Factor XII contributes to thrombotic complications and vaso-occlusion in sickle cell disease

•FXII-mediated activation of the contact pathway is increased in mice and patients with SCD at steady state.•FXII contributes to thrombin generation, inflammation, vascular stasis, venous thrombosis, and ischemic brain injury in SCD mice. [Display omitted] A hypercoagulable state, chronic inflammati...

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Published in:	Blood 2023-04, Vol.141 (15), p.1871-1883
Main Authors:	Sparkenbaugh, Erica M., Henderson, Michael W., Miller-Awe, Megan, Abrams, Christina, Ilich, Anton, Trebak, Fatima, Ramadas, Nirupama, Vital, Shantel, Bohinc, Dillon, Bane, Kara L., Chen, Chunsheng, Patel, Margi, Wallisch, Michael, Renné, Thomas, Gruber, Andras, Cooley, Brian, Gailani, David, Kasztan, Malgorzata, Vercellotti, Gregory M., Belcher, John D., Gavins, Felicity E., Stavrou, Evi X., Key, Nigel S., Pawlinski, Rafal
Format:	Article
Language:	eng
Subjects:	Anemia, Sickle Cell - complications Anemia, Sickle Cell - metabolism Animals Factor XII - metabolism Inflammation Mice Stroke Thrombosis - metabolism
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Summary:	•FXII-mediated activation of the contact pathway is increased in mice and patients with SCD at steady state.•FXII contributes to thrombin generation, inflammation, vascular stasis, venous thrombosis, and ischemic brain injury in SCD mice. [Display omitted] A hypercoagulable state, chronic inflammation, and increased risk of venous thrombosis and stroke are prominent features in patients with sickle cell disease (SCD). Coagulation factor XII (FXII) triggers activation of the contact system that is known to be involved in both thrombosis and inflammation, but not in physiological hemostasis. Therefore, we investigated whether FXII contributes to the prothrombotic and inflammatory complications associated with SCD. We found that when compared with healthy controls, patients with SCD exhibit increased circulating biomarkers of FXII activation that are associated with increased activation of the contact pathway. We also found that FXII, but not tissue factor, contributes to enhanced thrombin generation and systemic inflammation observed in sickle cell mice challenged with tumor necrosis factor α. In addition, FXII inhibition significantly reduced experimental venous thrombosis, congestion, and microvascular stasis in a mouse model of SCD. Moreover, inhibition of FXII attenuated brain damage and reduced neutrophil adhesion to the brain vasculature of sickle cell mice after ischemia/reperfusion induced by transient middle cerebral artery occlusion. Finally, we found higher FXII, urokinase plasminogen activator receptor, and αMβ2 integrin expression in neutrophils of patients with SCD compared with healthy controls. Our data indicate that targeting FXII effectively reduces experimental thromboinflammation and vascular complications in a mouse model of SCD, suggesting that FXII inhibition may provide a safe approach for interference with inflammation, thrombotic complications, and vaso-occlusion in patients with SCD. Sparkenbaugh and colleagues investigated the role of factor XII (FXII) in sickle cell disease (SCD)-related thrombo-inflammation. Patients with SCD have increased markers of activation of FXII and the contact pathway of coagulation. In the Townes mouse model of SCD, FXII contributes to thrombin generation and inflammation after challenge with TNFα, and FXII inhibition reduces venous thrombosis, congestion, and microvascular stasis. FXII inhibition may offer a novel approach to reducing thrombo-inflammation in SCD without incurring increased bleeding ri
ISSN:	0006-4971 1528-0020