UMLS:C0036690 - FACTA Search

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Query: UMLS:C0036690 (sepsis)
59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Administration of low doses endotoxin or tumor necrosis factor (TNF) in human experimental models for sepsis results in transient activation of both coagulation and fibrinolysis and subsequent inhibition of the fibrinolytic system by plasminogen activator inhibitor type 1 (PAI-1). We have investigated in a baboon model for sepsis, whether administration of a lethal or sublethal dose of living E. coli could induce similar activation patterns. Levels of thrombin-antithrombin III (TAT) complexes increased significantly to zeniths of 425 and 33 times the baseline values at t+360 in the lethal and sublethal group, respectively. Activation of fibrinolysis, as reflected by plasmin-alpha 2 antiplasmin (PAP) complexes, in the sublethal group was maximal at t+60 and was increasingly inhibited thereafter in spite of a sustained increase of tissue type plasminogen activator (t-PA) levels. In the lethal group PAP complexes increased to a zenith of 38 times the baseline values at t+240. PAI-1 levels increased to 15 times the baseline values at t+360 in the sublethal group, whereas in the lethal group they increased almost linearly to 20 times the baseline values at t+360. Despite high levels of PAI-1, effective inhibition of the fibrinolysis was not established until at T+240 in the lethal group. The difference in activation patterns of both mediator systems in the sublethal and lethal group of baboons indicate that extensive activation of coagulation contributes to the lethal complications in sepsis.
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PMID:Activation patterns of coagulation and fibrinolysis in baboons following infusion with lethal or sublethal dose of Escherichia coli. 768 56

Alpha-2-macroglobulin (alpha 2M) may function as a proteinase inhibitor in vivo. Levels of this protein are decreased in sepsis, but the reason these levels are low is unknown. Therefore, we analyzed the behavior of alpha 2M in a baboon model for sepsis. Upon challenge with a lethal (4 baboons) or a sublethal (10 baboons) dose of Escherichia coli, levels of inactivated alpha 2M (i alpha 2M) steadily increased, the changes being more pronounced in the animals that received the lethal dose. The rise in i alpha 2M significantly correlated with the increase of thrombin-antithrombin III, plasmin-alpha 2-antiplasmin, and, to a lesser extent, with that of elastase-alpha 1-antitrypsin complexes, raising the question of involvement of fibrinolytic, clotting, and neutrophilic proteinases in the inactivation of alpha 2M. Experiments with chromogenic substrates confirmed that thrombin, plasmin, elastase, and cathepsin G indeed had formed complexes with alpha 2M. Changes in alpha 2M similar to those observed in the animals that received E. coli occurred in baboons challenged with Staphylococcus aureus, indicating that alpha 2M formed complexes with the proteinases just mentioned in gram-positive sepsis as well. We conclude that alpha 2M in this baboon model for sepsis is inactivated by formation of complexes with proteinases, derived from activated neutrophils and from fibrinolytic and coagulation cascades. We suggest that similar mechanisms may account for the decreased alpha 2M levels in clinical sepsis.
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PMID:Alpha-2-macroglobulin functions as an inhibitor of fibrinolytic, clotting, and neutrophilic proteinases in sepsis: studies using a baboon model. 769 93

Induction of leukocytopenia by cytotoxic drugs protects against the generalized Shwartzman reaction induced by endotoxin. To elucidate the relationship between leukocyte number and in haemostatic and fibrinolytic disturbances in human sepsis, we studied 32 septic patients with abnormal leukocyte counts. Twenty patients had sepsis in the setting of leukopenia after chemotherapy for haematological malignancies. Twelve patients with leukocytosis developed sepsis associated with benign disorders. Concentrations of thrombin-antithrombin III complex (TAT), plasminogen activator inhibitor-1 (PAI-1) and plasma thrombomodulin (TM) in the leukocytosis group of (12.0 +/- 11.0, 40.2 +/- 27.0 and 5.5 +/- 2.3 ng/ml, respectively) were significantly elevated compared to the leukopenia group of (3.8 +/- 2.3, 18.0 +/- 15.0 and 3.1 +/- 1.0 ng/ml, respectively) and controls (3.3 +/- 0.4, 10.5 +/- 5.3, 3.0 +/- 0.5 ng/ml, respectively). On the other hand, there were no significant differences in these values between leukopenia group and controls. Thus leucocytes may play important roles in thrombin generation, PAI-1 release and injury to endothelial cells.
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PMID:Haemostatic and fibrinolytic parameters in septic patients with leukopenia or leukocytosis. 772 Aug 38

The organic symptoms and results of coagulation tests of disseminated intravascular coagulopathy (DIC) in 17 patients with infection were compared with those in 12 patients with malignancy. The infectious diseases were mainly sepsis and pneumonia, and the malignancy was mainly lung cancer. The mean antithrombin III (AT III) before treatment was 54% in infection and 68% in malignancy, and the AT III values improved after administration of 1500 U of AT III concentrates per day. The mean thrombin-antithrombin complex level decreased from 22 ng/ml to 9 ng/ml after the treatment in infection, but it increased in malignancy. There were no differences in DIC scores between infection and malignancy before treatment; however, the scores were significantly more improved in infection than in malignancy after treatment (p < 0.05). The fibrin/fibrinogen degradation product level, platelet count, and fibronectin level were also significantly more improved in infection than in malignancy. This better response to treatment in infection than in malignancy is probably due to eradication of the causative organisms by antibiotics in infection. These data suggest that therapy against both DIC and the underlying disease is crucial for successful treatment.
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PMID:Disseminated intravascular coagulopathy in infection compared with that in malignant neoplasia. 774 1

Disseminated intravascular coagulation (DIC) is characterized by extreme activation of intravascular coagulation, and clinical manifestations such as bleeding and/or multiple organ failure is sometimes observed in advanced cases of DIC. The balance of coagulation and fibrinolysis activation varies according to the underlying diseases of DIC. DIC cases are classified as the type with predominant coagulation activation and the type with predominant fibrinolysis activation in former type plasma levels of thrombin-antithrombin III complex (TAT) are greatly increased, and those of plasmin-alpha 2 plasmin inhibitor complex (PIC) are slightly increased. In addition plasma levels of plasminogen activator inhibitor 1 (PA1) are greatly increased, multiple organ failure is a major clinical manifestation in advanced cases and sepsis is a representative underlying disease. In the second type both plasma levels of TAT and PIC are greatly increased, plasma levels of PA1 are almost within normal limits. Bleeding is a major clinical manifestation in advanced cases and acute promyelocytic leukemia (APL) is a representative underlying disease. The classification of DIC should be considered when choosing treatment with DIC. Diagnosis of pre-DIC status is based on gradually decreasing platelets counts in sepsis and on mild elevation of FDP and D dimer in APL, leukemia and cancer.
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PMID:[Classification and treatment of DIC]. 778 36

Endotoxin(lipopolysaccharide = LPS), cell wall component of gram-negative bacteria, activates monocytes and macrophages to release cytokines, reactive nitrogen intermediates (RNI), and to generate tissue factor(TF) which initiate coagulation. We have purified 7kDa and 18kDa cationic antibacterial proteins (CAP-7 and CAP-18) with LPS-binding and LPS-neutralizing activities from rabbit granulocytes using as an assay the agglutination of erythrocytes coated with Re-LPS. From protein sequencing, CAP-7 was identified as the C-terminal 37 amino acid fragment of CAP-18. Synthetic peptide #197 (identical sequence to CAP-7, Gly1-Try37) and #36-1 (a truncation of CAP consisting of 32 amino acid residues, Gly1-Ala32) showed LPS-binding activity. Each peptide inhibited LPS-induced tissue factor(TF) generation by murine peritoneal macrophages, even added 1-3 hours after stimulation of cells with LPS. C57BL/6 mice treated with #197 were significantly protected from lethal LPS challenge. Peptide #36 also blocked the LPS-induced lethality. These peptides had antibacterial activity to gram-negative bacteria, such as E.coli, S.typhimurium, K.pneumonia, Ps.aeruginosa and also to gram-positive S.aureus (Methicillin sensitive and resistant strains). Both peptides inhibited TF- and Xa-induced plasma clotting. Using synthetic chromotogenic substrates, both CAP7 peptides blocked the coagulation cascade at two sites, activation of factor X to Xa and conversion of Factor II (prothrombin) to factor IIa (thrombin). In vivo treatment of peptide #197 prevented acute lethality in mice injected with tissue factor (rabbit brain thromboplastin). Two other peptides, #32(Gly1-Phe9) and #50(Ile13-Typ37) failed to demonstrate LPS-binding, LPS-neutralizing, antibacterial and anticoagulant activities. The active peptides but not the inactive peptide maintain a putative heparin binding domain at their N-termini. This heparin binding domain is participate in the LPS-binding, LPS neutralizing, antibacterial and anticoagulant activities of CAP7. These active peptides may have a therapeutic potential for treatment for DIC due to sepsis and endotoxin shock.
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PMID:Endotoxin-binding synthetic peptides with endotoxin-neutralizing, antibacterial and anticoagulant activities. 783 55

Plasma levels of thrombin-antithrombin III complex (TAT), plasmin-alpha 2-plasmin inhibitor complex (PIC) and active plasminogen activator inhibitor (PAI) were assayed in 66 cases of disseminated intravascular coagulation (DIC). Significant elevation of both TAT and PIC was observed in all cases of DIC. Most elevated levels of TAT were seen in DIC with acute promyelocytic leukaemia (APL) and sepsis. The highest levels of PIC were seen in DIC with APL but were much lower in sepsis. A significant elevation in active PAI was observed in DIC due to acute leukaemia (apart from APL), chronic myeloid leukaemia and sepsis, but not in APL, non-Hodgkin lymphoma and cancer. Active PAI was higher in patients with multiple organ failure (MOF) than in those without MOF while PIC was lower in patients with this complication. Thus, the balance of coagulation and fibrinolysis varied according to the underlying cause of DIC; APL had more dominant activation of fibrinolysis, while sepsis had greater activation of coagulation. It is suggested that the inhibition of secondary fibrinolytic activation plays an important role in the progression of MOF by the disturbance of the microcirculation.
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PMID:Study of the balance between coagulation and fibrinolysis in disseminated intravascular coagulation using molecular markers. 786 91

Osteopontin (OPN), a secreted phosphoprotein, has been implicated in various biological phenomena (e.g. bone development, sepsis, tumor progression, and metastasis). Its role in any context is poorly understood. OPN contains a conserved Gly-Arg-Gly-Asp-Ser (GRGDS) sequence, and binds to cells via integrin-mediated mechanisms. Using recombinant human osteopontin-glutathione S-transferase fusion protein and our improved hybridoma fusion partner (Sp2/mIL6), we raised murine monoclonal antibodies against osteopontin. We characterized two antibodies that recognize not only recombinant but also native human osteopontin. These antibodies do not cross-react with mouse osteopontin (recombinant protein or that secreted by ras-transformed NIH 3T3 cells), or bovine bone osteopontin, suggesting that they recognize epitopes unique to human OPN. One antibody specifically inhibited adhesion of MDA-MB-435 human breast cancer cells and ras-transformed NIH 3T3 cells to human osteopontin. This antibody failed to recognize osteopontin cleaved by thrombin, which cleaves adjacent to the cell binding domain. We previously showed that thrombin cleavage reduces osteopontin cell binding activity. Thus we postulate that this monoclonal antibody recognizes and interferes with the function of the RGD/thrombin cleavage region of human OPN.
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PMID:Inhibition of Arg-Gly-Asp (RGD)-mediated cell adhesion to osteopontin by a monoclonal antibody against osteopontin. 808 34

We measured various coagulable factors and molecular markers in plasma and serum in the disease group including DIC, DIC suspect, thrombosis, acute myocardial infarction, angina pectoris, sepsis, malignant tumor and type II diabetes and the healthy subject group, and surmised the intravascular coagulative-fibrinolytic activity in each disease group compared with the healthy group. Additionally we selected parameters useful for early detection of the pre-thrombotic state and hypercoagulable state. As a result, of the parameters for the coagulative system, those considered useful were the assay of soluble fibrin monomer complexes using the synthetic substrate (FM.Oita), assay of soluble fibrin monomer complexes using HPLC(SFMC.Oita) and thrombin-anti-thrombin III complex (TAT) in this order. Of the parameters for the fibrinolytic system, those considered useful were FDP assay using ELISA (FDP.Oita) and plasmin-alpha 2 plasmin inhibitor complex (PIC). This FDP.Oita had a considerably high detection sensitivity compared with the FDP assay (Diayatron Co.) using the latex photometric immunoassay which has been commercially available. When measurement was made with plasma and serum in the subject disease group as the sample by the high sensitivity assays mentioned above, it was made clear that both the coagulative activity and fibrinolytic activity are increased, albeit with some differences in intensity, in all the disease groups compared with the healthy group. In order for the hypercoagulable state and pre-thrombotic state to be detected, it is important to know the balance between the coagulative activity and fibrinolytic activity. According to the results of the present experiment, a significant directly proportional correlation was recognized between FM.Oita and FDP.Oita and between TAT and FDP.Oita. Therefore, examination of these ratios will be a more detailed indicator of coagulative-fibrinolytic activity than the TAT/PIC ratio, PAI-1/TPA ratio and ATIII/alpha 2 PI ratio hitherto in use. If useful molecular markers such as FM.Oita are measured over time in various cases and these data are compiled and analyzed statistically, it will not be long before the criteria for the hypercoagulable state and pre-thrombotic state are established.
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PMID:[Molecular marker for detecting hypercoagulable state]. 810 79

The clinical relevance of determination of plasma antithrombin III(ATIII) and alpha 2-plasmin inhibitor (alpha 2 PI) activities in patients with disseminated intravascular coagulation (DIC) was analyzed. Although the plasma ATIII activity was decreased in patients with DIC, no significant correlation was observed between plasma level of ATIII and that of thrombin-antithrombin III complex or prothrombin fragment 1+2. The extent of the decrease of ATIII in DIC was the most marked in cases associated with septicemia. The plasma level of ATIII in septicemia without DIC was significantly lower than that in DIC cases without septicemia, suggesting that the decrease of ATIII level could not be related to the pathophysiology of DIC, but to that of septicemia. The plasma half-life of ATIII in septicemia without DIC was significantly shortened in the absence of the increase of TAT level, suggesting that the extravasation of ATIII might be induced probably due to the endothelial damage in septicemia. The alpha 2-Plasmin inhibitor level was decreased in DIC patients. The decrease was the most marked (lower than 60% of normal) in patients with excessive fibrinolysis in which fibrinogen degradation was induced. The plasma level of alpha 2PI was significantly higher in the DIC cases with septicemia than in those without septicemia. The ATIII/alpha 2PI ratio was significantly lower in DIC cases with septicemia than in those with solid tumor or acute leukemia. Moreover, the ATIII/alpha 2PI ratio was significantly lower in MOF cases than in non-MOF cases in septicemia. The mortality of the MOF cases did not correlate with the ATIII/alpha 2PI ratio, but with the plasma level of PAI-1, suggesting that the decrease of ATIII/alpha 2PI ratio might not reflect the irreversible endothelial cell damage. Based on these observations, the calculation of ATIII/alpha 2PI in DIC patients would provide the following information; (1) a low ATIII/alpha 2PI ratio (less than 0.6) was frequently observed in septicemia, which could be related to the occurrence of organ dysfunction; (2) a high ATIII/alpha 2PI ratio (higher than 1.0) with the marked decrease of alpha 2PI level (lower than 60% of normal) suggests the occurrence of excessive fibrinolysis in which anti-fibrinolytic therapy should be considered when clinical bleeding was present; (3) The ATIII/alpha 2PI ratio near 1.0 was observed in DIC associated with the pathological conditions other than described above, such as solid tumors, in which the coagulation and fibrinolysis was almost equally activated.
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PMID:[Clinical relevance of determination of plasma ATIII and alpha 2 PI activities in patients with DIC--application of the molecular markers for the analysis of pathophysiology of DIC]. 810 83

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