Sickle cell disease carries a significant risk of venous thrombosis, yet evidence suggests that anti-coagulant therapy increases the risk of bleeding in individuals with SCD. Coagulation FXII, which contributes to thrombosis but not hemostasis, is an appealing target for treating thrombosis without carrying a bleeding risk. Work led by Erica Sparkenbaugh and Rafal Pawlinski demonstrates that FXII contributes to thrombin generation and inflammation, venous thrombosis, ischemic brain injury, and vascular occlusion in a mouse model of SCD. This publication is also the first to show that the intrinsic and contact pathways of coagulation are activated in sickle cell patients, using ELISAs designed by Nigel Key, Anton Ilich, and Michael Henderson. Other BRC members who contributed to this work include Megan Miller-Awe, Christina Abrams, Fatima Trebak, and Nirupama Ramadas. We also contribute to a growing body of evidence demonstrating that zymogen FXII expressed by neutrophils contributes to disease processes.