Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Coagulation disorders have been associated with the use of chemotherapeutic drugs. Pharmacological doses of cisplatin and adriamycin directly induced low levels of procoagulant on normal human blood monocytes and on a human myelomonocytic cell line, RC2a. Activity was maximal after 24 h and was not due to cell lysis as increasing drug doses which decreased cell viability were less effective. Procoagulant induction was markedly enhanced in the presence of bacterial lipopolysaccharide (LPS), with as little as 10-100 pg/ml LPS potentiating the cisplatin response by 2-5-fold and more than doubling the adriamycin response. Greater than 90% of the procoagulant activity was membrane-bound tissue factor as indicated by the factor VII-dependent generation of factor Xa by viable cells and by the neutralization of this activity by a monoclonal antibody to tissue factor. Tissue factor antigen was measured simultaneously by immunohistochemical staining and by cell ELISA. Blood monocytes activated with LPS expressed high levels of tissue factor antigen; by contrast, adriamycin and cisplatin did not appear to induce antigen expression, but to enhance the specific activity of that already present. Results suggest that membrane alterations which occur following treatment with DNA/RNA intercalating drugs, may result in a highly active form of monocyte/macrophage tissue factor which may contribute to the complications caused by activated coagulation. Secondary Gram-negative infection or cytokines released by an active immune response to a tumour may contribute to the procoagulant potential of these cytotoxic drugs.
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PMID:Modulation of tissue factor on human monocytes by cisplatin and adriamycin. 139 Feb 32

Monocyte-derived macrophages cultured under a variety of conditions were assessed for expression of procoagulant activity (PCA) upon induction by various triggers, using a semiautomated turbidimetric recalcification time assay in a kinetic ELISA reader. Macrophages cultured in a nonadherent (teflon) culture system and seeded in microtiter plates responded with PCA expression to lipopolysaccharide (LPS), to toxic shock-syndrom toxin-1 (TSST-1) and to surface-bound IgG, but not to surface-bound albumin, nor to interferon-gamma (IFN-gamma). In contrast, macrophages stimulated in teflon containers by IFN-gamma showed a strong PCA response peaking around 24 hr after stimulation, but they failed to secrete tumour necrosis factor (TNF). Suspended IFN-gamma-stimulated cells showed a similar response upon 2nd stimulation by LPS or IgG after adherence to microtiter plates as did nonprimed counterparts. In contrast, cells primed in suspension, then cultured in adherence secreted dramatically enhanced amounts of TNF when compared with nonprimed cells. Macrophages stimulated in suspension with LPS showed a PCA response of similar magnitude, which was accompanied by TNF secretion. PCA of both IFN-gamma-primed and LPS-exposed suspension culture cells was largely due to the surface expression of tissue factor, and to a lesser extent of a prothrombinase-like activity, as evidenced by PCA testing with factor-X-deficient plasma. The kinetics of LPS-induced PCA differed from IFN-gamma-induced PCA, in that PCA peaked at 6 hr and fell to insignificant levels after 24 hr. When transferred to microtiter plates at this time, they could be restimulated neither with LPS, nor with surface-adherent IgG nor with IFN-gamma. Evidence was obtained that the failure to express PCA was due to a refractory state of the cells rather than to the generation of cell-bound or secreted inhibitors of coagulation. The loss of PCA expression could be prevented by pre-exposure to IFN-gamma. Thus, PCA expression may be dissociated from other functional and/or activation parameters (e.g. TNF secretion). For the first time, a state in which cells are completely unresponsive to PCA induction has been identified. Should lower LPS concentrations also be found to induce such a refractory state, our results may be of pathophysiological significance.
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PMID:LPS-induced, but not interferon-gamma-induced procoagulant activity of suspended human macrophages is followed by a refractory state of low procoagulant expression. 163 65

An experimental model incorporating cultured endothelial cells (EC) was used to study the "factor VIII bypassing" activity of prothrombin complex concentrates (PCC), a property exploited in the treatment of hemophiliacs with alloantibodies to factor VIII. Two PCC preparations were ineffective as stimuli of tissue factor expression by EC. However, incubation with a combination of PCC plus endotoxin (lipopolysaccharide, LPS) or tumor necrosis factor (TNF) induced much greater tissue factor expression than was seen in response to either substance alone. PCC expressed an additional direct procoagulant activity at the EC surface, which could not be attributed to either thrombin or factor Xa, and which was diminished by an anti-tissue factor antibody. Therefore factor VIIa, which was detectable in both PCC preparations, likely provided this additional direct procoagulant activity at the EC surface. We also excluded the possibility that coagulation proteases contained in or generated in the presence of PCC are protected from inactivation by AT III. Therefore, PCC can indirectly bypass factor VIII by enhancing induced endothelial tissue factor expression, and also possess direct procoagulant activity, probably mediated by factor VIIa.
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PMID:The factor VIII bypassing activity of prothrombin complex concentrates: the roles of factor VIIa and of endothelial cell tissue factor. 180 20

A panel of 24 IgG2ak monoclonal antibodies was produced against murine hepatitis virus strain 3 (MHV-3)-induced procoagulant activity (PCA) from murine macrophages. The antibodies were specific and did not react in an enzyme-linked immunosorbent assay with purified MHV-3; lipopolysaccharide-induced PCA; crude mouse, human, or rabbit tissue factor, or unstimulated murine macrophages. Sixteen of 24 monoclonal antibodies inhibited functional PCA expression in a one-stage clotting assay. More detailed studies on one monoclonal antibody, 3D4.3, demonstrated that it inhibited prothrombin cleavage at concentrations of greater than or equal to 0.1 microgram/ml, and by Western blot this antibody reacted with proteins of a molecular mass of 140, 74, and 70 kDa on nonreduced gels and 74 and 70 kDa on reduced gels distinct from tissue factor known to have a molecular mass of 47 kDa. Induction of PCA was dependent on both host RNA and protein synthesis. Immunofluorescence studies showed specific binding to MHV-3-stimulated PCA-positive macrophage membranes. Both numbers of positive macrophages and intensity of staining correlated with multiplicity of infection. These monoclonal antibodies will be useful in isolation and characterization of the unique viral-induced PCA as well as in determining its biologic role in MHV infection and other diseases in which the prothrombinase has been implicated.
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PMID:Monoclonal antibody analysis of a unique macrophage procoagulant activity induced by murine hepatitis virus strain 3 infection. 184 63

Cisplatin, doxorubicin and daunorubicin (drugs which intercalate with DNA) influenced the membrane-bound procoagulant potential of murine thioglycollate-induced peritoneal exudate (TG-PEC) macrophages and the monocytoid cell line WEHI 265, whereas the antimetabolites 5-fluorouracil and methotrexate had no effect. Enhanced procoagulant was not caused by non-specific toxicity of these agents. Cisplatin directly increased the procoagulant expressed on WEHI 265 cells, whereas MPCA on TG-PEC was enhanced only when cisplatin was combined with a second stimulant, either bacterial lipopolysaccharide (LPS) or interferon (IFN gamma). WEHI 265 cells failed to respond to the anthracycline drugs, either alone or in combination with LPS, whereas they enhanced the IFN gamma response. Doxorubicin and daunorubicin increased the LPS response of TG-PEC by approximately 4-fold and the IFN gamma response by approximately 10-fold. Pulsing experiments suggested that the anthracyclines enhanced procoagulant expression by a mechanism different from cisplatin. Daunorubicin primed TG-PEC within 4 hr to respond to low levels of LPS, whereas either LPS or cisplatin primed these cells to respond to cisplatin or LPS respectively. Furthermore, the procoagulant expressed by TG-PEC stimulated by LPS/cisplatin had properties of tissue factor (TF: 50% total activity) and Factor VIIa (50% total procoagulant)-like activities, whereas the predominant procoagulant on LPS/anthracycline activated TG-PEC was TF-like (70% total activity) with weak Factor VIIa and prothrombinase-like properties.
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PMID:Induction of macrophage procoagulant expression by cisplatin, daunorubicin and doxorubicin. 212 Jan 34

The procoagulant activity (PCA) of disrupted monocytes was examined in 32 diabetic patients (26 with insulin-dependent and 6 with non-insulin-dependent diabetes) versus 30 control subjects. Diabetes monocytes exhibited a weak PCA before any incubation, associated in 10 cases with a significant amount of factor VII activity. Incubation led to a significant rise in PCA in diabetes cells, when stimulated with lipopolysaccharide or not, and in control cells only after stimulation. In incubated diabetes cells, PCA was prothrombinase-like when factor VII was associated with the freshly isolated cells, and tissue factor-like (as in the controls) when no factor VII was associated with the cells. The characteristics of PCA were not correlated with clinical features or with the type of diabetes. Our study suggests that diabetes monocytes exhibit a higher level of PCA than control ones, possibly corresponding to an in vivo stimulation, or at least a higher responsiveness to stimuli occurring in vitro.
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PMID:Distinctive features of procoagulant response of monocytes from diabetic patients. 273 77

Mononuclear phagocytes, a specialized cell lineage comprising bone-marrow precursors, blood monocytes and tissue macrophages, can interact with blood coagulation mechanisms with resulting thrombus formation or extravascular fibrin accumulation. Such procoagulant activity is usually activation dependent and requires interaction of the cells with immune or nonimmune stimuli. In the former case (e.g., alloantigens, soluble protein antigens) collaboration of mononuclear phagocytes with T lymphocytes is necessary and is mediated by cell-to-cell contact or lymphokines. Prototype of a direct acting stimulus is bacterial lipopolysaccharide. Mononuclear phagocyte procoagulant activity is expressed in the form of cell membrane-bound or released factors which display molecular heterogeneity. They include the initiator of the extrinsic clotting pathway, tissue factor, known clotting proteases such as factors V and VII, and novel proteolytic enzymes including prothrombinase and a factor X activator. Mononuclear phagocyte procoagulants are pathogenetically involved in generalized disorders with intravascular coagulation and thromboembolic phenomena. These disorders, exemplified by the Shwartzman reaction and possibly by paraneoplastic thromboembolism, are initiated by blood monocytes. Extravascular fibrin deposition can be initiated by tissue-infiltrating monocytes and macrophages in disease states such as acute renal allograft failure and solid tumours.
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PMID:Macrophage procoagulant factors--mediators of inflammatory and neoplastic tissue lesions. 353 56

Murine lymphoid cells respond rapidly to bacterial lipopolysaccharide or antigen-antibody complexes to initiate or accelerate the blood coagulation pathways. The monocyte or macrophage has been identified as the cellular source, although lymphocyte collaboration is required for the rapid induction of the procoagulant response. This procoagulant activity is identified in the present study as a direct prothrombin activator, i.e., a prothrombinase. Studies with plasmas deficient in single coagulation factors demonstrate that the induced murine procoagulant activity effector molecule does not require factors XII, VIII, VII, X, or V, but does require prothrombin to transform fibrinogen to fibrin. This enzyme(s) produces limited proteolysis of prothrombin to yield thrombin or thrombinlike products that are functionally capable of converting fibrinogen to fibrin. The prothrombinase is undetectable in freshly isolated Murine lymphoid cells respond rapidly to bacterial lipopolysaccharide or antigen-antibody complexes to initiate or accelerate the blood coagulation pathways. The monocyte or macrophage has been identified as the cellular source, although lymphocyte collaboration is required for the rapid induction of the procoagulant response. This procoagulant activity is identified in the present study as a direct prothrombin activator, i.e., a prothrombinase. Studies with plasmas deficient in single coagulation factors demonstrate that the induced murine procoagulant activity effector molecule does not require factors XII, VIII, VII, X, or V, but does require prothrombin to transform fibrinogen to fibrin. This enzyme(s) produces limited proteolysis of prothrombin to yield thrombin or thrombinlike products that are functionally capable of converting fibrinogen to fibrin. The prothrombinase is undetectable in freshly isolated
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PMID:Murine lymphoid procoagulant activity induced by bacterial lipopolysaccharide and immune complexes is a monocyte prothrombinase. 720 Jan 21

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

A monocyte procoagulant assay was developed based on the original method of Surprenant and Zuckerman, which quantitates a factor Xa-specific chromogenic substrate (at 405 nm) activated via the extrinsic coagulation pathway. Normal tissue factor initiation of the pathway is replaced by tissue factor generated from monocytes, stimulated by various agents including bacterial lipopolysaccharide, and antibody/antigen complexes. Hydrolysis of the chromogenic substrate is therefore directly proportional to the degree of monocyte activation. Using a chromogenic substrate as an end-point the assay was performed in a standard microtitre plate.
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PMID:Monocyte procoagulant activity: development of a microtitre plate chromogenic assay. 775 38


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