Antithrombin Deficiency Is Associated with Prothrombotic Plasma Fibrin Clot Phenotype

Abstract

Background Deficiency of antithrombin increases risk of venous thromboembolism. We hypothesized that antithrombin deficiency affects fibrin clot structure and function.

Methods We evaluated 148 patients (age: 38 [32–50] years; 70% women) with genetically confirmed antithrombin deficiency and 50 healthy controls. Fibrin clot permeability (K_s) and clot lysis time (CLT) along with thrombin generation capacity were assessed before and after antithrombin activity normalization in vitro.

Results Antithrombin-deficient patients had lower antithrombin activity (−39%) and antigen levels (−23%) compared with controls (both p < 0.01). Prothrombin fragment 1 + 2 levels were 26.5% higher in patients with antithrombin deficiency than in controls along with 94% increased endogenous thrombin potential (ETP) and 108% higher peak thrombin (all p < 0.01). Antithrombin deficiency was associated with 18% reduced K_s and 35% prolonged CLT (both p < 0.001). Patients with type I (n = 65; 43.9%) compared with type II antithrombin deficiency (n = 83; 56.1%) had 22.5% lower antithrombin activity (p < 0.001) and despite similar fibrinogen levels, 8.4% reduced K_s, 18% prolonged CLT, and 30% higher ETP (all p < 0.01). Reduced K_s was associated with lower antithrombin antigen level (β = − 6.1, 95% confidence interval [CI]: −1.7 to −10.5), while prolonged CLT was associated with lower antithrombin antigen (β = − 69.6, 95% CI: −9.6 to −129.7), activity (β = − 2.4, 95% CI: −0.3 to −4.5), higher PAI-1 (β = 12.1, 95% CI: 7.7–16.5), and thrombin-activatable fibrinolysis inhibitor levels (β = 3.8, 95% CI: 1.9–5.7). Addition of exogenous antithrombin reduced ETP (−42%) and peak thrombin (−21%), and improved K_s (+8%) and CLT (−12%; all p < 0.01).

Conclusion Our study suggests that enhanced thrombin generation and prothrombotic plasma fibrin clot phenotype can contribute to increased risk of thrombosis in patients with antithrombin deficiency.

Keywords

antithrombin deficiency - fibrin clot - fibrinolysis - thrombin generation - venous thromboembolism

Authors' Contribution

Conception and design of the study: M. Z.; data collection, analysis, and interpretation: J. N., J. C., M. E. M.-B., C. B.-P., Z. Ba., Z. Be., J. T., M. W., A. K., and A. U.; drafting the article: J. N. and M. Z.; revising the article: J. C., M. E. M.-B., C. B.-P., Z. Ba., Z. Be., J. T., M. W., A. K., and A. U.

Publikationsverlauf

Eingereicht: 09. Dezember 2022

Angenommen: 26. März 2023

Artikel online veröffentlicht:
18. Mai 2023

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