Factor XII contributes to thrombotic complications and vaso-occlusion in sickle cell disease
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Factor XII contributes to thrombotic complications and vaso-occlusion in sickle cell disease. / Sparkenbaugh, Erica M; Henderson, Michael W; Miller-Awe, Megan D; Abrams, Christina; Ilich, Anton; Trebak, Fatima; Ramadas, Nirupama; Vital, Shantel A; Bohinc, Dillon; Bane, Kara; Chen, Chunsheng; Patel, Margi; Wallisch, Michael; Renné, Thomas; Gruber, Andras; Cooley, Brian; Gailani, David; Kasztan, Malgorzata; Vercellotti, Gregory M; Belcher, John D; Gavins, Felicity N E; Stavrou, Evi X; Key, Nigel S; Pawlinski, Rafal.
in: BLOOD, Jahrgang 141, Nr. 15, 13.04.2023, S. 1871-1883.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Factor XII contributes to thrombotic complications and vaso-occlusion in sickle cell disease
AU - Sparkenbaugh, Erica M
AU - Henderson, Michael W
AU - Miller-Awe, Megan D
AU - Abrams, Christina
AU - Ilich, Anton
AU - Trebak, Fatima
AU - Ramadas, Nirupama
AU - Vital, Shantel A
AU - Bohinc, Dillon
AU - Bane, Kara
AU - Chen, Chunsheng
AU - Patel, Margi
AU - Wallisch, Michael
AU - Renné, Thomas
AU - Gruber, Andras
AU - Cooley, Brian
AU - Gailani, David
AU - Kasztan, Malgorzata
AU - Vercellotti, Gregory M
AU - Belcher, John D
AU - Gavins, Felicity N E
AU - Stavrou, Evi X
AU - Key, Nigel S
AU - Pawlinski, Rafal
N1 - Copyright © 2023 American Society of Hematology.
PY - 2023/4/13
Y1 - 2023/4/13
N2 - 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.
AB - 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.
U2 - 10.1182/blood.2022017074
DO - 10.1182/blood.2022017074
M3 - SCORING: Journal article
C2 - 36706361
VL - 141
SP - 1871
EP - 1883
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 15
ER -