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)

Glomeruli possess a complex hemostasis system with prothrombotic (procoagulant, antifibrinolytic) and antithrombotic (anticoagulant, fibrinolytic) properties that can act locally on platelet adhesion or aggregation, on plasmatic coagulation pathways, and on fibrinolysis. In vitro, inflammatory mediators, such as TNF, favor glomerular thrombogenic properties through enhancement of thromboplastin synthesis and of plasminogen activator inhibitor PAI-1, and through decrease in thrombomodulin activity. In some diseases, intraglomerular fibrin formation appears to be favored by increased glomerular prothrombotic properties, for example: augmented thromboplastin activity in immune glomerulonephritides and in Shwartzman phenomenon, excessive thromboxane A2 synthesis, and decreased fibrinolytic activity in severe renal allograft rejection. In other diseases glomerular hemostasis appears to function homeostatically, for example, in thrombin-induced disseminated intravascular coagulation with enhancement of fibrinolytic activity favoring fibrin dissolution. Novel methods allowing the study of glomerular hemostatic activities in renal biopsy fragments should help to understand the mechanisms of fibrin deposition in human diseases and to treat it on a logical basis.
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PMID:Glomerular coagulation system in renal diseases. 150 74

Sepsis or septic shock is frequently associated with activation of the complement system, coagulation and fibrinolytic changes and the release of several cytokines. In this study we analyzed the relation of complement activation to the inflammatory mediators, hemodynamic and biochemical parameters and severity of illness and outcome in 20 consecutive patients with clinically defined sepsis. Levels of C3a and C3d were elevated in 90% of the patients (median levels 0.19 mg/l and 8.6 mg/l respectively) in comparison to 14% and 42%, respectively of 7 patients with non-septic shock. Levels of C4 were decreased in only 1 of the 20 septic patients. Levels of TNF and IL-6 were elevated in 94% and 100% of the patients, Levels of TNF and IL-6 were elevated in 94% and 100% of the patients, respectively (median levels 122 ng/l and 1300 U/ml) and were clearly interrelated (r = 0.67, p less than 0.01). C3a levels correlated with the APACHE II score (r = 0.57, p less than 0.05) and high C3a levels were associated with fatal outcome (p less than 0.05). C3a was also correlated inversely with mean arterial pressure (r = 0.50, p less than 0.01). Levels of complement C3a and C3d significantly correlated with levels of plasminogen activator inhibitor-1 (PAI) and correlated inversely with AT-III levels. We found no correlation between these complement products and leukocyte counts or lactate levels, nor was there a correlation between C3a or C3d and the cytokines TNF and IL-6. Levels of C3a and C3d did not decrease significantly during the first 24 h of treatment, in contrast to a clear decrease in IL-6 levels in all patients and a decrease in TNF in the surviving patients. TNF levels remained stable or increased in the non-survivors. We conclude that both the complement system and the cytokine system are involved in the pathogenesis of septic shock and may be involved in the development of some of the fatal complications like hypotension and disseminated intravascular coagulation.
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PMID:Complement activation and the production of inflammatory mediators during the treatment of severe sepsis in humans. 164 97

The local and generalized Shwartzman reactions are models of thrombohemorrhagic skin necrosis and DIC, respectively. An intravenous preparatory injection of endotoxin followed by an intradermal injection of endotoxin 24 hours later elicits a thrombohemorrhagic lesion only at the site of intradermal injection of endotoxin in the local Shwartzman reaction. Two intravenous injections of endotoxin spaced 24 hours apart induced a systemic generalized Shwartzman reaction characterized by coagulopathy, petechial hemorrhages, microthrombi, and decreased circulating platelets similar to DIC. Of particular interest is the observation that thrombohemorrhagic lesions of the Shwartzman reaction only develop at sites of intradermal injections of endotoxin. Microthrombi composed of platelets and leukocytes only adhere or accumulate in dermal vessels after an intradermal injection of endotoxin. Prior to the endotoxin injection, biopsies of skin show normal vessels without microthrombi or significant inflammation. Since endothelial cells line the small vessels in the dermis, where a Shwartzman reaction appears to be initiated, it is likely that endothelial cells are important for initiating a local Shwartzman reaction. IL-1 and TNF can substitute for the intradermal injection of endotoxin in the local Shwartzman reaction, induce endothelial cells to become thrombogenic, and can induce the expression of cell adhesion molecules on endothelial cells making endothelial cells more sticky for leukocytes. These observations suggest that endothelial cells play a central role in the local Shwartzman reaction and may be important in understanding diseases associated with thrombohemorrhagic skin necrosis.
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PMID:Shwartzman reaction. 228 21

A phase I clinical and pharmacokinetic study of recombinant human tumor necrosis factor (rH-TNF) was conducted in a single dose schedule in 33 patients with advanced cancer. rH-TNF was given by i.v. infusion over 30 min with a starting dose of 1 x 10(5) units/m2. The dose was escalated up to 16 x 10(5) units/m2 according to the modified Fibonacci scheme. Toxic effects were similar but not identical to those reported with interferons and interleukin-2, and included fever, rigors, nausea and vomiting and anorexia in a non-dose-dependent manner, and hypotension, leukocytosis, thrombocytopenia and transient elevation of transaminases (SGOT and SGPT) in an approximately dose-dependent manner. DIC syndrome was observed in one patient who had received 16 x 10(5) units/m2. The dose-limiting toxicities were hypotension, thrombocytopenia and hepatotoxicity, and the maximum tolerated dose in a single i.v. infusion of rH-TNF appeared to be 12 x 10(5) units/m2 when thrombocytopenia and elevation of SGOT and SGPT were taken as the dose-limiting toxicities. However, if hypotension was included, the maximum safely tolerated dose appeared to be 5 x 10(5) units/m2.
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PMID:Phase I study of recombinant human tumor necrosis factor. 331 81

Leukocytes play an important role in the development of disseminated intravascular coagulation (DIC). In the reperfusion phase of OLT a DIC-like situation has been described and has been held responsible for the high blood loss during this phase. We investigated the role of leukocytes in the pathogenesis of DIC in OLT by measuring the leukocytic mediators released upon activation (cathepsin B, elastase, TNF, neopterin) and the levels of thrombin-antithrombin III (TAT) complexes, seen as markers of prothrombin activation. Arterial blood samples were taken at 10 different time points during and after OLT. Samples were also taken of the perfusate released from the liver graft vein during the flushing procedure before the reperfusion phase. Aprotinin was given as a continuous infusion (0.2-0.4 Mill. KIU/hr) and its plasma levels were determined. Significantly elevated levels of neopterin (15-fold; P < 0.01), cathepsin B (440-fold; P < 0.01) in the perfusate, as compared with the systemic circulation, as well as their significant increases in the early reperfusion phase suggested that they were released by the graft liver. This was paralleled by elevated levels of elastase (1.3-fold, P < 0.05), TNF (1.5-fold, P = NS), and TAT complexes (1.4-fold; P < 0.1) in the perfusate. Significant correlations could be identified between the parameters of leukocyte activation and TAT complexes, whereas no correlation was observed between any of the parameters investigated and the aprotinin levels. Our results strongly indicate a release of leukocytic mediators from the graft liver during its reperfusion which seems to be related to the parallely increased prothrombin activation. No correlation could be seen between levels of aprotinin and levels of leukocytic mediators.
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PMID:Mediators of leukocyte activation play a role in disseminated intravascular coagulation during orthotopic liver transplantation. 750 86

Plasma interleukin-6 (IL-6) was higher in patients with disseminated intravascular coagulation (DIC) than in those without DIC. Levels of IL-1 beta and TNF alpha were also significantly higher in patients with DIC. Plasma IL-6 was highest in patients with underlying sepsis and was also high in those with advanced solid cancer. Levels were high in some patients with acute promyelocytic leukaemia and were significantly higher in patients with organ failure than in those without this complication. Plasma IL-6 was higher in DIC patients showing a poor response to therapy than in those with a good response. Incubation with IL-6 caused significant increases in tissue factor activity in mononuclear cells and release of plasminogen activator-1 antigen from human umbilical vein endothelial cells. As increases in IL-6 might give rise to hypercoagulable and hypofibrinolytic states, this may be a cause of DIC and be related to prognosis and organ failure.
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PMID:Increased plasma level of interleukin-6 in disseminated intravascular coagulation. 821 55

Abnormalities in coagulation and fibrinolysis are frequently observed in septic shock. The most pronounced clinical manifestation is disseminated intravascular coagulation. Recent studies in human volunteers and animal models have clarified the early dynamics and route of activation of both coagulation and fibrinolytic pathways. In healthy subjects subjected to a low dose of either endotoxin or TNF an imbalance in the procoagulant and the fibrinolytic mechanisms is apparent, resulting in a procoagulant state. Also in patients with septic shock a dynamic process of coagulation and fibrinolysis is ongoing with evidence of impaired fibrinolysis. These abnormalities have prognostic significance; the extent of disturbances of coagulation and fibrinolysis is related to the development of multiple organ failure and death.
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PMID:Coagulation disorders in septic shock. 822 38

TNF, in addition to its antitumor activity, would play an important role in the pathogenesis of cancer-related severe complications, including ARDS and DIC. Therefore, the modulation of TNF secretion could be important in the supportive care of advanced cancer patients. At present, PTX is the only drug which has been proven to be able to inhibit in vitro the release of TNF. The present study was performed to evaluate the effect of PTX on TNF blood concentrations in disseminated cancer patients with abnormally high TNF values. The study included 14 cancer patients, with initial or conclamate signs of ARDS (n = 8) or DIC (n = 6). PTX was given intravenously at a dose of 300 mg/day for 7 days. Mean serum levels of TNF significantly decreased in response to PTX therapy, and they returned to normal range in 5/14 patients. These preliminary data would suggest that PTX may be considered as a biological response modifier, capable of inhibiting TNF secretion in humans, with a following potential use in the treatment of cancer-related severe complications.
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PMID:Inhibition of tumor necrosis factor-alpha secretion by pentoxifylline in advanced cancer patients with abnormally high blood levels of tumor necrosis factor-alpha. 826 18

CAP18 (cationic antimicrobial protein, 18kDa) is a 142 amino acid protein originally isolated from rabbit granulocytes using agglutination of LPS-coated erythrocytes as an assay. CAP-18 is composed of an N-terminal domain of unknown function (CAP181-105) and a C-terminal LPS-binding domain (CAP18106-142). Synthetic CAP18106-142 and CAP18106-137, a 32-amino acid peptide resulting from the truncation of 5 amino acids from the C-terminus of CAP18106-142, inhibited LPS-induced tissue factor generation, nitric oxide production and TNF release by macrophages. Mice treated with CAP18106-142 or CAP18106-137 were significantly protected from LPS lethality. Although CAP18106-142 and CAP18106-137 were highly active, other fragments of CAP18106-142, including CAP18110-142 with a truncated N-terminus, did not exhibit LPS-binding and LPS-neutralizing activities. Both peptides had broad anti-microbial activity against both Gram-negative bacteria such as Escherichia coli, Salmonella typhimurium, Klebsiella pneumoniae, Pseudomonas aeruginosa (IC50; 40-100 nM) and Gram-positive bacteria such as Staphylococcus aureus(Methicillin sensitive and resistant strains) and Streptococcus pneumoniae (IC50; 100-200nM). We cloned a CAP18 family protein from human granulocytes. The cloned cDNA encoded 140 amino acid residues. Human CAP18 (CAP181-140) was highly homologous to that of rabbit. A 32- amino-acid C-terminal fragment (CAP18104-135) was shown to bind LPS, inhibit LPS-induced tissue factor generation by murine macrophages, and protect mice from LPS lethality. This peptide exhibited antimicrobial activity against both Gram-negative and Gram-positive bacteria. We hypothesize that CAP18 and the derived peptides bind to LPS and alter the capacity of LPS to initiate disseminated intravascular coagulation. In this regard, CAP may act as host defense protein against infectious diseases, and have therapeutic potential for sepsis and endotoxin shock.
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PMID:Structure and functions of endotoxin-binding peptides derived from CAP18. 852 37

Septic shock remains a serious disorder associated with high mortality. Accumulating evidence indicates that TNF is a major and essential mediator of endotoxin shock. We report here that administration of an antibody against CD18 dramatically reduced endotoxin-induced shock in rabbits as revealed by prevention of severe hypotension, metabolic acidosis and a pathological change suggestive of disseminated intravascular coagulation with concomitant inhibition of elevation of plasma TNF activity. The anti-CD18 antibody also inhibited the hypotension induced by administering recombinant TNF. Furthermore, an antibody against a ligand for CD18 complexes, intercellular adhesion molecule-1, also prevented TNF-induced shock as well as endotoxin shock in rabbits. These observations suggest that adhesion of leukocytes to endothelium may be of primary importance in the action of TNF as well as in the production of TNF in vivo and that the antibody against adhesion molecules could be of therapeutic benefit in life-threatening septic shock in humans.
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PMID:Prevention of endotoxin shock by an antibody against leukocyte integrin beta 2 through inhibiting production and action of TNF. 852 1


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