43
Intensive Care Med. 2012 Aug;38(8):1326-35.
Persistent hypocoagulability in patients with septic
shock predicts greater hospital mortality: impact of
impaired thrombin generation.
Massion PB, Peters P, Ledoux D, Zimermann V, Canivet JL, Massion PP, Damas P, Gothot A.
Abstract
PURPOSE:
Sepsis induces hypercoagulability, hypofbrinolysis, microthrombosis, and endothelial dysfunc-
tion leading to multiple organ failure. However, not all studies reported beneft from anti-
coagulation for patients with severe sepsis, and time courses of coagulation abnormalities in
septic shock are poorly documented. Therefore, the aim of this prospective observational
cohort study was to describe the coagulation profle of patients with septic shock and to
determine whether alterations of the profle are associated with hospital mortality.
METHODS:
Thirty-nine patients with septic shock on ICU admission were prospectively included in the
study. From admission to day 7, analytical coagulation tests, thrombin generation (TG) assays,
and thromboelastometric analyses were performed and tested for association with survival.
RESULTS:
Patients with septic shock presented on admission prolongation of prothrombin time, activa-
ted partial thromboplastin time (aPTT), increased consumption of most procoagulant factors
as well as both delay and defcit in TG, all compatible with a hypocoagulable state compared
with reference values (P < 0.001). Time courses revealed a persistent hypocoagulability pro-
fle in non-survivors as compared with survivors. From multiple logistic regression, prolonged
aPTT (P = 0.007) and persistence of TG defcit (P = 0.024) on day 3 were strong predictors of
mortality, independently from disease severity scores, disseminated intravascular coagulation
score, and standard coagulation tests on admission.
CONCLUSIONS:
Patients with septic shock present with hypocoagulability at the time of ICU admission.
Persistence of hypocoagulability assessed by prolonged aPTT and unresolving defcit in TG on
day 3 after onset of septic shock is associated with greater hospital mortality.
J Thromb Haemost. 2012 Mar;10(3):453-65.
ATP-gated P2X1 ion channels protect against
endotoxemia by dampening neutrophil activation.
Lecut C, Faccinetto C, Delierneux C, van Oerle R, Spronk HM, Evans RJ, El Benna J, Bours V,
Oury C.
Abstract
BACKGROUND:
In sepsis, extracellular ATP, secreted by activated platelets and leukocytes, may contribute to
the crosstalk between hemostasis and infammation. Previously, we showed that, in addition
to their role in platelet activation, ATP-gated P2X(1) ion channels are involved in promoting
neutrophil chemotaxis.
OBJECTIVES:
To elucidate the contribution of P2X(1) ion channels to sepsis and the associated disturbance
of hemostasis.
METHODS:
We used P2X(1) (-/-) mice in a model of lipopolysaccharide (LPS)-induced sepsis. Hemostasis
and infammation parameterswere analyzed togetherwith outcome. Mechanismswere further
studied ex vivo with mouse and human blood or isolated neutrophils and monocytes.
RESULTS:
P2X(1) (-/-)miceweremoresusceptibletoLPS-inducedshock thanwild-typemice, despitenor-
malcytokineproduction.Plasmalevelsofthrombin-antithrombincomplexeswerehigher,throm-
bocytopeniawasworsened, andwholebloodcoagulation timewasmarkedly reduced, pointing
to aggravated hemostasis disturbance in the absence of P2X(1). However, whole bloodplatelet
aggregation occurred normally, and P2X(1) (-/-) macrophages displayed normal levels of total
tissue factor activity. We found that P2X(1) (-/-) neutrophils produced higher amounts of
reactive oxygen species. Increased amounts of myeloperoxidase were released in the blood
of LPS-treated P2X(1) (-/-) mice, and circulating neutrophils and monocytes expressed higher
levels of CD11b. Neutrophil accumulation in the lungs was also signifcantly augmented, as
was lipid peroxidation in the liver. Desensitization of P2X(1) ion channels led to increased
activation of human neutrophils and enhanced formation of platelet-leukocyte aggregates.
CONCLUSIONS:
P2X(1) ion channels play a protective role in endotoxemia by negatively regulating systemic
neutrophil activation, thereby limiting the oxidative response, coagulation, and organ damage.