Sickle cell disease (SCD) is caused by a single nucleotide mutation in the b-globin gene resulting in abnormal hemoglobin polymerization and formation of sickle red blood cells. Although vaso-occlusive crises and hemolytic anemia are the primary pathologies, SCD is also associated with chronic vascular inflammation and activation of coagulation. 1-3 This hypercoagulable state is characterized by increased tissue factor (TF) expression and elevated levels of thrombin generation measured by thrombin-antithrombin (TAT) complexes. 4 We have recently shown that short-term inhibition of all sources of TF in sickle mice attenuates activation of coagulation and reduces endothelial cell (EC) activation and systemic inflammation measured by plasma levels of soluble vascular cell adhesion molecule 1 (sVCAM-1) and interleukin-6 (IL-6), respectively. 3 Furthermore, SCD is 1 of a few pathological conditions in which increased TF expression is observed not only on leukocytes but also on ECs, 3, 5-7 in particular on the pulmonary endothelium. 8 Interestingly, we showed that EC-specific deletion of TF significantly attenuated plasma levels of IL-6, but had no effect on thrombin generation or EC activation. 3 This surprising result suggests that EC TF is primarily involved in inflammation rather than coagulation in SCD.

TF is constitutively expressed by perivascular cells surrounding blood vessels and parenchymal cells in certain organs. 9 During pathologic conditions that result in increased vascular permeability, this nonhematopoietic cellular source of TF will be exposed to circulating clotting factors and could activate the coagulation cascade, as we previously demonstrated in a mouse model of endotoxemia. 10 Because increased vascular permeability has been reported in mouse models of SCD, 11 we investigated if perivascular cell TF expression contributes to the activation of coagulation in sickle mice. To test this hypothesis, we used so-called “low TF mice” that are completely deficient in mouse TF but express human TF (mTF 2/2, hTF 1) from a transgene at about 1%