Antithrombin Deficiency Is Associated with Prothrombotic Plasma Fibrin Clot Phenotype

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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 (Ks) 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 Ks 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 Ks, 18% prolonged CLT, and 30% higher ETP (all p < 0.01). Reduced Ks 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 Ks (+8%) and CLT (−12%; all p < 0.01).

Conclusions 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.


Publication History

Received: 09 December 2022

Accepted: 26 March 2023

Article published online:
18 May 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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