Plasminogen Activator Inhibitor 1 Promotes a Poor Prognosis in Sepsis-Induced Disseminated Intravascular Coagulation

Madoiwa, Seiji; Nunomiya, Shin; Ono, Tomoko; Shintani, Yuichi; Ohmori, Tsukasa; Mimuro, Jun; Sakata, Yoichi

doi:10.1532/ijh97.05190

Cited by 112 publications

(93 citation statements)

References 38 publications

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“…Importantly, in patients with ventilator-associated pneumonia, it was recently shown that nonsurvivors showed significantly higher BALF levels of TATc and PAI-1 than survivors [24], and increased PAI-1 levels also correlated with mortality and adverse clinical outcome in patients from the ARDS-network study [25]. Similarly, higher systemic PAI-1 levels are associated with poor prognosis in septic patients [26]. Although the direct link between TATc and PAI-1 levels and mortality needs to be proven first, these data are very suggestive that MV strategies that promote coagulation and attenuate fibrinolysis may worsen prognosis.…”

Section: Discussionmentioning

confidence: 99%

Ventilator-induced coagulopathy in experimental Streptococcus pneumoniae pneumonia

Haitsma

Schultz²,

Hofstra³

et al. 2008

European Respiratory Journal

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Pneumonia, the main cause of acute lung injury, is characterised by a local proinflammatory response and coagulopathy. Mechanical ventilation (MV) is often required. However, MV can lead to additional injury: so-called ventilator-induced lung injury (VILI). Therefore, the current authors investigated the effect of VILI on alveolar fibrin turnover in Streptococcus pneumoniae pneumonia.Pneumonia was induced in rats, followed 48 h later by either lung-protective MV (lower tidal volumes (LVT) and positive end-expiratory pressure (PEEP)) or MV causing VILI (high tidal volumes (HVT) and zero end-expiratory pressure (ZEEP)) for 3 h. Nonventilated pneumonia rats and healthy rats served as controls. Thrombin-antithrombin complexes (TATc), as a measure for coagulation, and plasminogen activator activity, as a measure of fibrinolysis, were determined in bronchoalveolar lavage fluid (BALF) and serum.Pneumonia was characterised by local (BALF) activation of coagulation, resulting in elevated TATc levels and attenuation of fibrinolysis compared with healthy controls. LVT-PEEP did not influence alveolar coagulation or fibrinolysis. HVT-ZEEP did intensify the local procoagulant response: TATc levels rose significantly and levels of the main inhibitor of fibrinolysis, plasminogen activator inhibitor-1, increased significantly. HVT-ZEEP also resulted in systemic elevation of TATc compared with LVT-PEEP.Mechanical ventilation causing ventilator-induced lung injury increases pulmonary coagulopathy in an animal model of Streptococcus pneumoniae pneumonia and results in systemic coagulopathy.

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Section: Discussionmentioning

confidence: 99%

Ventilator-induced coagulopathy in experimental Streptococcus pneumoniae pneumonia

Haitsma

Schultz²,

Hofstra³

et al. 2008

European Respiratory Journal

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“…8,10,[14][15][16] Elevations in PAI-1 levels have been shown to correlate with disease severity and poor outcome in patients with sepsis. [38][39][40] Previous studies in which lipopolysaccharide was administered to human 41,42 or nonhuman 43 primates demonstrated that endotoxemia produces a temporary increase in tPA activity, and activation of fibrinolysis that is followed by a robust increase in PAI-1 levels that results in an antifibrinolytic state. Interestingly, activation of plasminogen by tPA and subsequent fibrinolytic activity in sepsis patients has been shown to remain ongoing despite increases in PAI-1 as determined by plasma levels of plasmin-α 2 -antiplasmin complexes and…”

Section: Discussionmentioning

confidence: 99%

Cell-Free DNA Modulates Clot Structure and Impairs Fibrinolysis in Sepsis

Gould

Stafford

et al. 2015

ATVB

134

144

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Objectives-Sepsis is characterized by systemic activation of inflammation and coagulation in response to infection. In sepsis, activated neutrophils extrude neutrophil extracellular traps composed of cell-free DNA (CFDNA) that not only trap pathogens but also provide a stimulus for clot formation. Although the effect of CFDNA on coagulation has been extensively studied, much less is known about the impact of CFDNA on fibrinolysis. To address this, we (1) investigated the relationship between CFDNA levels and fibrinolytic activity in sepsis and (2) determined the mechanisms by which CFDNA modulates fibrinolysis. Approach and Results-Plasma was collected from healthy and septic individuals, and CFDNA was quantified. Clot lysis assays were performed in plasma and purified systems, and lysis times were determined by monitoring absorbance. Clot morphology was assessed using scanning electron microscopy. Clots formed in plasma from septic patients containing >5 µg/mL CFDNA were dense in structure and resistant to fibrinolysis, a phenomenon overcome by deoxyribonuclease addition. These effects were recapitulated in control plasma supplemented with CFDNA. In a purified system, CFDNA delayed fibrinolysis but did not alter tissue-type plasminogen activator-induced plasmin generation. Using surface plasmon resonance, CFDNA bound plasmin with a K d value of 4.2±0.3 µmol/L, and increasing concentrations of CFDNA impaired plasmin-mediated degradation of fibrin clots via the formation of a nonproductive ternary complex between plasmin, CFDNA, and fibrin. Conclusions-Our studies suggest that the increased levels of CFDNA in sepsis impair fibrinolysis by inhibiting plasmin-mediated fibrin degradation, thereby identifying CFDNA as a potential therapeutic target for sepsis treatment. Gould et al DNA Impairs Fibrinolysis in Sepsis 2545patients increase thrombin generation by activating the intrinsic pathway of blood coagulation, 26 whereas DNA-histone complexes trigger platelet activation and aggregation by signaling through toll-like receptor-2 and toll-like receptor-4. [26][27][28] In addition, recent evidence suggests that fibrin, along with von Willebrand factor and chromatin, form a colocalized network within the thrombus that provides a scaffold for localized coagulation activation coupled with platelet and red blood cell adhesion, thereby promoting thrombus formation. 16,20,29 Although the contributions of CFDNA to coagulation activation and thrombus formation have been well characterized, studies on the influence of CFDNA on the fibrinolytic system are limited. NETs have previously been shown to intercalate with fibrin to form a structural network that is resistant to lysis by tissue-type plasminogen activator (tPA) or degradation by DNase. 20 Conversely, CFDNA has been shown to facilitate the recruitment of profibrinolytic enzymes, such as tPA, urokinase plasminogen activator, plasminogen, and plasmin, and their endogenous inhibitors, plasminogen activator inhibitor-1 (PAI-1) and α2-antiplasmin.30 Thus, although CFDNA may...

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“…Antithrombin III concentration has been proposed as a prognostic factor, as its levels are lower in septic patients who are not possible to survive. Low protein C levels in septic patient's blood are indicative of increased risk of morbidity and mortality (Zakariah et al, 2008, Madoiwa et al, 2006, Petilla et al, 2002, Fisher et al, 2000.…”

Section: Fig 2 Tnfa Activated Cellular Pathwaysmentioning

confidence: 99%