Background Drotrecogin alfa (activated), or recombinant human activated protein C, has antithrombotic, antiinflammatory, and profibrinolytic properties. In a previous study, drotrecogin alfa activated produced dose-dependent reductions in the levels of markers of coagulation and inflammation in patients with severe sepsis. In this phase 3 trial, we assessed whether treatment with drotrecogin alfa activated reduced the rate of death from any cause among patients with severe sepsis. Methods We conducted a randomized, double-blind, placebo-controlled, multicenter trial. Patients with systemic inflammation and organ failure due to acute infection were enrolled and assigned to receive an intravenous infusion of either placebo or drotrecogin alfa activated (24 μg per kilogram of body weight per hour) for a total duration of 96 hours. The prospectively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion. Patients were monitored for adverse events; changes i...

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Efficacy and safety of recombinant human activated protein C for severe sepsis.

In 2004, the first American Heart Association scientific statement on “Air Pollution and Cardiovascular Disease” concluded that exposure to particulate matter (PM) air pollution contributes to card...

https://cdr.lib.unc.edu/downloads/p2676x621

Particulate Matter Air Pollution and Cardiovascular Disease An Update to the Scientific Statement From the American Heart Association

To provide an update to “Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012”. A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.

https://link.springer.com/content/pdf/10.1007%2Fs00134-017-4683-6.pdf

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016

In the 1980s, exosomes were described as vesicles of endosomal origin secreted from reticulocytes. Interest increased around these extracellular vesicles, as they appeared to participate in several cellular processes. Exosomes bear proteins, lipids, and RNAs, mediating intercellular communication between different cell types in the body, and thus affecting normal and pathological conditions. Only recently, scientists acknowledged the difficulty of separating exosomes from other types of extracellular vesicles, which precludes a clear attribution of a particular function to the different types of secreted vesicles. To shed light into this complex but expanding field of science, this review focuses on the definition of exosomes and other secreted extracellular vesicles. Their biogenesis, their secretion, and their subsequent fate are discussed, as their functions rely on these important processes.

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Biogenesis, Secretion, and Intercellular Interactions of Exosomes and Other Extracellular Vesicles

Activated protein C (APC) is a serine protease with potent anticoagulant properties, which is formed in blood on the endothelium from an inactive precursor During normal haemostasis, APC limits clot formation by proteolytic inactivation of factors Va and VIIIa (ref 2) To do this efficiently the enzyme needs a nonenzymatic cofactor, protein S (ref 3) Recently it was found that the anticoagulant response to APC (APC resistance) was very weak in the plasma of 21% of unselected consecutive patients with thrombosis and about 50% of selected patients with a personal or family history of thrombosis; moreover, 5% of healthy individuals show APC resistance, which is associated with a sevenfold increase in the risk for deep vein thrombosis Here we demonstrate that the phenotype of APC resistance is associated with heterozygosity or homozygosity for a single point mutation in the factor V gene (at nucleotide position 1,691, G-->A substitution) which predicts the synthesis of a factor V molecule (FV Q506, or FV Leiden) that is not properly inactivated by APC The allelic frequency of the mutation in the Dutch population is approximately 2% and is at least tenfold higher than that of all other known genetic risk factors for thrombosis (protein C (ref 8), protein S (ref 9), antithrombin10 deficiency) together

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Mutation in blood coagulation factor V associated with resistance to activated protein C

Hyperinflammatory responses can lead to a variety of diseases, including sepsis. We now report that extracellular histones released in response to inflammatory challenge contribute to endothelial dysfunction, organ failure and death during sepsis. They can be targeted pharmacologically by antibody to histone or by activated protein C (APC). Antibody to histone reduced the mortality of mice in lipopolysaccharide (LPS), tumor necrosis factor (TNF) or cecal ligation and puncture models of sepsis. Extracellular histones are cytotoxic toward endothelium in vitro and are lethal in mice. In vivo, histone administration resulted in neutrophil margination, vacuolated endothelium, intra-alveolar hemorrhage and macro- and microvascular thrombosis. We detected histone in the circulation of baboons challenged with Escherichia coli, and the increase in histone levels was accompanied by the onset of renal dysfunction. APC cleaves histones and reduces their cytotoxicity. Co-infusion of APC with E. coli in baboons or histones in mice prevented lethality. Blockade of protein C activation exacerbated sublethal LPS challenge into lethality, which was reversed by treatment with antibody to histone. We conclude that extracellular histones are potential molecular targets for therapeutics for sepsis and other inflammatory diseases.

Extracellular histones are major mediators of death in sepsis

The roles of protein C and thrombomodulin in the regulation of blood coagulation.

The protein C anticoagulant pathway represents a newly described system for investigating the regulation of blood coagulation. A role for protein C in clinial thrombosis has been suggested by recent findings that patients with 50% normal levels of protein C are at rick of thrombosis and that protein C levels decrease markedly during intravascular coagulation. The data presented here suggest that deficiencics in protein S, thrombomodulin, or the platelet receptor for activated protein C might also result in a thrombotic tendency. The interplay among the cellular, vascular and humoral components in this system suggest that the protein C anticoagulant pathway may be perturbed by a variety of disease processes. Certainly, the system provides a new approach to investigate the molecular basis of thrombotic disease.

The role of protein C and thrombomodulin in the regulation of blood coagulation

Gram-negative septicemia elicits multiple abnormalities of the coagulation system. Although products of coagulation can lead to clot formation, thereby potentiating organ damage, recent work has shown that low concentrations of thrombin can protect animals from the shock state. Because these amounts of thrombin also lead to formation in vivo of the anticoagulant enzyme, activated protein C, we examined the role of protein C in modulation of Escherichia coli shock in baboons. First, we infused activated protein C and lethal concentrations of E. coli organisms, which prevented the coagulopathic, hepatotoxic, and lethal effects of E. coli. Second, using an antibody to protein C we blocked protein C activation in vivo to determine if this influenced the response to lethal and sublethal concentrations of E. coli organisms. Under these conditions the response to lethal concentrations of E. coli organisms was made more severe and the response to sublethal concentrations of E. coli was made lethal. The coagulopathic, hepatotoxic, and lethal responses in this latter case were prevented by infusion of exogenous protein C.

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Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon.

Inflammation initiates clotting, decreases the activity of natural anticoagulant mechanisms and impairs the fibrinolytic system. Inflammatory cytokines are the major mediators involved in coagulation activation. The natural anticoagulants function to dampen elevation of cytokine levels. Furthermore, components of the natural anticoagulant cascades, like thrombomodulin, minimise endothelial cell dysfunction by rendering the cells less responsive to inflammatory mediators, facilitate the neutralisation of some inflammatory mediators and decrease loss of endothelial barrier function. Hence, downregulation of anticoagulant pathways not only promotes thrombosis but also amplifies the inflammatory process. When the inflammation-coagulation interactions overwhelm the natural defence systems, catastrophic events occur, such as manifested in severe sepsis or inflammatory bowel disease.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2141.2005.05753.x

Charles T. Esmon

Papers

Extracellular histones are major mediators of death in sepsis

The roles of protein C and thrombomodulin in the regulation of blood coagulation.

The role of protein C and thrombomodulin in the regulation of blood coagulation

Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon.

The interactions between inflammation and coagulation