Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.7 (plasmin)
 9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prophylactic aprotinin therapy has become a popular method to reduce bleeding associated with cardiac operations. Today essentially two dose regimens are used, a high-dose regimen with administration throughout the complete operative procedure and a low-dose regimen with administration only during bypass. In unblinded studies both regimens were found to be equally effective. This double-blind placebo-controlled study in 115 patients undergoing elective coronary artery bypass grafting was done to confirm these results without potential investigator bias. Intraoperative hemoglobin loss was significantly reduced (p < 0.01) by 42% in the high-dose group and by 17% in the low-dose group compared with loss in control subjects. Blood loss 6 hours after operation was 377 ml in the low-dose and 266 ml in the high-dose group compared with 630 ml in the placebo group (p < 0.05 and p < 0.001, respectively). The average number of transfusions with packed red blood cells was reduced 31% in the low-dose group and 45% in the high-dose group, but the reductions were not significant. In a subgroup of patients, markers for coagulation and fibrinolysis were studied to investigate whether a different extent of activation existed. Fibrinolysis as measured by D-dimer levels was completely inhibited by the high-dose regimen, but was only partly suppressed in the low-dose group as compared with findings in the placebo group. Thrombin generation during cardiopulmonary bypass as reflected by F1 + 2 levels was lower in patients treated with aprotinin, but the difference was not significant. Concentrations of thrombin inactivated by antithrombin III were not different between the groups. The observation that low-dose aprotinin significantly improved hemostasis but did not inhibit hyperfibrinolysis supports our previous finding that low-dose aprotinin mainly protects platelet adhesive function. The better result obtained with high-dose aprotinin may indicate the contribution of hyperfibrinolysis to bleeding after cardiopulmonary bypass. Because high-dose aprotinin is administered outside the period of full heparinization and might therefore increase the risk of thromboembolic complications, we propose a modification of the low-dose schedule to increase aprotinin levels sufficient for plasmin inhibition before release of the aortic crossclamp.
J Thorac Cardiovasc Surg 1996 Aug
PMID:Low-dose and high-dose aprotinin improve hemostasis in coronary operations. 875 22

Direct interactions of plasminogen activators with arterial endothelial cells are important in the pathogenesis of vascular complications associated with thrombolytic therapy. We investigated the direct effects of various plasminogen activators on human aortic and pulmonary artery endothelial cell functions in vitro. The effects of plasminogen activators on endothelial cells were not caused by generation of plasmin, as shown by the absence of plasminogen and alpha(2)-plasmin inhibitor-plasmin complex both before and after addition of plasminogen activators to endothelial cells. High concentrations of plasminogen activators increased the permeability of aortic endothelial cells to albumin. Alteplase (50 x 10(3) IU/ml), a recombinant tissue-type plasminogen activator (t-PA), increased prostaglandin I(2) (PGI(2)) production by aortic endothelial cells from 175.5 +/- 13.8 to 870.8 +/- 131.0 pg/mg cellular protein during a 2-h incubation; other plasminogen activators increased PGI(2) production to a lesser extent. Alteplase (100 x 10(3) IU/ml) also increased PGI(2) production from 152.0 +/- 16.2 to 1,080 +/- 95.1 pg/mg cellular protein in human pulmonary artery endothelial cells. High concentrations of urokinases decreased the amount of endothelin-1 in the medium of aortic or pulmonary artery endothelial cells by as much as 93%; part of this decrease was attributable to degradation of endothelin-l by urokinases. Other plasminogen activators either had no effect on or slightly increased the production of endothelin-1. These changes in the function of human arterial endothelial cells induced by plasminogen activators may affect regional vascular tone, endothelial permeability, and platelet aggregability, all of which are important in the efficacy of thrombolysis and in the pathogenesis of such vascular complications as rethrombosis and hemorrhage.
J Cardiovasc Pharmacol 1996 May
PMID:Direct interactions of plasminogen activators with human aortic and pulmonary artery endothelial cells in vitro: implications for thrombolytic therapy. 885 31

During cardiopulmonary bypass (CPB), contact-phase activation of factor XII, prekallikrein, and high molecular weight kininogen initiates the intrinsic pathway of coagulation. To prevent gross clot formation during CPB, heparin is commonly used as an anticoagulant. There is a wide variability in the sensitivity of individual patients to the actions of heparin. We did not find a significant correlation between plasma heparin levels and concentrations of D-dimers, thrombin-antithrombin III complexes (TAT), and prothrombin fragments F1+2 as markers of fibrinolysis and coagulation activation. In addition, heparin cannot completely inhibit thrombin formation and action and may play a central role in the coagulation disorders associated with CPB. F1+2 and TAT rise throughout the course of CPB and fibrin monomers are generated. Attempts to improve anti-coagulation using heparin-coated bypass circuits and specific inhibitors of thrombin have not thus far proven successful. The serine protease inhibitor aprotinin can inhibit contact-phase activation, as evidenced by generation of significantly fewer prothrombin fragments F1+2, thrombin-antithrombin III complexes, fibrinopeptide A, and fibrin monomers in aprotinin-treated patients undergoing cardiac surgery. Studies performed with a simulated CPB system have shown attenuation of plasma kallikrein C1 inhibitor complex (PKC1 I) with aprotinin and the recombinant Arg 15 aprotinin. This action of aprotinin to inhibit contact-phase activation may influence the degree of anticoagulation with heparin. Patients treated with aprotinin require approximately 20% less heparin to achieve an activated clotting time (ACT) of 400 s than control patients. Despite lower plasma concentrations of heparin, aprotinin-treated patients had significantly lower concentrations of the markers of coagulation activation (thrombin-antithrombin III complex, fibrin monomers, and antiplasmin-plasmin complex). We have also investigated the role of aprotinin in contact-phase [correction of contact phase] activation of fibrinolysis. Patients treated with aprotinin showed higher concentrations of single-chain urinary type plasminogen activator (scuPA) at the end of CPB compared with control patients, indicating reduced contact- phase [correction of contact phase] activation.
J Cardiovasc Pharmacol 1996
PMID:Reducing thrombin formation during cardiopulmonary bypass: is there a benefit of the additional anticoagulant action of aprotinin? 893 84

Endothelial cells synthesize and secrete PA and PAI, and thus provide anticoagulant and procoagulant regulatory mechanisms, respectively. Both plasminogen and plasminogen activators (t-PA and u-PA) bind to specific cellular receptors; assembly of components of the fibrinolytic system at the endothelial cell surface results in stimulation of fibrinolytic activity. Several mechanisms contribute to this stimulation, eg, enhanced plasminogen activation by t-PA or u-PA, enhanced conversion of scu-PA to tcu-PA, and impaired inhibition of plasmin by alpha2-antiplasmin or of PAs by PAIs. Thus, the endothelial cell surface serves as a focal point for plasmin generation.
Prog Cardiovasc Dis
PMID:Endothelium in hemostasis and thrombosis. 905 Aug 19

To demonstrate its antifibrinolytic effects and establish an effective regimen of tranexamic acid for hemostasis, the authors measured alpha2-plasmin inhibitor-plasmin complexes, thrombin-antithrombin III complexes and postoperative blood loss in three groups undergoing different regimens during cardiac operations. Forty-six patients undergoing coronary artery bypass grafting or valve replacement were enrolled in this study. They were divided into three groups of drug administration. A bolus infusion of 50 mg/kg tranexamic acid was given to 17 patients at the end of cardiopulmonary bypass (control group) and to 14 patients at the beginning of cardiopulmonary bypass (group A). In addition to the same bolus infusion at the beginning of cardiopulmonary bypass as group A, a continuous infusion of 10 mg/kg per h, starting at the time of skin incision and maintained for 6 h after cardiopulmonary bypass was given to 15 patients (group B). The marked increase in alpha2-plasmin inhibitor-plasmin complexes at the end of cardiopulmonary bypass in the control group was significantly reduced in group A (P < 0.01) and a further reduction was observed in group B (P < 0.001). The difference in postoperative blood loss only reached significant levels between the control group and group B (P < 0.05). Although a significant increase in thrombin-antithrombin III complexes during cardiopulmonary bypass was similarly observed in all groups, no thromboembolic events occurred in any group, nor was any difference seen in graft patency. From the tranexamic acid therapy regimens tested in this study, a continuous infusion of 10 mg/kg per h starting at the time of skin incision to 6 h after cardiopulmonary bypass, with a bolus infusion of 50 mg/kg at the beginning of cardiopulmonary bypass, proved to be the most effective.
Cardiovasc Surg 1999 Mar
PMID:Antifibrinolytic therapy with tranexamic acid in cardiac operations. 1035 70

Postoperative bleeding was examined in patients undergoing cardiopulmonary bypass with a heparin-coated circuit and low-dose heparin. Out of 150 patients who underwent cardiopulmonary bypass for longer than 90 minutes, 74 received a standard dose (300 IU/kg) of heparin with an uncoated circuit (group C) and 76 received a low-dose (150 IU/kg) of heparin with a heparin-coated circuit (group H). The coagulation and fibrinolytic systems were investigated in 24 patients. Re-opening of the chest due to bleeding was performed in 5 patients in group C (7%), but none of the patients in group H (p=0. 03). The median of blood loss in the first 12 hours after surgery was 292 ml in group C, and 216 ml in group H (p=0.006). There were no significant differences in the peak thrombin-antithrombin complex concentration between the two groups. The plasmin-alpha 2 plasmin inhibitor complex concentrations after protamine administration were 1.9 ng/ml (median) in group C and 1.1 ng/ml in group H (p=0.002). The use of heparin-coated cardiopulmonary bypass circuits with low-dose heparin suppressed the activation of fibrinolysis. This may explain the reduction in postoperative bleeding.
Ann Thorac Cardiovasc Surg 1999 Aug
PMID:Use of heparin-coated cardiopulmonary bypass circuit with low-dose heparin reduces postoperative bleeding. 1050 46

The enzymatic cascade triggered by activation of plasminogen has been implicated in a variety of normal and pathologic events, such as fibrinolysis, wound healing, tissue remodeling, embryogenesis, and the invasion and spread of transformed tumor cells. Recent data established that the Ca(2+)- and phospholipid-binding protein, annexin II heterotetramer (AIIt) binds tissue-type plasminogen activator (tPA), plasminogen, and plasmin, and dramatically stimulates the tPA-dependent conversion of plasminogen to plasmin in vitro. Interestingly, the binding of plasmin to AIIt can inhibit the activity of the enzyme, suggesting that plasmin bound to the cell surface is regulated by AIIt. The existing experimental evidence suggests that AIIt is the key physiological receptor for plasminogen on the extracellular surface of endothelial cells.
Trends Cardiovasc Med
PMID:Role of annexin II tetramer in plasminogen activation. 1057 24

The annexins constitute a family of calcium-dependent membrane binding proteins. Recently, annexin II has been shown to accelerate the activation of the clot-dissolving protease plasmin by complexing with the plasmin precursor plasminogen and with tissue plasminogen activator. Binding of plasminogen to annexin II is inhibited by the atherogenic lipoprotein, lipoprotein(a), while binding of tissue plasminogen activator to annexin II is blocked by the thiol amino acid homocysteine. Formation of the plasminogen/tissue plasminogen activator/annexin II complex may represent a key regulatory mechanism in fibrinolytic surveillance.
Trends Cardiovasc Med 1999 Jul
PMID:Annexin II: a mediator of the plasmin/plasminogen activator system. 1063 27

Plasminogen activator inhibitor-1 (PAI-1) and alpha2-anti-plasmin (alpha2-AP) may contribute to arterial thrombolysis resistance. The role of these components on thrombus evolution in vivo was investigated in mice deficient for PAI-1 (PAI-1(-/-)) or alpha2-AP (alpha2-AP(-/-)) or their wild-type counterparts (PAI-1(+/+), alpha2-AP(+/+)). Moreover, the influence of either PAI-1 or alpha2-AP deficiency on the results of pharmacologic inhibition of glycoprotein IIb/IIIa of platelets or thrombin was also investigated. A thrombus was induced in the murine carotid artery by endothelial injury. The alpha2-AP(-/-) mice were indistinguishable from wild-type, whereas the time to occlusion in PAI-1(-/-) was significantly prolonged to 24.9 +/- 3.7 min. Vascular patency was markedly increased in both PAI-1- and alpha2-AP-deficient mice. In separate animals, either a glycoprotein IIb/IIIa antagonist or a thrombin inhibitor was applied. The time required to occlusion was prolonged in a dose-dependent manner in all types of mice. When each compound was administered to PAI-1(-/-) mice, significant changes were observed. In conclusion, lack of PAI-1 prolongs the time to occlusion and accelerates clot lysis, whereas alpha2-AP only has an effect on spontaneous reperfusion. Consequently, the inhibition of PAI-1, but not of alpha2-AP, could enhance the effects of anti-thrombotic therapy.
J Cardiovasc Pharmacol 2002 Feb
PMID:Inhibitors of fibrinolytic components play different roles in the formation and removal of arterial thrombus in mice. 1179 Oct 14

Retinoids exert their pleiotropic effects on several pathophysiologic processes, including neointima formation after experimental vascular injury. Plasminogen activator inhibitor-1 (PAI-1) has been proposed to play an inhibitory role in arterial neointima formation after injury. We examined whether retinoids regulate PAI-1 expression in cultured vascular smooth muscle cells (SMCs). Northern blot analysis showed that all-trans retinoic acid (atRA) and 9-cis retinoic acid (9cRA) increased PAI-1 mRNA levels in a dose-dependent manner. These responses were completely inhibited by tyrosine kinase inhibitors. The half-life of PAI-1 was not affected by atRA, suggesting that induction of PAI-1 mRNA was mainly regulated at the transcriptional levels. Stable and transient transfection assays of the human PAI-1 promoter-luciferase constructs indicate that DNA sequence responsive to either ligand-stimulated or overexpressed retinoic acid receptor-alpha expression vector lies downstream of -363 relative to the transcription start site, where no putative retinoic acid response element is found. These results indicate that atRA and 9cRA increase PAI-1 gene transcription through pathways involving tyrosine kinases in SMCs. Because PAI-1 inhibits the production of fibrinolytic protein plasmin that facilitates SMC migration, induction of the PAI-1 gene expression by atRA may at least partly account for the role of atRA as an important inhibitor of neointima formation.
J Cardiovasc Pharmacol 2002 Apr
PMID:Retinoids induce the PAI-1 gene expression through tyrosine kinase-dependent pathways in vascular smooth muscle cells. 1190 24


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