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)

Epidermal growth factor (EGF) domains are found in many proteins, particularly those of the coagulation/fibrinolytic system. We and others have demonstrated that tissue plasminogen activator (t-PA) and prourokinase are modified by the attachment of fucose to equivalent threonine residues within their EGF domains. Factor XII and protein C each contain two EGF domains; in both proteins, the EGF domain nearest the N terminus has a threonine residue in a position homologous to that which is fucosylated in t-PA. In protein C, this site is 3 residues from the position of another post-translational modification, beta-hydroxylation of Asp-71. We isolated peptides containing these sites to determine, primarily by mass spectrometric analysis, the presence of O-linked fucose and/or beta-hydroxyaspartate. We found that factor XII is fully fucosylated at Thr-90. Protein C is unmodified at the equivalent site (Thr-68) and is completely beta-hydroxylated at Asp-71. It has been recently reported that the first EGF domain of human factor VII has O-linked fucose at the equivalent position (Ser-60) (Bjoern, S., Foster, D. C., Thim, L., Wiberg, F. C., Christensen, M., Komiyama, Y., Pedersen, A. H., and Kisiel, W. (1991) J. Biol. Chem. 266, 11051-11057), while it is unmodified at Asp-63 despite having the consensus sequence for beta-hydroxylation at the latter site. These observations raise the possibility that O-linked fucosylation and beta-hydroxylation of EGF domains are mutually exclusive post-translational modifications.
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PMID:O-linked fucose is present in the first epidermal growth factor domain of factor XII but not protein C. 154 94

Low molecular weight heparin (LMW-heparin) enhanced the amidolytic activity of plasma when the chromogenic substrate, H-D-Ile-Pro-Arg-pNA (S-2288), was used. The amidolytic activity increased in a time-dependent manner as the LMW-heparin concentration increased and reached its peak at around 15 mu/ml. Factor XII-deficient plasma increased the S-2288 amidolytic activity by LMW-heparin. In order to clarify the mechanism of the heparin-induced enhancement of the amidolytic activity, a plasma factor was purified. The plasma factor was obtained from human normal plasma by ammonium sulfate fractionation, followed by successive column chromatography with heparin-Sepharose, zinc chelate-Sepharose, aprotinin-Sepharose and protein A-Sepharose. The plasma factor so purified revealed a major band (88% of total protein) at 80 kD with several minor bands on analysis by SDS-PAGE. The plasma factor exhibited an intrinsic amidolytic activity, which was enhanced by heparin. The plasma factor further enhanced the amidolytic activity of sct-PA and scu-PA, the enhancement of which was of much greater degree than that for LMW-heparin. However, when the two-chain form of t-PA or u-PA was reacted with the plasma factor and LMW-heparin, no enhancement of the amidolytic activity of these enzymes was observed. The plasma factor cleaved a peptide bond of sct-PA and scu-PA and induced a structural change from a single-chain to a two-chain form. The amidolytic activity of the plasma factor was not inhibited by anti-t-PA IgG, anti-u-PA IgG, anti-plasminogen IgG, anti-factor XII IgG or anti-plasma prekallikrein IgG. These findings suggest an important role for the plasma factor in the activation of sct-PA and scu-PA in heparin-dependent fibrinolysis.
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PMID:Purification and characterization of a plasma factor which cleaves single-chain form of t-PA and u-PA. 215 52

Pentosan polysulphate causes an increase in plasminogen activator activity in plasma both after oral ingestion and after subcutaneous injection. The effect is greatest after 3 h and has disappeared by 6 h. Repeat doses by mouth over 5 days elicit a similar response. The recorded increase in activity is due largely to the release of tissue-type plasminogen activator (tPA) from the endothelium according to the antigen assay although there could be a small contribution from Factor XII-related "intrinsic" fibrinolysis induced in vitro. SP54 enhances activity ex vivo by a non-specific surface effect, and this phenomenon may contribute the increased levels of activity seen in vitro. Administration of SP54 to animals elicits a similar increase in activator activity, the intramuscular route being slightly more effective. Results with an inferior vena cava thrombosis model in the rat suggest that pentosan polysulphate may induce a thrombolytic effect.
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PMID:The effect of pentosan polysulphate (SP54) on the fibrinolytic enzyme system--a human volunteer and experimental animal study. 241 27

The effect of 20 mg tenoxicam once daily for 7 days on various components of the fibrinolytic system was studied in 10 healthy volunteers. Plasma plasminogen, antithrombin 3, and prekallikrein decreased significantly while plasma plasminogen activator inhibitor increased significantly. The medication did not affect fibrin plate lysis area or the plasma level of plasminogen activator, alpha-2-antiplasmin, alpha-2-macroglobulin, C1 inactivator or Factor XII. It is suggested that these changes may be caused by interference with hepatic enzyme systems. The reduction in plasma prekallikrein may indicate that tenoxicam exerts its anti-inflammatory effect by more than one mechanism.
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PMID:The fibrinolytic system during short-term treatment with tenoxicam. 280 72

By incubation of human citrated plasma with acetone 25% v/v kallikrein inhibitors were destroyed and prekallikrein activated to kallikrein. When the incubation was carried out in the presence of benzamidine 7 mM, the cofactor capacity of high molecular weight kininogen (HMrK) was protected against destruction by a serine protease which was not plasma kallikrein. By analogy with studies in rat plasma this protease might be a plasminogen activator (Berstad & Briseid 1982; Johansen & Briseid 1983). Factor XII in the plasma preparation was activated to unfragmented factor XIIa by adsorption to kaolin, and assayed as prekallikrein activator (PKA). The extent of activation of factor XII was only insignificantly influenced by the 1 + 1 (v/v) dilution of the plasma preparation with a suspension of kaolin. When, however, the preparation was diluted greater than 1 + 5 (v/v) before incubation with the suspension, a stoichiometric HMrK concentration-effect curve could be established, allowing the assay of cofactor-active HMrK. Assays of HMrK in plasma preparations from healthy men and women demonstrated an average lower level of cofactor-active HMrK in the preparations from women. It is suggested that benzamidine is not capable of providing a complete protection of HMrK during the procedure in all plasma samples.
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PMID:Activation of factor XII in human plasma: protection by benzamidine of the cofactor function of high molecular weight kininogen. 668 67

In a previous study we have shown that monoclonal antibody F1 (MoAb F1), directed against an epitope on the heavy chain of factor XII distinct from the binding site for anionic surfaces, is able to activate factor XII in plasma (Nuijens JH, et al: J Biol Chem 264; 12941, 1989). Here, we studied in detail the mechanism underlying the activation of factor XII by MoAb F1 using purified proteins. Formation of factor XIIa was assessed by measuring its amidolytic activity towards the chromogenic substrate H-D-Pro-Phe-Arg-pNA (S-2302) in the presence of soybean trypsin inhibitor and by assessing cleavage on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Upon incubation with MoAb F1 alone, factor XII was auto-activated in a time-dependent fashion, activation being maximal after 30 hours. Factor XII incubated in the absence of MoAb F1 was hardly activated by kallikrein, whereas in the presence of MoAb F1, but not in that of a control MoAb, the rate of factor XII activation by kallikrein was promoted at least 60-fold. Maximal activation of factor XII with kallikrein in the presence of MoAb F1 was reached within 1 hour. This effect of kallikrein on the cleavage of factor XII bound to MoAb F1 was specific because the fibrinolytic enzymes plasmin, urokinase, and tissue-type plasminogen activator could not substitute for kallikrein. Also, trypsin could easily activate factor XII, but in contrast to kallikrein, this activation was independent of MoAb F1. SDS-PAGE analysis showed that the appearance of amidolytic activity correlated well with cleavage of factor XII. MoAb F1-induced activation of factor XII in this purified system was not dependent on the presence of high-molecular-weight kininogen (HK), in contrast to the activation of the contact system in plasma by MoAb F1. Experiments with deletion mutants revealed that the epitopic region for MoAb F1 on factor XII is located on the kringle domain. Thus, this study shows that binding of ligands to the kringle domain, which does not contribute to the proposed binding site for negatively charged surfaces, may induce activation of factor XII. Therefore, these findings point to the existence of multiple mechanisms of activation of factor XII.
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PMID:Monoclonal antibody F1 binds to the kringle domain of factor XII and induces enhanced susceptibility for cleavage by kallikrein. 749 70

We studied extrinsic and intrinsic fibrinolysis in 20 patients with cirrhosis (nine mild/moderate, group 1; 11 severe, group 2) and 19 normal controls to define the role of intrinsic (contact factor medaited) fibrinolysis in cirrhosis. Global plasma fibrinolytic activity (fibrin plate lysis) was similar in all groups. Dextran sulphate activated contact factor mediated fibrinolysis was decreased in group 2 (median 95.2%) compared with group 1 (121.0%) and controls (131.7%). Tissue plasminogen activator antigen (t-PA Ag) levels were increased in group 2 (28.2 ng/ml) compared both with group 1 (8.5 ng/ml) and controls (5.9 ng/ml). Plasma t-PA activity was raised in group 2 (5.50 IU/ml) and group 1 (5.25 IU/ml) versus controls (0.82 IU/ml). Plasminogen activator inhibitor-1 (PAI-1 Ag) levels were raised in group 2 (28.0 IU/ml) versus controls (8.5 IU/ml) but PAI activity was similar in all groups. Factor XII activity was decreased in group 2 (48.76 u/dl), but not group 1, versus controls (89.1 u/dl). Prekallikrein activity was decreased both in group 2 (27.27 u/dl) and group 1 (33.01 u/dl) versus controls (108.59 u/dl) and was lower in group 2 than group 1. C1-esterase inhibitor chromogenic activity was decreased in group 1 (102.30 u/dl) and group 2 (58.76 u/dl) versus controls (116.24 u/dl). The normal global fibrinolytic activity despite increased t-PA activity may be due to a concomitant increase in PAI. The decreased intrinsic fibrinolysis in severe cirrhosis, unaccompanied by a rise in C1-esterase inhibitor, may be explained by the decreased factor XII and prekallikrein activity. These changes are probably due to reduced liver cell mass.
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PMID:Decreased contact factor mediated fibrinolysis in cirrhosis. 813 76

This review considers the perhaps unappreciated role of contact pathway proteins in the pathogenesis of thrombotic/thromboembolic morbidity associated with mechanical circulatory support. Placement of ventricular assist devices (VADs) has been associated with consumption of circulating contact proteins and persistent generation of activated contact proteins such as Factor XII and high molecular weight kininogen. Importantly, activated contact proteins are absorbed to the surface of VADs via the Vroman effect. Further, hyperfibrinogenemia and persistent platelet activation exist in patients with VADs, likely contributing to speed of clot growth. Using thrombelastographic-based analyses, it has been determined that contact pathway protein activated coagulation results in a thrombus that develops strength at a significantly faster rate that tissue factor initiated coagulation. Further, thrombelastographic analyses that include the addition of tissue-type plasminogen activator have demonstrated that contact protein pathway activation results in thrombin activatable fibrinolysis inhibitor activation to a far greater extent than that observed with tissue factor initiated coagulation, resulting in a thrombus that takes significantly longer to lyse. These observations serve as the rational basis for clinical investigation to determine if regional suppression of thrombin generation with FXII/high molecular weight kininogen inhibition in concert with thrombin-activatable fibrinolysis inhibitor inhibition may decrease mechanical circulatory support-associated thrombotic morbidity.
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PMID:Mechanical circulatory device thrombosis: a new paradigm linking hypercoagulation and hypofibrinolysis. 1864 51