IntroductionEndothelial barrier breakdown is a hallmark of septic shock, and proteins that physiologically regulate endothelial barrier integrity are emerging as promising biomarkers of septic shock development. Patients with cancer and febrile neutropenia (FN) present a higher risk of sepsis complications, such as septic shock. Nonetheless, these patients are normally excluded or under-represented in sepsis biomarker studies. The aim of our study was to validate the measurement of a panel of microvascular permeability modulators as biomarkers of septic shock development in cancer patients with chemotherapy-associated FN.MethodsThis was a prospective study of diagnostic accuracy, performed in two distinct in-patient units of a university hospital. Levels of vascular endothelial growth factor A (VEGF-A), soluble fms-like tyrosine kinase-1 (sFlt-1) and angiopoietin (Ang) 1 and 2 were measured after the onset of neutropenic fever, in conditions designed to mimic the real-world use of a sepsis biomarker, based on our local practice. Patients were categorized based on the development of septic shock by 28 days as an outcome.ResultsA total of 99 consecutive patients were evaluated in the study, of which 20 developed septic shock and 79 were classified as non-complicated FN. VEGF-A and sFlt-1 levels were similar between both outcome groups. In contrast, Ang-2 concentrations were increased in patients with septic shock, whereas an inverse finding was observed for Ang-1, resulting in a higher Ang-2/Ang-1 ratio in patients with septic shock (5.29, range 0.58 to 57.14) compared to non-complicated FN (1.99, range 0.06 to 64.62; P = 0.01). After multivariate analysis, the Ang-2/Ang-1 ratio remained an independent factor for septic shock development and 28-day mortality.ConclusionsA high Ang-2/Ang-1 ratio can predict the development of septic shock in cancer patients with febrile neutropenia.
Heme has been characterized as potent trigger of inflammation. In hemostasis, although heme has been shown to both induce and inhibit different compartments of hemostasis, its net effect on the hemostatic balance, and the biological relevance of these effects remain to be determined. Herein we evaluated the effect of heme on hemostasis using a global assay able to generate clinically relevant data in several other complex hemostatic diseases. Citrated whole blood samples from healthy participants were stimulated by heme or vehicle and incubated for 4h at 37°C. Rotational thromboelastometry was immediately performed. The participation of tissue factor in coagulation activation was evaluated using inhibitory antibody. Heme was able of inducing ex vivo coagulation activation in whole blood, affecting predominantly parameters associated with the initial phases of clot formation. This activation effect was at least partially dependent on hematopoietic tissue factor, since the effects of heme were partially abrogated by the inhibition of human tissue factor. In conclusion, using a global hemostasis assay, our study confirmed that heme is able to activate coagulation in whole blood, in a tissue factor-dependent way. These findings could explain the disturbance in hemostatic balance observed in conditions associated with the release of heme such as sickle cell disease.
Introduction: It has been known for more than 50 years that patients with sickle cell disease (SCD) present higher plasma concentrations of heme. More recently, it was shown that heme is capable to activate innate immune response, and to trigger a toll-like receptor-dependent response that involves the expression of several pro-inflammatory genes. Accordingly, the role of heme as critical inflammatory mediator in SCD has been confirmed in different experimental models, suggesting that heme can be a trigger for microvascular occlusion and acute chest syndrome (ACS). The association between innate immune response and coagulation activation dates back to 450 million years in evolution, so that activation of the former is frequently accompanied by activation of the latter. Micro and macrovascular thrombosis are a hallmark of SCD, and the role of heme in the pathogenesis of these events has been recently suggested by demonstrations of heme-induced expression of tissue factor (TF) by endothelial cells and monocytes. However, the functional relevance of heme-induced TF expression on clinically-relevant coagulation markers has not been demonstrated. Methods: herein we evaluated heme-induced TF expression in peripheral blood mononuclear cells (PBMC), and used two different global assays of hemostasis, namely thromboelastometry (TEM) and Thrombin Generation Test (TGT) to evaluate the effect of heme on coagulation activation. Blood from healthy volunteers was drawn from an antecubital vein with minimal stasis in 0.106 sodium citrate tubes (1:10) or heparin. TEM was performed in whole-blood samples (n=10) incubated with 30 µM heme (Sigma-Aldrich) for four hours at 37oC, in a ROTEM equipment (Pentapharm). Coagulation was activated with the addition of CaCl2. Samples from same individuals incubated with vehicle were assayed concomitantly as controls (n=10). TGT was performed in double centrifuged plasma samples, separated from whole blood stimulated with heme or vehicle under the same conditions (n=16). TGT was performed using a Fluoroskan Ascent Flourimeter (Thermolab). Coagulation was activated with TF (5pM) and phospholipids (PPP reagent, Thrombinoscope). Expression of TF was evaluated by qRT-PCR. Heparin-anticoagulated blood was incubated with 30 µM heme (n=6) or vehicle (n=6) for 24 hours. PBMC and neutrophils were then separated by density gradient centrifugation (Ficoll). Non-parametric statistics were used in all analysis. Results: incubation of whole blood with heme 30 µM resulted in a potent induction of TF expression in PBMC compared to vehicle (AU)(0.03±0.06 vs 1.18±0.60; P=0.03). No TF expression could be detected in neutrophils. Heme-induced coagulation activation could be demonstrated by TEM. Heme significantly decreased the coagulation time (sec) (562.1±88.2 to 387±84.3; P=0.002) and the MaxV-t (time to maximum velocity) (651.4±119.2 to 451.1±87.4; P=0.002), which are two indicators of shift towards a hypercoagulable profile. A trend towards a lower clot formation time was also observed (P=0.07). No difference could be observed in the area under the TEM curve. A hypercoagulable profile was also observed in TGT in samples incubated with heme. Statistically significant changes compatible with a shift towards coagulation activation were observed in parameters such as peak thrombin (increased), time to peak thrombin (decreased), velocity index (increased), lagtime (decreased) and StarTail (decreased) (all P<0.05). No statistically significant change could be observed in the endogenous thrombin potential parameter (p=0.10). Discussion and conclusions: TEM and TGT are global hemostasis assays, widely used for evaluation of hypo- and hypercoagulable states. Both methods have been used in patients with SCD, who present hypercoagulable profiles similar to those obtained in our study, and characterized by faster onset and offset of coagulation activation. We demonstrate for the first time that heme, in concentrations similar to those observed in patients with SCD and other hemolytic disorders, is capable to not only stimulate the expression of TF by PBMC, but also to shift the coagulation balance towards a hypercoagulable state, similar to that observed in patients with SCD. These results provide additional support to the hypothesis that heme is a key mediator micro- and macrovascular thrombosis in SCD and possibly, in other hemolytic disorders. Disclosures No relevant conflicts of interest to declare.
Background: We hypothesized that one single episode of acute kidney injury (AKI) reduces long-term survival compared with no acute kidney injury (No AKI) following recovery from critical illness. Materials and methods: A prospective cohort of 2,010 patients admitted to the ICU between 2000 and 2009 at a provincial referral hospital was followed to determine whether AKI influences long-term survival. Results: Of the 1,844 eligible patients, 18.4% had AKI stage 1, 12.1% had stage 2, 26.5% had stage 3, and 43.0% had No AKI, using the KDIGO classification. The mean and median follow-up time was 8.1 and 8.7 years. The 28-day, 1-year, 5-year and 10-year survival rates were 59.6%, 44.9%, 37.4%, and 33.4%, in patients with any AKI (stage 1, stage 2, stage 3), which was significantly worse compared with the critically ill patients with no AKI at any time (P < 0.01). The adjusted 10-year mortality risk associated with AKI was 1.44 (95% CI = 1.2 to 1.7) among 28-day survivors. Patients who had mild AKI (stage 1) had significantly worse survival at 28 days, 1 year, 3 years, 5 years and 10 years compared with No AKI (P < 0.01) (Figure 1A). Patients with sepsis and AKI who survived 28 days had significantly poorer 5-year and 10-year survival compared with nonseptic AKI (P < 0.01) (Figure 1B). Conclusions: Patients with one episode of mild (stage 1) AKI have significantly lower survival rates over 10 years than critically ill patients without AKI. The causes and mechanisms of this association warrant further careful study. Close medical follow-up of these patients may be warranted and mechanistic research required understanding how AKI influences distant events.
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