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)

A simplified method for the assay of antithrombin III (AT) with the highly reactive thrombin substrate 2AcOH X H-D-CHG-Ala-Arg-pNA (substrate Th-1) is described. The assay may be performed at either 30 degrees C or 37 degrees C, and alternatively with the substrate H-D-Phe-Pip-Arg-pNA (S-2238). The standard curve is linear in the 12.5-150% range. For routine assays, 3 standard dilutions of plasma are sufficient, and these may be stored at -20 degrees C for 3 weeks. As only the test plasma must be diluted prior to the assay procedure, the test is more rapidly performed than previous manual assays. In 80 patients plasma samples, with AT in the 19-108% range, there was a high correlation with the results of immunoquantification (r = 0.96). There was also a high correlation between the results obtained with the manual method and the automated version described using the Cobas-Bio Centrifugal Analyser and substrate Th-1 (r = 0.96). Low AT levels in hereditary deficiency (particularly during heparin treatment), in liver cirrhosis, in disseminated intravascular coagulation (DIC), and heparin-treated thrombosis were confirmed.
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PMID:Simplified assay for antithrombin III activity using chromogenic peptide substrate. Manual and automated method. 664 56

Acute respiratory failure is a common complication in patients with disseminated intravascular coagulation associated with sepsis. To elucidate the role of coagulation abnormalities in acute lung injury in sepsis, we investigated the effect of anticoagulants on the pulmonary vascular injury in rat induced by lipopolysaccharide (LPS). When administered intravenously, LPS (5 mg/kg body weight) significantly increased the accumulation of 111indium-labeled neutrophils in lung 30 min after administration. Subsequently, the pulmonary vascular permeability and the serum level of fibrin and fibrinogen degradation products (E) [FDP (E)] increased and remained elevated for several hours. Neither heparin alone, heparin plus antithrombin III, or dansyl-Glu-Gly-Arg-chloromethyl ketone-treated factor Xa, a selective inhibitor of thrombin generation, prevented LPS-induced vascular injury 6 hours after LPS administration, whereas these substances significantly inhibited the increase in serum FDP (E) at that time. LPS-induced pulmonary vascular injury was significantly attenuated in rats with methotrexate-induced leukocytopenia or treated with ONO-5046, a potent granulocyte elastase inhibitor, although ONO-5046 did not inhibit the LPS-induced increase in serum FDP (E). Thus, activated leukocytes play a more important role than coagulation abnormalities in the pathogenesis of LPS-induced pulmonary vascular injury in an experimental rat model of endotoxemia.
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PMID:Endotoxin-induced pulmonary vascular injury is mainly mediated by activated neutrophils in rats. 748 29

1. We have investigated the effect of pretreatment of rats with nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) on the E. coli lipopolysaccharide (LPS)-induced changes in the plasma fibrinolytic system, platelet count, fibrinogen level, as well as in gross and microscopic pathophysiological changes indicative of disseminated intravascular coagulation (DIC) in rats. 2. E. coli LPS (6 mg kg-1, i.p.) produced a decrease in the levels of plasma fibrinogen and a drop in the blood platelet count 6 h after administration. The decrease in fibrinogen but not the drop in platelet count was reversed by pretreatment with L-NAME (30 mg kg-1, i.p., 24 h and 15 min before administration of LPS). 3. Pretreatment with L-NAME antagonized the LPS-induced activation of fibrinolysis as measured by changes in the euglobulin clot lysis time (ECLT) and enhanced the LPS-induced rise in the plasma level of plasminogen activator inhibitor (PAI). In animals pretreated with L-NAME there was also a marked reduction in the histological changes indicative of DIC. 4. We propose that L-NAME can act as a protective agent in LPS-induced DIC, and this protection is due to an increased generation of PAI following inhibition of NO synthase.
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PMID:The effect of nitric oxide synthase inhibition on the plasma fibrinolytic system in septic shock in rats. 751 6

Adult respiratory distress syndrome (ARDS) is a serious complication of disseminated intravascular coagulation (DIC) or multiple organ failure. To determine whether recombinant soluble human thrombomodulin (rsTM) may be useful in treating ARDS due to sepsis, we investigated the effect of rsTM on lipopolysaccharide (LPS)-induced pulmonary vascular injury in rats. The intravenous administration of rsTM prevented the increase in pulmonary vascular permeability induced by LPS. Neither heparin plus antithrombin III (AT III) nor dansyl Glu Gly Arg chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, prevented LPS-induced vascular injury. The agents rsTM, heparin plus AT III, and DEGR-Xa all significantly inhibited the LPS-induced intravascular coagulation. Recombinant soluble TM pretreated with a monoclonal antibody (moAb) that inhibits protein C activation by rsTM did not prevent the LPS-induced vascular injury; in contrast, rsTM pretreated with a moAb that does not affect thrombin binding or protein C activation by rsTM prevented vascular injury. Administration of activated protein C (APC) also prevented vascular injury. LPS-induced pulmonary vascular injury was significantly reduced in rats with leukopenia induced by nitrogen mustard and by ONO-5046, a potent inhibitor of granulocyte elastase. Results suggest that rsTM prevents LPS-induced pulmonary vascular injury via protein C activation and that the APC-induced prevention of vascular injury is independent of its anticoagulant activity, but dependent on its ability to inhibit leukocyte activation.
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PMID:Recombinant human soluble thrombomodulin reduces endotoxin-induced pulmonary vascular injury via protein C activation in rats. 860 7

1. Nitric oxide (NO) suppresses platelet aggregation and plasminogen activator inhibitor (PAI) release from platelets, playing physiological and/or pathological roles in the haemostatic system. We investigated the effect of NG-nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor, on the disseminated intravascular coagulation (DIC)-like phenomena in rats under environmental stress, induced by prolonged fluctuation in air temperature, known as SART (specific alternation of rhythm in temperature) stress. 2. Exposure of rats to SART stress for 7 days caused mild DIC-like symptoms such as thrombocytopenia, hypofibrinogenemia, decreased factor VIII: coagulant activity and shortened euglobulin clot lysis time (ECLT). The enhanced fibrinolysis was accompanied by a marked decrease in the activity of plasma PAI. 3. L-NAME, but not its D-enantiomer, when administered orally at 0.3-10 mg kg-1, twice a day for 7-day exposure to stress, inhibited the stress-induced decrease in fibrinogen levels in a dose-dependent manner, whereas it failed to alter platelet count, factor VIII:coagulant activity and plasma protein levels in stressed rats. All these parameters in unstressed rats were resistant to L-NAME at 10 mg kg-1. 4. Repeated treatment with 10 mg kg-1 of L-NAME blocked the shortening of ECLT and the decrease in PAI activity following stress exposure, although it was without effect in unstressed rats. 5. The inhibitory effects of L-NAME at 10 mg kg-1 on the stress-induced alterations in fibrinogen levels and in ECLT were significantly reduced by coadministered L-arginine at 1000 mg kg-1. 6. These findings demonstrate that repeated administration of L-NAME attenuates the enhanced fibrinolysis, without aggravating thrombocytopenia, in SART-stressed rats. Endogenous NO appears to contribute to the stress-induced development of fibrinolysis by suppressing, plasma PAI activity, most probably as a result of inhibition of the PAI release from platelets.
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PMID:Attenuation by prolonged nitric oxide synthase inhibition of the enhancement of fibrinolysis caused by environmental stress in the rat. 888 19

Adult respiratory distress syndrome (ARDS) and disseminated intravascular coagulation (DIC) are serious complications of sepsis. Thrombomodulin, an important endothelial anticoagulant, binds thrombin to generate activated protein C (APC). To determine whether thrombomodulin purified from human urine (urinary thrombomodulin, UTM) is useful for the treatment of DIC and ARDS in sepsis, we examined the effect of UTM on endotoxin (ET)-induced coagulation abnormalities and pulmonary vascular injury in rats. Intravenous administration of UTM prevented the ET-induced pulmonary accumulation of leukocytes and the increase in pulmonary vascular permeability, as well as ET-induced histological changes such as leukocyte infiltration and pulmonary interstitial edema. On the other hand, dansyl-Glu-Gly-Arg-chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, did not prevent these effects of ET. UTM did not prevent ET-induced pulmonary accumulation of leukocytes and pulmonary vascular injury in rats pretreated with DEGR-Xa. Our findings suggest that UTM attenuates ET-induced coagulation abnormalities and pulmonary vascular injury. Furthermore, the latter effect may be dependent on the capacity of UTM to activate protein C.
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PMID:Effect of human urinary thrombomodulin on endotoxin-induced intravascular coagulation and pulmonary vascular injury in rats. 903 85

Collagen-related peptides, Gly-Pro-Arg and its analogues, were examined for their inhibitory effects on platelet aggregation induced by the addition of ADP. Human platelet aggregation was suppressed by more than 50% with each of Gly-Pro-Arg and such Gly-Pro-Arg-containing peptides as Gly-Pro-Arg-Gly, Gly-Pro-Arg-Gly-Pro, Gly-Pro-Arg-Pro-Pro, and Gly-Pro-Arg-Pro-Pro-Pro at a concentration of 0.3 mM. The inhibitory effects of these peptides were about 10 times higher in human PRP than in rat PRP. Other Gly-Pro-Arg analogues such as Sar-Pro-Arg, Gly-Pro-Lys, Gly-Ala-Arg, and Ala-Gly-Pro-Arg had no inhibitory effect at a concentration from 0.1 to 0.8 mM even in human PRP. Intravenous and oral administrations of Gly-Pro-Arg and enzymatic hydrolysates of collagen suppressed the decrease in platelet count for endotoxin-induced DIC in rats. Collagen itself has been regarded as a potent inducer of platelet aggregation, but these findings suggest that collagen-related peptides and enzymatic hydrolysates of collagen prevent platelet aggregation.
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PMID:In vitro and in vivo anti-platelet effects of enzymatic hydrolysates of collagen and collagen-related peptides. 917 51

The effect of two arginine-specific cysteine proteinases (gingipain Rs) from Porphyromonas gingivalis, a causative bacterium of adult periodontitis, on human blood coagulation was investigated. Activated partial thromboplastin time and prothrombin time were shortened by these proteinases, with a 95-kDa gingipain R containing adhesin domains being 5-fold more efficient in comparison to a 50-kDa gingipain R containing the catalytic domain alone. The 50-kDa enzyme reduced each coagulation time in several plasmas deficient in various coagulation factors, while it was ineffective in factor X-deficient plasma unless reconstituted with this protein. Each proteinase activated factor X in a dose- and time-dependent manner, with Michaelis constants (Km) being found to be lower than the normal plasma factor X concentration, strongly suggesting that factor X activation by gingipain Rs, especially the 95-kDa form which is strongly activated by phospholipids, could occur in plasma. This is the first report of factor X activation by bacterial proteinases and indicates that the gingipain Rs could be responsible for the production of thrombin and, indirectly, with the generation of prostaglandins, interleukin-1, etc., which have been found to be associated with the development of periodontitis induced by P. gingivalis infections. Furthermore, the data support the hypothesis that induction of blood coagulation by bacterial proteinases may be a causative agent in the pathogenesis of disseminated intravascular coagulation in sepsis.
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PMID:Activation of blood coagulation factor X by arginine-specific cysteine proteinases (gingipain-Rs) from Porphyromonas gingivalis. 918 12

A fibrinogen variant was identified in a patient with disseminated intravascular coagulation and in one member of her family. Coagulation studies showed marked prolongation of both the thrombin and reptilase times and discrepancy was noted between the levels of plasma fibrinogen, determined by a kinetic vs immunological determination or light scattering assay. Studies on purified fibrinogen revealed an impaired release of fibrinopeptides by thrombin. DNA sequencing revealed a heterozygous A to G point mutation in exon 2 of the A alpha chain, which substituted Arg for His at position 16. This mutation creates a Nla III cleavage site which was used to confirm the mutation.
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PMID:Fibrinogen Poissy I: a new case of the A alpha Arg 16His fibrinogen variant. 939 26

In preliminary studies, the generation of thrombin in vivo was found to induce a 92% loss of functional activity of factor IX (F.IX) despite the detection by Western blotting of a product resembling activated F.IX (F.IXa) and a 25% increase in F.IX antigen levels (Hoogendoorn et al, Thromb Haemost 69:1127, 1993 [abstr]). These changes were associated with evidence of increased elastase availability. To study the possibility that these two observations were related, a detailed physical and functional characterization of the hydrolysis of purified human F.IX by human neutrophil elastase (HNE) was performed in vitro. An activated partial thromboplastin time (aPTT) clotting assay demonstrated that, although HNE eliminated the potential of F.IX to be activated, it only marginally reduced the F.IXa activity. Reducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) indicated that HNE treatment of F.IX generated cleavage products of 30 and 20 kD that could not be distinguished from the respective heavy and light chain peptides that were identified in parallel studies when F.IX was activated by activated bovine F.XI (F.XIa), one of its physiological activators. In addition, nonreducing SDS-PAGE demonstrated that HNE-treated F.IX formed no complexes with antithrombin III (ATIII) in the presence of heparin. Furthermore, HNE-treated F.IX was unable to (1) bind the active site probe p-aminobenzamidine; (2) hydrolyze the synthetic peptide substrate CH3SO2-Leu-Gly-Arg-p-nitroanilide; and (3) activate human factor X (F.X). In contrast to dansyl-Glu-Gly-Arg-chloromethyl ketone (dEGR)-inactivated F.IXa, HNE-treated F.IX (0.01 to 10,000 pmol/L) failed to inhibit the clotting activity of F.IXa (10 pmol/L) in the aPTT. NH2-terminal sequencing indicated that HNE cleaved human F.IX at Thr140, Thr144, Ile164, Thr172, and Val181. The cleavages at Thr140/Thr144 and at Thr172/Val181 are both very close to the normal F.XIa alpha-(Arg145) and beta-(Arg180) cleavage sites, respectively. In summary, the results suggest that the activatability of F.IX is eliminated after cleavage by HNE and that the inability of HNE-treated F.IX to support F.IXa-like coagulant function is a consequence of improper active site formation. These in vitro observations support the possibility that increased HNE cleavage of F.IX in vivo may contribute to the disregulation of hemostasis that occurs in conditions such as disseminated intravascular coagulation (DIC).
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PMID:Neutrophil elastase cleavage of human factor IX generates an activated factor IX-like product devoid of coagulant function. 969 17


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