Increased venous thrombosis has been detected in C1 inhibitor (C1INH)-deficient mice, while contact pathway-initiated thrombin generation may be increased in both mice and people with hereditary angioedema (HAE) caused by C1 inhibitor efficiency (C1INH-HAE), according to a new study published in the journal Blood.

For the purpose of this study, the authors examined 19 patients with C1INH-HAE during remission and 20 age- and sex-matched healthy controls. They also used C1INH-deficient mice to further investigate the effect of C1INH deficiency on basal coagulation and thrombosis. Blood samples were collected from all human participants, as well as mice.

The researchers analyzed thrombin generation in human plasma and mouse whole blood and conducted mouse plasma assays and the IVC stenosis, carotid artery ferric chloride, and tail tip amputation bleeding models.

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According to the results, the plasma of patients with C1INH-HAE contained markers of increased contact pathway-mediated thrombin generation. The analysis of C1INH-deficient mice whole blood indicated increased contact pathway-mediated thrombin generation as well, while mouse models had notably increased baseline circulating levels of prothrombin fragment 1+2 and thrombin-antithrombin complexes.

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The tests also found enhanced venous thrombus formation in C1INH-deficient mice, but no evidence of increased thrombosis was discovered in their arterial blood. Moreover, purified human C1INH was able to normalize contact pathway-mediated thrombin generation and venous thrombosis in C1INH-deficient mice. 

“C1INH replacement therapy has been associated with a significant reduction in the incidence of venous thromboembolism in C1INH-HAE patients. It will be valuable to determine if newer therapies targeting plasma kallikrein and activated factor XII have similar protective effects on venous thrombosis,” Grover and colleagues noted.

Congenital C1INH deficiency, frequently associated with HAE, may result in failure to prevent excessive activation of the classical and lectin pathways of complement activation, excessive activation of the contact pathway of coagulation, and excessive plasma kallikrein activation.


Grover SP, Kawano T, Wan J, Tanratana P, et al. C1 inhibitor deficiency enhances contact pathway mediated activation of coagulation and venous thrombosisBlood. Published online January 26, 2023. doi:10.1182/blood.2022018849