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)

Human endothelial cells respond to bacterial endotoxin (lipopolysaccharide [LPS]) with changes that transform the endothelium into a surface with prominent procoagulant properties. Production of tissue factor (TF) in response to LPS is a major alteration that favors coagulation. Biologic activities of LPS have previously been shown to be enhanced by the presence of hemoglobin. Therefore, the ability of human hemoglobin (Hb) to modulate TF production by cultured human umbilical vein endothelial cells (HUVEC) was investigated. Cell-free Hb (10 mg/mL), either purified native (HbAo) or chemically cross-linked (alpha alpha Hb), was incubated with LPS (0.1 microgram/mL), and the mixtures then were added to HUVEC in culture. TF activity was quantified with a clotting assay and TF protein was measured with an enzyme-linked immunosorbent assay. Hb preparations greatly enhanced the production of TF activity (11- to 25-fold greater than TF produced by HUVEC alone) compared with minimal TF activity generated by LPS alone (only twofold greater than HUVEC alone). The enhancement of LPS-induced TF activity was Hb concentration-dependent over a range of 1 to 100 mg/mL. Cross-linked alpha alpha Hb also greatly enhanced the production of TF protein compared with TF protein generated by LPS alone (12-fold greater v 3.5-fold greater than HUVEC alone, respectively). The enhancement of LPS-induced TF protein was Hb concentration-dependent over a range of 0.1 to 2 mg/mL. Enhancement of TF activity by Hb required new protein synthesis. These results show that human Hb can augment the ability of LPS to induce endothelial cell TF and suggest that hemolysis associated with disseminated intravascular coagulation during sepsis may further stimulate coagulation. In addition, these results suggest a potential mechanism for generalized thrombosis in animals that has been associated with the infusion of cell-free Hb for resuscitation.
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PMID:Hemoglobin enhances the production of tissue factor by endothelial cells in response to bacterial endotoxin. 818 Mar 81

The acute inflammatory response is frequently accompanied by serious thrombotic events. We show that C-reactive protein (CRP), an acute-phase reactant that markedly increases its serum concentration in response to inflammatory stimuli, induced monocytes to express tissue factor (TF), a potent procoagulant. Purified human CRP in concentrations commonly achieved in vivo during inflammation (10 to 100 micrograms/mL) induced a 75-fold increase in TF procoagulant activity (PCA) of human peripheral blood mononuclear cells (PBM), with a parallel increase in TF antigen levels. CRP-induced PCA was completely blocked by a monoclonal antibody against human TF but not by irrelevant murine IgG. Dot blot analysis showed a significant increase of TF mRNA after 4 hours of incubation with CRP, followed by a peak of PCA within 6 and 8 hours. Actinomycin D and cycloheximide blocked CRP-stimulated PCA, suggesting that de novo TF protein synthesis was required. Endotoxin (LPS) contamination of CRP was excluded as the mediator of TF synthesis because: (1) CRP was Limulus assay negative; (2) induction of TF PCA by CRP was not blocked by Polymyxin B, in contrast to LPS-induced PCA; (3) antihuman CRP IgG inhibited CRP-induced PCA, but not LPS-induced PCA; (4) CRP was able to stimulate TF production in LPS-pretreated PBM refractory to additional LPS stimulation; and, (5) unlike LPS, CRP was incapable of inducing TF in human umbilical vein endothelial cells. We suggest that CRP-mediated TF production in monocytes may contribute to the development of disseminated intravascular coagulation and thrombosis in inflammatory states.
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PMID:C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor. 832 6

Induction of tissue factor (TF) expression on monocytes and endothelial cells is central to the development of septic coagulopathy. Serum concentrations of endotoxin in septic patients who develop disseminated intravascular coagulation (DIC) do not, however, reach the levels that would directly stimulate TF expression on either monocytes or endothelium. We show, using an in vitro coculture system, that the interaction of monocytes with endothelium induces the expression of significant levels of TF. Unstimulated cocultures of monocytes (2 x 10(4)/well) and endothelial cells (2 x 10(4)/well) produced 35.3 +/- 8.5 mU of PCA/well, representing a 5-fold increase over the combined PCA of each cell type cultured alone (7.1 +/- 1.5 mU, n = 6, P < 0.001). Significant enhancement was also found in the presence of low concentrations of LPS. Induction of TF protein was confirmed by Western blotting. Fixation of monocytes with paraformaldehyde completely abolished TF induction in cocultures, whereas fixation of endothelium had no effect, suggesting that TF induction occurred in monocytes rather than endothelial cells. Induction of TF in cocultures could be further augmented by preincubating the endothelial cells with IFN-gamma. When endothelium was prestimulated with 500 U/ml IFN-gamma there was 142 +/- 11% increase over unstimulated cocultures (n = 5, P < 0.01). TF induction was inhibited by 32 +/- 6% in the presence of anti-ICAM-1 mAb (n = 5, P < 0.01). Our results suggest that monocyte interactions with vascular endothelium, regulated by inflammatory cytokines, and mediated by adhesive ligand binding, leads to the induction of functional monocyte TF protein, which may be responsible for the initiation of DIC in sepsis.
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PMID:Induction of tissue factor expression in human monocyte/endothelium cocultures. 854 49

Disseminated intravascular coagulation is a prominent manifestation of Ebola virus (EBOV) infection. Here, we report that tissue factor (TF) plays an important role in triggering the hemorrhagic complications that characterize EBOV infections. Analysis of samples obtained from 25 macaques showed increased levels of TF associated with lymphoid macrophages, whereas analysis of peripheral blood-cell RNA showed increased levels of TF transcripts by day 3. Plasma from macaques contained increased numbers of TF-expressing membrane microparticles. Dysregulation of the fibrinolytic system developed during the course of infection, including a rapid decrease in plasma levels of protein C. Infection of primary human monocytes/macrophages (PHMs) was used to further evaluate the role of TF in EBOV infections. Analysis of PHM RNA at 1-48 h showed increased TF transcripts, whereas levels of TF protein were dramatically increased by day 2. Thus, chemotherapeutic strategies aimed at controlling overexpression of TF may ameliorate the effects of EBOV hemorrhagic fever.
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PMID:Mechanisms underlying coagulation abnormalities in ebola hemorrhagic fever: overexpression of tissue factor in primate monocytes/macrophages is a key event. 1463 30

Stromal cell-derived factor-1 (SDF-1) is a CXC chemokine that activates and directs the migration of leukocytes that have CXCR4, which is the unique receptor for SDF-1. Although SDF-1/CXCR4 interaction has been implicated in various inflammatory conditions, its role in modulating coagulation has not been determined. We studied the plasma SDF-1 levels in 90 patients with suspected disseminated intravascular coagulation (DIC) and we found that circulating SDF-1 was significantly increased in the overt DIC patients and was also increased in overt DIC patients who have a poor outcome. We then tested in vitro whether SDF-1 can affect the expression of monocyte tissue factor (TF) and endothelial thrombomodulin (TM), and both of these play important roles in coagulopathy. SDF-1 did not affect the expression of surface TF protein and its function and the TF mRNA level in both monocytes and the monocytic leukemia cell line THP-1. SDF-1 also did not change the surface TM expression of endothelial cells. SDF-1 could enhance low-dose ADP induced platelet aggregation, although it failed by itself to induce aggregation. These findings suggest that plasma SDF-1 might be closely associated with hypercoagulability though its action as a platelet activator.
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PMID:Plasma level of stromal derived factor-1 (SDF-1) is increased in disseminated intravascular coagulation patients who have poor outcomes: in vitro effect of SDF-1 on coagulopathy. 1723 27