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 PAR-2 on non-hematopoietic cells. FXa inhibition and PAR-2 deficiency on non-hematopoietic cells attenuated systemic inflammation, measured by plasma levels of IL-6. In contrast, neither thrombin inhibition nor PAR-1 deficiency on non-hematopoietic 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 non-hematopoietic cells. Furthermore, the TF-dependent increase in plasma levels of sVCAM-1 in sickle mice was not mediated by FXa or thrombin. Our data indicate that TF, FXa and thrombin differentially contribute to the vascular inflammation in a mouse model of SCD.