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. Further, 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 supported 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. Further, purified human C1INH normalized contact pathway-mediated
thrombin generation and venous thrombosis in C1INH-deficient mice. These findings
suggest 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.
