Acute promyelocytic leukemia (APL) is associated with a severe and often fatal coagulopathy characterized by activation of coagulation followed by consumption of coagulation factors, hyperfibrinolysis, and thrombocytopenia. One of the major clinical challenges in these patients is early hemorrhagic death, particularly due to intracranial hemorrhage. We have recently developed two mouse models of APL that recapitulate key features observed in patients, including activation of coagulation, hyperfibrinolysis, thrombocytopenia, and bleeding. Specifically, the allograft model exhibits spontaneous intracranial hemorrhage like patients with APL. Using these models, we found that tissue factor (TF) contributes to coagulation activation in both models and promotes enhanced tail bleeding in the xenograft model.
Pathways of acute promyelocytic leukemia-associated bleeding. Tissue factor (TF) is a transmembrane protein and receptor for FVII/FVIIa. The TF/FVIIa complex triggers activation of coagulation. APL cells express high levels of TF which induces overactivation of coagulation that leads to consumption of coagulation factors. In addition, APL cells express both S100A10 (S100) and annexin A2 (AA2). They form a heterotetrameric complex that serves as a receptor for both tissue plasminogen activator (tPA) and plasminogen. APL cells also express urokinase plasminogen activator (uPA) and uPA receptor (uPAR). Both S100/AA2 and uPA/uPAR complexes cleave plasminogen to plasmin which degrades fibrin. Because of high expression of both S100/AA2 and uPA/uPAR complexes, APL induces hyperfibrinolysis. A recent study showed that APL cells express higher levels of podoplanin (PDPN) compared to AML cells. PDPN contributes to activation and consumption of platelets that can lead to bleeding in APL.
