C1 inhibitor deficiency linked to thrombosis

Hereditary angioedema (HAE) was associated with an increased contact pathway-mediated coagulation and a heightened risk for venous thromboembolic events. Interestingly, C1 inhibitor-deficient mice displayed key aspects of the pro-coagulant phenotype that is associated with HAE, revealing the crucial role of this pathway.

“Congenital C1 inhibitor deficiency causes HAE,” stated Dr Steven Grover (University of North Carolina, NC, USA) [1,2]. An epidemiological study, clinical samples, and mouse models were used to assess whether C1 inhibitor deficiency increases contact pathway-mediated activation of coagulation and thrombosis.

The epidemiological study included 239 patients with HAE and 2,383 healthy controls from a Swedish registry [3]. The results showed that there was an increased risk for venous thromboembolic events for patients with HAE compared with healthy controls (OR 3.59; 95% CI 2.17–5.84; P<0.0001). For arterial thromboembolic events, no such association was observed (OR 1.30; 95% CI 0.81–2.09; P=0.28).

Next, the research team investigated the thrombin generation potential of the plasma of patients with HAE (n=19) and of healthy controls (n=20) through automated calibrated thrombography. Patients with severe HAE (C1 inhibitor activation <25%; n=10) had a reduced thrombin generation lag time and an increased thrombin generation peak compared with healthy controls. Dr Grover added that there was no difference in tissue factor-initiated thrombin generation, indicating that severe C1 inhibitor deficiency is associated with a selective enhancement of contact pathway-mediated thrombin generation.

Furthermore, in C1 inhibitor-deficient mice, the investigators found a significantly increased thrombin generation peak compared with control mice. Also, an enhanced risk for venous thrombus formation was observed in mice with severe C1 inhibitor deficiency. In line with the results of the epidemiological study, no such association was found for arterial thrombosis, therefore displaying consistency with the phenotype of HAE.

1. Grover S, et al. C1 Inhibitor Deficiency Results in Increased Activation of Coagulation and Enhanced Venous Thrombosis. Abstract 5, ASH 64^th Annual Meeting, 10–13 December 2022, New Orleans, LA, USA.
2. Davis AE, et al. Thromb Haemost. 2010;104(5):886–893.
3. Sundler Björkman L, et al. Clin Transl Allergy. 2022;12(3):e12135.

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Posted on 20 February, 2023