摘要:

Plasminogen activator inhibitor type 1 (PAI-1), a member of the serpin family of serine protease inhibitors, inhibits both tissue-type plasminogen activator (t-PA) and urokinase type plasminogen activator (u-PA). High PAI-1 levels are associated with an increased risk of thromboembolic disease while PAI-1 deficiency may represent an inherited autosomal recessive bleeding disorder. This review describes the biochemistry of PAI-1 including its purification, conversion between active and latent forms, and interaction with its target serine proteases and its protein cofactor, vitronectin. In addition, an overview of animal studies with PAI-1 is presented to examine its role in regulating fibrinolysis in vivo. For this review, particular emphasis is placed on studies with a recombinant form of bacterially expressed PAI-1 (rPAI-1), which shares many features in common with the active form of native PAI-1.

ISSN:0957-5235    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Antithrombin is a serine protease inhibitor that participates in the inactivation and removal from the circulation of thrombin and a variety of other procoagulant serine proteases. Antithrombin is also the major plasma cofactor of heparin which exerts its therapeutic effect primarily through its ability to substantially increase the rate of inactivation by antithrombin of the procoagulant serine proteases. Binding of heparin to antithrombin is thus believed to be a prerequisite for this rate enhancement effect. Heparin binding to antithrombin is mediated by a well-defined unique heparin pentasaccharide sequence. Interaction between this pentasaccharide sequence and antithrombin induces a conformational change in antithrombin, an alteration that appears to be sufficient to explain the enhanced ability of antithrombin to inhibit factor Xa and related serine proteases, but not thrombin. Heparin species with longer polysaccharide chains appear to be required in order to enhance the inhibition of thrombin by antithrombin. This may be because the enhancement of this reaction requires that heparin interacts simultaneously with both the antithrombin and the thrombin molecules. This review describes the interactions between heparin and antithrombin, focusing on the antithrombin residues which are involved in the binding of heparin. The role of the heparin-induced conformational change in enhancing serine protease inhibition by antithrombin is also explored. Then, based on available data, an hypothesis is proposed to explain the mechanisms by which heparin accelerates the rate of inactivation by antithrombin of the various serine proteases.

ISSN:0957-5235    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The GP Ib-IX complex is part of a conglomerate of polypeptides on the platelet surface that perform several key roles of central importance to the haemostatic function of platelets. When deranged, these interactions can also lead to pathological thrombosis, with potentially disastrous consequences for the organism. In this manuscript, several aspects of the structure and biology of the complex are reviewed, including the structures of its polypeptides and their relationships to other members of a phylogenetically widespread protein family, its topology on the platelet membrane and relationship with cytoskeletal components, peptide sequences involved in binding its ligands, von Willebrand factor and thrombin, its polymorphisms, its biosynthesis, and the organizations of the genes that encode its subunits.

ISSN:0957-5235    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The role of platelet activation in clinical settings is controversial, partly because the methods used to detect platelet activation (e.g. platelet aggregation and radioimmunoassays of plasma β-thromboglobulin and platelet factor 4) are plagued by major methodological problems. Clinical studies that utilize flow cytometric assays of washed platelets are also susceptible to artefactualin vitroplatelet activation. Whole blood flow cytometry circumvents many of these methodological problems. However, a major limitation in previously described whole blood flow cytometric assays is their inability to study the effect on platelet activation of thrombin, the most important platelet agonist in vivo. This article reviews the method and clinical applications of a new flow cytometric assay in which platelet activation by thrombin is directly measured in whole blood through the use of the peptide Gly-Pro-Arg-Pro (GPRP). GPRP inhibits thrombin-induced fibrin clot formation and platelet aggregation, but not thrombin-induced platelet activation. The presently described assay of platelet activation by thrombin in the physiological milieu of whole blood should be widely applicable to the many clinical settings (e.g. arterial thrombosis) in which platelet activation by thrombin is postulated to play an important role.

ISSN:0957-5235    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

A 67-year-old man with a severe bleeding due to a high level of factor V inhibitor (maximum level of 350 Bethesda units) is described. Coagulation abnormalities improved initially during treatment with prednisolone in combination with cyclophosphamide. Subsequent treatment with either cyclophosphamide or cyclosporin alone was ineffective. After more than 2 years the inhibitor became undetectable after a prolonged period of high dose steroid therapy, but the patient remained steroid dependent. Therapeutic strategies for patients having a factor V inhibitor are discussed.

ISSN:0957-5235    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Clotting of human plasma by human a-thrombin was prolonged in the presence of haemoglobin as was human and bovine fibrinogen. Specifically, the clot time doubled for human plasma, human fibrinogen and bovine fibrinogen at 483, 233, and 116 μM haemoglobin, respectively. Fibrinopeptide A release was not inhibited at concentrations in ~16000 molar excess compared with α-thrombin. Turbidometric analysis of fibrin polymerization showed a lengthening of the lag phase as well as the fibrin assembly process in the presence of haemoglobin. These findings suggested that neither fibrinogen recognition nor catalytic efficiency of thrombin was affected, implying that haemoglobin interferes with fibrin polymerization. Since human blood contains sufficient haemoglobin in erythrocytes to generate concentrations of up to 2.3 mM upon cell lysis, and haemoglobin concentrations of 0.16–0.48 mM caused 1.25 to two times longer clotting times in fresh human plasma, respectively, haemoglobin may act to modulate clot formation under conditions of haemolysis.

ISSN:0957-5235    

出版商:OVID    

年代:1994

数据来源: OVID

ISSN:0957-5235    

出版商:OVID    

年代:1994

数据来源: OVID

ISSN:0957-5235    

出版商:OVID    

年代:1994

数据来源: OVID

ISSN:0957-5235    

出版商:OVID    

年代:1994

数据来源: OVID