Tissue factor activates coagulation in mouse models of acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is associated with a high risk of bleeding and thrombosis. The coagulopathy involves activation of coagulation, hyperfibrinolysis and thrombocytopenia. APL cells express tissue factor (TF), which is the receptor and cofactor for factor VII/VIIa. This study had two goals. First, we measured biomarkers of activation of coagulation and fibrinolysis as well as platelet counts and bleeding in both mouse xenograft and allograft models of APL. Second, we determined the effect of inhibiting TF on the activation of coagulation in these models. We observed increased levels of plasma thrombin-antithrombin complexes (TAT), D-dimer, plasmin-antiplasmin complexes, reduced platelet counts and increased tail bleeding in both mouse models of APL. Fibrinogen levels were decreased in the xenograft model but not in the allograft model. In contrast, the red blood cell count was decreased in the allograft model but not in the xenograft model. Inhibition of APL-derived human TF with an anti-human TF monoclonal antibody reduced levels of TAT, increased the platelet count and normalized tail bleeding in the xenograft model. Inhibition of all sources of TF (APL cells and host cells) in the allograft model with a rat anti-mouse TF monoclonal antibody decreased levels of TAT but did not affect the platelet count. Our study demonstrated that TF plays a central role in the activation of coagulation in both the xenograft and allograft mouse models. These mouse models of APL can be used to investigate the mechanisms of coagulopathy in APL.