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Beyond antibiotics in severe community-acquired pneumonia: the role and rationale for tissue factor pathway inhibition.

Laterre PF - Crit Care (2008)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: St Luc University Hospital, Université Catholique de Louvain, UCL, 1200 Brussels, Belgium. Pierre-Francois.Laterre@uclouvain.be

ABSTRACT
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.

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TFPI anti-coagulant and anti-inflammatory activities. TFPI limits the conversion by the TF-FVIIa complex from factor X to Xa and thrombin formation, and thereby reduces proinflammatory intracellular signaling via PAR-1 and PAR-2 receptors. TFPI attaches the LPS-binding protein complex and alters the host responses to bacteria through interaction with TLRs and CD14. hegr-1, human early growth response protein-1; hGADD45, growth arrest and DNA damage inducible gene; hIL-6, human interleukin-6; hIL-8, human interleukin-8; hJunB, oncogene; hNOS, human nitric oxide synthase; JNK, Jun amino-terminal kinase; LPS, lipopolysaccharide; lyn, oncogene homolog, Src; MAPK, mitogen-activated protein kinases; PAK, p21-activated protein kinase; PAR, protease-activated receptor; Pl3 K, phosphatidylinositol-3-kinase; PKC, protein kinase C; PLCb, phospholipase Cβ; SAPK, stress-activated protein kinase; Smad, moderates activity of TGF-β ligands; TF, tissue factor; TFPI, tissue factor pathway inhibitor; TLR, Toll-like receptor; Yes, a tyrosine protein kinase.
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Figure 1: TFPI anti-coagulant and anti-inflammatory activities. TFPI limits the conversion by the TF-FVIIa complex from factor X to Xa and thrombin formation, and thereby reduces proinflammatory intracellular signaling via PAR-1 and PAR-2 receptors. TFPI attaches the LPS-binding protein complex and alters the host responses to bacteria through interaction with TLRs and CD14. hegr-1, human early growth response protein-1; hGADD45, growth arrest and DNA damage inducible gene; hIL-6, human interleukin-6; hIL-8, human interleukin-8; hJunB, oncogene; hNOS, human nitric oxide synthase; JNK, Jun amino-terminal kinase; LPS, lipopolysaccharide; lyn, oncogene homolog, Src; MAPK, mitogen-activated protein kinases; PAK, p21-activated protein kinase; PAR, protease-activated receptor; Pl3 K, phosphatidylinositol-3-kinase; PKC, protein kinase C; PLCb, phospholipase Cβ; SAPK, stress-activated protein kinase; Smad, moderates activity of TGF-β ligands; TF, tissue factor; TFPI, tissue factor pathway inhibitor; TLR, Toll-like receptor; Yes, a tyrosine protein kinase.

Mentions: TF pathway inhibitor (TFPI) is an endogenous molecule with both anti-inflammatory and anti-coagulant activities (Figure 1). However, in severe infection endogenous TFPI is overwhelmed by increased expression of TF [7]. Data from both animal models and from the clinic suggest that, in this setting, administration of recombinant TFPI (tifacogin) can reduce acute lung injury and improve prospects for survival.


Beyond antibiotics in severe community-acquired pneumonia: the role and rationale for tissue factor pathway inhibition.

Laterre PF - Crit Care (2008)

TFPI anti-coagulant and anti-inflammatory activities. TFPI limits the conversion by the TF-FVIIa complex from factor X to Xa and thrombin formation, and thereby reduces proinflammatory intracellular signaling via PAR-1 and PAR-2 receptors. TFPI attaches the LPS-binding protein complex and alters the host responses to bacteria through interaction with TLRs and CD14. hegr-1, human early growth response protein-1; hGADD45, growth arrest and DNA damage inducible gene; hIL-6, human interleukin-6; hIL-8, human interleukin-8; hJunB, oncogene; hNOS, human nitric oxide synthase; JNK, Jun amino-terminal kinase; LPS, lipopolysaccharide; lyn, oncogene homolog, Src; MAPK, mitogen-activated protein kinases; PAK, p21-activated protein kinase; PAR, protease-activated receptor; Pl3 K, phosphatidylinositol-3-kinase; PKC, protein kinase C; PLCb, phospholipase Cβ; SAPK, stress-activated protein kinase; Smad, moderates activity of TGF-β ligands; TF, tissue factor; TFPI, tissue factor pathway inhibitor; TLR, Toll-like receptor; Yes, a tyrosine protein kinase.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2607114&req=5

Figure 1: TFPI anti-coagulant and anti-inflammatory activities. TFPI limits the conversion by the TF-FVIIa complex from factor X to Xa and thrombin formation, and thereby reduces proinflammatory intracellular signaling via PAR-1 and PAR-2 receptors. TFPI attaches the LPS-binding protein complex and alters the host responses to bacteria through interaction with TLRs and CD14. hegr-1, human early growth response protein-1; hGADD45, growth arrest and DNA damage inducible gene; hIL-6, human interleukin-6; hIL-8, human interleukin-8; hJunB, oncogene; hNOS, human nitric oxide synthase; JNK, Jun amino-terminal kinase; LPS, lipopolysaccharide; lyn, oncogene homolog, Src; MAPK, mitogen-activated protein kinases; PAK, p21-activated protein kinase; PAR, protease-activated receptor; Pl3 K, phosphatidylinositol-3-kinase; PKC, protein kinase C; PLCb, phospholipase Cβ; SAPK, stress-activated protein kinase; Smad, moderates activity of TGF-β ligands; TF, tissue factor; TFPI, tissue factor pathway inhibitor; TLR, Toll-like receptor; Yes, a tyrosine protein kinase.
Mentions: TF pathway inhibitor (TFPI) is an endogenous molecule with both anti-inflammatory and anti-coagulant activities (Figure 1). However, in severe infection endogenous TFPI is overwhelmed by increased expression of TF [7]. Data from both animal models and from the clinic suggest that, in this setting, administration of recombinant TFPI (tifacogin) can reduce acute lung injury and improve prospects for survival.

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: St Luc University Hospital, Université Catholique de Louvain, UCL, 1200 Brussels, Belgium. Pierre-Francois.Laterre@uclouvain.be

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus