Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plasma levels of antithrombin III, alpha 2-macroglobulin and inter-alpha-trypsin inhibitor, as well as those of various clotting, complement and other plasma factors, were significantly decreased in 18 patients suffering from hyperdynamic septic shock. A similar statistically significant reduction of the concentrations of several plasma factors (prothrombin and antithrombin III, plasminogen and alpha 2-plasmin inhibitor, complement factor C3 and clotting factor XIII) was observed in experimental endotoxaemia. In this model the reduction in the plasma levels of these factors was considerably diminished by the intravenous injection of a granulocytic elastase--cathepsin G inhibitor of lower molecular weight from soybeans. The results of both studies indicate that consumption of plasma factors in the course of Gram-negative sepsis proceeds not only via the classical routes (by activation of the clotting, fibrinolytic and complement cascades by system-specific proteinases such as thrombokinase or the plasminogen activator) but also to an appreciable degree of unspecific degradation of plasma factors by neutral proteinases such as elastase and cathepsin G. The endotoxin-induced release of both sorts of proteinases, the system-specific ones and the unspecific lysosomal proteinases from leucocytes and other cells, is likely to be mainly responsible for the consumption of antithrombin III and alpha-2-macroglobulin via complex formation (followed by elimination of the complexes) and the increased turnover of the inter-alpha-trypsin inhibitor as observed in the clinical study. The therapeutic use of an exogenous elastase--cathepsin G inhibitor in the experimental model was stimulated by the observation that human mucous secretions contain and acid-stable inhibitor of the neutral granulocytic proteinases, called HUSI-I or antileucoproteinase. This inhibitor protects mucous membranes and soluble proteins against proteolytic attack by leucocytic proteinases released in the course of a local inflammatory response. Preliminary results indicate that HUSI-I, which is produced by the epithelial cells of mucous membranes, does not belong to any known structural type of acid-stable proteinase inhibitor. The search for other candidates suitable for medication in humans led to the discovery of a potent elastase--cathepsin G inhibitor, called eglin, in the leech Hirudo medicinalis. This acid-stable inhibitor with a molecular weight close to 8100 has an unusual structural property in that the structure of the molecule is not stabilized by any disulphide bridge.
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PMID:Proteinase inhibitors in severe inflammatory processes (septic shock and experimental endotoxaemia): biochemical, pathophysiological and therapeutic aspects. 39 95

The relation of (multiple) organ failure (OF) to the release of inflammatory mediators and the incidence of infection and sepsis was studied prospectively in 100 patients with multiple trauma (injury severity score = 37). Sixteen patients died of OF, 47 patients survived OF, and 37 patients had no OF. Fifteen (24%) of the patients with OF showed no signs of infection. In patients with early onset of OF (n=45), infection followed with a lag of 2 or more days. In 16 (44%) of these patients, infection led to a deterioration in organ function. With late onset of OF (n=18), infection preceded OF in nine patients. Polymorphonuclear leukocyte-elastase, neopterin, C-reactive protein, lactate, antithrombin III, and phospholipase A discriminated significantly among the three outcome groups. Of all factors, only polymorphonuclear leukocyte-elastase showed a difference between patients with and without infection or sepsis, respectively. These data indicate that infection might not play a crucial role in the pathogenesis of posttraumatic OF in a substantial portion of patients with trauma. Early OF, especially, seems to be mainly influenced by the direct sequelae of tissue damage and shock (eg, the release of inflammatory mediators). Since infection and sepsis did not lead to an augmented release of mediators in patients with trauma, the role of both entities remains unclear.
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PMID:Inflammatory mediators, infection, sepsis, and multiple organ failure after severe trauma. 134 12

To estimate the degree of coagulopathy in abdominal sepsis, we measured the plasma levels of prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin III complex (TAT) and plasmin-alpha 2-plasmin inhibitor complex (PIC) by the enzyme-linked immunosorbent assay in 38 patients with disseminated intravascular coagulation (DIC). In 20 patients with DIC due to abdominal sepsis, plasma levels of F1 + 2, TAT and PIC were 2.6 nmol/l, 27.9 micrograms/l and 1.5 micrograms/ml, respectively, with a mean antithrombin III (AT III) activity of 41.7%. F1 + 2, TAT, PIC and AT III levels were 4.7 nmol/l, 75.8 micrograms/l, 8.8 micrograms/ml and 70.9% in 18 patients with DIC as the result of malignancy. Though AT III levels in DIC due to sepsis were lower than those in DIC due to malignancy, the levels of F1 + 2, TAT and PIC in the former were not significantly more increased than those in the latter. The plasma levels of F1 + 2 were positively correlated with TAT and PIC in DIC patients with malignancy; however, there was no correlation between F1 + 2 and TAT or PIC in DIC patients with sepsis. In addition, the levels of serum albumin in the two groups were similar. These results suggest that activation of coagulation and fibrinolytic systems may not be so prominent in cases of DIC due to abdominal sepsis, compared to related events in DIC due to malignancy. It is also suggested that the depletion of AT III in cases of sepsis is not only caused by a consumption related to intravascular coagulation or to an alternate distribution of protein.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Coagulopathy in disseminated intravascular coagulation due to abdominal sepsis: determination of prothrombin fragment 1 + 2 and other markers. 138 63

In a rhesus monkey endotoxin sepsis model established by intravenous administration of 300 mg/kg D-galactosamine and 0.1 microgram/kg lipopolysaccharide from Salmonella abortus equi, hemodynamic, respiratory, metabolic and hematologic variables; levels of blood gases; monkey leukocyte elastase levels, and blood plasma concentrations of tumor necrosis factor--alpha (TNF) were monitored for 6 hours after administration, and again after 24 hours. Thirty minutes after administration of lipopolysaccharide, either 15 mg/kg anti-TNF monoclonal antibody (MoAB; n = 6) or vehicle placebo (saline solution; n = 4) were given intravenously. During this short-term experiment the organ functions were not different between the treatment groups. However, anti-TNF MoAb afforded morphologic protection from heart, lung, liver, and kidney damage after lipopolysaccharide challenge. Coagulation responses (platelet count and levels of fibrinogen, antithrombin III, and thrombin-antithrombin III complex) were smaller in anti-TNF MoAB-treated monkeys. Plasma TNF levels (WEHI cell cytotoxicity assay) reached a peak (350 pg/ml) 60 minutes after lipopolysaccharide administration in vehicle control subjects but no TNF was detected in the anti-TNF MoAB-treated monkeys. All control animals died 67 +/- 30 hours after lipopolysaccharide administration from multiorgan failure. On the contrary, all anti-TNF MoAB-treated animals survived 14 days (p > 0.005 vs placebo group mortality). Thus in short-term monkey experiments our study indicates protection against lipopolysaccharide-induced endotoxin sepsis by anti-TNF MoAB, which may have clinical relevance for the treatment of human septicemia.
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PMID:Monoclonal antibody to tumor necrosis factor--alpha prevents lethal endotoxin sepsis in adult rhesus monkeys. 140 33

We measured plasma heparin cofactor II (HC II) activity in patients with disseminated intravascular coagulation (DIC) due to various underlying diseases together with the levels of antithrombin III (AT III), pseudocholinesterase (a marker of hepatic synthesis), and various haemostatic molecular markers. Both HC II and AT III were decreased in DIC secondary to all the underlying diseases studied, except acute promyelocytic leukemia (APL), when compared with healthy subjects. The lowest HC II and AT III levels was observed in coagulopathy secondary to liver disease, the HC II level in sepsis was the second lowest. In DIC due to APL, the decrease in HC II was not accompanied by a decrease in AT III. Thus, we divided all 124 samples tested into APL and non-APL groups. The HC II level correlated positively with fibrinogen and plasminogen in both the APL and non-APL groups. In the APL group, the HC II level had a significant negative correlation with the thrombin-AT III complex (TAT), fibrinogen/fibrin degradation products, and D-dimer levels as well as the prothrombin time, while AT III showed no correlations with any of the haemostatic parameters. These results suggest that HC II may be consumed preferentially by thrombin in APL patients with DIC, and thus may spare the consumption of AT III. Accordingly, HC II seems to be a superior indicator of DIC than AT III in APL patients. Moreover, replacement therapy with HC II instead of AT III may be useful to treat DIC associated with APL. In the non-APL group, the HC II levels were positively correlated with the levels of AT III and pseudocholinesterase activity. This indicates that plasma HC II levels are closely related not only to consumption coagulopathy but also to hepatic synthetic activity, as is the case for plasma AT III.
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PMID:Preferential consumption of heparin cofactor II in disseminated intravascular coagulation associated with acute promyelocytic leukemia. 141 8

The processes that underlie the coagulopathy observed in severe infection are not fully understood, but seem to be due to an imbalance in the antithrombotic, and prothrombotic properties of the vascular endothelium. Sulphated glycosaminoglycans (GAGs) present on the vessel wall represent an important component of the non-thrombogenic nature of the endothelium. We have modified an amidolytic assay to study the functional ability of GAGs on human umbilical vein endothelial cells (HUVECS), and investigate the effect of E. coli endotoxin and neutrophils on HUVEC surface anticoagulant activity (SAA). Neither endotoxin alone, nor separated neutrophils at lower concentrations (less than 10(6) neutrophils per ml), had major effects on endothelial SAA. When activated neutrophils were incubated with HUVECS pre-stimulated with endotoxin, a significant decrease in SAA was seen using either plasma (mean percentage of control 67.8% +/- sem 7.8; p < 0.02) or purified ATIII (mean percentage of control 69% +/- sem 4.6; p < 0.001). We suggest that alterations in endothelial surface GAGs may occur during sepsis and inflammation, and that this may have important consequences for vascular function. This system will allow the further study of the role of GAGs in the intravascular thrombosis of severe sepsis, and other inflammatory diseases.
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PMID:Reduction of the anticoagulant activity of glycosaminoglycans on the surface of the vascular endothelium by endotoxin and neutrophils: evaluation by an amidolytic assay. 144 May 32

The effect of burn wound size on the activation of fibrinolysis, coagulation, and contact factors was analyzed in 60 thermal injury patients. Blood samples from 47 male patients and 13 female patients, (average age 37 years; range 1.5-70 years) were collected within the first 36 hours and at 5-7 days following injury. The patient population was categorized by percentage of burn (second degree and/or third degree): less than 20%, n = 22; 20%-40%, n = 18; greater than 40%, n = 20. The average percentage of burn was 32% (range, 4%-95%). The mechanism of injury was by flame (25), explosion and flame (19), scald (12), electric (3), or chemicals (1). An associated inhalation injury was present in 12 patients. The overall mortality rate was 13% (8). Sepsis or serious infection occurred in 23% (14) of the patients. On admission, 83% of the patients had normal prothrombin times (PT) and activated partial thromboplastin times (APTT). However, specific hemostatic variables showed marked changes. Admission hemostatic markers that correlated with the severity of injury were: tissue-plasminogen activator (tPA), plasminogen activator inhibitor (PAI), D-dimer (D-di), plasminogen (Plg), proteins C and S (PrC and PrS), antithrombin III (ATIII), thrombin-antithrombin complex (TAT), kallikrein (Kal:c), kinin (Kin), C1 esterase inhibitor (C1Inh), and factor VII clotting and antigen (FVII:c, FVII:ag). These data suggest that during the early course following burn injury, thrombogenicity is increased (TAT increases) because of a decrease in ATIII, PrC, and PrS; and fibrinolysis activation (D-di increases) occurs via an increase in tPA with a p value increase in PAI.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of burn wound size on hemostasis: a correlation of the hemostatic changes to the clinical state. 163 6

In order to assess the thrombin and plasmin generation in vivo in disseminated intravascular coagulation (DIC), plasma levels of thrombin-antithrombin III (ATIII) complex (TAT) and plasmin-alpha 2-antiplasmin (a2AP) complex (PAP) were measured together with standard coagulation and fibrinolytic parameters in 80 patients with DIC. Both TAT and PAP were markedly elevated in patients with DIC. When plotted by the underlying disease categories, differences in the magnitude of the elevations of these complexes were recognized among groups. Patients with acute promyelocytic leukemia (APL) had the highest PAP, the lowest TAT/PAP ratio, low a2AP, and low fibrinogen, indicating that the most excessive fibrinolysis can occur in APL. Similar profiles, although less marked, were observed in patients with other leukemias and vascular diseases. Patients with sepsis showed the highest TAT/PAP ratio and the lowest PAP with no decrease in a2AP or fibrinogen, demonstrating a relatively impaired fibrinolysis. Patients with cancer had a relatively high TAT and high TAT/PAP ratio. In addition, both TAT and PAP were markedly elevated in patients with shock. From these, it was suggested that, although laboratory manifestations in DIC are extremely variable from patient to patient, underlying disorders are, at least in part, responsible for the observed variations. Recognition of this variable activation of coagulation and fibrinolysis would be helpful for the proper management of patients with DIC.
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PMID:Thrombin vs. plasmin generation in disseminated intravascular coagulation associated with various underlying disorders. 200 32

To elucidate the role of leukocytes in intravascular coagulation in patients with septicemia, plasma levels of thrombin-antithrombin III complex (TAT), soluble fibrin monomer complex (SFMC) and fibrinogen (Fbg) were determined in 33 patients with septicemia. Twenty of 33 patients revealed marked leukopenia caused by suppression of hematopoiesis by the administration of chemotherapeutic agents for the treatment of hematological malignancies; the total leukocyte count of these patients was less than 1,000/microliters. Thirteen of 33 patients showed normal or increased leukocyte counts. Plasma levels of TAT and SFMC in septicemic patients without leukopenia were significantly higher than in patients with leukopenia. Although plasma TAT and SFMC levels correlated well with the number of leukocytes, a more significant positive correlation was found between the number of monocytes and the levels of TAT and SFMC. Plasma levels of Fbg were significantly lower in patients without leukopenia than in patients with leukopenia. No significant correlation was found between the number of leukocytes and the levels of Fbg. However, a significant negative correlation was found between the number of monocytes and the levels of Fbg. TAT levels did not correlate with the number of platelets. The fibrinolytic system was activated only in septicemic patients without leukopenia, which may be explained by secondary fibrinolysis following leukocyte-activated coagulation. These findings suggest that leukocytes, in particular monocytes, may play a critical role in the pathogenesis of intravascular coagulation in septicemia.
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PMID:Role of leukocytes in the activation of intravascular coagulation in patients with septicemia. 170 28

In disseminated intravascular coagulation (DIC) with acute promyelocytic leukemia (APL) in the absence of severe infection, marked fibrinolysis was noted in comparison with normal levels of antithrombin III, which is a major inhibitor of the coagulation system. Increased plasminogen activator inhibitor-1 (PAI-1) antigen levels in plasma from patients with septicemia decreased the ratio of the plasma clot lysis rate induced by an anti-alpha 2-plasmin inhibitor monoclonal antibody to the tissue-type plasminogen activator (t-PA) concentration. This decrease was not as prominent in plasma from patients with DIC, especially those with APL. To explore the character of PAI-1 in these plasmas, we measured the specific activity of PAI-1 by determining the ratio of active PAI-1 antigen to t-PA-unbound PAI-1 antigen. To calculate the amount of active PAI-1 antigen, the amount of t-PA/PAI-1 complex before and after the addition of a fixed amount of t-PA to the sample was measured by a sandwich solid-phase enzyme-linked immunosorbent assay using anti-PAI-1 and anti-t-PA monoclonal antibodies. The assay to measure total PAI-1 antigen used three monoclonal anti-PAI-1 antibodies and had similar sensitivities to free active, latent, vitronectin-bound and t-PA-bound PAI-1. The specific activity of PAI-1 decreased in patients with DIC (43.7% +/- 30.6%) and in DIC cases with APL (10.3% +/- 6.0%) in comparison to patients with septicemia (83.7% +/- 20.2%) or normal controls (85.8% +/- 27.3%). In DIC associated with APL, degraded forms of PAI-1 were detected in plasma by immunoblotting. These results suggest that a decrease in the specific activity of PAI-1 and an increase in secondary fibrinolysis result in a hyperfibrinolytic state in DIC patients with APL.
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PMID:The specific activity of plasminogen activator inhibitor-1 in disseminated intravascular coagulation with acute promyelocytic leukemia. 170 94


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