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High plasma levels of C1 esterase inhibitor reduce intrinsic pathway-initiated coagulation and are associated with reduced future risk of venous thromboembolism

1University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States, 2UiT – The Arctic University of Norway, Tromso, Troms, Norway, 3Thrombosis Research Center, Department of Clinical Medicine, UiT - The Arctic University of Norway, Tromsø, Norway, Tromso, Troms, Norway, 4Semmelweis University, Budapest, Pest, Hungary, 5UiT - The Arctic University of Norway, Tromsø, Norway, Tromsø, Troms, Norway, 6University of Oslo, Oslo, Oslo, Norway

Abstract Number: OC 44.4

Meeting: ISTH 2022 Congress

Theme: Coagulation and Natural Anticoagulants » Coagulation Factors and Inhibitors

Background: C1 esterase inhibitor (C1INH) is a broad acting serine protease inhibitor that, as a major endogenous inhibitor of factor (F) XIIa, FXIa and plasma kallikrein, may have important anticoagulant functions in the setting of venous thromboembolism (VTE).

Aims: In this study, we investigated the effect of exogenous and endogenous C1INH on plasma thrombin generation and the association between plasma C1INH levels and risk of future VTE in a large, nested case-control cohort.

Methods: Thrombin generation was evaluated in normal human plasma supplemented with purified C1INH by calibrated automated thrombography. Thrombin generation was also assessed in plasma from patients with hereditary angioedema (HAE) caused by C1INH deficiency (n=20) and compared to age and sex matched controls (n=20). In the nested case-control cohort, containing 405 VTE patients and 829 age and sex matched controls derived from the Tromsø 4 study, plasma C1INH levels were determined by immunoassay. Logistic regression analysis was used to determine the odds ratios (ORs) for deep vein thrombosis (DVT) and VTE across C1INH quartiles.

Results: Addition of exogenous C1INH dose-dependently inhibited intrinsic pathway-initiated thrombin generation (P < 0.0001) but not tissue factor-initiated thrombin generation (P>0.05). In contrast, plasma from patients with HAE, particularly those with C1INH activity < 25% of normal, supported increased intrinsic pathway-initiated thrombin generation compared to controls (P < 0.05). In the nested case-control study, high plasma C1INH levels were associated with lowered ORs for DVT and VTE. Subjects with plasma C1INH levels in the highest quartile had an OR of 0.68 (95% CI, 0.49-0.96) for DVT and 0.58 (95% CI, 0.39-0.89) for VTE when compared to individuals with C1INH in the lowest quartile.

Conclusion(s): Plasma C1INH demonstrates significant anticoagulant activity in intrinsic pathway-initiated thrombin generation. Consistent with the anticoagulant activity of C1INH high plasma levels of C1INH were associated with reduced risk of VTE.

To cite this abstract in AMA style:

Grover S, Snir O, Hindberg K, Englebert T, Brækkan S, Pólai Z, Morelli V, Farkas H, Jensen S, Wolberg A, Mollnes T, Ueland T, Mackman N, Hansen J. High plasma levels of C1 esterase inhibitor reduce intrinsic pathway-initiated coagulation and are associated with reduced future risk of venous thromboembolism [abstract]. https://abstracts.isth.org/abstract/high-plasma-levels-of-c1-esterase-inhibitor-reduce-intrinsic-pathway-initiated-coagulation-and-are-associated-with-reduced-future-risk-of-venous-thromboembolism/. Accessed September 29, 2023.

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