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: UMLS:C0012739 (disseminated intravascular coagulation)
8,673 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ancrod is a purified coagulant venom which renders blood incoagulable by cleaving fibrinopeptide A (FPA) from fibrinogen, but the mechanism involved in the clearance of fibrin from the circulation is unknown. To investigate the fibrinolytic response to ancrod, and to increase understanding of clearance mechanisms, six patients with peripheral vascular disease causing claudication were infused with ancrod at 2 u/kg over 6 h followed by 2 u/kg at 12 h intervals for 38 h. Venous blood samples were taken at time 0, 3, 6, 25 and 49 h for assay of fibrinogen (Fbg), fibrinopeptide A (FPA), total fibrin(ogen) degradation products (TDP), fibrin degradation products (FbDP), fibrinogen degradation products (FgDP), cross-linked fibrin degradation products (XL-FDP), tissue plasminogen activator (tPA), urinary type plasminogen activator (u-PA), plasminogen, alpha 2 antiplasmin (alpha 2 AP) and plasminogen activator inhibitor-1 (PAI-1). Fibrinogen (median and range) was 2.3 (1.4-3.90) g/l at time 0 and thereafter was undetectable. FPA rose from 2.5 (1.8-3.6) to 600 and 188 pmol/l at 3 h and 6 h and remained elevated. TDP, FbDP and FgDP increased greatly following ancrod while there was no evidence of XL-FDP. The surprising increase in FgDP during defibrination suggests either that fibrinogen is digested following its incorporation into circulating fibrin protofibrils or that some of the fibrin subunits in the photofibril retain one of the two fibrinopeptide A's. tPA and uPA remained unchanged. Plasminogen fell from 125 (100-155)% to 79 (40-118)% at 49 h and alpha 2 AP fell from 91 (75-107)% to 24 (10-35)% at 49 h. The level of PAI-1 was depressed during defibrination, with the exception of the 6 h data. The results demonstrate that ancrod removes FPA from fibrinogen to produce non-cross-linked (soluble) fibrin. This is cleared from the circulation without evidence of an increase in the circulating activities of the plasminogen activators, tPA or UK, but with evidence of plasminogen activation and consumption.
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PMID:The fibrinolytic response to ancrod therapy: characterization of fibrinogen and fibrin degradation products. 845 76

Reproducible disseminated intravascular coagulation in rabbits was provoked by two intravenous injections 24 hours apart of endotoxin from Salmonella enteritidis. There were mild symptoms of DIC before the second injection which considerably increased thereafter. In detail there was a sharp drop of the platelet count and a considerable diminution of Antithrombin III, of Protein C, Plasminogen and Antiplasmin as well as an appearance of fibrin monomer complexes and an increase of the aPTT. When PEG-hirudin in a single dose of 1 mg/kg BW was given simultaneously with the second injection of endotoxin the following alterations were observed: The drop of the platelet count and of the activities of Antithrombin III, Protein C, Plasminogen and Antiplasmin was significantly less pronounced. The fibrin monomer complexes were lower and the aPTT was less prolonged. The thrombin time, however, as a sign of a direct action of hirudin on thrombin was considerably more prolonged than in the controls. The combined effect of these alterations strongly points in the direction of a favourable influence of PEG-hirudin on the course of DIC. It is of special interest that 6 h after the intravenous injection of PEG-hirudin its full effect on the thrombin time was still detectable. This is apparently due to a longer half-life in circulation of PEG-hirudin than of natural hirudin.
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PMID:The effect of a long-acting recombinant hirudin (PEG-hirudin) on experimental disseminated intravascular coagulation (DIC) in rabbits. 847 80

Disseminated intravascular coagulation (DIC) may lead to severe thrombotic or hemorrhagic complications. The present work was undertaken to study the effect of interleukin 6 (IL-6) on variations of key coagulation and fibrinolytic parameters in plasma in a baboon model of experimental DIC induced by injection of factor Xa and phospholipids at dosages leading to partial (48%) or complete fibrinogen depletion. Transient increases of D-dimer, fibrinopeptide A, thrombin-antithrombin and the activated partial thromboplastin time were observed. Each parameter had a particular (time and Xa/phospholipid dose dependent) pattern of changes. The principal effect of IL-6 was a more rapid restoration of fibrinogen concentrations and of overall coagulation tests. Injection of factor Xa/phospholipids led also to a rapid increase of tissue-type plasminogen activator (t-PA) the extent of which was dependent on Xa/phospholipid dose. Pretreatment with IL-6 induced a threefold increase of basal t-PA and a corresponding increase of the t-PA response. Plasminogen activator inhibitor type 1 (PAI-1) concentrations did not change after low dose Xa/phospholipids, but increased eightfold after high dose Xa/phospholipids, IL-6 pretreatment induced within 8 h a twentyfold increase of PAI-1 but no further increase was observed after injection of factor Xa/phospholipids. Thus, in vivo thrombin generation leads to dynamic modifications of the coagulation and fibrinolytic systems. The principal effect of IL-6 is a more rapid normalization of overall coagulation tests, due to normalization of fibrinogen, and an increased t-PA release response which is partially counteracted by increased PAI-1 concentrations.
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PMID:The coagulation and fibrinolytic responses of baboons after in vivo thrombin generation--effect of interleukin 6. 918 1

Reptilase, defibrase and ancrod are thrombin-like venom enzymes that cleave fibrinogen to release fibrinopeptide-A and generate fibrin monomers. Although these enzymes decrease fibrinogen levels in vivo, presumably by enhancing fibrinolytic activity, the mechanism has not been identified. In the present study, we analyzed their effects on the inhibitors of fibrinolysis. Plasminogen activator inhibitor-1 (PAI-1) was cleaved at its C-terminus by reptilase and lost its specific activity. Alpha2-antiplasmin (alpha2-AP) was cleaved both at the Pro19-Leu20 peptide bond and at its C-terminus by reptilase, and also lost its specific activity. The apparent second-order rate constants (mol/l per min per Batroxobin unit) were 0.22 for the cleavage of PAI-1 (3.2 micromol/l) and 0.19 for that of alpha2AP (6.4 micromol/l), which were approximately 200-fold lower than that (47.0) for the cleavage of fibrinogen (1.1 micromol/l). Neither defibrase nor ancrod cleaved and inactivated these inhibitors. Only reptilase enhanced euglobulin clot lysis in vitro at high concentration, due probably to PAI-1 inactivation. Since all these three enzymes enhance fibrinolysis similarly during defibrination therapy, the neutralization or inactivation of the inhibitors of fibrinolysis appeared not to represent the main mechanism for the enhancement.
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PMID:The cleavage and inactivation of plasminogen activator inhibitor type 1 and alpha2-antiplasmin by reptilase, a thrombin-like venom enzyme. 1075 7

Measurement of plasminogen, the key component of fibrinolysis system, is one of the basic methods for estimation of fibrinolysis. Methods based on the use of chromogenic substrates are often used in diagnosis. Plasminogen measurements are important for laboratory diagnosis of thrombophilia caused by deficiency or abnormalities of this fiber, for detection and evaluation of the DIC syndrome, and for monitoring the treatment by fibrinolytic preparations (streptokinase, t-PA, urokinase, etc.). An original chromogenic substrate having no foreign analogs has been created at Institute of Genetics and Selection of Industrial Microorganisms and Research Center of Hematology (Moscow). Unlike previously described plasmin substrates, pNa has been obtained by microbiological methods with Russian commercial enzymes subtilisine 72 and megaterine. This paper presents the results of plasminogen measurements in patients with DIC with the use of the original chromogenic substrate. The results were compared with those of tests with Berihrom-Plasminogen diagnostic kit (Behringwerke AG).
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PMID:[A method for determining plasminogen with a Russian chromogenic substrate and its diagnostic significance]. 1087 27

Plasminogen activator inhibitor-1 (PAI-1) increases in endotoxemia thus possibly cooperating in altering the hemostatic balance in a prothrombotic direction. The effect of the inhibition of PAI-1 with the monoclonal antibody MA-33B8 was studied systemically and in kidneys in a lapine model of endotoxin-induced disseminated intravascular coagulation (DIC). The increase in plasmatic PAI activity in the control group (n = 9) was inhibited in the MA-33B8 treated rabbits (n = 5). Control rabbits showed renal fibrin deposits, whereas only one of the MA-33B8 rabbits did so. These results were confirmed immunohistochemically in kidneys as PAI-1 immunostaining was seen inside the glomeruli and larger vessels in the control group, whereas MA-33B8 rabbits showed a remarkable decrease, demonstrating that MA-33B8 successfully inhibited PAI-1 in the kidneys as well. Therefore evidence for the important role of PAI-1 in fibrin generation in endotoxin-induced DIC is presented, suggesting that strategies aiming at its reduction can be useful in this pathology.
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PMID:Prevention of renal fibrin deposition in endotoxin-induced DIC through inhibition of PAI-1. 1092 72

We report two cases of atypical defibrination syndromes in patients with respectively acute monoblastic leukemia (chronic myeloid leukemia initially) and acute lymphoblastic leukemia. Hemostasis studies show low fibrinogen level, elevated D-dimers, decreased alpha 2 antiplasmin and factor V, normal antithrombin III values. Plasminogen is below the normal range in one patient. Soluble complexes, which are an important argument for diagnosis of intravascular coagulation disease, are not detected in both patients. Primary or secondary hyperfibrinolysis seems also excluded since euglobulin clot lysis time was normal. Enzymatic proteolysis of fibrinogen (or fibrin) by the blast cells has been reported by some authors; this mechanism could account for the hemostasis abnormalities observed in these two patients.
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PMID:[Atypical defibrination syndromes and acute leukemias with a t(9,22) translocation, apropos of 2 cases]. 1136 58

Lipopolysaccharide-containing outer membrane vesicles (OMV-LPS) which are spontaneously released from Neisseria meningitidis during logarithmic growth were studied for their ability to induce procoagulant (tissue factor), profibrinolytic (urokinase-type plasminogen activator) and antifibrinolytic (plasminogen activator inhibitor-2) factors in purified human monocytes. Cell-associated tissue factor was 5.0-fold (n=5) increased, peaking after 8 h, in the presence of OMV-LPS (1 microg/ml, final concentration). Plasminogen activator inhibitor-2 release from monocytes was maximal after 24 h OMV-LPS (1 microg/ml) stimulation and 13.7-fold (n=5) increased compared to controls; whereas urokinase-type plasminogen activator antigen in culture medium remained uninfluenced by OMV-LPS. In conclusion, these OMV-induced imbalances favor fibrin deposition in the monocyte microenvironment and is probably of great importance in the development of disseminated intravascular coagulation, microthrombosis and organ dysfunction related to fulminant meningococcal septicemia.
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PMID:Outer membrane vesicles from Neisseria meningitidis: effects on tissue factor and plasminogen activator inhibitor-2 production in human monocytes. 1136 30

Monoclonal antibody therapies have conducted to not only hematologic malignancies but also disorders of hemostasis and coagulation. This article describes the recent advances of monoclonal antibody therapy for bleeding disorders such as idiopathic thrombocytopenic purpura(ITP), hemophilia A, disseminated intravascular coagulation(DIC), and thrombosis. Rituximab, chimeric anti-CD20 monoclonal antibody treatment has a valuable effect in the patients with ITP, and clinical trials using anti-CD40 ligand monoclonal antibody for ITP are underway. Anti-CD40 ligand monoclonal antibody can be an alternative therapy for hemophilia A patients with inhibitors to factor VIII. In thrombosis, anti-tissue factor monoclonal antibody and anti-factor IX(a) monoclonal antibody were established as novel anticoagulant regents. Plasminogen activator inhibitor-1(PAI-1) increases in endotoxin-induced DIC and many thrombotic diseases such as myocardial infarction, type 2 diabetes mellitus, and hyperlipidemia. Anti-PAI-1 monoclonal antibody reduced fibrin deposition in DIC mouse model. Treatment of these monoclonal antibodies for the molecules regulating coagulation-fibrinolysis system may be utilized for acute coronary syndrome and venous thrombosis.
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PMID:[Monoclonal antibody therapy for disorders of hemostasis and coagulation]. 1190 68

Haemostatic disorders caused by Lonomia obliqua caterpillars has reached epidemic proportions in southern Brazil. Here we evaluated coagulation and fibrinolysis in 105 patients after accidental contact with Lonomia obliqua caterpillars. Global coagulation tests were prolonged in most cases and patients were divided into 3 groups according to fibrinogen (Fg) level: <or=0.5 g/l (group A); 0.51-1.5 g/l (group B), >1.5 g/l (group C). There was a significant reduction of factors V, XIII, VIII and prekallikrein in group A, with no change in factors X, II and von Willebrand factor. Thrombin-antithrombin and prothrombin F1+2 were elevated in most patients. Antithrombin and protein S were not changed whereas protein C levels were reduced in group A. Plasminogen and alfa2-antiplasmin levels were significantly reduced in group A and D-Dimer levels were extremely high in all groups, showing that fibrinolysis had been activated, possibly secondary to fibrin production. Levels of t-PA were normal and PAI-1 was mildly elevated in group A. The platelet count remained above 150 x 109 platelets/ml in 97% of cases. In summary, our results suggest that Lonomia obliqua envenoming is characterized by a consumption coagulopathy and secondary fibrinolysis.
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PMID:Blood coagulation and fibrinolytic factors in 105 patients with hemorrhagic syndrome caused by accidental contact with Lonomia obliqua caterpillar in Santa Catarina, southern Brazil. 1257 17


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