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)

Tissue factor pathway inhibitor (TFPI) is the factor Xa-dependent inhibitor of the factor VIIa/tissue factor complex. The plasma concentration of this 276 amino acid, 40 kDa glycoprotein is normally about 100 ng/ml. There are three intravascular pools of TFPI: 50-90% is on the endothelium, 10-50% is in plasma and less than 2.5% is in platelets. The TFPI in plasma is mainly associated with lipoproteins-only about 5% is free TFPI. The lipoprotein-associated TFPI seems to be of less anticoagulant effect than the free TFPI. Both unfractionated heparin, low-molecular-weight heparins and pentosan polysulphate induce release of TFPI after intravenous injection, whereas dermatan sulphate does not. The interactions with TFPI account for a considerable amount of the anticoagulant effect of heparin. Studies have shown increased TFPI levels in plasma from patients with advanced malignancy and in subjects with fatal DIC or septicaemia. The reason for this is unknown. For measuring the anticoagulant activity of TFPI in plasma, end-point or antigen assays may be less useful than the clotting assay with dilute tissue factor. Animal studies indicate that the main physiological role of TFPI is the inhibition of small amounts of tissue factor. TFPI is probably essential for a normal haemostatic balance.
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PMID:The present status of tissue factor pathway inhibitor. 142 Aug 19

Extrinsic pathway inhibitor (EPI) is a Kunitz type serine protease inhibitor. EPI is a potent inhibitor of the factor VIIa/thromboplastin (TP) complex in the presence of factor Xa and is also a direct inhibitor of factor Xa. The inhibitory mechanism is complex and is currently thought to involve, in a first step, the formation of a EPI-factor Xa complex, and, in a second step, the formation a quaternary EPI-factor Xa-factor VIIa-TP complex. In the blood vessels, EPI is confined to three different pools. A major pool of EPI is bound to the endothelial surface, and this fraction may be released by heparin. Plasma contains a second, but smaller pool of EPI (approximately 10-50% of the endothelial surface pool) at a concentration of 50-100 ng/ml. This pool consists mostly of EPI-lipoprotein complexes and only less than 10% is carrier-free EPI. A third pool of EPI is confined to platelets (less than 10% of the plasma pool). The biological role of these pools has not yet been clarified, but some evidence suggest that the carrier-free EPI is biologically most active. In patients, disseminated intravascular coagulation may continue despite normal or even elevated EPI levels. However, evidence has now been provided to indicate that EPI can inhibit factor VIIa/TP complexes formed in vivo to prevent the effect of limited amounts of TP. Taken together, the present knowledge of EPI indicates that EPI functions as a key inhibitor to feedback control of blood coagulation initiated by TP.
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PMID:Extrinsic pathway inhibitor--the key to feedback control of blood coagulation initiated by tissue thromboplastin. 179 48

Although in vitro experiments have established that extrinsic pathway inhibitor (EPI) is the only known plasma inhibitor of factor VIIa-tissue factor (TF) catalytic activity of potential physiologic significance, evidence of its function in vivo has been lacking. TF-induced intravascular coagulation may occur in patients despite normal plasma levels of EPI and, in our earlier studies, normal plasma EPI levels did not protect rabbits from intravascular coagulation induced by an infusion of purified TF (1 microgram/kg). Studies have now been carried out in which plasma EPI levels were reduced in rabbits to below 20% of the initial level by injection of anti-rabbit EPI IgG. Infusion into such animals of purified rabbit TF apoprotein (0.25 microgram/kg) reconstituted into phospholipid vesicles induced substantial disseminated intravascular coagulation. Infusion of control saline or phospholipid vesicles not containing TF was without significant effect as was infusion of TF (0.25 microgram/kg) into animals injected with nonimmune goat IgG. These data establish that EPI can dampen TF-induced intravascular coagulation in rabbits. They support the hypothesis that EPI plays a significant role in regulating coagulation resulting from the exposure of blood to trace concentrations of TF during the illnesses and minor injuries of normal existence.
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PMID:Depletion of extrinsic pathway inhibitor (EPI) sensitizes rabbits to disseminated intravascular coagulation induced with tissue factor: evidence supporting a physiologic role for EPI as a natural anticoagulant. 189 82

We have reported earlier that immunodepletion of extrinsic pathway inhibitor (EPI) sensitizes rabbits to disseminated intravascular coagulation (DIC) induced by infusing a low concentration of tissue factor (TF). We now describe the effect of immunodepletion of EPI in rabbits administered endotoxin. Cortisone-treated rabbits were administered anti-rabbit EPI immunoglobulin (IgG) or Fab fragments or were administered control nonimmune material before an injection of endotoxin. In four of seven rabbits administered anti-EPI, plasma EPI activity levels were reduced by 70% to 80% of initial levels for 6 to 8 hours. In these rabbits the endotoxin induced extensive DIC, as evidenced by substantial decreases in fibrinogen, factor V, factor VIII, and platelets, and gross hemorrhagic necrosis of the kidneys due to massive deposition of fibrin in the glomerular microcirculation (the generalized Shwartzman reaction). In three rabbits administered anti-EPI, plasma EPI levels were only transiently reduced. In these rabbits and in four rabbits administered nonimmune IgG or Fab, endotoxin induced minimal to moderate intravascular clotting and deposits of fibrin were not found in the glomerular capillaries. Because it is believed that TF expressed on monocytes triggers endotoxin-induced coagulation, these data are taken as evidence that EPI functions as a natural anticoagulant that can regulate factor VIIa/TF activity expressed on cell surfaces in vivo. They support a hypothesis that EPI prevents thrombotic complications that might otherwise result from exposure of blood to cytokine-induced generation of small amounts of TF on cell surfaces in many inflammatory and infectious disease states.
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PMID:Immunodepletion of extrinsic pathway inhibitor sensitizes rabbits to endotoxin-induced intravascular coagulation and the generalized Shwartzman reaction. 190 95

Human plasma contains an inhibitor of tissue factor-initiated coagulation known as the lipoprotein-associated coagulation inhibitor (LACI) or also known as the extrinsic pathway inhibitor (EPI). A competitive fluorescent immunoassay was developed to measure the plasma concentration of LACI in samples from normal individuals and patients with a variety of diseases. The LACI concentration in an adult control population varied from 60% to 160% of the mean with a mean value corresponding to 89 ng/mL or 2.25 nmol/L. Plasma LACI levels were not decreased in patients with severe chronic hepatic failure, warfarin therapy, primary pulmonary hypertension, thrombosis, or the lupus anticoagulant. Plasma LACI antigen was decreased in some, but not all patients with gram-negative bacteremia and evidence for disseminated intravascular coagulation. Plasma LACI levels were elevated in women undergoing the early stages of labor (29%), in patients receiving intravenous tissue-type plasminogen activator (45%), and in patients receiving intravenous heparin (375%). A radioligand blot of the pre- and post-heparin plasma samples shows the increase to be in a 40-Kd form of LACI. Very low levels of plasma LACI antigen were found in patients with homozygous abetalipoproteinemia and hypobetalipoproteinemia, diseases associated with low plasma levels of apolipoprotein B containing lipoproteins. Following the injection of heparin into one patient with homozygous abetalipoproteinemia, the plasma LACI antigen level increased to a level comparable with that in normal individuals after heparin treatment.
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PMID:Plasma antigen levels of the lipoprotein-associated coagulation inhibitor in patient samples. 207 76

Tissue factor is the initiator of the extrinsic coagulation pathway and is an important regulator of haemostasis. Tissue factor is constitutively expressed in numerous cells and tissues, and can be induced in monocytes and endothelial cells by different inflammatory agents. Lymphocytes and serum factors can modulate the expression of tissue factor in monocytes. The regulation of tissue factor expression in monocytes appears to be different from that in endothelial cells. Phorbol myristate acetate can inhibit as well as induce tissue factor activity in monocytes, whereas phorbol myristate acetate only induces the expression of tissue factor in endothelial cells. Tissue factor expression in monocytes from patients with infections is not always associated with DIC. The extrinsic pathway inhibitor may play a role in the development of DIC in patients with sepsis. Deposition of extravascular fibrin may be an important determinant of tissue injury.
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PMID:Cellular regulation of tissue factor. 213 17

Rabbits were given polyclonal anti-tissue factor (TF) immunoglobulin G (IgG) before an injection of endotoxin to test the hypothesis that TF triggers disseminated intravascular coagulation (DIC) after endotoxin. The rabbits had been prepared with cortisone to develop DIC after one injection of endotoxin. Anti-TF IgG substantially reduced the falls in fibrinogen, factors V and VIII, and platelets noted in control rabbits given preimmune IgG before endotoxin. At autopsy 24 hours later, fibrin was present in glomerular capillaries of 4 of 5 control rabbits, but in none of 11 rabbits given anti-TF IgG. DIC was also induced in a second group of rabbits by the infusion, over 4 hours, of 1 microgram/kg of purified, reconstituted rabbit brain TF. This resulted in striking falls in plasma fibrinogen, factors V, and VIII that were diminished, but not prevented by prior treatment with anti-TF IgG. Circulating activated factor VII, induced by either TF infusion or endotoxin, could not be detected after DIC. Mean plasma extrinsic pathway inhibitor (EPI) activity did not fall significantly after endotoxin, and only to about 65% of the preinfusion after infusion of TF. Thus, DIC induced by both agents proceeded despite nearly normal plasma EPI levels. Because EPI neutralizes factor VIIa/TF in vitro only after a short lag period, the DIC that persisted for up to 6 hours after injection of endotoxin suggests that TF activity continued to be generated during this period on cells to which the circulating blood was exposed. All animals given endotoxin became ill with cyanosis, tachypnea, cold ears, and diarrhea, regardless of whether they had received anti-TF IgG to attenuate DIC. Infusion of TF caused some animals to die acutely with pulmonary arterial thromboses, but surviving animals did not appear ill. The findings support the hypothesis that exposure of blood to TF triggers DIC after endotoxin, but is not important for the pathogenesis of endotoxin-induced shock.
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PMID:Disseminated intravascular coagulation in rabbits induced by administration of endotoxin or tissue factor: effect of anti-tissue factor antibodies and measurement of plasma extrinsic pathway inhibitor activity. 231 59

We have evaluated the quantitative relationship between lipopolysaccharide (LPS, endotoxin), fibrinopeptide A (FPA), antithrombin (AT), protein C (PC) and extrinsic pathway inhibitor (EPI) in plasma from 39 consecutively admitted patients with systemic meningococcal disease (SMD). The most severely ill patients with fulminant meningococcal septicemia (n = 13, 6 dead) had significantly (p less than 0.01) higher plasma levels of LPS and FPA and lower levels of PC and AT on admission as compared with the less severe clinical presentations (n = 26, 1 dead). The levels of EPI on admission were significantly (p less than 0.05) higher in nonsurvivors vs survivors with fulminant septicemia. As the disease progressed, the levels of LPS, FPA, AT and PC declined, while the levels of EPI increased. Three of six nonsurviving septicemic patients had levels of EPI greater than 200% within 16 hours of admission vs two of 30 survivors (p = 0.02). The results suggest that increasing levels of LPS in SMD elicit increasing consumption coagulopathy, contributing to the organ pathophysiology. The kinetics of EPI, inhibiting the thromboplastin-FVIIa-FXa complex, differs markedly from the kinetics of AT and PC i.e. increases as opposed to decreases.
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PMID:The quantitative association of plasma endotoxin, antithrombin, protein C, extrinsic pathway inhibitor and fibrinopeptide A in systemic meningococcal disease. 251 Mar 54

Plasma or serum extrinsic pathway inhibitor (EPI) activity was measured in 24 patients with disseminated intravascular coagulation (DIC) and in 23 patients with severe hepatocellular disease. EPI was measured as activity in a test sample that inhibited factor VIIa/tissue factor (TF)-catalyzed activation of 3H-factor IX (activation peptide release) in the presence of factor X. Of the 24 patients with DIC, 13 had sepsis and five had metastatic carcinoma, disorders in which tissue factor is believed to initiate DIC. EPI activity ranged from 68% to 300% (mean 134% +/- 50%). Serial measurements in nine patients failed to show depletion of EPI activity coincident with worsening DIC. DIC induced by tissue factor or other activating materials may progress despite normal EPI levels. In the patients with liver disease, of whom 15 had decompensated chronic hepatocellular disease (two fatal cases) and eight had acute fulminant liver failure (seven fatal cases), plasma or serum EPI activity varied from less than 20% to 194%. Values were distributed in a bimodal fashion. EPI activity could not be correlated with either the etiology of the liver disease or the degree of prolongation of the prothrombin time. Patients with chronic hepatocellular disease who survived had normal or elevated EPI activity. Patients with fatal hepatic dysfunction had low, normal, or high values for EPI activity. This must mean that secretion of EPI from cells other than hepatocytes can maintain normal plasma EPI levels.
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PMID:Human plasma extrinsic pathway inhibitor activity: II. Plasma levels in disseminated intravascular coagulation and hepatocellular disease. 278 83

Tissue factor pathway inhibitor (TFPI) controls activation of blood coagulation while antithrombin (AT) regulates the final stage. Both inhibitors inhibit the intermediate stage of activation. Subnormal levels of TFPI increase the risk of disseminated intravascular coagulation (DIC) in septic conditions, and the risk of occlusive thrombi over damaged vascular intima or fissured arteriosclerotic plaques. The risk of venous thrombosis is increased by subnormal AT or subnormal activity of the protein C system. In contrast, TFPI may be little involved in the control of deep venous thrombosis. Heparin strongly accelerates AT and releases TFPI to the blood. Both these effects may contribute to the antithrombotic effect of heparin. In septic DIC, heparin may contribute little to quench activation of coagulation. Once hereditary deficiency of TFPI is described, its biological role will be better understood.
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PMID:Relative roles of tissue factor pathway inhibitor and antithrombin in the control of thrombogenesis. 764 20


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