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Plasmin Inhibitors (plasmin + inhibitor)
Selected AbstractsFibrinolysis is amplified by converting ,2 -antiplasmin from a plasmin inhibitor to a substrateJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 10 2007I. Y. SAZONOVA Summary., ,2 -antiplasmin (,2 -AP) is the fast serpin inhibitor of plasmin and appears to limit the success of treatment for thrombosis. We examined the mechanisms through which monoclonal antibodies (mAbs) against ,2 -AP amplify fibrinolysis. The mAbs RWR, 49 and 77 interfered with the ability of ,2 -AP to inhibit plasmin, microplasmin and trypsin. In solution, mAbs 49 and 77 bound to ,2 -AP with 5-fold to 10-fold higher relative affinity than mAb-RWR, while mAb-RWR bound with greater avidity to immobilized or denatured ,2 -AP. Binding studies with chimeric ,2 -APs revealed that none of the mAbs bound to sites in ,2 -AP that form putative contacts with plasmin, namely the carboxy terminal lysines of ,2 -AP, or the reactive center loop in the serpin domain of ,2 -AP. Rather, mAb-RWR recognized an epitope in the amino-terminus of ,2 -AP (L13GNQEPGGQTALKSPPGVCS32) near the site at which ,2 -AP cross-links to fibrin. mAbs 49 and 77 bound to another conformational epitope in the serpin domain of ,2 -AP. mAbs 49 and 77 markedly increased the stoichiometry of plasmin inhibition by ,2 -AP (from 1.1 ± 0.1 to 51 ± 4 and 67 ± 7) indicating that they convert ,2 -AP from an inhibitor to a substrate of plasmin. This was confirmed by sodium dodecylsulfate polyacrylamide gel electrophoresis analysis showing cleavage of ,2 -AP by plasmin in the presence of these mAbs. In summary, these mAbs appear to act at sites distinct from known ,2 -AP,plasmin contacts to enhance fibrinolysis by converting ,2 -AP from an inhibitor to a plasmin substrate. [source] More on: discovery of ,2 -plasmin inhibitor and its congenital deficiencyJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 1 2006M. J. GALLIMORE No abstract is available for this article. [source] Effects of Minimal Dose Aprotinin on Blood Loss and Fibrinolytic System-Complement Activation in Coronary Artery Bypass Grafting SurgeryJOURNAL OF CARDIAC SURGERY, Issue 4 2006Ferit Cicekcioglu M.D. Methods: Forty-four patients scheduled for primary CABG were randomly assigned to the aprotinin (n = 24) or control group (n = 20). In aprotinin group, aprotinin was administered in two equal doses (before skin incision and added to the pump prime). Ventilation time, intensive care unit stay, mediastinal tube drainage, hospitalization, transfusion requirements, and postoperative morbidities and mortality were noted. Hematologic markers of fibrinolytic activity and complement activation were also measured pre- and postoperatively. Results: Although less mediastinal drainage occurred in aprotinin group, the difference was not statistically significant. Other postoperative variables like transfusion requirements, morbidities, and mortality were also found to be similar between groups. Among hematologic parameters, only postoperative levels of ,2-antiplasmin and plasminogen activator inhibitor-1 were significantly higher in aprotinin group. Conclusions: Although plasmin inhibitors begin to rise at this very low aprotinin dosage, it is not advisable to use this aprotinin regimen in CABG patients. [source] Complete inhibition of fibrinolysis by sustained carboxypeptidase B activity: the role and requirement of plasmin inhibitorsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 6 2007J. B. WALKER Summary.,Background:,The antifibrinolytic effect of activated thrombin-activatable fibrinolysis inhibitor (TAFIa) and carboxypeptidase B (CPB) displays threshold behavior. When CPB was used to simulate conditions mimicking continuous TAFIa activity, it affected the lysis of plasma clots differently to clots formed from a minimal fibrinolytic system comprising fibrinogen, plasminogen and ,2 -antiplasmin. Whereas CPB saturably prolonged clot lysis in the purified system, the effect of CPB did not appear saturable in plasma clots. Methods:,To rationalize this difference, we investigated the effects of ,2 -antiplasmin, ,2 -macroglobulin, antithrombin and aprotinin on CPB-mediated antifibrinolysis. Results:,CPB alone prolonged fibrinolysis in a saturable manner and the efficacy of CPB increased with decreasing tissue-type plasminogen activator (t-PA) concentration. The inhibitors by themselves did not halt fibrinolysis and the potency of each inhibitor in the absence of CPB mirrored their solution-phase plasmin inhibitory potentials: ,2 -antiplasmin , aprotinin >> ,2 -macroglobulin >> antithrombin. With both CPB and inhibitor present, a synergistic effect was observed. The antifibrinolytic sensitivity to CPB was related to the plasmin inhibitory potential of the inhibitor. Conclusions:,Fibrinolysis could be completely inhibited by ,2 -antiplasmin, ,2 -macroglobulin and antithrombin, but not aprotinin, in the presence of CPB, and occurred only when the irreversible inhibitor or pool of inhibitors were in excess of plasminogen. Western blot analysis indicated that the CPB-mediated shutdown of fibrinolysis was a result of plasminogen consumption prior to clot lysis. The CPB concentration required for fibrinolytic shutdown was dependent on t-PA concentration and the inhibitory potential of the irreversible inhibitor pool. [source] Estrogen-induced uterine abnormalities in TIMP-1 deficient mice are associated with elevated plasmin activity and reduced expression of the novel uterine plasmin protease inhibitor serpinb7MOLECULAR REPRODUCTION & DEVELOPMENT, Issue 2 2009Xuan Zhang Abstract Tissue inhibitor of metalloproteinase-1 (TIMP-1) is a multifunctional protein capable of regulating a variety of biological processes in a wide array of tissue and cell types. We have previously demonstrated that TIMP-1 deficient mice exhibit alterations in normal uterine morphology and physiology. Most notably, absence of TIMP-1 is associated with an altered uterine phenotype characterized by profound branching of the uterine lumen and altered adenogenesis. To begin to assess the mechanism by which TIMP-1 may control these uterine events, we utilized steroid-treated ovariectomized wild-type and TIMP-1 null mice exposed to estrogen for 72 hr. Administration of estrogen to TIMP-1 deficient mice resulted in development of an abnormal uterine histo-architecture characterized by increased endometrial gland density, luminal epithelial cell height, and abnormal lumen structure. To determine the mediators which may contribute to the abnormal uterine morphology in the TIMP-1 deficient mice, cDNA microarray analysis was performed. Analysis revealed that expression of two plasmin inhibitors (serpbinb2 and serbinb7) was significantly reduced in the TIMP-1 null mice. Associated with the reduction in expression of these inhibitors was a significant increase in plasmin activity. Localization of the novel uterine serpinb7 revealed that expression was confined to the luminal and glandular epithelial cells. Further, expression of uterine serpinb7 was decreased by estrogen and showed an inverse relationship with plasmin activity. We conclude from these studies that in addition to controlling MMP activity, TIMP-1 may also control activity of serine proteases through modulation of serine protease inhibitors such as serpinb7. Mol. Reprod. Dev. 76: 160,172, 2009. © 2008 Wiley-Liss, Inc. [source] | ||||||||||