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)

We evaluated the effect of r-hirudin and/or tissue-plasminogen activator (t-PA) in a model of DIC in rabbits induced by i.v. infusion of 100 micrograms/kg/h/6 h endotoxin. Rabbits were treated with saline (endotoxin control group), r-hirudin at 0.3 mg/kg/h/6 h, t-PA at 0.3 mg/kg for 90 min and r-hirudin plus t-PA at the doses described above. The best results were achieved when r-hirudin and t-PA were infused together. This treatment reduced the consumption of platelets and protein C and attenuated the increase of PAI-1 more efficiently than r-hirudin or t-PA alone. r-Hirudin plus t-PA also resulted in the lowest formation of fibrin deposits in the kidneys. Finally, mortality at 24 h dropped from 70% in the endotoxin control group to 40%, 10% and 0% in the t-PA, r-hirudin and r-hirudin plus t-PA groups respectively. None of the t-PA-infused rabbits which had died by 24 h showed macroscopic signs of haemorrhage. r-Hirudin alone was better than t-PA alone, as was shown by fibrin deposits and mortality. We conclude that r-hirudin and t-PA given simultaneously were more efficient than either given alone in this model of DIC. Effective thrombin inhibition, which could influence other pathophysiological mechanisms apart from coagulation, together with the improvement in fibrinolysis, would explain these results.
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PMID:Effect of the administration of recombinant hirudin and/or tissue-plasminogen activator (t-PA) on endotoxin-induced disseminated intravascular coagulation model in rabbits. 1023 73

In this study, we have established a pig model that can combine extensive hemodynamic monitoring with simultaneous repetitive (serial) blood sampling for the study of multiple variables related to the hemostatic system. Sixteen healthy young pigs were studied to evaluate the influence of continuous endotoxin infusion on hemodynamic patterns and activation of coagulation and fibrinolysis. The chief aim of the study was to investigate the applicability of analytical methods primarily developed for use with human plasma samples in quantification of factors and reaction products of the porcine coagulation and fibrinolytic systems, and further, to use these methods to study the longitudinal changes in the plasma levels of these hemostatic variables as a consequence of endotoxin infusion. We found that acute, controlled endotoxemia induced a hemodynamic state of shock and reduced pulmonary gas exchange. Simultaneously, a gradual increase in peripheral blood mononuclear cell tissue factor activity was demonstrated, and increased maximally 5.5-fold 4 hours after onset of endotoxin infusion. Thrombin-antithrombin complexes increased in plasma to maximum levels after 3 hours, accompanied by an ethanol gelation test that was regularly positive after 1 to 2 hours, and fibrin monomer levels that gradually increased maximally 3.8-fold after 6 hours. These changes were followed by gradual decreases of both fibrinogen and factor VII levels, mainly due to consumption. Plasma levels of tissue type plasminogen activator activity peaked at 1.5 hours (11.3-fold increase), whereas the peak of plasminogen activator inhibitor-1 activity (14-fold increase at 4.5 hours) was delayed compared to tissue plasminogen activator and completely extinguished plasma tissue plasminogen activator activity. The sequential activation of coagulation and fibrinolysis established a procoagulant state favoring disseminated intravascular coagulation and microthrombus formation, potentially leading to multiple organ dysfunction.
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PMID:Hemodynamic changes and systemic activation of coagulation and fibrinolysis during controlled endotoxemia in pigs. 1089 51

In a porcine model of Gram-positive sepsis, 28 juvenile pigs were studied to evaluate the effect of a continuous infusion of live serogroup A streptococci (GAS) on the activation of coagulation and fibrinolysis. Plasma levels of thrombin-antithrombin (TAT) complexes, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) activities were measured using commercially available kits. The continuous infusion of GAS [(3-5) x 10(8) colony-forming units/kg per h] caused early signs of severe septicaemia in the pigs, with pulmonary hypertension, systemic hypotension, reduced cardiac output and liver hypoperfusion, ultimately leading to shock with a high mortality. There was a sequential and ordered activation of the coagulation, fibrinolytic and antifibrinolytic systems. GAS infusion induced a gradual, maximally 2.5-fold increase in plasma TAT levels. Plasma t-PA activity levels peaked at 2 h (nine-fold increase), whereas the peak of PAI-1 activity was delayed (eight-fold increase at 4 h). These findings are similar to changes observed during endotoxin infusion. This procoagulant state favours disseminated intravascular coagulation and microthrombus formation, ultimately threatening tissue viability.
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PMID:Systemic activation of coagulation and fibrynolysis in a porcine model of serogroup A streptococcal shock. 1093 4

Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by intravascular fibrin formation occurring in the course of a variety of severe diseases. In gram-negative sepsis, endotoxin is the bacterial component eliciting a cascade of tissue factor dependent hypercoagulable reactions mediated by cytokines, including tumor necrosis factor-alpha and interleukin-6. Fibrinolysis is activated in this process by the action of tumor necrosis factor-alpha, but its activity is impaired by the predominant inhibitory effect of plasminogen activator inhibitor-1. Natural inhibitory mechanisms include antithrombin, the protein C system, and tissue factor pathway inhibitor. Each of these defense systems counteracts the harmful effects of DIC, and its acquired deficiency is associated with increased mortality in observational studies. The generation of several proteases in DIC, including factor Xa and thrombin, has potential interactions with inflammatory pathways that may potentiate the systemic inflammatory syndrome that often accompanies DIC. Experimental studies support the notion that defects in the protein C pathway modulate the inflammatory response, and illustrate that coagulation and inflammation are coupled systems in DIC.
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PMID:Pathophysiology of disseminated intravascular coagulation in sepsis. 1100 90

Protein C is the zymogen of an anticoagulant serine protease and is converted to its active form (activated protein C: APC) by thrombin in the presence of thrombomodulin. APC plays an important role in regulating coagulation and fibrinolysis by inactivating not only blood coagulation factors Va and VIIIa but also type-1 plasminogen activator inhibitor (PAI-1). The aim of the present study was to examine the effect of a human APC product (designated as CTC-111), compared with that of heparin, on the disseminated intravascular coagulation (DIC) induced by lipopolysaccharide (LPS) in rats. LPS (1 mg/kg/h) infusion was performed through a femoral vein for 4 h. One-fifth amount of the total dosage of CTC-111 or heparin was injected into the other femoral vein, followed by a 4-h infusion of the remainder. Both CTC-111 (10,000-100,000 U/kg) and heparin (400-800 IU/kg) inhibited the decrease in platelet count and fibrinogen level equally. The prolonged activated partial thromboplastin time and prothrombin time observed in DIC rats were further elongated in both CTC-111- and heparin-treated rats. But, this prolongation was less in CTC-111-treated rats than in the heparin-treated ones. Heparin inhibited the increase in fibrin and fibrinogen degradation products more prominently than CTC-111. On the other hand, CTC-111 strongly inhibited the increase in PAI-1 activity but heparin did not. These results suggest that CTC-111 may enhance fibrinolysis through its direct inhibitory effect on PAI-1. The parameters for liver or renal damage, i.e., plasma glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), creatinine (Cre) and blood urea nitrogen (BUN), were significantly increased by LPS infusion. Both CTC-111 (100,000 U/kg) and heparin (800 IU/kg) decreased the increase in GOT and GPT levels significantly, whereas neither affected the increase in Cre or BUN. From these results, the activation of the blood coagulation system might partially contribute to the progression of liver damage caused by LPS, and might be less involved in the progression of renal damage in this model. In conclusion, CTC-111 showed both anticoagulant and profibrinolytic activity in the LPS-induced DIC model without excessive prolongation of coagulation time. From these results, CTC-111 is expected to be a useful remedy for DIC without the risk of bleeding.
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PMID:Effect of activated human protein C on disseminated intravascular coagulation induced by lipopolysaccharide in rats. 1105 Jun 97

Protein C (PC) is an important anticoagulant protein in blood and converted to its active form, activated protein C (APC), by thrombin bound with thrombomodulin. APC exhibits an anticoagulant effect by the inactivation of FV a and FVIII a. In addition, APC exerts a profibrinolytic effect by inactivation of PAI-1 and inhibition of TAFI activation. APC is strongly anti-thrombotic because of its anticoagulant and profibrinolytic effect. APC has gamma-carboxyglutamic acid residues that bind to acidic phospholipids expressed on activated platelet or injured endothelial cells. Thus APC works only at the site where clots are formed and has a weak effect in primary hemostasis; this means that the use of APC is expected not to have any hemorrhagic risk. In both DIC animal models and clinical studies, we confirmed safer amelioration by APC than heparin. Recently, a specific receptor for PC/APC was found on endothelial cell membrane and anti-inflammatory effects of APC were also reported. Thus APC is thought to play an important regulatory role in blood coagulation, fibrinolysis and inflammation, especially in thrombotic diseases.
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PMID:[Anti-thrombotic effect of activated protein C]. 1121 79

In this study, we examined changes in the plasma levels of total plasminogen activator inhibitor-I (PAI-I) and tissue-type plasminogen activator (tPA)/PAI-I complex in patients with disseminated intravascular coagulation (DIC) and in those with thrombotic thrombocytopenic purpura (TTP) to investigate the fibrinolytic function and its relation to organ failure. The plasma levels of total PAI-1 and tPA/PAI-I complex were significantly higher in patients with DIC, pre-DIC, and TTP than in those with non-DIC. The plasma levels of thrombin-antithrombin complex (TAT), plasmin-plasmin inhibitor complex (PPIC), D-dimer, thrombomodulin (TM), total PAI-I, and tPA/PAI-I complex were significantly higher in patients with organ failure than in those without organ failure. The plasma levels of total PAI-I and tPA/PAI-I complex were markedly increased in patients with acute leukemia. The plasma levels of total PAI-I, but not those of tPA/PAI-I complex, were significantly increased in patients with sepsis or with solid cancer. In all cases, total PAI-I or tPA/PAI-I complex was not significantly correlated with any hemostatic marker. Measurement of total PAI-I and tPA/PAI-I complex may be useful in the diagnosis of DIC.
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PMID:Plasma levels of total plasminogen activator inhibitor-I (PAI-I) and tPA/PAI-1 complex in patients with disseminated intravascular coagulation and thrombotic thrombocytopenic purpura. 1144 85

We measured the plasma levels of thrombin-activatable fibrinolysis inhibitor (TAFI) activity and antigen in patients with disseminated intravascular coagulation (DIC) to examine the relationship between hypofibrinolysis and the pathogenesis of DIC. TAFI activity and antigen levels in the plasma were both significantly low in patients with DIC. TAFI activity in plasma was correlated with TAFI antigen, indicating that activity and antigen correspond well. The decrease of TAFI activity in DIC may be due to enhanced consumption. Since the plasma thrombin-antithrombin III complex (TAT) level was found to be elevated in DIC, increase of thrombomodulin-thrombin complex generation is suggested in this state. TAFI activity and antigen levels were negatively correlated with TAT and D-dimer, suggesting that the plasma levels of TAFI are reduced by thrombin generation. Since TAFI was not correlated with fibrinogen, plasma-alpha(2)plasmin inhibitor complex (PPIC) and tissue type plasminogen activator/plasminogen activator inhibitor-1 (tPA/PAI-1) complex, TAFI might be a secondary modulator of fibrinolysis. The TAFI activity in plasma was significantly low in patients with infection and in those with organ failure, suggesting that TAFI may play an important role in the mechanism of organ failure in DIC-associated sepsis. In brief, TAFI may play an important role in the pathogenesis of DIC and organ failure.
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PMID:Activity and antigen levels of thrombin-activatable fibrinolysis inhibitor in plasma of patients with disseminated intravascular coagulation. 1158 33

Disseminated intravascular coagulation (DIC) is characterized by the in vivo activation of the coagulation system, which results in the intravascular deposition of fibrin and consumption bleeding. DIC is a serious hemostatic complication of trauma. It can be clearly distinguished from physiological hemostatic response to trauma by using sensitive coagulofibrinolytic molecular markers. Physiological hemostasis to injuries is similar in all kinds of trauma without exception. There is an increase in circulating proinflammatory cytokines in DIC patients after trauma. Elevated cytokines induce tissue factor-mediated activation of coagulation, suppression of the anticoagulant pathway, and plasminogen activator inhibitor-1 (PAI-1)-mediated inhibition of fibrinolysis followed by disseminated fibrin deposition in the microvasculature. In addition to the occlusive microvascular thrombosis and hypoxia, sustained systemic inflammatory response characterized by neutrophil activation and endothelial damage plays a pivotal role in the development of multiple organ dysfunction syndrome (MODS) in posttrauma DIC patients. DIC associated with sustained systemic inflammatory response syndrome (SIRS) after trauma leads to the development of MODS, which is the main determinant of patients' outcome after trauma.
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PMID:Disseminated intravascular coagulation in trauma patients. 1174 Jun 82

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


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