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Title: Differential contribution of FXa and thrombin to vascular inflammation in a mouse model of sickle cell disease
Authors: Erica M. Sparkenbaugh
Pichika Chantrathammachart
Jacqueline Mickelson
Joanne Van Ryn
Robert P. Hebbel
Dougald M. Monroe
Nigel Mackman
Nigel S. Key
Rafal Pawlinski
The University of North Carolina at Chapel Hill
Mahidol University
Boehringer Ingelheim Pharma GmbH & Co. KG
University of Minnesota Medical School
Keywords: Biochemistry, Genetics and Molecular Biology;Immunology and Microbiology;Medicine
Issue Date: 13-Mar-2014
Citation: Blood. Vol.123, No.11 (2014), 1747-1756
Abstract: Activation of coagulation and vascular inflammation are prominent features of sickle cell disease (SCD). Previously, we have shown that inhibition of tissue factor (TF) attenuates activation of coagulation and vascular inflammation in mouse models of SCD. In this study, we examined the mechanism by which coagulation proteases enhance vascular inflammation in sickle BERK mice. To specifically investigate the contribution of FXa and thrombin, mice were fed chow containing either rivaroxaban or dabigatran, respectively. In addition, we used bone marrow transplantation to generate sickle mice deficient in either protease activated receptor-1 (PAR-1) or protease activated receptor-2 (PAR-2) on nonhematopoietic cells. FXa inhibition and PAR-2 deficiency in nonhematopoietic cells attenuated systemic inflammation, measured by plasma levels of interleukin-6 (IL-6). In contrast, neither thrombin inhibition nor PAR-1 deficiency in nonhematopoietic cells affected plasma levels of IL-6 in sickle mice. However, thrombin did contribute to neutrophil infiltration in the lung, independently of PAR-1 expressed by nonhematopoietic cells. Furthermore, the TF-dependent increase in plasma levels of soluble vascular cell adhesion molecule-1 in sickle mice was not mediated by FXa or thrombin. Our data indicate that TF, FXa, and thrombin differentially contribute to vascular inflammation in a mouse model of SCD. © 2014 by The American Society of Hematology.
ISSN: 15280020
Appears in Collections:Scopus 2011-2015

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