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 burn wound size on the activation of fibrinolysis, coagulation, and contact factors was analyzed in 60 thermal injury patients. Blood samples from 47 male patients and 13 female patients, (average age 37 years; range 1.5-70 years) were collected within the first 36 hours and at 5-7 days following injury. The patient population was categorized by percentage of burn (second degree and/or third degree): less than 20%, n = 22; 20%-40%, n = 18; greater than 40%, n = 20. The average percentage of burn was 32% (range, 4%-95%). The mechanism of injury was by flame (25), explosion and flame (19), scald (12), electric (3), or chemicals (1). An associated inhalation injury was present in 12 patients. The overall mortality rate was 13% (8). Sepsis or serious infection occurred in 23% (14) of the patients. On admission, 83% of the patients had normal prothrombin times (PT) and activated partial thromboplastin times (APTT). However, specific hemostatic variables showed marked changes. Admission hemostatic markers that correlated with the severity of injury were: tissue-plasminogen activator (tPA), plasminogen activator inhibitor (PAI), D-dimer (D-di), plasminogen (Plg), proteins C and S (PrC and PrS), antithrombin III (ATIII), thrombin-antithrombin complex (TAT), kallikrein (Kal:c), kinin (Kin), C1 esterase inhibitor (C1Inh), and factor VII clotting and antigen (FVII:c, FVII:ag). These data suggest that during the early course following burn injury, thrombogenicity is increased (TAT increases) because of a decrease in ATIII, PrC, and PrS; and fibrinolysis activation (D-di increases) occurs via an increase in tPA with a p value increase in PAI.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of burn wound size on hemostasis: a correlation of the hemostatic changes to the clinical state. 163 6

Disseminated thrombotic processes in the microcirculation are considered to be an important cause of multiple organ failure in septic patients. Fibrinolysis is one endogenous mechanism protecting the circulation from overwhelming thrombosis. Therefore, we looked for alterations of fibrinolytic parameters (tissue plasminogen activator (t-PA), tissue plasminogen activator inhibitor (PAI), D-dimer, euglobulin-clot-lysis-time (ECLT), plasminogen, alpha 2-antiplasmin) and of some coagulation parameters (prothrombin time, fibrinogen, platelets, antithrombin III, protein C, factor XII) in clearly defined septic patients and for the relations of these values to the severity of the disease (APACHE II-score). An increase in D-dimer and t-PA-antigen was registered in all patients, while factor XII and plasminogen were decreased, indicating an activated fibrinolysis. In contrast the systemic fibrinolytic capacity of the blood was strongly inhibited: t-PA-activity was not detectable, PAI-function was elevated, the ECLT was prolonged and alpha 2-antiplasmin was normal. Coagulation was moderately activated: the platelets, antithrombin III and protein C were decreased, the prothrombin time was prolonged and fibrinogen was normal. The changes in t-PA-antigen, PAI-function, factor XII, prothrombin time and antithrombin III were significantly related to the APACHE II-score of the patients. We conclude that the activation of coagulation is accompanied by an activation of fibrinolysis in the microcirculation, but that systemically the increased inhibitors of fibrinolysis (PAI, alpha 2-antiplasmin) induce a decrease of the fibrinolytic capacity of the blood. The severity of the disease determines the extent of the alterations.
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PMID:Activation and inhibition of fibrinolysis in septic patients in an internal intensive care unit. 169 55

The solution structure of a recombinant tissue-type plasminogen activator kringle 2 domain, complexed with the antifibrinolytic drug 6-aminohexanoic acid (6-AHA) was determined via 1H nuclear magnetic resonance spectroscopy and dynamical simulated annealing calculations. The structure determination is based on 610 intramolecular kringle 2 and 14 intermolecular kringle 2-6-AHA interproton distance restraints, as well as on 82 torsion angle restraints. Three sets of simulated annealing structures were computed from three different classes of starting structures: (1) random conformations devoid of disulfide bridges; (2) random conformations that contain correct disulfide bonds; and (3) a folded conformation modeled after the homologous prothrombin kringle 1 X-ray crystallographic structure. All three sets of structures are well defined, with averaged atomic root-mean-square deviations between individual structures and mean set structures of 0.77, 0.99 and 0.70 A for backbone atoms, and 1.36, 1.55 and 1.41 A for all atoms, respectively. Kringle 2 is an oblate ellipsoid with overall dimensions of approximately 34 A x 30 A x 17 A. It exhibits a compact globular conformation characterized by a number of turns and loop elements as well as by one right-handed alpha-helix and five (1 extended and 4 rudimentary) antiparallel beta-sheets. The extended beta-sheet exhibits a right-handed twist. Close van der Waals' contacts between the Cys22-Cys63 and Cys51-Cys75 disulfide bridges and the central hydrophobic core composed of the Trp25, Leu46, His48a and Trp62 side-chains are among the distinguishing features of the kringle 2 fold. The binding site for 6-AHA appears as a rather exposed cleft with a negatively charged locus defined by the Asp55 and Asp57 side-chains, and with an aromatic pocket structured by the Tyr36, Trp62, His64 and Trp72 side-chains. The Trp62 and His64 rings line the back surface of the pocket, while the Tyr36 and Trp72 rings confine it from two sides. The Trp62 and Trp72 indole rings conform a V-shaped groove. The methyl groups of Val35 also contribute lipophilic character to the ligand-interacting surface. It is suggested that the positively charged side-chains of Lys34 and, potentially, Arg69 may favor interactions with the carboxylate group of the ligand. The Trp25 and Tyr74 aromatic rings, although conserved elements of the binding site structure, seem not to undergo direct contacts with the ligand.
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PMID:Solution structure of the tissue-type plasminogen activator kringle 2 domain complexed to 6-aminohexanoic acid an antifibrinolytic drug. 176 44

A broad-based, dynamic model of intrinsic coagulation is described. Non-anticoagulated whole blood was perfused through polyethylene tubing under standard conditions, and coagulation (cessation of flow) was monitored by pressure changes. The dynamic coagulation test (DCT) is a sequel to the shear-induced haemostasis, a platelet function test routinely performed prior to coagulation. DCT has two important advantages over stagnant overall clotting tests: i./DCT reflects platelet coagulant activities; selective activation by adenosine diphosphate or shear-stress or inhibition of platelets by prostacyclin greatly enhanced or prolonged dynamic coagulation, respectively. Furthermore, activation of platelets by plasminogen activators (streptokinase, t-PA) was manifested in a significantly shortened coagulation. ii./ DCT allows the rapid assessment of fibrin crosslinking, the mechanical stability of the clot formed. Antibody against factor XIIIa greatly prolonged the time until completion of clotting. In patients taking oral anticoagulant (n = 54), strong correlations were observed between DCT, the prothrombin time (INR) and the thrombelastograph measurements. It is concluded that this simple assay could be useful in the overall screening for coagulation abnormalities.
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PMID:Coagulation of flowing native blood: advantages over stagnant (tube) clotting tests. 180 65

In our present placebo-controlled study on recombinant tissue-type plasminogen activator (rt-PA) and heparin treatment of patients with acute ischaemic heart disease (IHD), we studied the extent of fibrin resolution and generation of coagulant activity. In rt-PA treated patients the lysis of fibrin in vivo (median 60 nmol of fibrin--estimated as fibrinogen equivalents) was significantly higher (p less than 0.02) than can be accounted for solely by lysis of a coronary thrombus (approximately 2 nmol) and circulating soluble fibrin (median 15 nmol). We observed a 200% increase of plasma concentrations of both prothrombin fragment 1 + 2 (p less than 0.001) and thrombin-antithrombin III complexes (p less than 0.001) as a consequence of rt-PA treatment, indicating that the coagulant activity is primarily caused by a physiological activation of the coagulation system. We conclude that an important contribution to the activation of coagulation in patients undergoing coronary thrombolysis is lysis of fibrin deposited widespread on the vascular intima, and that this process causes an intimal-dependent activation of the coagulation system.
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PMID:Possible role of vascular intima for generation of coagulant activity in patients undergoing coronary thrombolysis with recombinant tissue-type plasminogen activator. A randomized, placebo-controlled study. 181 18

A recombinant 90-residue polypeptide fragment containing the three-loop kringle-2 domain of human tissue-type plasminogen activator (t-PA) has been studied by two-dimensional 1H-NMR spectroscopy at 500 MHz. Complete sequence-specific resonance assignments were derived. Overall, the kringle exhibits a compact, folded conformation with more than 50% of the residues in irregular structures. Elements of secondary structure were identified from sequential, medium- and long-range dipolar (Overhauser) interproton interactions. These identifications were corroborated by analysis of spin-spin scalar 3J alpha N splittings and identification of backbone amide NH protons exhibiting retarded 1H/2H exchange in 2H2O. Three antiparallel beta-sheets and six tight turns were located. In addition, one short alpha-helical region was found in the Ser43-Ala44-Gln44a-Ala44b-Leu44c-Gly45+ ++ segment; this region contains three-residue insertions unique to the t-PA and urokinase kringles. Although the secondary structure of the t-PA kringle 2 in solution is in overall agreement with that observed in the crystallographic structure of the prothrombin kringle 1 [Tulinsky, A., Park, C.H. & Skrzypczak-Jankun, E. (1988) J. Mol. Biol. 202, 885-901], the alpha-helical segment and other details of the secondary structure differ somewhat from the prothrombin homolog.
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PMID:Kringle-2 domain of the tissue-type plasminogen activator. 1H-NMR assignments and secondary structure. 190 89

Fluid cadaveric blood is generally known as a characteristic of sudden death. However, it has been reported that soft blood clots have been observed in a number of cases of sudden death after alcohol drinking. Such a tendency was also recognized on autopsy cases in our laboratory. This study was carried out to reveal the effects on clotting and fibrinolytic system in golden hamsters under acute alcohol intoxication. Furthermore, the influences of ether anaesthesia were also observed. Activities of clotting and fibrinolytic factors were measured with fluorogenic peptide substrate. Prothrombin and factor X activities began to decrease 1 hr after administration of alcohol. But thrombin-like and factor Xa-like activities significantly increased after 1 hr and then returned to the initial value 4 hr after administration. Plasminogen activity began to decrease 1 hr after administration, whereas plasmin-like and t-PA-like activities increased after 1 hr and returned to the initial values or decreased after 4 hr. These results show that under acute alcohol intoxication clotting and fibrinolytic factors (prothrombin, factor X and plasminogen) in golden hamsters were converted temporarily to their active forms (thrombin, factor Xa and plasmin). No influence of only ether anaesthesia on clotting and fibrinolytic activities was observed. At 1 hr after administration of alcohol some effects of ether anaesthesia on prothrombin, prekallikrein and kallikrein were observed and then were not observed after 4 hr. But it seems that the influence of ether anaesthesia on clotting and fibrinolytic activities was negligible in the process after alcohol consumption.
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PMID:[Clotting and fibrinolytic activities in acute alcoholic golden hamsters with or without ether anaesthesia]. 192 Sep 21

Fibrin deposition in response to bacterial peritonitis appears to predispose to residual infection in the peritoneal cavity. Our previous studies have demonstrated that intraperitoneal fibrinolysis using human recombinant tissue plasminogen activator (t-PA) prevented abscess formation in a rat intra-abdominal sepsis model. To investigate the potential adverse side effects of its use in the peritoneal cavity, the effect of t-PA on colonic anastomotic wound healing and on systemic coagulation parameters was examined in the rat. T-PA did not adversely affect colonic healing five and ten days after anastomosis. In animals infected intraperitoneally at the time of the anastomosis, t-PA reversed the inhibition of healing induced by perianastomotic abscesses at five days. This effect was mediated by the ability of t-PA to prevent perianastomotic abscess formation. After intraperitoneal administration, t-PA had no effect on prothrombin and partial thromboplastin times in either uninfected or infected animals and there was no evidence of clinical bleeding related to its use. These studies suggest that intraperitoneal fibrinolysis using t-PA may provide a safe, effective form of adjuvant therapy in the management of fibrinopurulent peritonitis.
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PMID:Tissue plasminogen activator reverses the deleterious effect of infection on colonic wound healing. 210

Endotoxemia was evoked by bolus injection of Escherichia coli endotoxin (2 ng/kg body weight) in six healthy subjects to investigate the early kinetics of cytokine release in relation to the development of clinical and hematologic abnormalities frequently seen in gram-negative septicemia. The plasma concentration of tumor necrosis factor (TNF) increased markedly after 30 to 45 minutes, and reached a maximal level after 60 to 90 minutes. In each volunteer, the initial increase of plasma interleukin 6 (IL-6) concentrations occurred 15 minutes after the initial TNF increase, and maximal IL-6 concentrations were reached at 120 to 150 minutes. A transient increase in body temperature and pulse rate occurred simultaneously with the initial TNF and IL-6 increases, whereas a significant decrease in blood pressure occurred after 120 minutes. These changes were proportional to the changes in TNF and IL-6 concentrations. Coagulation activation, as assessed by a rise of prothrombin fragments and thrombin-antithrombin III complexes, was noted after 120 minutes, in the absence of activation of the contact system. A two- to sixfold increase in the concentrations of tissue plasminogen activator (t-PA) and von Willebrand factor antigen indicated endothelial cell activation. This increase started at 120 and 90 minutes, respectively. The release of t-PA coincided with activation of the fibrinolytic pathway, as measured by plasmin-alpha 2-antiplasmin complexes. The fibrinolytic activity of t-PA was subsequently offset by release of plasminogen activator inhibitor, observed 150 minutes after the endotoxin injection, and reaching a peak at 240 minutes. No complement activation was detected. These results show that in humans endotoxin induces an early, rapidly counteracted fibrinolytic response, and a more long-lasting activation of thrombin by a mechanism other than contact system activation. In addition, our data suggest that endotoxin-induced leukopenia and endothelial cell activation are mediated by TNF.
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PMID:Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. 212 34

Various parameters of the haemostatic and, more importantly, of the fibrinolytic systems were examined in 5 patients with severe pre-eclampsia/eclampsia. All 5 showed signs of haemolysis, elevated liver enzymes and low platelet count (HELLP syndrome). A significant decrease in platelet count (46.4 X 10(9)/litre) and an increase in beta-thromboglobulin (137 ng/ml) were observed in the HELPP patients in comparison with normal pregnant women (267 X 10(9)/litre and 49.3 ng/ml, respectively). No significant differences in fibrinogen levels, activated partial thromboplastin time, prothrombin time and fibrin(ogen) degradation products between the HELLP patient group and the normal pregnant group were observed. However, the antigenic levels of tissue-type plasminogen activator and type 1 plasminogen activator inhibitor were significantly higher in the HELLP pre-eclamptic women than in gestational age-matched controls. In contrast, the antigen levels of type 2 plasminogen activator inhibitor were significantly lower in the patients. These results indicate that platelet activation and alterations in plasminogen activator inhibitors type 1 and type 2 may be involved in the pathophysiological pathway of this syndrome.
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PMID:Clinical and haemostatic parameters in the HELLP syndrome: relevance of plasminogen activator inhibitors. 214 63


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