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)

Blood was obtained from four patients envenomated by the Australian common brown snake, Pseudonaja textilis textilis. This elapid snake has one of the most toxic venoms in the world, containing extremely potent neurotoxic and coagulant components. The latter is a potent complete prothrombinase, converting prothrombin to alpha-thrombin, and comprises more than 30% of the total venom protein. The four envenomated patients developed a typical consumption coagulopathy. Serial serum and plasma samples from patients were studied by immunoaffinity adsorption, 2-alanine precipitation of fibrinogen and fibrinogen-related products and 2-dimensional immunoelectrophoresis, and assayed for crosslinked fibrin degradation products as D dimer, using the monoclonal antibody, DD-3B6/22. These procedures showed the virtually complete disappearance of fibrinogen, accompanied by the appearance of large quantities of fibrinogen and fibrin degradation products consisting of both crosslinked and noncrosslinked species. With recovery, a homogeneous high molecular weight fibrinogen was observed. The data suggest that the prothrombin activator of this venom causes the generation of thrombin which subsequently converts fibrinogen to fibrin and stimulates partial crosslinking of both alpha and gamma-chains. The resultant disseminated intravascular coagulation is accompanied by very active secondary fibrinolysis which apparently limits the extent of any microvascular thrombosis but which may contribute to a bleeding tendency.
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PMID:Fibrinolysis as a feature of disseminated intravascular coagulation (DIC) after Pseudonaja textilis textilis envenomation. 223 40

The plasma inhibitor(s) of factor VIIa-tissue thromboplastin cooperates with factor Xa. This "Extrinsic Pathway Inhibitor" has been quantitated with a sensitive chromogenic substrate assay. Gel filtration of plasma separates 3 EPI peaks. Postoperatively, both EPI and the other coagulation inhibitors decrease. Unlike the other inhibitors, EPI is usually normal in severe liver cirrhosis. In disseminated intravascular coagulation, EPI levels vary considerably.
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PMID:The inhibitor of F VIIa in plasma measured with a sensitive chromogenic substrate assay: comparison with antithrombin, protein C and heparin cofactor II in a clinical material. 246 15

Inhibition of Factor VIIa-tissue factor activity by a plasma component(s) that requires factor Xa has been described recently. In this communication, we have developed a specific radiometric assay (which utilizes 3H-Factor IX and is sensitive to less than 1% of plasma level) for this inhibitor and have measured its activity in various disease states. Strikingly, the levels of this inhibitor were found to be normal in patients with advanced chronic hepatocellular disease but low in patients with disseminated intravascular coagulation (DIC). When endotoxin was used to induce DIC in rabbits, the levels of this inhibitor fell by 25-90%. Human umbilical vein endothelial cells (HUVE), bovine pulmonary artery endothelial cells, and a human hepatoma cell line (HepG2) all synthesized and secreted this inhibitor, whereas a promyelocytic cell line (HL-60) did not and a monocytic cell line (U937) appears to synthesize only small amounts. When ammonium sulfate-fractionated human plasma and serum-free conditioned media from both HUVE and HepG2 cells were electrophoresed on sodium dodecyl sulfate acrylamide gels, two activity peaks corresponding to Mr approximately 45,000 and Mr approximately 33,000 were eluted in each case. These observations suggest that (a) the inhibitor is consumed in DIC and that (b) endothelial cells (or other cells) synthesize sufficient amounts of this inhibitor in vivo to compensate for any decreased production by liver cells.
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PMID:Inhibitor of the factor VIIa-tissue factor complex is reduced in patients with disseminated intravascular coagulation but not in patients with severe hepatocellular disease. 303 84

The inhibitory effect of gabexate mesylate, which is used therapeutically in the treatment of pancreatitis and disseminated intravascular coagulation, and as a regional anticoagulant agent for hemodialysis, has been measured on bovine factor Xa, bovine alpha-thrombin, human Lys77-plasmin, human urinary kallikrein, human urokinase, porcine pancreatic beta-kallikrein-B, and bovine beta-trypsin catalyzed hydrolysis of p-nitrophenyl esters of N-alpha-carbobenzoxy-L-arginine and N-alpha-carbobenzoxy-L-lysine. On the basis of enzyme:gabexate mesylate affinities, the serine proteases can be arranged as follows: human urinary kallikrein approximately porcine pancreatic beta-kallikrein-B much less than bovine beta-trypsin approximately bovine factor Xa approximately human Lys77-plasmin approximately human urokinase approximately bovine alpha-thrombin. The mode of binding of gabexate mesylate to the serine proteases conforms to the active-reactive site geometries observed in their complexes with natural and synthetic inhibitors. Differences in gabexate mesylate affinities for these proteases reflect structural differences at their primary specificity subsite, which have been investigated by comparative analysis of amino acid sequences and by computer-graphics techniques.
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PMID:Gabexate mesylate inhibition of serine proteases: thermodynamic and computer-graphics analysis. 310 78

Numerous investigators have postulated that a hypercoagulable state exists in humans for a period of time before the development of thrombotic episodes. A clear biochemical definition of the prethrombotic state, however, has proved elusive due in part to the lack of reliable techniques for monitoring pertinent changes in blood coagulability. Based on recent advances in our knowledge of the biochemistry of the coagulation system, a series of highly sensitive and specific immunochemical tools has been developed that can quantitate the activities of various steps of the hemostatic mechanism in vivo at the subnanomolar level. We have established assays for F1+2 and the protein C activation peptide, which measure the cleavage of the prothrombin molecule by factor Xa and the scission of protein C by the thrombin-thrombomodulin complex, respectively. Nossel and coworkers had previously constructed similar assays for fibrinopeptide A (FPA) and fragment B beta 1-42, which monitor the cleavage of fibrinogen by thrombin and the proteolysis of fibrin I by plasmin, respectively. Substantial elevations in the levels of these markers have been found in patients with disseminated intravascular coagulation and many subjects with acute deep venous thrombosis. The F1+2 and FPA assays have been used to demonstrate that significant increments in factor Xa activity but not thrombin activity regularly occur in the blood of nonanticoagulated individuals with congenital deficiencies of antithrombin or protein C. These two disorders are known to be correlated with the subsequent development of thrombosis. Patients with protein C deficiency have also been noted to have significantly reduced plasma levels of protein C activation peptide. By using the immunoassays for FPA and B beta 1-42 in studies of postoperative patients, it has been shown that an imbalance between the procoagulant action of thrombin and the anticoagulant effect of plasmin on fibrin I polymer may induce an acquired thrombotic diathesis. Finally, we have recently demonstrated that prothrombin activation as measured by the F1+2 assay is suppressed by oral anticoagulants in the blood of patients with thrombotic diatheses. These investigations suggest that these assay techniques can be used to improve our understanding of the hypercoagulable state as well as to develop more effective treatment strategies for the prevention of thromboembolic events.
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PMID:The pathophysiology of the prethrombotic state in humans: insights gained from studies using markers of hemostatic system activation. 360 75

We have developed a radioimmunoassay (RIA) for prethrombin 2 (Pr2), a potential intermediate in the transformation of prothrombin to thrombin. Antisera against human Pr2 were raised in rabbits and the respective immunoglobulin G fractions were chromatographed on prothrombin-Sepharose. The specific antibody population obtained was used to construct a double-antibody RIA capable of measuring as little as 0.05 nmol/L of this component. The immunoreactivity of prothrombin was approximately 40,000 times less than that of Pr2 on a molar basis. Because of nonspecific contributions of plasma constituents to the immunoreactive signal, the measurement of Pr2 in this milieu required the use of a titration curve in which Pr2 was added back to Pr2-depleted plasma. This assay was then used to determine the levels of this species in two patient populations with increased prothrombin activation as determined by the prothrombin fragment F1 + 2 RIA, a measure of the in vivo cleavage of prothrombin by factor Xa. The mean Pr2 concentrations in eight patients with disseminated intravascular coagulation and six asymptomatic individuals with congenital antithrombin deficiency not receiving antithrombotic therapy were not significantly elevated as compared with those of normal controls (0.244 nmmol/L and 0.242 nmol/L vs. 0.184 nmol/L, respectively). Our studies show that Pr2 is cleared from the plasma of dogs with a t1/2 of approximately 25 minutes. Given that the t1/2 of F1 + 2 is estimated to be approximately 90 minutes, the low plasma levels of Pr2 observed in patients with thrombophilia cannot result from rapid clearance of this component.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Development of a radioimmunoassay for quantitating prethrombin 2 in human plasma. 366 58

Tissue thromboplastin generation in monocytes was studied during various stages of Escherichia coli endotoxinaemia in pigs. The pigs were monitored in halothane anaesthesia and mechanically ventilated. Blood was sampled from the superior caval vein before and during endotoxin infusion and up to 6 hours after its start. Monnuclear leukocytes were harvested with Lymphoprep separation and monocyte counts were made, using TRITC-labelled sheep erythrocytes, acridine orange and a fluorescence microscope. Thromboplastin was quantified in a two-stage assay by incubating the test sample together with purified factor X, factor VII and Ca++. The generated factor Xa was thereafter assayed. There was statistically significant increase of tissue thromboplastin activity in monocytes after endotoxin infusion. Maximum level was reached at the end of the infusion and was maintained throughout the observation period. Decrease occurred in platelets, leukocytes, antithrombin III, fibrinogen and clotting factors V, VII and VIII, and clotting time was prolonged. These findings indicated significant disseminated intravascular coagulation. The endotoxin-stimulated monocytes with their elevated tissue thrombo-plastin activity thus may play an important part in development of the DIC which so often follows septicemia.
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PMID:Tissue thromboplastin generation in circulating mononuclear phagocytes and development of coagulation disorders during E. coli endotoxinaemia in pigs. 392 66

We have evaluated the efficacy of utilizing radioimmunoassays (RIAs) for prothrombin activation fragments (F2/F1 + 2) and for thrombin--antithrombin complex (TAT) in purified systems and in whole blood. During venipuncture, appropriate anticoagulants were employed in order to prevent the generation of thrombin and factor Xa. The RIAs were shown to be specific for F2/F1 + 2 as well as TAT and did not interact with other plasma components. Initially, thrombin generation was studied in a purified human system of prothrombin, antithrombin, factor Xa, and factor V as well as phospholipid and Ca++. Under these conditions, the kinetics of F2/F1 + 2 and TAT generation were virtually superimposable. However, when factor V was omitted from the reaction mixture, a significantly greater amount of F2/F1 + 2 as compared to TAT was observable. Subsequently, prothrombin activation was monitored during the spontaneous coagulation of freshly drawn blood. Throughout the entire course of thrombin generation, the observable rate of formation of F2/F1 + 2 was considerably greater than that of TAT. We have examined the levels of F2/F1 + 2 and TAT in normal individuals. Our studies indicate that the concentrations of F1 + 2 and TAT average 1.97 nM and 2.32 nM, respectively. We have also quantitated the concentrations of F2/F1 + 2 and TAT in patients with disseminated intravascular coagulation. In these individuals, the levels of both components are elevated. However, the ratio of F1 + 2 to TAT ranges from 2.37 to 5.55. Thus, we conclude that under in vivo conditions, prothrombin activation is characterized by the accumulation of a stable precursor, such as prethrombin-2, and that this phenomenon may be related to an alteration of factor V function.
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PMID:Studies of the prothrombin activation pathway utilizing radioimmunoassays for the F2/F1 + 2 fragment and thrombin--antithrombin complex. 707 14

A rapid automated method for the estimation of factor Xa was developed using the "Centrifichem' rotary fast analyser and the substrate S-2222. The problem of interference from fibrin was overcome by performing the activation of factor X during centrifugation, so that defibrination and activation were achieved in a single step. A range of factor Xa concentrations was determined on 50 normal plasmas. This assay was correlated with a clotting assay of factor Xa using serial dilutions of normal plasma and plasma from 30 patients receiving warfarin therapy.
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PMID:Automated estimation of factor Xa using the chromogenic substrate S-2222. 727 79

The search for activated products of coagulation factors in blood is of considerable clinical interest because its detection would indicate activation of the clotting system. Factor XIII circulates as inactive zymogen and becomes enzymatically active after thrombin or factor Xa activation. Employing an amine-incorporating system, activated factor XIII was measured in normal and pathological plasma from leukemic patients with overt laboratory signs of disseminated intravascular coagulation (DIC). Only traces of the activated factor were detected in both normal and DIC plasma. The method, sensitive and specific, as shown by the results of measurements on the plasma of 8 patients with congenital deficiency and on normal serum, did not prove to be useful for detecting pathological in vivo thrombin generation.
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PMID:Failure to measure plasma activated factor XIII during disseminated intravascular coagulation. 732 10


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