Treatment of Sepsis-Induced Acquired Protein C Deficiency Reverses Angiotensin-Converting Enzyme-2 Inhibition and Decreases Pulmonary Inflammatory Response (original) (raw)
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Activation of the protein C pathway in acute sepsis
Thrombosis Research, 1995
To obtain quantitative information on the in vivo activation of the protein C system during the acute phase of sepsis, several components of the protein C pathway were studied in 18 patients. Blood samples were obtained one day after diagnosis (day 1) and, in 11 patients, also on the fourth and tenth days after diagnosis (days 4 and 10). On day 1, patients showed laboratory signs of haemostatic alterations such as positive fibrinogen/fibrin degradation products, and increased thrombin:antithrombin-III (TAT) complex levels. Compared with the control group, patients on day 1 had significantly decreased (p c 0.001) antigenic protein C (69 ? 28 %) and protein C inhibitor (PCI) (33 + 22 %) whereas a significant increase in the levels of activated protein C (APC) complexed with a,-antitrypsin (alAT) (APC:a,AT, 26? 15 ng/mL) and APC:PCI complex (3.0 ? 2.0 ng/mL), and in the level of plasma kallikrein (KK) complexes with PC1 (KK:PCI) (31 t 22 ng/mL) was observed. There was a positive correlation between APC:a,AT and TAT complex levels (r=0.597, p=O.O09). In the follow-up a trend toward normal values in antigenic protein C and PCI, and in APC:PCI and KK:PCI complex levels was found. However, PC1 remained significantly decreased compared to normal values. C4b-binding protein, a,AT, and TAT and APC:a,AT complexes did not show any significant variations during the course of the disease, suggesting the contribution of the inflammatory and haemostatic responses, in spite of the good recovery of the patients. This study shows that in the course of sepsis, patients experience a generalized activation of the protein C pathway which was more prominent on day 1, resulting in the consumption of protein C and PC1 and in the increase of APC:inhibitor complexes. Moreover, these data provide further evidence that KK:PCI circulating complexes occur in vivo.
The protein C pathway and sepsis
Thrombosis Research, 2012
After the discovery of the key components of the protein C (PC) pathway a beneficial effect on survival of the infusion of activated protein C (APC) in animal models of sepsis was demonstrated, leading to the development of recombinant human activated protein C (rh-APC) as a therapeutic agent. It soon became clear that rather than the anticoagulant and profibrinolytic activities of APC, its anti-inflammatory and cytoprotective properties played a major role in the treatment of patients with severe sepsis. Such properties affect the response to inflammation of endothelial cells and leukocytes and are exerted through binding of APC to at least five receptors with intracellular signaling. The main APC protective mechanism involves binding of the Gladomain to the endothelial protein C receptor (EPCR) and cleavage of protease activated receptor 1 (PAR-1), eliciting suppression of proinflammatory cytokines synthesis and of intracellular proapoptotic pathways and activation of endothelial barrier properties. However, thrombin cleaves PAR-1 with much higher catalytic efficiency, followed by pro-inflammatory, pro-apoptotic and barrier disruptive intracellular signaling, and it is unclear how APC can exert a protective activity through the cleavage of PAR-1 when thrombin is also present in the same environment. Interestingly, in endothelial cell cultures, PAR-1 cleavage by thrombin results in anti-inflammatory and barrier protective signaling provided occupation of EPCR by the PC gla-domain, raising the possibility that the beneficial effects of rh-APC might be recapitulated in vivo by administration of h-PC zymogen to patients with severe sepsis. Recent reports of h-PC infusion in animal models of sepsis support this hypothesis.
Activated Protein C and Sepsis
Frontiers in Bioscience, 2006
Protein C is a plasma protease that when activated plays a central role in modulating the function of the vascular endothelium and its interface with the innate immune system. A recombinant form of human activated protein C (APC), drotrecogin alfa (activated), has shown efficacy in a ...
Role of human recombinant activated protein C and low dose corticosteroid therapy in sepsis
Indian Journal of Anaesthesia, 2010
Despite advances in modern medicine, sepsis remains a complex syndrome that has been associated with significant morbidity and mortality. Multiple organ failure associated with sepsis leads to high mortality and morbidity. About 28 – 50% deaths have been reported in patients with sepsis. The number of sepsis patients is increasing, with considerable burden on healthcare facilities. Various factors leading to a rise in the incidence of sepsis are (1) Improvement of diagnostic procedures (2) Increase in the number of immunocompromised patients taking treatment for various autoimmune disease, carcinomas, organ transplantation (3) Advances in intensive procedures (4) Nosocomial infections (5) Extensive use of antibiotics. With the better understanding of sepsis various modalities to modify pathophysiological response of septic patients have developed. Activated protein C and low-dose corticosteroid therapy have been tried in patients, with variable results.
2004
Recombinant human activated protein C (rhAPC) is a natural anticoagulant with potentially important anti-inflammatory properties. In humans with severe sepsis, rhAPC treatment reduces mortality, but mechanisms responsible have not been well characterized. Accumulation of activated neutrophils in the lungs and other organs during severe infection contributes to sepsis-induced organ dysfunction, including acute inflammatory lung injury. Because neutrophils express an APC receptor, we hypothesized that immunomodulatory effects of rhAPC occur, in part, via modulation of neutrophil responses. To examine this issue, we performed a double-blinded, placebo-controlled study of rhAPC in a human model of endotoxin-induced pulmonary inflammation. Administration of rhAPC significantly reduced leukocyte accumulation to the airspaces, independent of pulmonary cytokine or chemokine release. Neutrophils recovered from bronchoalveolar lavage fluid of volunteers receiving rhAPC demonstrated decreased chemotaxis ex vivo. Decreased neutrophil chemotaxis following exposure to rhAPC was confirmed in vitro. No differences were detected in gene expression, kinase activation , cytokine release, cell survival, or apoptosis of neutrophils recovered in the presence or absence of rhAPC. These studies demonstrate that rhAPC reduces both endotoxin-induced accumulation of leukocytes in the airspaces and neutrophil chemotaxis. These rhAPC-induced effects on neutrophil function may represent a mechanism by which rhAPC improves survival in patients with sepsis.
Shock, 2013
We tested the effects of activated protein C (APC) in macrovascular and microvascular beds within 60 min of treatment. Twelve patients treated with APC for severe sepsis were included. We assessed macrovascular reactivity by phenylephrine arterial dose response. Pharmacological modeling (EC 50 , E max , and Hill coefficient) and individual doseresponse curve were tested. Microvascular reactivity was tested with skin laser Doppler by using postocclusive reactive hyperemia with measurements of peak, time to peak (T max), time to half recovery (T1/2R), and myogenic and sympathetic tones. All measurements were done 30 min before, just before, and 30 and 60 min after APC infusion. Microvascular reactivity was also tested in eight healthy volunteers. In patients, arterial pressure did not increase significantly. However, 60 min after the beginning of APC infusion, reactivity to !-1 stimulation was improved: EC 50 decreased from 15.3 (0.9Y56) to 3.1 (1.0Y6.2) (P = 0.04), and 5 of 12 patients improved their dose-response curve. As for microcirculatory parameters, as early as 30 min after the beginning of APC infusion, postocclusive reactive hyperemia peak increased from 102 (40Y168) to 162 (35Y196) (P = 0.04), T max was shorter: 30 s (14Y52 s) versus 56 s (22Y83 s) (P = 0.03), and the T1/2R also decreased, from 72.4 s (41.9Y134.6 s) to 49.8 s (31.0Y129.8 s) (P = 0.02). Myogenic tone increased (P = 0.03), whereas sympathetic tone decreased (P = 0.03), and myogenic tone was lower than controls before but not after APC treatment. In conclusion, APC improves vascular reactivity both at macrocirculatory and microcirculatory levels very quickly, suggesting that this is not due to protein synthesis or anticoagulant effect. The myogenic properties of vessels could partly drive this effect.
A Comparative Study of the Protein C Pathway in Septic and Nonseptic Patients with Organ Failure
American Journal of Respiratory and Critical Care Medicine, 2007
Rationale: Severe sepsis is associated with an exacerbated procoagulant state with protein C (PC) system impairment. In contrast, the inflammatory and coagulation status of nonseptic patients with organ failure (OF) is less documented. Objectives: To compare coagulation activation, focusing on the PC system, and inflammatory status in septic and nonseptic patients with OF. Methods: Thirty patients with severe sepsis and 30 nonseptic patients were recruited at the onset of OF and compared with 30 matched healthy subjects. We performed an extensive analysis of the PC pathway, including plasma protein measurements and quantification of leukocyte expression of PC system receptors. In addition, we analyzed the inflammatory status, based on inflammation-related gene leukocyte expression. Measurements and Main Results: We observed coagulation activation, reflected by a similar increase in tissue factor mRNA expression, in the two patient groups when compared with the healthy subjects. Soluble thrombomodulin levels were higher in septic patients than in healthy control subjects, whereas PC, protein S, and soluble endothelial cell PC receptor levels were lower. Similar results were obtained in nonseptic patients with OF. Monocyte thrombomodulin overexpression, together with increased circulating levels of activated PC, suggests that the capacity for PC activation is at least partly preserved in both settings. No difference in the inflammatory profile was found between septic and nonseptic patients. Conclusions: The pathogenesis of OF in critical care patients is characterized by an overwhelming systemic inflammatory response and by exacerbated coagulation activation, independently of whether or not infection is the triggering event. Clinical trial registered with www.clinicaltrials.gov (NCT 00361725).
Activated protein C for the treatment of severe sepsis
Clinical Microbiology and Infection, 2009
In 2001, the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial demonstrated a 6.1% absolute decrease in mortality in patients with severe sepsis. Recombinant human activated protein C was subsequently licensed for use by both the US Food and Drug Administration and the European Medicines Evaluation Agency. There has been some controversy over aspects of the original study protocol, and subsequent trials have raised concerns about both the efficacy and the side effect profile of recombinant human activated protein C. Significant doubt remains as to the role of recombinant human activated protein C in the management of severe sepsis, and this review aims to summarize the evidence both for and against its use.