Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0012739 (disseminated intravascular coagulation)
 8,673 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antithrombin III (AT III) supplementation has proven to be effective in the treatment of disseminated intravascular coagulation. Administration of AT III is also useful for prevention of organ failure in animals challenged with endotoxin or bacteria and it increases the survival rate of such animals. Since inhibition of coagulation abnormalities failed to prevent organ failure in animals given bacteria, AT III may exert a therapeutic effect independent of its anticoagulant effect. This therapeutic mechanism of AT III has been explored using an animal model of septicemia. AT III prevented pulmonary vascular injury by inhibiting leukocyte activation in rats given endotoxin. This effect is mediated by the promotion of endothelial release of prostacyclin which inhibits leukocyte activation. Interaction of AT III with heparin-like glycosaminoglycans (GAGs) on the endothelial cell surface appears to be important for this effect. Heparin inhibits these therapeutic effects of AT III by preventing AT III from interacting with the cell surface heparin-like GAGs. This activity of AT III may explain why AT III prevents organ failure as well as coagulation abnormalities in patients with sepsis. This antiinflammatory activity of AT III may be useful for the treatment of organ failure such as in ischemia/reperfusion-induced organ dysfunction, in which activated leukocytes play a critical role.
 ...
PMID:The anti-inflammatory properties of antithrombin III: new therapeutic implications. 951 77

Disseminated intravascular coagulation (DIC) and associated multi-organ failure are serious and often terminal events of a variety of non-septic conditions. For the most part, these conditions are a result of tissue factor (thromboplastin) release from damaged tissues creating situations that favor thrombin formation. Thrombin's role in this process is critical and serves to induce the coagulopathy, as well as many of the other aspects of inflammation that contribute to the associated morbidity and mortality. Clinical disorders giving rise to DIC fall into categories of trauma, obstetrical complications, malignancies and a variety of inflammatory conditions. Diagnostic patterns for these disorders are well established with an expected decrease in platelets and fibrinogen, as well as antithrombin III, in addition to elevated levels of thrombin-antithrombin III complex, prothrombin fragment 1 + 2, and D-dimer; all of which serve to identify the hypercoagulable state. Management of these coagulopathies requires attention to the bleeding diathesis and the ongoing thrombotic complication. Supportive therapy usually is required to provide hemostasis. However, control of the coagulopathy is of equal importance and requires not only early intervention, but also administration of sufficient antithrombotic agents to reduce thrombin's ability to consume coagulation factors, as well as to stimulate inflammatory processes. Heparin has been employed effectively in many of these situations, but suffers from its potential to induce hemorrhage. Antithrombin III concentrate, however, is devoid of this risk and provides a unique alternative that has had a limited, but effective record of benefits. Further proof of its efficacy in multi-organ failure disorders is awaited.
 ...
PMID:Disseminated intravascular coagulation in patients with multiple organ failure of non-septic origin. 951 79

Replacement of antithrombin has proved to be effective for treating disseminated intravascular coagulation. The administration of antithrombin is also useful for preventing organ failure in animals challenged with endotoxin or bacteria, and it increases the survival rate of such animals. Since inhibition of coagulation abnormalities by heparin failed to prevent organ failure in animals challenged with bacteria, antithrombin might exert therapeutic effects independently of its anticoagulant effect. These therapeutic mechanisms of antithrombin have been explored by using animal models of septicemia. Antithrombin prevents pulmonary vascular injury by inhibiting leukocyte activation in rats challenged with endotoxin. A higher dose of antithrombin was required to prevent pulmonary vascular injury than was required to inhibit disseminated intravascular coagulation. This preventive effect of antithrombin is mediated by the promotion of endothelial release of prostacyclin, an inhibitor of leukocyte activation. An interaction between antithrombin and heparin-like glycosaminoglycans on the endothelial cell surface appears to be important for this effect. Heparin inhibits such therapeutic effects of antithrombin by preventing it from interacting with the cell surface heparin-like glycosaminoglycans. Since activated leukocytes are of critical importance in patients with sepsis-associated organ failure, this anti-inflammatory activity of antithrombin may explain why it can prevent organ failure as well as coagulation abnormalities in patients with sepsis.
 ...
PMID:Antithrombin prevents endotoxin-induced pulmonary vascular injury by inhibiting leukocyte activation. 966 67

Heparin induced thrombocytopenia is encountered in clinical practice as type I and type II. Heparin induced thrombocytopenia type II is one of the most serious complications of heparin treatment. Its incidence is between 0.5-5% of all patients treated with heparins. Contrary to type I which is most probably caused by simple interaction of heparin with platelets, in type II factors of the immune system are involved. The laboratory diagnosis is complicated and negative, in vitro tests do not rule out the diagnosis in vivo. The latter is assessed most frequently per exclusionem when there is a marked drop of platelets associated with the clinical picture of thrombotic complications. Heparin must then be immediately discontinued and at the same time usually alternative antithrombotic treatment is necessary. Low-molecular heparins are contraindicated by the majority of authors because of possible immunological cross reactions, and coumarins are also unsuitable as drugs of first choice because of their late onset of effect and initial drop of protein C. Ideal preparations are most probably direct thrombin inhibitors (recombinant hirudin and its analogues, oligopetides). Anti-thrombocyte drugs can be used, possibly the defibrination enzyme ancrode (Arwin).
 ...
PMID:[Heparin-induced thrombocytopenia]. 982 74

Heparin Cofactor II (HCII) is a glycoprotein in human plasma which inactivates thrombin rapidly in the presence of dermatan sulfate. Inhibition occurs by formation of a stable equimolar complex between HCII and thrombin. HCII association with thrombotic events has not always been observed, thus decreased HCII does not appear to be a strong risk factor for thromboembolic events. Reduced HCII levels have been detected in different clinical conditions, such as hepatic failure, disseminated intravascular coagulation, thalasemina, sickle cell anemia. Increased physiological levels have been found in pregnant women and oral contraception. In our laboratory, we measured HCII plasmatic levels in the normal Buenos Aires city population and in patients under different clinical conditions, such as sepsis, diabetis, burns, oral anticoagulation and in patients treated with heparin, hyperhomcysteinemia in whom septic and diabetic patients showed decreased values. HCII thrombin inhibition possibly takes place in extravascular sites where dermatan sulfate is present. HCII activity would be important in the regulation of wound healing, inflammation, or neuronal development.
 ...
PMID:[Heparin cofactor II, a thrombin inhibitor with a still not clarified physiologic role]. 1034 31

In order to determine whether prednisolone has a protective effect against the development of disseminated intravascular coagulation (DIC), we measured the effect of prednisolone on changes in hemostatic parameters and plasma levels of inflammatory cytokines in endotoxin-treated rats. Decreases in platelet count and fibrinogen levels, prolongation of prothrombin time, and increases in the plasma fibrin degradation products and levels of thrombin-antithrombin III (TAT) complex following the administration of endotoxin, all of which are associated with DIC, were significantly suppressed by the administration of prednisolone. Heparin administration significantly suppressed changes in all these parameters except for the decrease in platelet count. The combination of prednisolone and heparin was more effective than either treatment alone. In order to determine whether these effects of prednisolone are correlated with the suppression of inflammatory cytokine production, we examined the relationship between changes in plasma levels of cytokine, the hemostatic parameters listed above, and mortality using a number of intervention regimens designed to alter events of the experimentally induced DIC. Changes in hemostatic parameters associated with DIC following 30 mg/kg per 4 h of endotoxin infusion were significantly suppressed by treatment with 1 mg/kg prednisolone 30 min before beginning endotoxin infusion, followed by administration of 250 U/kg heparin 2 h after the start of endotoxin infusion (prednisolone-endotoxin-heparin regimen). The heparin and prednisolone were administrated subcutaneously. The administration of prednisolone and heparin in the reverse order (i.e. heparin first and prednisolone second: heparin-endotoxin-prednisolone regimen) also suppressed changes in hemostatic parameters, albeit to a smaller degree. Cytokine production was also significantly suppressed by the first treatment, but was not affected by the regimen in which heparin was administered first. Administration of prednisolone alone or heparin alone 30 min before endotoxin significantly reduced the number of renal glomeruli with fibrin thrombi. Plasma levels of creatinine and alanine transferase were reduced only by prednisolone. Increased plasma levels of interleukin-1beta, tissue necrosis factor-alpha and interleukin-6 were suppressed by prednisolone but not by heparin, and there were significant correlations between plasma levels of TAT and cytokines. Prednisolone was more effective than heparin in reducing mortality at 24 h after 100 mg/kg over 4 h of endotoxin infusion (four of 20 versus 15 of 20 deaths for prednisolone and heparin, respectively). These findings suggest that prednisolone inhibits the development of endotoxin-induced DIC and reduces mortality by a different mechanism than heparin, possibly through suppressing the production of inflammatory cytokines. Prednisolone may be efficacious in preventing DIC and multiple organ dysfunction caused by endotoxin.
 ...
PMID:Prednisolone inhibits endotoxin-induced disseminated intravascular coagulation and improves mortality in rats: importance of inflammatory cytokine suppression. 1049 13

Thrombogenicity of factor IX complex or prothrombin complex concentrates (PCC) is a well-acknowledged problem. The exact incidence is unknown but has decreased with the improvement of the quality of coagulation factor concentrates and a more judicious use of these products. The clinical spectrum of thrombogenicity ranges from superficial thrombophlebitis, deep-vein thrombosis and pulmonary embolism, and arterial thrombosis to disseminated intravascular coagulation. Several risk factors have been identified: (a) predisposing clinical factors (underlying disease and clinical condition), (b) therapy factors (dosing, concomitant therapy and drug interactions), and (c) quality of the PCC used. It is generally assumed that the risk of thromboembolic adverse effects is greater in patients with acquired disorders of hemostasis than in patients with inherited coagulation factor deficiencies. In hemophilia B, clinical conditions with an increased risk include large muscle hematomas, immobilization, surgery (especially orthopedic surgery), and liver disease. In acquired disorders of hemostasis, a prethrombotic state can be assumed in all patients where an indication for PCC concentrates is considered. Liver disease and/ or antithrombin deficiency are considered as major risk factors. Therapy factors with an increased risk include large, repetitive doses of PCC. It is assumed that heparin and, in the case of antithrombin deficiency, antithrombin substitution decrease the incidence of thromboembolic adverse effects. Heparin neutralisation with protamine and aprotinin therapy may be additional risk factors. The declining incidence and the recent cluster of fatal thromboembolic adverse events in Germany with one brand of PCC is strong evidence for the crucial role of the quality of PCC in the occurrence of thromboembolic adverse effects.
 ...
PMID:Thrombogenicity of prothrombin complex concentrates. 1049 4

The activation of mast cells (MC) and liberation of their mediators can play an essential role in initiating and controlling inflammatory processes in the wall of the gastrointestinal tract (GIT) due to ischemia. The role of MC in changes induced by hemorrhagic shock (HS) remains unknown. Heparin provided by MC seems to inhibit local inflammation and prevent DIC. The aim of this study was to evaluate the morphometric changes and biochemical activity of MC in the stomach wall after 75 minutes of hemorrhagic shock. The MC in mucosal, submucosal, muscular and serosal compartments of the various stomach wall regions were examined in shocked rats and in the control group. Additionally, the contents of glycosaminoglycans (GAG), measured as uronic acids concentration, as well as anticoagulative activity in the stomach wall were assessed. HS resulted in an evident increase in the number of mast cells detected in the stomach mucosa and serosa, in slight alterations in number of MC in the submucosal and muscular layers, a significant increase in size and changes of the shape of the MC. The elevation of the width, area, and circular shape of MC in all layers were noted. No clear and significant differences between various stomach regions in MC numbers and MC sizes could be shown. No reaction of other inflammatory cells at this stage of shock was observed. Highly significant increases in GAG concentration, and anticoagulative activity in the stomach wall due to shock were noted. The morphometric and biochemical data may indicate MC activation, especially in mucosa and serosa. The shock-induced migration of MC settled in the stomach wall seems to be possible. The results suggest an essential role of MC reaction in the stomach wall in the early phase of hemorrhagic shock.
 ...
PMID:Hemorrhagic shock activates mast cells in the rat stomach wall. 1098 43

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.
 ...
PMID:Effect of activated human protein C on disseminated intravascular coagulation induced by lipopolysaccharide in rats. 1105 Jun 97

We evaluated the effectiveness of antithrombin III (AT III) infusions designed to achieve supraphysiologic plasma levels of this serine protease inhibitor in preventing vascular permeability and disseminated intravascular coagulation in a pig model of sepsis. In addition, we determined whether high AT III doses were associated with increased bleeding risk. Sepsis was induced in 18 pigs by injection of lipopolysaccharide (LPS) (0.25 microg/kg per h for 3 h). At 90 min after the start of LPS infusion, pigs were randomized (n = 6 per group) to receive either human serum albumin as a placebo, AT III 120/5 (120 U/kg, 30-min bolus + 5 U/kg per h for 240 min), or AT III 250/10 (250 U/kg + 10 U/kg per h). Three additional animals served as negative controls (no LPS, no AT III). Treatment with AT III significantly reduced the amount of effluents in body cavities and fibrin monomers. AT III did not significantly increase bleeding risk as determined by organ hemorrhage. An additional assessment of AT III's bleeding risk [skin bleeding time (SBT)] was carried out in 35 nonseptic pigs treated with either AT III alone (120/5 or 250/10) or in the combination with heparin. Heparin administration alone produced a dose-dependent increase in SBT, but AT III alone did not. Addition of AT III 120/5 to heparin did not induce a further increase in bleeding time over heparin alone. These results indicate that administration of AT III in doses designed to achieve very high plasma concentrations significantly ameliorates symptoms of sepsis-induced vascular leakage and disseminated intravascular coagulation without increasing bleeding risk.
 ...
PMID:Treatment of porcine sepsis with high-dose antithrombin III reduces tissue edema and effusion but does not increase risk for bleeding. 1155 99


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>