thromboplastin and Bacteremia

An occlusive thrombus in the coronary arteries is the critical pathological event that immediately precedes most cases of myocardial infarction. Often the thrombus originates with a bleed from a fissured atheroma. Atheroma formation, therefore, creates risk of thrombosis; asymptomatic episodes of thrombosis and healing contribute to the pathogenesis of atherosclerosis and the development of atherosclerotic plaques. Based largely on in vitro and animal model evidence, infectious agents and their products can activate the coagulation cascade enzymatically or by up-regulating tissue factor. By initiating a procoagulant response, infectious agents can indirectly trigger a prothrombotic response. Alternatively, some microbes can directly trigger platelet aggregation in vitro and in animal models, suggesting direct prothrombotic potential in human cardiovascular disease. Activation of coagulation and thrombosis characterizes the pathological response to infectious agents in human disseminated intravascular coagulation and infective endocarditis. Given the underlying biological plausibility, the cumulative lifetime burden of chronic pathogens may be expected to create risk of atherosclerosis and thrombosis, and, indirectly, signs of cardiovascular disease.

Topics: Animals; Antigens, Bacterial; Bacteremia; Bacterial Proteins; Blood Coagulation; Cardiovascular Diseases; Collagen; Coronary Artery Disease; Coronary Thrombosis; Disease Models, Animal; Disseminated Intravascular Coagulation; Endocarditis, Bacterial; Humans; Platelet Aggregation; Risk Factors; Thromboplastin; Thrombosis

Topics: Animals; Bacteremia; Biomarkers; Disseminated Intravascular Coagulation; Dogs; Edema; Escherichia coli Infections; Inflammation; Papio; Protein C; Rats; Shock, Septic; Thromboplastin; Tumor Necrosis Factor-alpha

Essentials Complement, Toll-like receptors and coagulation cross-talk in the process of thromboinflammation. This is explored in a unique human whole-blood model of S. aureus bacteremia. Coagulation is here shown as a downstream event of C5a-induced tissue factor (TF) production. Combined inhibition of C5 and CD14 efficiently attenuated TF and coagulation.. Background There is extensive cross-talk between the complement system, the Toll-like receptors (TLRs), and hemostasis. Consumptive coagulopathy is a hallmark of sepsis, and is often mediated through increased tissue factor (TF) expression. Objectives To study the relative roles of complement, TLRs and TF in Staphylococcus aureus-induced coagulation. Methods Lepirudin-anticoagulated human whole blood was incubated with the three S. aureus strains Cowan, Wood, and Newman. C3 was inhibited with compstatin, C5 with eculizumab, C5a receptor 1 (C5aR1) and activated factor XII with peptide inhibitors, CD14, TLR2 and TF with neutralizing antibodies, and TLR4 with eritoran. Complement activation was measured by ELISA. Coagulation was measured according to prothrombin fragment 1 + 2 (PTF

Topics: Antibodies, Neutralizing; Bacteremia; Bacterial Load; Blood Coagulation; Complement Activation; Complement C5a; Complement Inactivating Agents; Host-Pathogen Interactions; Humans; Lipopolysaccharide Receptors; Microbial Viability; Monocytes; Receptor, Anaphylatoxin C5a; Signal Transduction; Staphylococcal Infections; Staphylococcus aureus; Thromboplastin; Time Factors; Toll-Like Receptor 2

Tissue factor (TF) is a transmembrane glycoprotein that plays an essential role in hemostasis by activating coagulation. TF is also expressed by monocytes/macrophages as part of the innate immune response to infections. In the current study, we determined the role of TF expressed by myeloid cells during Mycobacterium tuberculosis (M. tb) infection by using mice lacking the TF gene in myeloid cells (TF(Δ) ) and human monocyte derived macrophages (MDMs). We found that during M. tb infection, a deficiency of TF in myeloid cells was associated with reduced inducible nitric oxide synthase (iNOS) expression, enhanced arginase 1 (Arg1) expression, enhanced IL-10 production and reduced apoptosis in infected macrophages, which augmented M. tb growth. Our results demonstrate that a deficiency of TF in myeloid cells promotes M2-like phenotype in M .tb infected macrophages. A deficiency in TF expression by myeloid cells was also associated with reduced fibrin deposition and increased matrix metalloproteases (MMP)-2 and MMP-9 mediated inflammation in M. tb infected lungs. Our studies demonstrate that TF expressed by myeloid cells has newly recognized abilities to polarize macrophages and to regulate M. tb growth.

Topics: Animals; Bacteremia; Blood Coagulation; Cell Differentiation; Female; Fibrin; Host-Pathogen Interactions; Humans; Immunity, Innate; Lung; Macrophages; Mice, Inbred C57BL; Mice, Knockout; Mycobacterium tuberculosis; Pneumonia; Thromboplastin; Tuberculoma; Tuberculosis, Pulmonary

Mycobacterium tuberculosis, the causative agent of tuberculosis, drives the formation of granulomas, structures in which both immune cells and the bacterial pathogen cohabit. The most abundant cells in granulomas are macrophages, which contribute as both cells with bactericidal activity and as targets for M. tuberculosis infection and proliferation during the entire course of infection. The mechanisms and factors involved in the regulation and control of macrophage microenvironment-specific polarization and plasticity are not well understood, as some granulomas are able to control bacteria growth and others fail to do so, permitting bacterial spread. In this issue of the European Journal of Immunology, Venkatasubramanian et al. [Eur. J. Immunol. 2016. 46: 464-479] show that mice lacking the tissue factor gene in myeloid cells have augmented M. tuberculosis growth and increased inflammation in the lungs. This suggests that tissue factor, an initiator of coagulation, is important for the generation of fibrin, which supports granuloma formation. This article demonstrates for the first time the involvement of tissue factor in inducing effective immunity against M. tuberculosis, and sheds new lights on the complex interplay between host inflammatory response, the coagulation system, and the control of M. tuberculosis infection.

Topics: Animals; Bacteremia; Blood Coagulation; Cell Differentiation; Fibrin; Host-Pathogen Interactions; Humans; Immunity, Innate; Lung; Macrophages; Mice; Mice, Knockout; Mycobacterium tuberculosis; Pneumonia; Thromboplastin; Tuberculoma; Tuberculosis, Pulmonary

Inhibition of tissue factor, the primary initiator of coagulation in sepsis, attenuates morbidity in primates infused with Escherichia coli. In a human endotoxemia model, microparticles expressing procoagulant TF (MP-TF) are released in blood concurrently with markers of inflammation and coagulation. We investigated whether the release of MP-TF into blood is accompanied by procoagulant and inflammatory changes in patients with E. coli urinary tract infection.. In a multicenter cohort study, we determined clinical disease severity using APACHE II scores and measured plasma MP-TF activity, TAT, sE-selectin, sVCAM-1, procalcitonin and monocyte count in blood of 215 patients with community-acquired febrile E. coli urinary tract infections.. Plasma MP-TF activity on admission corresponded with clinical disease severity (APACHE II score; P=0.006) and correlated significantly but weakly with plasma markers of disease severity (sE-selectin, sVCAM-1, procalcitonin). Additionally, median plasma MP-TF activity was higher in patients than in healthy controls (197 vs. 79 fM Xa/min; P<0.0001), and highest in bacteremic patients (325 fM Xa/min). MP-TF activity showed a weak inverse correlation with monocyte count (rs -0.22; P=0.016) and a weak correlation with TAT (rs 0.23, P=0.017). After 3 days of antibiotic treatment, upon resolution of the infection, plasma MP-TF activity and TAT concentrations declined.. Microparticle-associated procoagulant tissue factor activity is related to disease severity and bacteremia in febrile E. coli UTI patients and may contribute to the prothrombotic state in gram-negative sepsis.

Topics: Adult; Aged; Aged, 80 and over; Bacteremia; Cell-Derived Microparticles; Cohort Studies; Escherichia coli Infections; Female; Fever; Humans; Male; Middle Aged; Severity of Illness Index; Thromboplastin; Urinary Tract Infections; Young Adult

The ability of pro-inflammatory cytokines to promote coagulation prompted the hypothesis that pro-inflammatory cytokines induced by oral streptococci might play a role in the pathogenesis of viridans endocarditis. We used supernatant fluids from peripheral blood mononuclear monocyte (PBMC) cultures, stimulated for just 4-6 hrs with representative streptococcal isolates, to study cytokines that promoted endothelial tissue factor (TF) activity. Neutralizing antibodies demonstrated that interleukin-1beta (IL-1beta) was a major early endothelial TF inducer, and that recombinant IL-1beta was comparable with the supernatant fluid in activity. IL-1beta-rich supernatant fluids from oral streptococci-stimulated or lipopolysaccharide-stimulated PBMC cultures up-regulated the expression of endothelial ICAM-1 and E-selectin. These molecules could help trap TF-producing monocytes or dendritic cells bearing streptococci at the site. Thus, the rapid IL-1beta-inducing capacity of oral streptococci could facilitate the early deposition of bacteria in fibrin clots and promote endocarditis.

Topics: Analysis of Variance; Bacteremia; Cell Adhesion; Cells, Cultured; Culture Media, Conditioned; Dendritic Cells; E-Selectin; Endothelial Cells; Endothelium, Vascular; Humans; Intercellular Adhesion Molecule-1; Interleukin-1beta; Lipopolysaccharides; Monocytes; Mouth; Recombinant Proteins; Thromboplastin; Up-Regulation; Viridans Streptococci

Sepsis-induced abnormalities of coagulation may contribute to mortality during severe bacterial infection. The aim of this study was to examine changes in coagulation parameters and to assess the role of protein C supplementation during murine S. aureus sepsis. Gram-positive sepsis was characterized by a hypercoagulable state with predominant activation of the external coagulation pathway, registered as an early increase of tissue factor activity and concomitant reduction in protein C. The internal coagulation pathway was unaffected. No correlation between the changes of coagulation parameters and the intensity of inflammation, determined as serum IL-6 levels, was found. Supplementation with neither protein C or APC favoured survival in S. aureus sepsis. Reduction in thrombin generation in response to protein C supplementation was associated with significantly increased survival.

Topics: Animals; Anticoagulants; Bacteremia; Blood Coagulation; Blood Coagulation Factors; Interleukin-6; Mice; Protein C; Staphylococcal Infections; Staphylococcus aureus; Thrombin; Thromboplastin

Sepsis-induced tissue factor (TF) expression activates coagulation in the lung and leads to a procoagulant environment, which results in fibrin deposition and potentiates inflammation. We hypothesized that preventing initiation of coagulation at TF-Factor VIIa (FVIIa) complex would block fibrin deposition and control inflammation in sepsis, thereby limiting acute lung injury (ALI) and other organ damage in baboons. A model of ALI was used in which adult baboons were primed with killed Escherichia coli (1 x 10(9) CFU/kg), and bacteremic sepsis was induced 12 h later by infusion of live E. coli at 1 x 10(10) CFU/kg. Animals in the treatment group were given a competitive inhibitor of TF, site-inactivated FVIIa (FVIIai), intravenously at the time of the infusion of live bacteria and monitored physiologically for another 36 h. FVIIai dramatically protected gas exchange and lung compliance, prevented lung edema and pulmonary hypertension, and preserved renal function relative to vehicle (all p < 0.05). Treatment attenuated sepsis-induced fibrinogen depletion (p < 0.01) and decreased systemic proinflammatory cytokine responses, for example, interleukin 6 (p < 0.01). The protective effects of TF blockade in sepsis-induced ALI were confirmed by using tissue factor pathway inhibitor. The results show that TF-FVIIa complex contributes to organ injury in septic primates in part through selective stimulation of proinflammatory cytokine release and fibrin deposition.

Topics: Acute Kidney Injury; Animals; Bacteremia; Blood Coagulation; Disease Models, Animal; Drug Evaluation, Preclinical; Escherichia coli Infections; Factor VIIIa; Fibrinogen; Hemodynamics; Inflammation; Interleukin-6; Kidney Function Tests; Lung Compliance; Male; Papio; Pulmonary Edema; Pulmonary Gas Exchange; Random Allocation; Respiratory Distress Syndrome; Thromboplastin; Tumor Necrosis Factor-alpha

The expression of surface tissue factor procoagulant activity and its shedding by blood monocytes can be induced by several stimuli. Few of these defined situations, other than the presence of bacteria and their toxins, are commonly present in the young human infant. In this study, measurements were made of the percentage of monocytes expressing surface tissue factor apoprotein (TFA) in blood taken from babies in the early weeks of life. Mononuclear cells were separated from blood in an environment free of detectable endotoxin. After exposure to a polyclonal rabbit antibody raised to purified brain TFA and subsequent exposure to a fluorescin-labeled murine anti-rabbit IgG, the cell fluorescent activity was analyzed by flow cytometry. The percentage of monocytes showing strong fluorescence was determined. In every instance when systemic bacterial infection was present, more than 60% of the monocytes examined showed fluorescence indicative of the presence of surface TFA. In a single case of fungal Candida septicemia, none of the monocytes was positive. More than 60% of cells were found to be positive in certain instances where infection was highly probable but not proven. Positive cells were found in three cases of isoimmune hemolytic disease of the newborn, as had been anticipated from previous studies, whereas less than 25% of monocytes derived from babies in the absence of discernible infection or isoimmune hemolytic disease expressed surface TFA (p less than 0.001). These findings provide insight into a possible mechanism of coagulation activation in sepsis and may prove to be a useful predictor of the presence of infection or endotoxemia in young infants.

Topics: Apoproteins; Bacteremia; Bacterial Infections; Endotoxins; Erythroblastosis, Fetal; Humans; Infant; Infant, Newborn; Monocytes; Thromboplastin; Toxemia