C1 Inhibitor Deficiency Results in Increased Activation of Coagulation and Enhanced Venous Thrombosis

Introduction: C1 esterase inhibitor (C1INH) is a broad acting serine protease inhibitor that functions as a major endogenous inhibitor of activated factor (F) XII, FXI and kallikrein of the contact system. Congenital deficiency for C1INH results in hereditary angioedema (HAE) that can cause potentially life-threatening episodes of bradykinin induced swelling. Patients with HAE have increased circulating markers of activation of coagulation, however, the effect of this procoagulant state on thrombosis remains unclear. Methods: Contact pathway triggered thrombin generation was assessed in citrated plasma from patients with HAE (n=19) or age and sex matched healthy controls (n=20) using calibrated automated thrombography. The association between HAE and risk of composite arterial thromboembolism (ATE) and composite venous thromboembolism (VTE) was analyzed in a registry-based study of HAE patients (n=239) and age and sex matched controls (n=2383) with data analyzed by conditional logistic regression. Markers of activation of coagulation were measured in the plasma of C1INH deficient mice or wildtype littermate controls. C1INH deficient mice or wildtype littermate controls were evaluated in the inferior vena cava stenosis model of venous thrombosis and the carotid artery ferric chloride model of arterial thrombosis. Hemostasis was assessed in C1INH deficient mice or wildtype littermate controls using a tail transection model. Results: Plasma from patients with HAE supported significantly increased intrinsic pathway-initiated thrombin generation compared to healthy controls reflected by significantly reduced lagtime and increased peak. Furthermore, the enhanced thrombin generation negatively correlated with residual plasma levels of C1INH activity. Given that enhanced plasma thrombin generation has been associated with an increased risk of VTE in the general population the association between HAE and VTE was further explored. HAE was found to be associated with a significantly increased risk of composite VTE (OR 3.57, 95% CI 2.16-5.81, P<0.0001) but not composite ATE (OR 1.20, 95% CI 0.81-2.09, P=0.278). Consistent with this finding the cumulative incidence of composite VTE, but not ATE, was significantly higher in patients with HAE compared to controls. C1INH deficient mice had significantly increased plasma levels of coagulation markers prothrombin fragment 1+2, thrombin-antithrombin complexes and D-dimer at baseline compared to wildtype littermate controls. In addition, C1INH deficient mice exhibited enhanced venous thrombus formation in the inferior vena cava stenosis model compared to wildtype littermate controls evidenced by increased thrombus weight. Interestingly, loss of C1INH had no effect on venous thrombus composition. Arterial thrombus formation in the carotid artery ferric chloride model was not significantly different between C1INH deficient mice and wildtype controls.Further, hemostasis, assessed using a tail transection model, did not differ significantly between C1INH deficient mice and wildtype littermate controls. Conclusions: Plasma from patients with HAE supported significantly increased contact pathway-initiated thrombin generation that was dependent on the degree of C1INH deficiency. HAE was found to be associated with a selective increase in the risk of composite VTE but not composite ATE. C1INH deficient mice had evidence of increased basal activation of coagulation consistent with impaired endogenous anticoagulant activity. Further, C1INH deficient mice exhibited increased venous thrombus formation but not arterial thrombus formation phenocopying findings in humans with HAE. This work strongly suggests that plasma C1INH is an important endogenous anticoagulant regulating basal activation of coagulation and providing selective protection against venous thrombus formation.