Publication: Differential contribution of FXa and thrombin to vascular inflammation in a mouse model of sickle cell disease
2
Issued Date
2014-03-13
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ISSN
15280020
00064971
00064971
Other identifier(s)
2-s2.0-84897481862
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Mahidol University
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SCOPUS
Bibliographic Citation
Blood. Vol.123, No.11 (2014), 1747-1756
Suggested Citation
Erica M. Sparkenbaugh, Pichika Chantrathammachart, Jacqueline Mickelson, Joanne Van Ryn, Robert P. Hebbel, Dougald M. Monroe, Nigel Mackman, Nigel S. Key, Rafal Pawlinski Differential contribution of FXa and thrombin to vascular inflammation in a mouse model of sickle cell disease. Blood. Vol.123, No.11 (2014), 1747-1756. doi:10.1182/blood-2013-08-523936 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/33286
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Title
Differential contribution of FXa and thrombin to vascular inflammation in a mouse model of sickle cell disease
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.