C1-inhibitor and Venous Thrombosis
Serine protease inhibitors (SERPINs) are a large family of glycoproteins that inhibit serine proteases. SERPINs act as molecular bait containing a sequence of amino acids in the N-terminal reactive center loop recognized by target serine proteases. In the process of attempting to cleave a SERPIN the target protease undergoes a rapid conformational change resulting in loss of proteolytic activity and formation of a stable SERPIN:protease complex. A subset of SERPINs demonstrate anticoagulant activity by binding to and inhibiting serine proteases in the coagulation cascade . These anticoagulant SERPINs include antithrombin, heparin cofactor II, protein z dependent protease inhibitor, protease nexin I and of particular interest to our research C1-inhibitor.
Hereditary Angioedema and venous thromboembolism
Hereditary Angioedema (HAE) is a rare genetic disease primarily caused by mutations in the SERPING1 gene that encodes C1-inhibitor resulting in a deficiency in this SERPIN. Patients with HAE suffer from episodes of bradykinin induced swelling that can lead to fatal asphyxiation when involving the larynx. HAE has also been associated with a procoagulant state. Compared to healthy controls patients with HAE have increased plasma markers of activation of coagulation including thrombin-antithrombin complexes and D-dimer. These markers of activation of coagulation have been independently associated with an increased risk of venous thromboembolism. In a case control study we have found that patients with HAE caused by C1-inhibitor deficiency have a significantly increased risk of venous thromboembolism compared to healthy controls . We have also found that plasma from patients with HAE supports significantly increased contact pathway-initiated thrombin generation compared to plasma from healthy controls . These finding suggests that the clinical manifestations of HAE extend beyond the classical presentation of swelling.
Thrombin (green) interacting with the antithrombin (blue/grey) reactive center loop (red) in the presence of heparin (orange). (Grover and Mackman Front Cardiovasc Med 2022)
Increased cumulative incidence of venous thromboembolism in HAE cases versus controls. (Grover et. al. J Thromb Haemost 2022)
To further understand the role of C1-inhibitor as a negative regulator of coagulation we have conducted a series of preclinical studies using C1-inhibitor deficient mice. We have demonstrated that C1-inhibitor mice, like patients with HAE, have increased circulating markers of activation of coagulation and increased contact pathway-initiated thrombin generation . Moreover, C1-inhibitor deficient mice have significantly increased venous thrombus formation modeling our recent observation in HAE patients . Interestingly, we found that C1-inhibitor replacement, used as a therapy for HAE, reduced the enhanced coagulation and venous thrombosis associated with C1-inhibitor deficiency in mice .
C1-inhibitor and venous thromboembolism in the general population
In collaboration with colleagues at the University of Tromso we have also evaluated the association between plasma levels of C1-inhibitor and venous thromboembolims in the general population . Here we observed that high plasma levels of C1-inhibitor were associated with a lower future risk of venous thromboembolism and in particular unprovoked deep vein thrombosis . In complementary studies we have demonstrated that high plasma levels of C1-inhibitor, at the upper end of the range observed in humans, significantly reduced contact pathway-initiated thrombin generation .
Current work in the lab is focussed on establishing the precise molecular mechanism by which loss of C1-inhibitor leads to increased activation of coagulation and venous thrombosis leveraging available in vitro and in vivo model systems and a range of biologic and pharmacologic tools.
C1 inhibitor reduces contact pathway initiated thrombin generation (Grover et. al. J Thromb Haemost 2023).
1. Grover SP, Mackman N. Anticoagulant SERPINs: Endogenous Regulators of Hemostasis and Thrombosis. Front Cardiovasc Med. 2022; 9: 878199
2. Grover SP, Sundler Bjorkman L, Egesten A, Moll S, Mackman N. Hereditary angioedema is associated with an increased risk of venous thromboembolism. J Thromb Haemost. 2022; 20(11):2703-2706
3. Grover SP, Kawano T, Wan J, Tanratana P, Polai Z, Shim YJ, Snir O, Brækkan S, Dhrolia S, Kasthuri R, Bendapudi PK, McCrae KR, Wolberg AS, Hansen JB, Farkas H, Mackman N. C1 inhibitor deficiency enhances contact pathway mediated activation of coagulation and venous thrombosis. Blood. 2023; 141(19):2390-2401
4. Grover SP, Snir O, Hindberg K, Englebert TM, Brækkan SK, Morelli VM, Jensen SB, Wolberg AS, Mollnes TE, Ueland T, Mackman N, Hansen JB. High plasma levels of C1-inhibitor are associated with lower risk of future venous thromboembolism. J Thromb Haemost. 2023: In Press