Local activation of the tissue factor-factor VIIa pathway in patients with pneumonia and the effect of inhibition of this pathway in murine pneumococcal pneumonia*

Rijneveld, Anita W.; Weijer, Sebastiaan; Bresser, Paul; Florquin, Sandrine; Vlasuk, George P.; Rote, William E.; Spek, C. Arnold; Reitsma, Pieter H.; Zee, Jaring S. van der; Levi, Marcel; Poll, Tom van der

doi:10.1097/01.ccm.0000218807.20570.c2

Cited by 73 publications

(103 citation statements)

References 41 publications

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“…43 We also note that others have reported a "paradoxically" increased granulocyte accumulation in the lung of mice with reduced hematopoietic TF expression 44 (which would be consistent with the enhancing effect of reduced Irf8 expression on granulopoiesis 38,45 ), whereas pharmacologic targeting of the ternary TF-VIIa-Xa complex with NapC2 (which blocks TF-initiated coagulation activation, but preserves TF-EPCR-PAR2 signaling, as shown in Figure 3C-D) had no such effects. 46,47 The described contributions of TF, EPCR, and PAR2 to the normal integration of TLR4-and interferon-regulated gene expression extend the biological rationale for the mechanistic coupling of inflammation and TF-mediated coagulation activation. Traumatic inflammatory states.…”

Section: Discussionmentioning

confidence: 99%

EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice

Liang

Kerschen

Hernández

et al. 2015

Blood

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Infection and inflammation are invariably associated with activation of the blood coagulation mechanism, secondary to the inflammation-induced expression of the coagulation initiator tissue factor (TF) on innate immune cells. By investigating the role of cell-surface receptors for coagulation factors in mouse endotoxemia, we found that the protein C receptor (ProcR; EPCR) was required for the normal in vivo and in vitro induction of lipopolysaccharide (LPS)-regulated gene expression. In cultured bone marrowderived myeloid cells and in monocytic RAW264.7 cells, the LPS-induced expression of functionally active TF, assembly of the ternary TF-VIIa-Xa initiation complex of blood coagulation, and the EPCR-dependent activation of protease-activated receptor 2 (PAR2) by the ternary TF-VIIa-Xa complex were required for the normal LPS induction of messenger RNAs encoding the TLR3/4 signaling adaptor protein Pellino-1 and the transcription factor interferon regulatory factor 8. In response to in vivo challenge with LPS, mice lacking EPCR or PAR2 failed to fully initiate an interferon-regulated gene expression program that included the Irf8 target genes Lif, Iigp1, Gbp2, Gbp3, and Gbp6. The inflammation-induced expression of TF and crosstalk with EPCR, PAR2, and TLR4 therefore appear necessary for the normal evolution of interferon-regulated host responses. (Blood. 2015;125(18):2845-2854

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Section: Discussionmentioning

confidence: 99%

EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice

Liang

Kerschen

Hernández

et al. 2015

Blood

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“…We measured circulating levels of a select group of coagulation markers thought to be important in the coagulation response to infection (28,(37)(38)(39). In addition to the changes we observed, changes may well occur at the local level (31,40) or within other coagulation system components or factors that are not reflected in our selection of biomarkers.…”

Section: Discussionmentioning

confidence: 99%

“…Local activation of the coagulation system is known to occur in pneumonia, with fibrin deposition in the alveolar compartment helping to contain infection but also enhancing vascular permeability, stimulating proinflammatory cytokines, and promoting neutrophil accumulation (31). This local coagulation activation appears to be driven primarily by tissue factor (32).…”

Section: Discussionmentioning

confidence: 99%

Prevalence and Significance of Coagulation Abnormalities in Community-Acquired Pneumonia

Milbrandt

Reade

Lee

et al. 2009

Mol Med

126

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Coagulation abnormalities are common in severe pneumonia and sepsis, yet little is known about the presence of coagulopathy or its significance in patients with lesser illness severity. We examined coagulation abnormalities in 939 subjects hospitalized with community-acquired pneumonia (CAP) in 28 US hospitals, hypothesizing that abnormalities would increase with illness severity and poor outcomes. We measured plasma coagulation markers (D-dimer, plasminogen activator inhibitor [PAI], antithrombin, factor IX, and thrombin-antithrombin complex [TAT]) at the time of patient presentation to the emergency department and daily during the first wk of hospitalization. Day-1 clinical laboratory test results for international normalized ratio, activated partial thromboplastin time, and platelet count were recorded from the medical record. In our cohort, 32.5% of patients developed severe sepsis and 11.1% died by d 90. Day-1 coagulation abnormalities were common, especially for D-dimer (80.6%) and TAT (36.0%), and increased with illness severity and poor outcomes. However, abnormalities also occurred in those patients who never developed organ dysfunction and differences between groups were modest. The proportion of patients with abnormalities changed over time, yet the magnitude of change was small and not always in the direction of normality. Many patients remaining in the hospital continued to manifest coagulation abnormalities on d 7, especially for D-dimer (86.5%) and TAT (36.9%). In conclusion, coagulation abnormalities were common and persistent in CAP patients, even among the least ill. These findings underscore the complexity of the coagulation response to infection and may offer insights into coagulation-based therapeutics in clinical sepsis trials.

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“…Earlier it has been demonstrated that pulmonary coagulopathy is an important feature of pulmonary infection (38,39), with changes in fibrin generation being restricted to the site of infection in patients with community-acquired pneumonia caused by S. pneumoniae (46) or ventilator-associated pneumonia caused by several pathogens, among others P. aeruginosa (47,48). Pulmonary coagulopathy now gains more and more interest as a new target in therapeutic studies of acute lung injury of pneumonia (49)(50)(51).…”

Section: Discussionmentioning

confidence: 99%

Platelet-Activating Factor Receptor Contributes to Host Defense against Pseudomonas aeruginosa Pneumonia but Is Not Essential for the Accompanying Inflammatory and Procoagulant Response

Zoelen

Florquin²,

Meijers

et al. 2008

The Journal of Immunology

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Pseudomonas aeruginosa is a major cause of nosocomial pneumonia, which is associated with high morbidity and mortality. Because of its ubiquitous nature and its ability to develop resistance to antibiotics, it is a problematic pathogen from a treatment perspective. Platelet-activating factor receptor (PAFR) is involved in phagocytosis of several pathogens. To determine the role of PAFR in the innate immune response to P. aeruginosa pneumonia, pafr gene-deficient (PAFR−/−) mice and normal wild-type (Wt) mice were intranasally inoculated with P. aeruginosa. PAFR deficiency impaired host defense as reflected by increased bacterial outgrowth and dissemination in mice with a targeted deletion of the PAFR gene. PAFR−/− neutrophils showed a diminished phagocytosing capacity of P. aeruginosa in vitro. Relative to Wt mice, PAFR−/− mice demonstrated increased lung inflammation and injury as reflected by histopathology, relative lung weights and total protein concentrations in bronchoalveolar lavage fluid, which was accompanied by higher levels of proinflammatory cytokines in lung homogenates and plasma. In addition, PAFR deficiency was associated with exaggerated local and systemic activation of coagulation as determined by fibrin staining of lung tissue and pulmonary and plasma concentrations of thrombin-antithrombin complexes and D-dimer. These data suggest that PAFR is an essential component of an effective host response to P. aeruginosa pneumonia, at least partly via its contribution to the phagocytic properties of professional granulocytes. Additionally, our results indicate that PAFR signaling is not essential for the induction of a local and systemic inflammatory and procoagulant response to Pseudomonas pneumonia.

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Local activation of the tissue factor-factor VIIa pathway in patients with pneumonia and the effect of inhibition of this pathway in murine pneumococcal pneumonia*

Abstract: These data suggest that TF-FVIIa activity contributes to activation of coagulation in the lung during pneumococcal pneumonia but does not play an important role in the antibacterial host defense in this murine model.

Cited by 73 publications

References 41 publications

EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice

EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice

Prevalence and Significance of Coagulation Abnormalities in Community-Acquired Pneumonia

Platelet-Activating Factor Receptor Contributes to Host Defense against Pseudomonas aeruginosa Pneumonia but Is Not Essential for the Accompanying Inflammatory and Procoagulant Response

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