Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

To investigate abnormalities in the hemostatic and fibrinolytic system in CAPD patients, parameters of coagulation, anticoagulation, fibrinolysis, and platelet function were measured in 21 CAPD patients and 20 healthy controls. The CAPD patients had significantly higher levels of factor (F) IX, FVII, FX, antithrombin III, thrombin/antithrombin III complex, protein C, protein S, thrombomodulin, fibrinogen, fibrinopeptide A, plasminogen, FXIII, alpha2-plasmin inhibitor, alpha2-plasmin inhibitor/plasmin complex, D-dimer, fibrinopeptide B beta 15-42, and beta-thromboglobin than the healthy controls. The CAPD patients also showed a shorter prothrombin time. However, tissue plasminogen activator, plasminogen activator inhibitor-1 and platelet factor-4 did not show any significant differences from the levels in healthy controls. There was a significant positive correlation between many of the blood parameters and serum lipids. These results demonstrate that hypercoagulability and secondary hyperfibrinolysis occur in CAPD patients, and suggest that these changes may be related to abnormalities in lipid metabolism.
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PMID:Hypercoagulability and secondary hyperfibrinolysis may be related to abnormal lipid metabolism in patients treated with continuous ambulatory peritoneal dialysis. 917 1

Vipera lebetina fibrinogenase (VlF) was shown to render fibrinogen incoagulable and to solubilize fibrin. The fibrinogenolytic activity of this enzyme was found to be 33 mg fibrinogen/min/mg protein. The study of the specificity of this enzyme revealed that it has no effect on purified factor X, prothrombin and protein C and on the specific chromogenic substrates of their active form. Plasminogen was not activated by VlF but slightly degraded. We have also compared the effect of VlF and plasmin on fibrinogen and shown that these two enzymes have a different sites of cleavage. This enzyme inhibited human platelet aggregation on PRP initiated by ADP and collagen but was without effect on the aggregation of washed rabbit platelets using thrombin as agonist. Administration of VlF in rat did not show any necrosis or hemorrhage in treated rats organ's. We therefore, examined the thrombolytic activity of VlF in a rat model of venous thrombosis. Thrombus was produced in the posterior vena cava by injection of human fibrinogen and thrombin. Injection of 5 mg/Kg body weight showed an evident flow restoration after one hour and measurement of the fibrinogen level a decrease of about 30% after 3 hrs. VlF's action is not dependent on plasminogen activators and may act synergistically with them, thereby providing an intriguing potential clinical application for dissolution of blood clots.
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PMID:Further characterization and thrombolytic activity in a rat model of a fibrinogenase from Vipera lebetina venom. 917 44

To find if there is a relation between levels of haemostatic variables at low and high hormonal levels (oestradiol and progesterone) in an individual, blood samples were drawn from 12 women repeatedly during one menstrual cycle (Study I) and from 14 women undergoing in vitro fertilization, before hormonal stimulation and daily during the periovulatory period (Study II). Regression coefficients were calculated between minimum (independent) and maximum (dependent) values in both studies. In Study II highly significant regression coefficients were found between oestradiol minimum (pretreatment) and maximum (median 105 and 4730 pmol/l, respectively) for coagulation factors FVIII, von Willebrand Factor (antigen), FVII (activity and antigen), fibrinogen, protein C, protein S (free), antithrombin, plasminogen and plasminogen activator inhibitor-1; furthermore, between progesterone-minimum at day -3 or -2 (related to ovum pick up) and maximum (median 4.7 and 98 nmol/l, respectively) for FVIII, von Willebrand Factor, FVII (activity and antigen), protein C, protein S (free), and plasminogen. In Study I, where much lower hormonal levels were obtained at maximum (oestradiol median 297 pmol/l and progesterone 47 nmol/l), the same pattern was observed especially for FVII, FX, fibrinogen, plasminogen and plasmin inhibitor. Thus, the concentration of a haemostatic variable at a low oestradiol or progesterone level can predict the level at a high hormonal level.
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PMID:Prediction of changes in levels of haemostatic variables during natural menstrual cycle and ovarian hyperstimulation. 918

To clarify the abnormalities of coagulation and fibrinolytic systems on predialysis patients with chronic renal failure, we measured indices of coagulation and fibrinolytic systems in 33 predialysis patients whose creatinine (Cr) levels were over 3.0 mg/dl. We termed twenty-four patients with chronic glomerulonephritis the "CGN group". We also termed nine patients wit diabetes mellitus the "DM group". We measured thrombin.antithrombin III complex (TAT), alpha 2-plasmin inhibitor plasmin complex (PIC), D-dimer, protein C, protein S, thrombomodulin (TM), vitronectin, tissue plasminogen activator.plasminogen activator inhibitor-1 complex (tPAI-C) in theses two groups. Furthermore, we measured the same indices after 6 months in the CGN group. As a result, the plasma levels of both TAT, PIC, TM/Cr ration in the DM group were significantly higher that those in the CGN group, changes in both protein S activities and plasma levels of tPAI-C were reduced significantly after 6 months. In conclusion, the abnormalities of coagulation and fibrinolytic systems in predialysis diabetic patients were stronger than those in predialysis patients with CGN. Furthermore, these abnormalities were worsened after 6 months in predialysis patients with chronic renal failure.
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PMID:[Study on coagulation fibrinolytic systems in predialysis patients with chronic renal failure--comparison between patients with chronic glomerulonephritis and patients with diabetic nephropathy]. 928 13

Pulmonary and cerebral infarctions have come to be noticed as life-threatening complications of Duchenne muscular dystrophy (DMD). In order to elucidate the underlying mechanism of hypercoagulable state, was studied following markers of coagulation and fiblinolysis in 69 DMD and 50 control patients showing no signs of thrombosis: prothrombin time, activated partial thrombin time, thrombotest, fibrinogen, fibrinogen degradation product, thrombin-antithrombin III complex (TAT), alpha 2-plasmin inhibitor plasmin complex (PIC), D-dimer, protein C activity, protein S, antithrombin III, XII factor, thrombomodulin and plasminogen activity. 66 out of 69 patients (96%) showed abnormal results in more than one of these studies, among which abnormally low thrombotest (78%), high TAT (61%) and high PIC (40.3%), were very frequently observed. The results were not correlated to the age, the activity of daily living and the respiratory of cardiac functions. Significantly smaller number of the control patients suffering from other neuromuscular diseases showed abnormal results, while the ambulatory DMD patients not infrequently showed hypercoagulable state. These results strongly suggest that unknown inherent factor(s) as well as inevitable immobilization and cardiac dysfunction play(s) an important role in the development of hypercoagulable state in this intractable disorder.
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PMID:[Hypercoagulable state in Duchenne muscular dystrophy]. 929 22

Selective, sensitive assays for the quantitation of serine proteases involved in coagulation and fibrinolysis have been developed employing fluorogenic substrates containing a 6-amino-1-naphthalenesulfonamide leaving group (PNS-substrates). Over one hundred substrates were evaluated for hydrolysis by the serine proteases of blood coagulation and fibrinolysis, and substrate structure-efficiency correlations were examined. PNS-substrates which contain Lys in the P1 position are specific for Lys-plasmin and are either not hydrolyzed or hydrolyzed at a relatively low rate by factor Xa, thrombin, or urokinase-type plasminogen activator (uPA). These substrates allow quantitation of Lys-plasmin at concentrations as low as 1 pM. Eighteen of over 90 substrates tested for factor XIa are hydrolyzed by this enzyme at a relatively high rate reaching a k(cat), value of 170 s(-1) and allowing quantitation of factor XIa at 10 fM. Eighteen of almost 90 PNS-substrates tested display high specificity for thrombin, some exceeding that for factor Xa by >10,000-fold and >100-fold for activated protein C (APC). Seven of these substrates have a k(cat) over 100 s(-1) and three of them have a K(M) below 1 microM. They allow the quantitation of thrombin at concentrations as low as 20 fM. For APC, uPA and the factor VIIa/tissue factor complex, quantitation is feasible at 1 pM concentration. For factor Xa and factor VIIa the limits are 0.4 pM and 40 pM respectively. The PNS-substrates presented in this study may be employed for the development of direct and sensitive serine protease assays.
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PMID:Ultrasensitive fluorogenic substrates for serine proteases. 936 84

Using enzymatic microassays, the potency of a series of new boroarginine tripeptides was determined versus thrombin and a panel of serine-proteases implicated in the coagulation and fibrinolysis pathways. The inhibition of the serine-protease complement factor I was also studied. Factor I regulates the alternate pathway of the complement and its inhibition appears to be responsible for the toxic effects of the orally available thrombin inhibitor Ac-D-Phe-Pro-boroArg (DuP-714). The structure of the new boronic acid derivatives tested was modified from that of DuP-714 by replacing the proline in the P2 position by N-cycloalkyl-glycine residues of increasing size (S18989: cyclopropyl; S18563: cyclobutyl; S18326: cyclopentyl; S18229: cyclohexyl). All compounds were found to be slow-tight binding inhibitors of thrombin versus purified human fibrinogen. Replacement of proline by N-cycloalkyl-glycines did not decrease the anti-thrombin potency of the substances up to the cyclopentyl size and this result was confirmed by classical coagulation assays with human plasma in vitro. In contrast, the inhibitory activities of the four new boronic acids were found to be lower than those of DuP-714 versus plasmin, urokinase (u-PA), plasmatic kallikrein, activated protein C (aPC) and complement factor I. The cyclopentyl derivative S18326 is a slightly more active inhibitor of thrombin than DuP-714 (initial IC50 values 3.99 +/- 0.18 nM versus 4.73 +/- 0.27 nM, respectively). Moreover S18326 was identified as the most selective compound of the series with relative potencies being 2 to 29 fold higher than that of DuP-714 versus the panel of serine-proteases tested; the rank order of potency versus the other serine-proteases for S18326 was t-PA>kallikrein>aPC>factor I>plasmin>fXa>u-PA. These results indicate that the size of the thrombin hydrophobic pocket S2 is sufficient to accept larger residues than proline in the P2 position of Ac-D-Phe-X-boroArg derivatives while this is not the case for other important serine-proteases of the fibrinolysis, coagulation and complement pathways. The N-cyclopentyl glycine containing derivative S 18326, which is the most potent and the most selective anti-thrombin compound of the series, currently undergoes major preclinical testing.
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PMID:Selection of S18326 as a new potent and selective boronic acid direct thrombin inhibitor. 936 88

Solvent/detergent virus-inactivated plasma (VIP) contains markedly reduced protein S (PS) and alpha 2-antiplasmin (APL) beside other slightly decreased inhibitors. This could possibly be critical for the balance of hemostasis in diseases in which plasma inhibitors are reduced. A heterogeneous group of 14 patients with 18 plasma transfusions (12 FFP/24 VIP, 2 units per transfusion) was investigated. The patients suffered from dilution coagulopathy, liver disease, disseminated intravascular coagulation (DIC), hyperfibrinolysis, or received massive transfusions. Prothrombin fragment 1 + 2, fibrin monomers, D-Dimers, thrombin-AT III complexes, antiplasmin-plasmin complexes and fibrinogen degradation products as markers of activated coagulation (MAC) were measured. Blood samples were taken before and after plasma replacement. Significant differences between VIP and FFP should be recognized by comparing the ratio of MAC after/MAC before plasma transfusion. Patients showed an average inhibitor plasma level of AT III 51%, protein C 44%, PS 63%, and APL 52%. Only the F 1 + 2 ratio was obviously higher in the VIP group but not significantly. So the remaining MAC ratios did not show any significant difference. Our preliminary data showed no indication for a higher state of activation of coagulation in patients receiving VIP in comparison with those receiving FFP, if the VIP had the quality required. Solvent/detergent (SD) inactivation of transfusion-relevant viruses in plasma was successfully performed by Horowitz et al. [1]. The procedure leads to a partial reduction of the activity of clotting factors [2]. PS and APL are more severely affected. Therefore, treatment with VIP might activate or at least increase the activation of coagulation, especially in patients with reduced plasma inhibitors. To clarify this problem, the following disorders with the indication for plasma replacement were included in a prospective randomized study of FFP vs. VIP: massive transfusion; dilution coagulopathy; disturbance in liver synthesis; disseminated intravascular coagulation (DIC); primary hyperfibrinolysis. Low PS levels could induce hypercoagulability by reduced F VIII and FV inhibition, and low APL could induce hyperfibrinolysis by reduced plasmin inhibition.
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PMID:Protocol and preliminary results of a clinical study for comparison of solvent/detergent-inactivated plasma VIP versus FFP with special consideration of the balance of hemostasis. 942 23

Activated protein C (APC) is a potent physiologic anticoagulant with profibrinolytic properties, and has been shown to prevent thrombosis in different experimental models. We investigated the effect of human APC on thrombin-induced thromboembolism in mice, a model of acute intravascular fibrin deposition leading to death within minutes. APC given intravenously (i.v.) as a bolus 2 min before thrombin challenge (1,250 U/kg) reduced mortality in a dose-dependent manner despite the lack of thrombin inhibitor activity. Significant inhibition of thrombin-induced death was observed at the dose of 0.05 mg/kg, and maximal protection was obtained with 2 mg/kg (> 85% reduction in mortality rate). Histology of lung tissue revealed that APC treatment (2 mg/kg) reduced significantly vascular occlusion rate (from 89.2 to 46.6%, P < 0.01). The protective effect of APC was due to the inhibition of endogenous thrombin formation as indicated by the fact that (a) the injection of human thrombin caused a marked decrease in the coagulation factors of the intrinsic and common pathways (but not of Factor VII), suggesting the activation of blood clotting via the contact system; (b) APC pretreatment reduced markedly prothrombin consumption; (c) the lethal effect of thrombin was almost abolished when the animals were made deficient in vitamin K-dependent factors by warfarin treatment, and could be restored only by doubling the dose of thrombin, indicating that the generation of endogenous thrombin contributes significantly to death; and (d) APC failed to protect warfarin-treated animals, in which mortality is entirely due to injected thrombin, even after protein S supplementation. Other results suggest that APC protects from thrombin-induced thromboembolism by rendering the formed fibrin more susceptible to plasmin degradation rather than by reducing fibrin formation: in thrombin-treated mice, fibrinogen consumption was not inhibited by APC; and inhibition of endogenous fibrinolysis by epsilon-aminocaproic or tranexamic acid resulted in a significant reduction of the protective effect of APC. Since APC did not enhance plasma fibrinolytic activity, as assessed by the measurement of plasminogen activator (PA) or PA inhibitor (PAI) activities, PAI-1 antigen, or 125I-fibrin degrading activity, we speculate that the inhibition of additional (endogenous) thrombin formation by APC interrupts thrombin-dependent mechanisms that make fibrin clots more resistant to lysis, so that the intravascular deposited fibrin can be removed more rapidly by the endogenous fibrinolytic system.
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PMID:Activated human protein C prevents thrombin-induced thromboembolism in mice. Evidence that activated protein c reduces intravascular fibrin accumulation through the inhibition of additional thrombin generation. 944 1

To elucidate the relationship between glomerular deposition of protein S (PS) and renal lesions or dysfunction, 30 patients with various glomerulopathies were examined. Glomerular PS deposition was found in 20 patients (group A), and other 10 patients showed no deposition (group B). PS was found mainly along the capillary loops and segmentally in the mesangium. Group A showed significantly more severe proteinuria than group B (p < 0.05). Group A patients showed significant decreases in glomerular filtration rate (p < 0.01). Patients in group A had significantly lower plasma levels of plasmin-alpha2-plasmin inhibitor complexes (p < 0.05) and thrombin-antithrombin III complexes (p < 0.01) than those in group B. Group A showed significant decreases in the mean values of plasma total PS (p < 0.01) and protein C (PC) antigens (p < 0.01) and C4b-binding protein (C4bp; p < 0.05) as compared with group B patients. There was a positive correlation between plasma PS and C4bp (p < 0.02). Histologically, group A showed a significantly higher incidence of glomerular deposition of factor XIII (subunit a), alpha2-plasmin inhibitor, PC (p < 0.05), and C4bp (p < 0.01). The present study demonstrates that glomerular PS deposition indicates the existence of PC and C4bp in the glomeruli and suggests that the glomerular PS deposition may modify the activation of fibrinolytic and coagulation systems within the glomeruli in various glomerulopathies.
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PMID:Significance of glomerular deposition of protein S in various glomerulopathies. 945 2


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