C1 inhibitor deficiency enhances contact pathway–mediated activation of coagulation and venous thrombosis
Issued Date
2023-05-11
Resource Type
ISSN
00064971
eISSN
15280020
Scopus ID
2-s2.0-85152410055
Pubmed ID
36701760
Journal Title
Blood
Volume
141
Issue
19
Start Page
2390
End Page
2401
Rights Holder(s)
SCOPUS
Bibliographic Citation
Blood Vol.141 No.19 (2023) , 2390-2401
Suggested Citation
Grover S.P., Kawano T., Wan J., Tanratana P., Polai Z., Shim Y.J., Snir O., Brækkan S., Dhrolia S., Kasthuri R.R., Bendapudi P.K., McCrae K.R., Wolberg A.S., Hansen J.B., Farkas H., Mackman N. C1 inhibitor deficiency enhances contact pathway–mediated activation of coagulation and venous thrombosis. Blood Vol.141 No.19 (2023) , 2390-2401. 2401. doi:10.1182/blood.2022018849 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/81593
Title
C1 inhibitor deficiency enhances contact pathway–mediated activation of coagulation and venous thrombosis
Other Contributor(s)
Abstract
C1 inhibitor (C1INH) is a multifunctional serine protease inhibitor that functions as a major negative regulator of several biological pathways, including the contact pathway of blood coagulation. In humans, congenital C1INH deficiency results in a rare episodic bradykinin-mediated swelling disorder called hereditary angioedema (HAE). Patients with C1INH deficiency–associated HAE (C1INH-HAE) have increased circulating markers of activation of coagulation. Furthermore, we recently reported that patients with C1INH-HAE had a moderate but significant increased risk of venous thromboembolism. To further investigate the impact of C1INH deficiency on activation of coagulation and thrombosis, we conducted studies using patient samples and mouse models. Plasmas from patients with C1INH-HAE had significantly increased contact pathway–mediated thrombin generation. C1INH-deficient mice, which have been used as a model of C1INH-HAE, had significantly increased baseline circulating levels of prothrombin fragment 1+2 and thrombin-antithrombin complexes. In addition, whole blood from C1INH-deficient mice supported significantly increased contact pathway–mediated thrombin generation. Importantly, C1INH-deficient mice exhibited significantly enhanced venous, but not arterial, thrombus formation. Furthermore, purified human C1INH normalized contact pathway–mediated thrombin generation and venous thrombosis in C1INH-deficient mice. These findings highlight a key role for endogenous C1INH as a negative regulator of contact pathway–mediated coagulation in humans and mice. Further, this work identifies endogenous C1INH as an important negative regulator of venous thrombus formation in mice, complementing the phenotype associated with C1INH-HAE.