TY - JOUR
T1 - Thrombin-mediated activation of PAR-1 contributes to microvascular stasis in mouse models of sickle cell disease
AU - Sparkenbaugh, Erica M
AU - Chen, Chunsheng
AU - Brzoska, Tomasz
AU - Nguyen, Julia
AU - Wang, Shaobin
AU - Vercellotti, Gregory M
AU - Key, Nigel S
AU - Sundd, Prithu
AU - Belcher, John D
AU - Pawlinski, Rafal
N1 - Copyright © 2020 American Society of Hematology.
PY - 2020
Y1 - 2020
N2 - Vaso-occlusive crisis (VOC) is the primary cause of morbidity and hospitalization in sickle cell disease (SCD). However, only three therapies (hydroxyurea, L-glutamine, and crizanlizumab) are currently approved in SCD. These agents limit the duration, severity, and frequency of crises. Activation of coagulation is a hallmark of SCD. Studies in animal models of SCD have shown that coagulation contributes to the chronic inflammation and end-organ damage associated with the disease. However, it is unknown if coagulation directly contributes to the microvascular stasis that causes VOC. Herein, we demonstrate that inhibition of tissue factor (TF) and the downstream coagulation proteases, factor Xa and thrombin, significantly attenuates heme-induced microvascular stasis in mouse models of VOC. Pharmacologic inhibition of the principal thrombin receptor, protease activated receptor-1 (PAR-1) as well as deficiency of PAR-1 in all non-hematopoietic cells, also reduces stasis in sickle mice. PAR-1 deficiency was associated with reduced endothelial von Willebrand factor (vWF) expression, which has been shown to mediate microvascular stasis. In addition, TF inhibition reduces lung vaso-occlusion in sickle mice mediated by arteriolar neutrophil-platelet microemboli. In sum, these results suggest that prophylactic anticoagulation might attenuate the incidence of VOC.
AB - Vaso-occlusive crisis (VOC) is the primary cause of morbidity and hospitalization in sickle cell disease (SCD). However, only three therapies (hydroxyurea, L-glutamine, and crizanlizumab) are currently approved in SCD. These agents limit the duration, severity, and frequency of crises. Activation of coagulation is a hallmark of SCD. Studies in animal models of SCD have shown that coagulation contributes to the chronic inflammation and end-organ damage associated with the disease. However, it is unknown if coagulation directly contributes to the microvascular stasis that causes VOC. Herein, we demonstrate that inhibition of tissue factor (TF) and the downstream coagulation proteases, factor Xa and thrombin, significantly attenuates heme-induced microvascular stasis in mouse models of VOC. Pharmacologic inhibition of the principal thrombin receptor, protease activated receptor-1 (PAR-1) as well as deficiency of PAR-1 in all non-hematopoietic cells, also reduces stasis in sickle mice. PAR-1 deficiency was associated with reduced endothelial von Willebrand factor (vWF) expression, which has been shown to mediate microvascular stasis. In addition, TF inhibition reduces lung vaso-occlusion in sickle mice mediated by arteriolar neutrophil-platelet microemboli. In sum, these results suggest that prophylactic anticoagulation might attenuate the incidence of VOC.
U2 - 10.1182/blood.2019003543
DO - 10.1182/blood.2019003543
M3 - Article
C2 - 31977004
SN - 0006-4971
JO - Blood
JF - Blood
ER -