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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, Vol. 141, No. 15, 13.04.2023, p. 1871-1883.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Sparkenbaugh, EM, Henderson, MW, Miller-Awe, MD, Abrams, C, Ilich, A, Trebak, F, Ramadas, N, Vital, SA, Bohinc, D, Bane, K, Chen, C, Patel, M, Wallisch, M, Renné, T, Gruber, A, Cooley, B, Gailani, D, Kasztan, M, Vercellotti, GM, Belcher, JD, Gavins, FNE, Stavrou, EX, Key, NS & Pawlinski, R 2023, 'Factor XII contributes to thrombotic complications and vaso-occlusion in sickle cell disease', BLOOD, vol. 141, no. 15, pp. 1871-1883. https://doi.org/10.1182/blood.2022017074

APA

Sparkenbaugh, E. M., Henderson, M. W., Miller-Awe, M. D., Abrams, C., Ilich, A., Trebak, F., Ramadas, N., Vital, S. A., Bohinc, D., Bane, K., Chen, C., Patel, M., Wallisch, M., Renné, T., Gruber, A., Cooley, B., Gailani, D., Kasztan, M., Vercellotti, G. M., ... Pawlinski, R. (2023). Factor XII contributes to thrombotic complications and vaso-occlusion in sickle cell disease. BLOOD, 141(15), 1871-1883. https://doi.org/10.1182/blood.2022017074

Vancouver

Sparkenbaugh EM, Henderson MW, Miller-Awe MD, Abrams C, Ilich A, Trebak F et al. Factor XII contributes to thrombotic complications and vaso-occlusion in sickle cell disease. BLOOD. 2023 Apr 13;141(15):1871-1883. https://doi.org/10.1182/blood.2022017074

Bibtex

@article{e32fde621de847a090ccbfb4c5422fa8,
title = "Factor XII contributes to thrombotic complications and vaso-occlusion in sickle cell disease",
abstract = "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.",
author = "Sparkenbaugh, {Erica M} and Henderson, {Michael W} and Miller-Awe, {Megan D} and Christina Abrams and Anton Ilich and Fatima Trebak and Nirupama Ramadas and Vital, {Shantel A} and Dillon Bohinc and Kara Bane and Chunsheng Chen and Margi Patel and Michael Wallisch and Thomas Renn{\'e} and Andras Gruber and Brian Cooley and David Gailani and Malgorzata Kasztan and Vercellotti, {Gregory M} and Belcher, {John D} and Gavins, {Felicity N E} and Stavrou, {Evi X} and Key, {Nigel S} and Rafal Pawlinski",
note = "Copyright {\textcopyright} 2023 American Society of Hematology.",
year = "2023",
month = apr,
day = "13",
doi = "10.1182/blood.2022017074",
language = "English",
volume = "141",
pages = "1871--1883",
journal = "BLOOD",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "15",

}

RIS

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 -