1. Factor XII contributes to thrombotic complications and vaso-occlusion in sickle cell disease
- Author
-
Erica M. Sparkenbaugh, Michael W. Henderson, Megan Miller-Awe, Christina Abrams, Anton Ilich, Fatima Trebak, Nirupama Ramadas, Shantel Vital, Dillon Bohinc, Kara L. Bane, Chunsheng Chen, Margi Patel, Michael Wallisch, Thomas Renné, Andras Gruber, Brian Cooley, David Gailani, Malgorzata Kasztan, Gregory M. Vercellotti, John D. Belcher, Felicity E. Gavins, Evi X. Stavrou, Nigel S. Key, and Rafal Pawlinski
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Data are available on request from the corresponding author, R. Pawlinski (rafal_pawlinski@med.unc.edu). The online version of this article contains a data supplement. The American Society of Hematology 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. This work was funded in part by National Institutes of Health (NIH) R01s HL142604 (RP), HL157441 (RP, NK) and NIH U01 HL117659 (RP, NK). EMS is supported by NIH R01 HL 155193. MK was supported by R00HL144817 from NHLBI and UAB AMC21 MULTIPI6724 grant. GMV and JDB were supported by research funding from NIH 5R01 HL114567. TR acknowledges Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) grants P6 - KFO306, 80750187 - SFB841 and 470698011 -SFB877. DG was supported by NIH R35 HL140025. FG was supported by Royal Society Wolfson Foundation (RSWF\R3\183001). AG and MW were supported by NIH R44 HL126235. This work was supported by the NIH R01 HL137695 (E.X.S.), Merit Review Awards BX003851 (E.X.S.) and the Oscar D. Ratnoff Endowed Professorship (E.X.S.). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH, the U.S. Department of Veterans Affairs, or the United States Government.
- Published
- 2023