Evaluation of the host response to endotoxemia of FVIII and FIX deficient mice

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)For several years, coagulation has been implicated in the pathogenesis of sepsis. However, results from clinical trials with natural anticoagulants, as well as studies with knock-out mice for specific coagulation factors yielded conflicting results on the role of coagulation in the pathogenesis of sepsis. The aim of this study was to evaluate the impact of severe The factor VIII: C (FVIII: C) and factor IX: C (FIX: C) deficiency on a lipopolysaccharide (LPS)-induced murine model of sepsis. FVIII: C and FIX: C deficient mice, and their haemostatic normal littermate controls were challenged with LPS, and several parameters of the host response were evaluated: seven-day survival experiments were performed using two dose levels of LPS; biochemical and histological markers of tissue damage, coagulation parameters, and pro-inflammatory cytokines were evaluated at baseline and after 3 h and 6 h after an injection of LPS. Severe FVIII and FIX deficiency were compatible with normal survival in experimental sepsis. In addition, LPS-induced tissue damage and coagulation activation were similar in FVIII or FIX deficient mice compared to their respective controls. A lower release of pro-inflammatory cytokines was observed in FIX but not in FVIII deficient mice. Severe FIX or FVIII deficiency does not protect mice from mortality or from tissue damage in the endotoxemia model, supporting the hypothesis that FVIII and FIX are not critical to the pathogenesis of experimental sepsis.175800807Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)FAPESP [2008/50729-9

Impairment of thrombin generation in the early phases of the host response of sepsis

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Purpose: The purpose was to investigate the presence of hypercoagulability in the very early phase of the host response to an infection in the clinical course of sepsis and septic shock. Material and Methods: Twenty-four patients with chemotherapy-associated febrile neutropenia were evaluated at baseline, at the time of fever onset, and 48 hours thereafter using the thrombin generation test, a more physiological and global assay of hemostasis. Results: The rate of thrombin generation was decreased and no signals of systemic hypercoagulability could be observed during the first 48 hours of sepsis. Moreover, patients that evolved to septic shock presented a more significant impairment in thrombin generation than those with noncomplicated sepsis. Conclusions: Patients with sepsis and febrile neutropenia present an impairment in thrombin generation from very early stages of their disease course. These results suggest that the procoagulant in vitro alterations described during sepsis do not necessarily translate into a clinically relevant systemic hypercoagulable state. These findings could help explain why treatment with systemic anticoagulants did not translate to clinical benefits in human sepsis and highlight the need for a better understanding of the hemostatic alterations in sepsis before new treatments targeting coagulation activation are developed. (C) 2014 Elsevier Inc. All rights reserved.2913136Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)FAPESP [2011/02829-7