thromboplastin and Pneumonia

An enhanced risk of cardiovascular mortality has been observed after pneumonia. Epidemiological studies have shown that respiratory tract infections are associated with an increased risk of thrombotic-related vascular disease such as myocardial infarction, ischemic stroke and venous thrombosis. Myocardial infarction and stroke have been detected essentially in the early phase of the disease (i.e. within 48 h from hospital admission), with an incidence ranging from as low as 1% to as high as 11%. Age, previous cardiovascular events and high pneumonia severity index were independent predictors of myocardial infarction; clinical predictors of stroke were not identified. Deep venous thrombosis and pulmonary embolism may also occur after pneumonia but incidence and clinical predictors must be defined. The biological plausibility of such an association may be deduced by experimental and clinical studies, showing that lung infection is complicated by platelet aggregation and clotting system activation, as documented by up-regulation of tissue factor and down-regulation of activated protein C. The effect of antithrombotic drugs has been examined in experimental and clinical studies but results are still inconclusive.

Topics: Age Factors; Anticoagulants; Blood Coagulation; Clinical Trials as Topic; Fibrinolytic Agents; Humans; Myocardial Infarction; Patient Admission; Platelet Aggregation; Pneumonia; Protein C; Research Design; Stroke; Thromboplastin; Thrombosis; Treatment Outcome; Vascular Diseases

Despite effective antibiotic therapy, about one-third of patients admitted to an intensive care unit (ICU) with severe community-acquired pneumonia (CAP) and organ dysfunction die within a month. This high death rate demonstrates the need for additional interventions. Both animal models and clinical data suggest that pathological expression of tissue factor (TF), with consequent activation of coagulation and inflammatory processes, contributes to the morbidity and mortality associated with CAP. TF pathway inhibitor (TFPI) is an endogenous molecule with both anti-inflammatory and anti-coagulant activity. In severe CAP, endogenous TFPI is overwhelmed by increased expression of TF. In this setting administration of recombinant TFPI (tifacogin) could restore hemostasis. The OPTIMIST phase 3 trial of tifacogin in severe sepsis did not show overall mortality benefit from tifacogin. However, retrospective analysis suggested improved survival among tifacogin treated patients who had severe CAP. Benefit seemed clearest when such patients had not received concurrent heparin and/or when they had documented microbial infection. These findings led to a prospective study (CAPTIVATE) in which 2,100 patients with severe CAP requiring ICU admission were randomized to standard care plus either placebo or one of two dose levels of tifacogin. The study excluded concomitant heparin and encouraged documentation of infection. Enrolment was completed in July 2008 but data are not yet available. The primary outcome measure is 28-day all-cause mortality. In addition to short-term and long-term survival, the study is collecting data on adverse events (particularly when related to bleeding or thrombosis) and the effect of tifacogin on disease progression, resource use, and duration of ICU and hospital stay.

Topics: Anti-Bacterial Agents; Community-Acquired Infections; Humans; Pneumonia; Severity of Illness Index; Signal Transduction; Thromboplastin

To review the involvement of coagulation and fibrinolysis in the pathogenesis of acute lung injury during severe infection. To review the cross-talk between coagulation and inflammation that may affect this response.. Published articles on experimental and clinical studies of coagulation and fibrinolysis during infection, inflammation, acute lung injury, and evolving acute respiratory distress syndrome.. Fibrin deposition is an important feature of pulmonary infection or severe inflammation. The mechanisms that contribute to this fibrin deposition are bronchoalveolar tissue factor-mediated thrombin generation and localized depression of urokinase plasminogen activator-mediated fibrinolysis, caused by the increase of plasminogen activator inhibitors. These effects on pulmonary coagulation and fibrinolysis are regulated by various proinflammatory cytokines. Rather than being a unidirectional relationship, the interaction between inflammation and coagulation involves significant cross-talk. Coagulation and fibrinolytic proteins may have an additional role beyond fibrin turnover and inflammation, e.g., in mechanisms mediating cell recruitment and migration.

Topics: Bronchoalveolar Lavage Fluid; Cytokines; Endotoxemia; Fibrin; Fibrinolysis; Humans; Pneumonia; Respiratory Distress Syndrome; Thromboplastin

Platelet activation contributes to organs failure in inflammation and plays an important role in endotoxemia. Clopidogrel inhibits platelet aggregation and activation. However, the role of clopidogrel in modulating inflammatory progression of endotoxemia remains largely unexplored. Therefore, we investigated the role of clopidogrel on the activation of platelet and leukocytes in lipopolysaccharide (LPS)-induced inflammation in mice. Animals were treated with clopidogrel or vehicle before LPS induction. The expression of neutrophil-platelet aggregates and platelet activation and tissue factor was determined. Immunofluorescence was used to analyze platelet-leukocyte interactions and tissue factor (TF) expression on leukocytes. Clopidogrel pretreatment markedly decreased lung damage, inhibited platelet-neutrophil aggregates and TF expression. In addition, clopidogrel reduced thrombocytopenia and affected the number of circulating white blood cell in endotoxemia mice. Moreover, clopidogrel also reduced platelet shedding of CD40L and CD62P in endotoxemic mice. Taken together, clopidogrel played an important role through reducing platelet activation and inflammatory process in endotoxemia.

Topics: Animals; Blood Platelets; CD40 Ligand; Clopidogrel; Endotoxemia; Inflammation; Interleukin-1beta; Lipopolysaccharides; Mice, Inbred BALB C; Models, Animal; Neutrophils; P-Selectin; Platelet Aggregation Inhibitors; Pneumonia; Purinergic P2Y Receptor Antagonists; Thromboplastin; Tumor Necrosis Factor-alpha

Essentials Tissue factor (TF) represents a central link between hemostasis and inflammation. We studied the roles of myeloid and airway epithelial TF in acid-caused acute lung injury (ALI). TF on myeloid cells displays a non-coagulatory role regulating the inflammatory response in ALI. Airway epithelial TF contributes to hemostatic functions, but is dispensable in ALI pathogenesis.. Introduction Acute lung injury (ALI) is a life-threatening condition characterized by damaged alveolar-capillary structures and activation of inflammatory and hemostatic processes. Tissue factor (TF) represents a crucial link between inflammation and coagulation, as inflammatory mediators induce myeloid TF expression, and TF initiates extrinsic coagulation. Objective As pulmonary inflammation stimulates TF expression and TF modulates immune responses, we aimed to elucidate its impact on ALI. In particular, we wanted to distinguish the contributions of TF expressed on airway epithelial cells and TF expressed on myeloid cells. Methods Mice with different cell type-specific TF deficiency and wild-type littermates were intratracheally treated with hydrochloric acid, and leukocyte recruitment, cytokine levels, thrombin-antithrombin (TAT) complexes and pulmonary protein-rich infiltrates were analyzed. Results Our data demonstrate that a lack of epithelial TF did not influence acute responses, as bronchoalveolar neutrophil accumulation 8 h after ALI induction was unaltered. However, it led to mild, prolonged inflammation, as pulmonary leukocyte and erythrocyte numbers were still increased after 24 h, whereas those in wild-type mice had returned to basal levels. In contrast, myeloid TF was primarily involved in regulating the acute phase of ALI without affecting local coagulation, as indicated by increased bronchoalveolar neutrophil infiltration, pulmonary interleukin-6 levels, and edema formation, but equal TAT complex formation, 8 h after ALI induction. This augmented inflammatory response associated with myeloid TF deficiency was confirmed in vitro, as lipopolysaccharide-stimulated TF-deficient alveolar macrophages released increased levels of chemokine (C-X-C motif) ligand 1 and tumor necrosis factor-α as compared with wild-type macrophages. Conclusion We conclude that myeloid TF dampens inflammation in acid-induced ALI.

Topics: Acute Lung Injury; Animals; Antithrombin III; Blood Coagulation; Cells, Cultured; Chemotaxis, Leukocyte; Cytokines; Disease Models, Animal; Epithelial Cells; Genetic Predisposition to Disease; Hydrochloric Acid; Inflammation Mediators; Lung; Macrophages, Alveolar; Mice, Inbred C57BL; Mice, Knockout; Neutrophil Infiltration; Peptide Hydrolases; Phenotype; Pneumonia; Pulmonary Edema; Thromboplastin; Time Factors

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

Tissue factor (TF) is a critical mediator of direct acute lung injury (ALI) with global TF deficiency resulting in increased airspace inflammation, alveolar-capillary permeability, and alveolar hemorrhage after intra-tracheal lipopolysaccharide (LPS). In the lung, TF is expressed diffusely on the lung epithelium and intensely on cells of the myeloid lineage. We recently reported that TF on the lung epithelium, but not on myeloid cells, was the major source of TF during intra-tracheal LPS-induced ALI. Because of a growing body of literature demonstrating important pathophysiologic differences between ALI caused by different etiologies, we hypothesized that TF on myeloid cells may have distinct contributions to airspace inflammation and permeability between direct and indirect causes of ALI. To test this, we compared mice lacking TF on myeloid cells (TF(∆mye), LysM.Cre(+/-)TF(flox/flox)) to littermate controls during direct (bacterial pneumonia, ventilator-induced ALI, bleomycin-induced ALI) and indirect ALI (systemic LPS, cecal ligation and puncture). ALI was quantified by weight loss, bronchoalveolar lavage (BAL) inflammatory cell number, cytokine concentration, protein concentration, and BAL procoagulant activity. There was no significant contribution of TF on myeloid cells in multiple models of experimental ALI, leading to the conclusion that TF in myeloid cells is not a major contributor to experimental ALI.

Topics: Acute Lung Injury; Animals; Cytokines; Disease Models, Animal; Female; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Transgenic; Myeloid Cells; Permeability; Phagocytosis; Pneumonia; Respiratory Distress Syndrome; Thromboplastin

Coagulation and fibrinolysis abnormalities are observed in acute lung injury (ALI) in both human disease and animal models and may contribute to ongoing inflammation in the lung. Tissue factor (TF), the main initiator of the coagulation cascade, is upregulated in the lungs of patients with ALI/acute respiratory distress syndrome (ARDS) and likely contributes to fibrin deposition in the air space. The mechanisms that govern TF upregulation and activation in the lung are not well understood. In the vascular space, TF-bearing microparticles (MPs) are central to clot formation and propagation. We hypothesized that TF-bearing MPs in the lungs of patients with ARDS contribute to the procoagulant phenotype in the air space during acute injury and that the alveolar epithelium is one potential source of TF MPs. We studied pulmonary edema fluid collected from patients with ARDS compared with a control group of patients with hydrostatic pulmonary edema. Patients with ARDS have higher concentrations of MPs in the lung compared with patients with hydrostatic edema (25.5 IQR 21.3-46.9 vs. 7.8 IQR 2.3-27.5 micromol/l, P = 0.009 by Mann-Whitney U-test). These MPs are enriched for TF, have procoagulant activity, and likely originate from the alveolar epithelium [as measured by elevated levels of RAGE (receptor for advanced glycation end products) in ARDS MPs compared with hydrostatic MPs]. Furthermore, alveolar epithelial cells in culture release procoagulant TF MPs in response to a proinflammatory stimulus. These findings suggest that alveolar epithelial-derived MPs are one potential source of TF procoagulant activity in the air space in ARDS and that epithelial MP formation and release may represent a unique therapeutic target in ARDS.

Topics: Adult; Aged; Blood Coagulation Factors; Body Fluids; Cell-Derived Microparticles; Epithelial Cells; Humans; Middle Aged; Pneumonia; Pulmonary Alveoli; Pulmonary Edema; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Respiratory Distress Syndrome; Subcellular Fractions; Thromboplastin

Ozone is a well-known oxidant air pollutant, inhalation of which can result in oxidative stress, and lead to pulmonary inflammation. The aim of this study was to evaluate the time-course events after a single ozone exposure in transcription-coupled repair defective Csb and wild type mice. Mice were exposed for 3 h to 2 ppm ozone and biological parameters related to oxidative stress and inflammation were examined in the lungs at 0, 4, 9, 24 and 48 h after exposure. In addition the procoagulant and thrombomodulin activities were explored by a combination of assays for tissue factor and thrombin generation. This study revealed a significant biological response to ozone, for both Csb and wild type mice. The onset of inflammation in Csb mice, as indicated by an increase in interleukin-6, tumor necrosis factor-alpha and total cell influx, occurred earlier compared with those seen in wild type mice. On the other hand, Csb mice showed a delayed antioxidant reaction compared with wild type mice. Both genotypes developed a procoagulant reaction characterized by a stably increased tissue factor activity and a progressive increase in thrombin generation after 2 days. These experiments have shown that ozone, a well-known toxic substance from the environment, induces not only inflammation, but also procoagulant reactions in the lungs of mice. These results have implications for understanding the systemic effects induced by oxidant air pollutants.

Topics: Air Pollutants, Occupational; Animals; Body Weight; Bronchoalveolar Lavage Fluid; Calibration; DNA Repair; Male; Mice; Mice, Inbred C57BL; Organ Size; Oxidants, Photochemical; Oxidative Stress; Ozone; Pneumonia; RNA, Messenger; Thromboplastin; Thrombosis; Time Factors

Inhaled ultrafine particles trigger peripheral thrombotic complications.. We have analyzed the systemic prothrombotic risk following lung inflammation induced by pulmonary carbon nanotubes (CNTs).. Intratracheal instillation in Swiss mice of 200 and 400 microg of multiwall ground CNTs triggered substantial lung neutrophil, but not macrophage influx, 24 h later. The detection of circulating platelet-leukocyte conjugates exclusively 6 h after CNT instillation pointed to early but transient activation of circulating platelets. At 24 h, elevated plasma procoagulant microvesicular tissue factor activity was found in CNT-exposed but not in saline-exposed mice. However, at 24 h, both the tail and jugular vein bleeding times were prolonged in CNT-exposed but not in saline-exposed mice, arguing against strong CNT-induced platelet activation at this point. Nevertheless, at 24 h, enhanced peripheral thrombogenicity was detected in CNT-exposed but not in saline-exposed mice, via quantitative photochemically induced carotid artery thrombosis measurements. P-selectin neutralization abrogated platelet-leukocyte conjugate formation and microvesicular tissue factor generation, and abolished the CNT-induced thrombogenicity amplification. In contrast, the weak vascular injury-triggered thrombus formation in saline-treated mice was not affected by P-selectin neutralization at 24 h.. The mild CNT-induced lung inflammation translates via rapid but mild and transient activation of platelets into P-selectin-mediated systemic inflammation. Leukocyte activation leads to tissue factor release, in turn eliciting inflammation-induced procoagulant activity and an associated prothrombotic risk.

Topics: Animals; Blood Platelets; Disease Models, Animal; Female; Granulocytes; Leukocytes; Male; Mice; Nanotubes, Carbon; P-Selectin; Platelet Activation; Pneumonia; Thromboplastin; Thrombosis

Topics: Biomarkers; Bronchoalveolar Lavage Fluid; Humans; Plasminogen Activator Inhibitor 1; Pneumonia; Thromboplastin

Substantial progress has been made in understanding the contribution of alterations in coagulation and fibrinolysis to the pathogenesis of acute lung injury (ALI). Findings from mouse, rat, baboon, and human studies indicate that alterations in coagulation and fibrinolysis may be of major pathogenetic importance in ALI and other inflammatory conditions in the lung including pneumonia, sepsis, and ventilator-induced lung injury. Therapies targeted at both activation of coagulation through the extrinsic coagulation cascade and modulation of coagulation through the protein C system have the potential to favorably impact clinical ALI/acute respiratory distress syndrome.

Topics: Animals; Blood Coagulation; Disease Models, Animal; Fibrinolysis; Humans; Models, Immunological; Papio; Pneumonia; Protein C; Receptors, Proteinase-Activated; Respiration, Artificial; Respiratory Distress Syndrome; Sepsis; Thrombomodulin; Thromboplastin

Abnormalities in local coagulation may explain alveolar fibrin deposition which often accompanies human lung injuries. The purpose of this study was to investigate the generation of procoagulant activity (PCA) and tissue factor pathway inhibitor (TFPI) in selected bronchoalveolar lavage fluids (BAL) from controls (n = 7) and from patients with interstitial lung diseases (n = 9), Pneumocystis carinii (PCP) pneumonia (n = 11) and bacterial pneumonia (n = 8). As compared with controls a significant increase of PCA was observed in the three groups with lung diseases. PCA in BAL from patients with untreated interstitial lung diseases (PC Units mean of 162 +/- 48) was significantly higher than PCA of treated patients (PC Units 36 +/- 10; p less than 0.05). Increases of PCA paralleled protein levels in BAL and the protein/albumin ratios were comparable in the four groups. TFPI was significantly increased in PCP (p less than 0.02) and bacterial pneumonia (p less than 0.03), but only marginally increased in interstitial lung diseases when compared with controls. No correlation was found between TFPI and PCA in any of the four groups. These data indicate that increased procoagulant activity observed in various lung diseases is not counterbalanced by TFPI.

Topics: Adult; Aged; Blood Coagulation Factors; Bronchoalveolar Lavage Fluid; Factor VII; Female; Humans; Lipoproteins; Male; Middle Aged; Pneumonia; Pneumonia, Pneumocystis; Thromboplastin

Acute exposure of humans to 0.4 ppm ozone results in reversible respiratory function decrements, and cellular and biochemical changes leading to the production of substances which can mediate inflammation and acute lung injury. While pulmonary function decrements occur almost immediately after ozone exposure, it is not known how quickly the cellular and biochemical changes indicative of inflammation occur in humans. Changes in neutrophils and PGE2 have been observed in humans as early as 3 hr (28) and as late as 18 hr post exposure (19). The purpose of this study was to determine whether inflammatory changes occur relatively rapidly (within 1 hr) following exposure to ozone, or if the cascade of events which are initiated by ozone and lead to inflammation, take some time to develop. We exposed 10 healthy volunteers twice: once to filtered air and once to 0.4 ppm ozone. Each exposure lasted for 2 hr at an exercise level of 60 L/min, and bronchoalveolar lavage was performed 1 hr following exposure. The data from this study were compared to those from a previous study in which 10 subjects were exposed to O3 under identical conditions except that bronchoalveolar lavage was performed 18 hr following exposure. The results of the present study demonstrate that O3 is capable of inducing rapid cellular and biochemical changes in the lung. These changes were detectable as early as 1 hr following a 2 hr exposure of humans to ozone. The profiles of these changes were different at 1 hr and 18 hr following ozone exposures.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Bronchoalveolar Lavage Fluid; Dinoprostone; Humans; Interleukin-6; Male; Neutrophils; Ozone; Pneumonia; Thromboplastin; Time Factors

Experiments were carried out to examine relationships between alveolar macrophage maturity and amounts of tissue factor (Clotting Factor III) in these cells under physiologic conditions and during immunologically induced pneumonitis. Using discontinuous density gradient centrifugation, alveolar macrophages from healthy rabbits were rapidly isolated into five subpopulations at different stages of maturation, as demonstrated by morphologic and morphometric evaluation. Very large amounts of tissue factor activity were found in fully mature cells that were purified in the lowest density subpopulation and assayed without preliminary in vitro stimulation or culture. In the remaining four subpopulations of increasing density, amounts of tissue factor were found to progressively diminish in direct correlation with declines of cell maturity. These differences at mean levels were as great as 35-fold. In addition, blood monocytes had less than 1/219 and less than 1/6 of the activity of the fully mature and the least mature subpopulations, respectively. After 16 h culture of the five isolated subpopulations in the absence of lymphokines or of significant numbers of lymphocytes, tissue factor activity increased in inverse correlation with the preincubation stage of cell maturity (2,387 and 109% in the least mature and most mature subpopulations, respectively). These increases required protein synthesis and were accompanied by morphologic and morphometric changes which indicated cellular maturation during the period of tissue factor activity generation in vitro, thus further demonstrating relationships between macrophage maturity and tissue factor content. In additional experiments, direct correlations between cell maturity and tissue factor activity content were also found in activated alveolar macrophage populations from rabbits with Bacillus Calmette Guering (BCG)-induced granulomatous pneumonitis. However, as compared with controls, the BCG populations had increased total amounts of tissue factor activity due to the presence of large numbers of mature alveolar macrophage forms that had high levels of the procoagulant. Thus, tissue factor activity in alveolar macrophages is a marker of cellular maturation in vivo and in vitro. Increased amounts of this initiator of the extrinsic clotting pathway, as found in alveolar macrophage populations from animals with granulomatous pneumonitis induced by BCG hypersensitivity, suggest that alveolar macrophage tissue factor may

Topics: Animals; Cell Separation; Cells, Cultured; Female; Macrophages; Monocytes; Mycobacterium bovis; Pneumonia; Rabbits; Thromboplastin; Tuberculosis

Topics: Adult; Aged; Blood Coagulation; Chronic Disease; Female; Fibrinogen; Humans; Male; Middle Aged; Pneumonia; Thrombelastography; Thromboplastin

Topics: Animals; Ascariasis; Ascaris; Ascaris lumbricoides; Humans; Pneumonia; Sutures; Thromboplastin