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 [1]. 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 [2]. We have also found that plasma from patients with HAE supports significantly increased contact pathway-initiated thrombin generation compared to plasma from healthy controls [3]. These finding suggests that the clinical manifestations of HAE extend beyond the classical presentation of swelling.