (7-fold at 3 h with 5 ng/ml) and complete within 10 h. The response was not attenuated by cycloheximide (25 micrograms/ml). Factor X and glyceraldehyde-3-phosphate dehydrogenase mRNA did not increase. Increased levels of PAI-1 antigen were detected in conditioned media of Hep G2 cells by 4 h and were maximal at 8 h (6-fold). We conclude that the expression of PAI-1 mRNA is tissue-specific and regulated by epidermal growth factor in Hep G2 cells.
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PMID:Regulation of the expression of type 1 plasminogen activator inhibitor in Hep G2 cells by epidermal growth factor. 284 25

It has been demonstrated that the surface of large VLDL Sf 100-400 can bind both prothrombin and Factor X(Xa) and that on VLDL Factor Xa can convert prothrombin to thrombin, which degrades apo B and apo E. It has been reported also that the VLDL kinetically supports the conversion of prothrombin to thrombin. The binding of vitamin K-dependent proteins to phospholipid is partially Ca2+-dependent and probably involves their Gla residues. The complex of VLDL, prothrombin, Factor Xa, and Ca2+ lacks only Factor Va, a lipid associating, non-Gla residue containing 330 kd protein, to complete the "prothrombinase complex." Factor V (Va) is found at very low concentrations in the circulation, but is localized on platelets, monocytes, and the endothelium. VLDL can bind both to monocytes and to the endothelium, for example, through both receptor and non-receptor pathways. When carrying this complement of the prothrombinase complex, this subpopulation of VLDL, in the presence of Factor Va on cell surfaces, could conceivably upset the local balance of pro- and anticoagulant activities. Thus, directly or indirectly the increased triglyceride levels, reflected in increased VLDL in patients, may alter this balance, and thereby produce a "hypercoagulable state." This is a simplistic view of the potential role of VLDL in the interplay of cells, coagulation proteins, and the regulatory systems involved in vivo. To realize the degree of complexity that we may need to address, we need only look at the work of Booyse et al in this issue of Seminars, in which they demonstrate that hypertriglyceridemic VLDL, in contrast to normal VLDL, do not support the early release of t-PA from endothelial cells, an antifibrinolytic event.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vitamin K-dependent proteins bind to very low-density lipoproteins. 305 90

The effect of Norplant subdermal implants on 22 different hemostatic variables was determined in 100 women attending the Fertility Control Clinic of the Singapore National University Hospital before and after 6 and 12 months of use. The factors analyzed were: hematocrit, hemoglobin (Hb), prothrombin time (PT), activated partial thromboplastin time (APTT), platelet count, fibrinogen, coagulation factor II, Factor V,Factor VII, Factor VIII, Factor VIIIR:Ag, Factor X, plasminogen activator, FDP, plasminogen (imm), antithrombin III (functional), antithrombin (antigen), protein C, alpha2-antiplasmin, alpha2-macroglobulin, alpha2-antitrypsin, platelet count, platelet aggregation (ADP), and platelet aggregation (collagen). The factors that differed significantly after 12 months were: Hb,PT,APTT, Factors II,V,VII, and VIIIR:Ag, Plasminogen (imm), antithrombin III(antigen), alpha2-antiplasmin, platelet count, and platelet aggregation. Most of these differences, while significant, were still within the normal range, except for PT,APTT, and platelet count. The subjects were considered to be in an enhanced risk for hypercoagulation and thrombosis.
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PMID:The effects of Norplant-2 rods on clinical chemistry in Singaporean acceptors after 1 year of use: haemostatic changes. 314 69

Both fibrin and tissue macrophages are prominent in the histopathology of chronic inflammatory pulmonary disease. We therefore examined the procoagulant activity of freshly lavaged human alveolar macrophages in vitro. Intact macrophages (5 X 10(5) cells) from 13 healthy volunteers promoted clotting of whole plasma in a mean of 65 s. Macrophage procoagulant activity was at least partially independent of exogenous Factor VII as judged by a mean clotting time of 99 s in Factor VII-deficient plasma and by neutralization of procoagulant activity by an antibody to Factor VII. Immunoprecipitation of extracts of macrophages metabolically labeled with [35S]methionine by Factor VII antibody and analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed a labeled protein consistent in size with the known molecular weight of blood Factor VII, 48,000. The addition of 50 micrograms of unlabeled, purified Factor VII blocked recovery of the 48,000-mol wt protein. In addition, supernatants of cultured macrophages from six normal volunteers had Factor X-activating activity that was suppressed an average of 71% after culture in the presence of 50 microM coumadin or entirely by the Factor VII antibody indicating that Factor VII synthesized by the cell was biologically active. Endotoxin in vitro induced increases in cellular tissue factor but had no consistent effect on macrophage Factor VII activity. We also examined the tissue factor and Factor VII activities of freshly lavaged alveolar cells from nine subjects with clinical and/or histologic evidence of sarcoidosis. Four of the nine subjects expressed increased tissue factor and seven of nine had increased Factor VII activity over the normal range (P less than 0.01). We estimate the mean Factor VII associated with the cells of sarcoid patients to be 4.7 ng/10(6) cells (range 0.4-20) as compared to a mean of 0.74 ng/10(6) cells (range 0.2-2) for that of normal subjects. Along with previous data showing synthesis of plasminogen activator, these findings indicate that human alveolar macrophages normally synthesize and express measurable amounts of the initial enzymes of proteolytic reactions regulating both fibrin deposition and fibrin resorption. Abnormalities in Factor VII activity in a small group of patients with sarcoidosis raise the possibility that modulation of fibrin turnover by macrophages may contribute to the pathology of this and perhaps other interstitial lung diseases.
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PMID:Human alveolar macrophages synthesize factor VII in vitro. Possible role in interstitial lung disease. 400 51

Monocyte infiltration and activation of the coagulation system have been implicated in the pathophysiology of glomerulonephritis. In this study, spontaneous procoagulant activity (PCA) was measured in circulating mononuclear cells to determine whether elevated PCA correlated with the presence of proliferative glomerulonephritis in patients with systemic lupus erythematosus (SLE). No increase in PCA was found in 20 patients with end-stage renal failure, 8 patients with glomerulonephritis without SLE, and 10 patients undergoing abdominal surgical or orthopedic procedures as compared with 20 normal controls. In eight patients with SLE but with no apparent active renal disease, PCA was not elevated above normal basal levels. Seven additional patients with SLE who had only mesangial proliferation on biopsy also had no increase in PCA. In contrast, eight patients with focal or diffuse proliferative lupus nephritis, and one patient with membranous nephritis who ultimately developed a proliferative lesion, had a marked increase in PCA with greater than 100 times the base-line levels. The activity was shown to originate in the monocyte fraction of the mononuclear cells and was shown to be capable of cleaving prothrombin directly. The prothrombinase activity was not Factor Xa, because it was not neutralized by anti-Factor X serum and was not inhibited by an established panel of Factor Xa inhibitors. Monocyte plasminogen activator determinations did not correlate with renal disease activity. We conclude that monocyte procoagulant activity, a direct prothrombinase, seems to correlate with endocapillary proliferation in lupus nephritis and could be a mediator of tissue injury.
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PMID:Monocyte procoagulant activity in glomerulonephritis associated with systemic lupus erythematosus. 403 82

An endothelial cell-associated cofactor that greatly enhances the rate of protein C activation by thrombin has recently been described. The observation that the cofactor binds thrombin with unusually high affinity (K(d) = 0.5 nM) suggested that low level thrombin infusion into dogs might lead to the selective activation of protein C. Infusion of thrombin (1 U/min per kg body wt) into the jugular vein of dogs leads to the formation of a systemic anticoagulant activity within 5 min of starting the infusion. The plasma has a prolonged partial thromboplastin time and Factor X(a) clotting time, but there is no change in the thrombin clotting time. The systemic anticoagulant activity is identified as activated protein C for the following reasons: (a) anti-canine activated protein C IgG antibodies inhibit the anticoagulant activity; (b) the anticoagulant activity can be partially purified from the plasma of dogs infused with thrombin by barium citrate adsorption; (c) the anticoagulant has chromatographic properties on QAE Sephadex indistinguishable from those of activated protein C, and (d) the rate at which this anticoagulant is inhibited in citrated canine plasma is identical to that of canine activated protein C. The in vivo activation of protein C appears to be receptor mediated since it occurs at low thrombin concentration and since it can be progressively inhibited by simultaneous infusion of diisopropylphospho-thrombin with thrombin. The activation of protein C at low levels of thrombin is selective, since neither the platelet count nor the Factor V levels are altered. Thrombin infusion leads to an elevation in circulating plasminogen activator levels. This appears to be mediated through the activation of protein C since coinfusion of diisopropylphospho-thrombin with thrombin inhibits the increase in plasminogen activator levels. Pretreatment of dogs with dicumarol blocks both the formation of anticoagulant activity and the rise in plasminogen activator. When the dicumarol-treated dogs are supplemented with isolated protein C and thrombin is infused, the anticoagulant activity again appears and the circulating levels of plasminogen activator are again elevated. These studies illustrate that low levels of thrombin in vivo can activate protein C, which in turn can inhibit blood coagulation and initiate fibrinolysis by elevating circulating plasminogen activator levels.
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PMID:Activation of protein C in vivo. 617 16

The relation of habitual diet and cardiorespiratory fitness to plasma fibrinogen concentration, Factor VII activity (F VIIc), Factor X activity (F X), tissue plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1) concentrations, anti-thrombin III (AT III) and apolipoprotein(a) (Apo[a]) was analyzed in 111 normolipidemic men aged 51-53 years. Diet was evaluated by seven day food records. Maximal oxygen consumption and aerobic threshold were determined in maximal bicycle ergospirometry test based on breath-by-breath analysis of expired respiratory gas. Plasma fibrinogen was measured by thrombin method, F VIIc by one-stage coagulation method, AT III and F X colorimetrically, t-PA and PAI-1 antigens by ELISA and Apo(a) concentration radioimmunologically. Carbohydrate intake was negatively (r = -0.31, p < 0.001; r = -0.24, p < 0.01; r = -0.36, p < 0.001) and fat intake positively (r = 0.24, p < 0.01; r = 0.29, p < 0.001; r = 0.32, p < 0.001) related to F X, PAI-1, and t-PA, respectively. Aerobic threshold correlated negatively with fibrinogen (r = -0.33, p < 0.001) and F X (r = -0.30, p < 0.001). Fasting insulin was the strongest determinant for PAI-1 (r = 0.55, p < 0.001) and a significant positive correlate to F VIIc (r = 0.30, p < 0.001), F X (r = 0.28, p < 0.01) and t-PA (r = 0.47, p < 0.001). These data emphasize the importance that carbohydrate rich diet and cardiorespiratory fitness may have against thrombogenesis.
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PMID:Relation of habitual diet and cardiorespiratory fitness to blood coagulation and fibrinolytic factors. 819 95

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