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

Lung injury induced by 100% O2 over 6 days is characterized by markedly less alveolar fibrin and rare hyaline membranes in premature versus adult baboons. To determine the mechanism(s) underlying alveolar fibrin deposition in the evolution of hyaline membrane disease (HMD) through diffuse alveolar damage (DAD) and bronchopulmonary dysplasia (BPD), we measured procoagulant and fibrinolytic activities in lung lavage of premature baboons with HMD, those treated with 100% O2 for 6 days (DAD) or for 7 days followed by 14 days 80% O2 (BPD). Lavage procoagulant activity, mainly due to tissue factor associated with Factor VII, was increased by hyperoxia. Plasminogen-dependent fibrinolytic activity, due to both tissue plasminogen activator and urokinase, was stable or increased after hyperoxia. Plasminogen activator inhibitor 1 (PAI-1) was detectable in lavage of animals with HMD but not those with evolving DAD or BPD. Antiplasmin activity was stable or decreased. Although plasminogen was undetectable in lavage, D-dimer was increased in lavage of the groups exposed to hyperoxia versus HMD. The defect in plasminogen activator activity in lavage fluids of adult baboons with DAD induced by O2 does not occur in premature baboons with HMD, evolving DAD, or BPD. Expression of fibrinolytic activity in the lower respiratory tract of premature baboons is dependent on local access to plasminogen, which is present in relatively low concentrations in plasma of these animals.
 ...
PMID:Pathways of fibrin turnover in lavage of premature baboons with hyperoxic lung injury. 811 20

Ecotin, a serine protease inhibitor found in the periplasm of Escherichia coli, has been characterized as an extremely potent anticoagulant and reversible tight-binding inhibitor of human factor Xa (FXa). The ecotin gene was cloned by PCR, highly expressed in E. coli, and purified from the E. coli periplasm. The binding of ecotin to FXa was stoichiometric with an equilibrium dissociation constant Ki of 54 pM. The association rate constant was 1.35 x 10(6) M-1 s-1, and the dissociation rate constant, measured in the presence of human leukocyte elastase (HLE) to prevent reassociation of ecotin with FXa, was 6.5 x 10(-5) s-1. Ecotin prolonged clotting time ca. 10-fold at 0.3 microM and at 2 microM in activated partial thromboplastin time and prothrombin time assays, respectively. Ecotin did not effectively inhibit the human plasma proteases thrombin, tissue factor.factor VIIa, factor XIa, activated protein C, plasmin, or tissue plasminogen activator (t-PA); however, it did potently inhibit factor XIIa, plasma kallikrein, HLE, and bovine trypsin and chymotrypsin. Coincubation of ecotin and FXa at 10 microM each resulted in a (ecotin)2.(FXa)2 complex as determined by gel filtration. Dimerization of ecotin alone was measured by fluorescence titration which yielded a Kd of ca. 390 nM. FXa cleaved ecotin slowly at pH 4.0 between M84 and M85. Replacement of the P1 Met84 residue with Arg and Lys led to FXa inhibitors with Ki values of 11 and 21 pM, respectively. The P1 Arg and Lys mutants also significantly inhibited thrombin, factor XIa, activated protein C, plasmin, factor XIIa, kallikrein, and bovine trypsin and chymotrypsin but did not inhibit tissue factor.factor VIIa, t-PA, or HLE.
 ...
PMID:Ecotin is a potent anticoagulant and reversible tight-binding inhibitor of factor Xa. 814 99

Tissue factor (TF) markedly enhances the ability of factor VIIa (FVIIa) to cleave both macromolecular and small peptidyl substrates. Using soluble mutant TF (sTF) to investigate TF-enhanced FVIIa amidolytic activity in solution, we screened thirty-four commercially available peptidyl-p-nitroanilide substrates and found that substrate hydrolysis rates were influenced by both the peptide sequence and the N-terminal blocking group (MeSO2 > MeO-CO or free N-terminus >> benzoyl). Two substrates (Chromozym t-PA: MeSO2-D-Phe-Gly-Arg-pNA; and CBS 34.47: H-D-cyclohexylglycyl-alpha-aminobutyryl-Arg-pNA) were cleaved at rates higher than those of previously reported chromogenic substrates for FVIIa. The pH range of FVIIa amidolytic activity toward Chromozym t-PA was 6.5 to 10 with an optimum at pH 7.8, while sTF.VIIa had a higher pH optimum (pH 8.4 to 8.5). The degree of enhancement of FVIIa activity by sTF varied from 12-fold at pH 7.5 to 73-fold at pH 9.9. The effect of a variety of agents on FVIIa amidolytic activity was surveyed: most decreased activity, while glycerol and ethylene glycol enhanced the activity of FVIIa but not sTF.VIIa. These results indicate that the effect of sTF on the catalytic center of FVIIa is pH-dependent, and that certain polyalcohols can partially substitute for TF.
 ...
PMID:Importance of substrate composition, pH and other variables on tissue factor enhancement of factor VIIa activity. 816 20

This article has stressed the common hereditary and acquired blood protein defects associated with thrombosis. The commonest hereditary defects appear to be antithrombin, protein C, and protein S deficiency, and the commonest acquired defects are anticardiolipin antibodies and the lupus anticoagulant. Therefore these are the defects that should first be looked for in an individual with unexplained thrombosis. If these commoner defects are not found, the rarer defects, including HC-II, plasminogen or t-PA deficiency, dysfibrinogenemia, or elevated PAI-1, should next be sought. The incidence of activated protein C cofactor deficiency is not yet clear but may also represent a common defect. Likewise, PAI-1 defects may, with time, be shown to be quite common. The importance of finding these defects has significant implications for therapy of the individual patient and for institution of family studies to identify, inform, and possibly treat others at risk. It is expected that as knowledge of hemostasis expands, more hereditary and acquired defects, such as elevated lipoprotein (a) or defects of extrinsic (tissue factor) pathway inhibitor may be associated with enhanced risks of thrombosis.
 ...
PMID:Hypercoagulability and thrombosis. 817 Feb 63

Plasma interleukin-6 (IL-6) was higher in patients with disseminated intravascular coagulation (DIC) than in those without DIC. Levels of IL-1 beta and TNF alpha were also significantly higher in patients with DIC. Plasma IL-6 was highest in patients with underlying sepsis and was also high in those with advanced solid cancer. Levels were high in some patients with acute promyelocytic leukaemia and were significantly higher in patients with organ failure than in those without this complication. Plasma IL-6 was higher in DIC patients showing a poor response to therapy than in those with a good response. Incubation with IL-6 caused significant increases in tissue factor activity in mononuclear cells and release of plasminogen activator-1 antigen from human umbilical vein endothelial cells. As increases in IL-6 might give rise to hypercoagulable and hypofibrinolytic states, this may be a cause of DIC and be related to prognosis and organ failure.
 ...
PMID:Increased plasma level of interleukin-6 in disseminated intravascular coagulation. 821 55

The plasminogen activator systems in the blood, the coagulation system, and the complement pathways are reviewed. The review describes the role of the vascular intima in activation of coagulation and fibrinolysis and the interrelations between the complement system and haemostatic mechanisms. Physiological activation of fibrinolysis may be triggered by and limited to fibrin because of a special affinity of plasminogen and plasminogen activators. The binding of plasminogen to fibrin is regulated by histidine-rich glycoprotein, and the primary physiological inhibitor of generated plasmin is alpha 2-antiplasmin and especially the plasminogen-binding form of this immediate plasmin inhibitor. Plasminogen activator inhibitors in the blood, that is, notably plasminogen activator inhibitor type 1 (PAI-1), bind circulating tissue-type plasminogen activator (t-PA). However, local fibrinolysis in vivo mediated by t-PA may be independent of complex formation between plasminogen activator inhibitors and t-PA in the fluid phase. Circulating plasminogen activator inhibitors might regulate fibrinolysis by increasing the clearance of t-PA from the blood. The urokinase-type and factor XII-dependent fibrinolytic proactivator system can be activated following t-PA-mediated generation of plasmin, and could thus serve as an amplification system of t-PA-induced fibrinolysis. It is claimed that the as yet uncharacterized proactivator is essential for optimal generation of plasminogen activator activity by the factor XII-dependent fibrinolytic system. The normal antithrombotic condition of the vascular intima probably results from lack of tissue factor activity and the presence of significant antithrombotic components comprising, among others, antithrombin III and the protein C-protein S system. A number of pathophysiologic stimuli, notably mediators of the acute phase response such as the cytokines interleukin-1 and tumour necrosis factor-alpha (cachectin), have the potential to induce the vascular endothelium to express procoagulant activity. Vascular endothelium promoting coagulant activity releases increased amounts of t-PA antigen and PAI-1 antigen into the circulation, and elevated levels in the blood of both may be regarded as a marker of a generalized procoagulant condition involving the vascular endothelium. In a prospective study in patients with unstable angina pectoris, patients in whom disease progresses and acute myocardial infarction develops, have increased amounts of t-PA antigen and PAI-1 antigen in the blood. This suggests that the procoagulant potential and atherosclerotic process of the vascular intima is more pronounced in the risk group.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Fibrinolysis in patients with acute ischaemic heart disease. With particular reference to systemic effects of tissue-type plasminogen activator treatment on fibrinolysis, coagulation and complement pathways. 822 63

The clotting and fibrinolytic systems are activated by tissue factor and by tissue-type plasminogen activator in the pericardial cavity, where the thrombogenicity is greater than that of the surface of modern extracorporeal circuits. This local activation may have consequences for the systemic activation processes during cardiopulmonary bypass. To test this hypothesis, we investigated blood activation by interrupting the blood suction from the pericardial cavity during cardiopulmonary bypass in clinical coronary artery bypass operations. In blood collected in the pericardial cavity, thrombin-antithrombin III complex (p < 0.01), tissue-type plasminogen activator antigen (p < 0.05), fibrinogen degradation products (p < 0.01), and fibrin degradation products (p < 0.01) were significantly higher than in the systemic blood. Plasma heparin was significantly consumed in the pericardial cavity (p < 0.01). Once the pericardial blood was returned to the systemic circulation after resumed suction during cardiopulmonary bypass, thrombin-antithrombin III complex (p < 0.05), fibrinogen degradation products (p < 0.05), and fibrin degradation product (p < 0.05) concentrations increased significantly in the systemic blood. The effects of pericardial tissue on activation of clotting and fibrinolysis were also studied in vitro. When human plasma was incubated for 5 minutes with rabbit pericardium at reduced heparin concentrations, we found significant generation of thrombin (p < 0.05) and plasmin (p < 0.05). If the thrombin inhibitor hirudin was added, plasmin generation was also inhibited (p < 0.05). The results of the clinical and experimental study are in agreement with our hypothesis that tissue factor and tissue-type plasminogen activator accelerate the activation of clotting and sequentially of fibrinolysis under conditions of low heparin concentrations in the pericardial cavity and that this local activation contributes highly to the systemic activation, affecting hemostasis during cardiopulmonary bypass. Topical use of heparin in the pericardial cavity therefore seems indicated to reduce blood activation during cardiopulmonary bypass.
 ...
PMID:Activation of fibrinolysis in the pericardial cavity during cardiopulmonary bypass. 823 Dec 4

Knowledge of the pathogenetic mechanisms responsible for the activation of the coagulation system associated with endotoxemia is important for the development of improved modalities for prevention and treatment. We analyzed the appearance in plasma of TNF, IL-6, and indices of coagulation and fibrinolytic system activation in normal chimpanzees after intravenous infusion of endotoxin. Endotoxin infusion elicited reproducible and dose-dependent elevations in serum TNF and IL-6, as well as marked increases in thrombin generation in vivo as measured by immunoassays for prothrombin activation fragment F1 + 2, thrombin-antithrombin III complexes, and fibrinopeptide A. Activation of the fibrinolytic mechanism was monitored with assays for plasminogen activator activity and plasmin-alpha 2-antiplasmin complexes. To potentially intervene in the molecular pathways elicited by endotoxin, pentoxifylline, an agent that interrupts "immediate early" gene activation by monocytes, or a potent monoclonal antibody that neutralizes tissue factor-mediated initiation of coagulation, were infused shortly before endotoxin. Pentoxifylline markedly inhibited increases in the levels of TNF and IL-6, as well as the effects on coagulation and fibrinolysis. In contrast, the monoclonal antibody to tissue factor completely abrogated the augmentation in thrombin generation, but had no effect on cytokine levels or fibrinolysis. We conclude that the endotoxin-induced activation of coagulation appears to be mediated by the tissue factor-dependent pathway, the fibrinolytic response triggered by endotoxin is not dependent on the generation of thrombin, and that the release of cytokines may be important in mediating the activation of both the coagulation and the fibrinolytic mechanisms in vivo.
 ...
PMID:Inhibition of endotoxin-induced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti-tissue factor antibody in chimpanzees. 828 78

Endotoxin released from different strains of Neisseria meningitidis were studied for their ability to induce procoagulant (tissue factor, TF), fibrinolytic (plasminogen activator, PA) and antifibrinolytic (plasminogen activator inhibitor 2, PAI-2) factors in human monocytes. Two meningococcal strains that liberate endotoxin (E+; 270+ and 840+) and 2 non-liberating (E-; 270- and 840-) strains were used. The endotoxin activity in culture filtrates of these strains was monitored with the Limulus amoebocyte lysate (LAL) test. There was a marked difference between E+ and E- strains in their ability to liberate endotoxin. Suspensions of whole bacteria of all 4 strains induced a significant (14-19-fold) increase in monocyte TF expression when present in concentrations > 10(5) CFU/ml. At lower concentrations (10(4) CFU/ml), E+ strains were clearly more potent stimulators of TF synthesis than E- strains. Culture filtrates of E+ strains were up to 10(4)-fold more potent in inducing TF synthesis than filtrates from E- strains. This marked difference in inducing potency between E+ and E- strains was also observed when monocyte PAI-2 synthesis was examined. The PA expression, on the other hand, was suppressed when monocytes were incubated in the presence of culture filtrates, especially filtrates from the E+ strains. The increased procoagulant and antifibrinolytic activity, together with reduced profibrinolytic activity of monocytes, was closely correlated to the amount of endotoxin measured in the culture filtrates. These changes may contribute substantially to the coagulopathic state seen during systemic meningococcal disease.
 ...
PMID:Endotoxin liberation from Neisseria meningitidis correlates to their ability to induce procoagulant and fibrinolytic factors in human monocytes. 828 43

A detailed understanding of the hemostatic process and the pathogenesis of thrombosis provides the basis for the development of more selective and potentially more efficient antithrombotic agents. These may allow to tailor antithrombotic treatment strategies for specific disease entities according to relative risk and prevailing pathogenetic mechanisms. Conversely, the use of selective pharmacological inhibitors has become an indispensable tool in experimental hemostasis and thrombosis research. Recent advances in the field have prompted profound reappraisal of concepts and hypotheses related to blood coagulation, thrombogenesis and the biologic role of the plasminogen activator-plasmin system. The present article will focus on the various mediator functions of thrombin, on the key role of tissue factor in the initiation of blood coagulation, and on the potential relevance of the tissue factor pathway inhibitor (TFPI).
 ...
PMID:[Blood coagulation and fibrinolysis]. 832 11


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>