Abstract
Background: Inherited antithrombin deficiency is associated with an increased risk of developing venous thromboembolism. Current first-line functional methods for the detection of antithrombin deficiency have limitations, and conventional coagulation assays are unable to measure the level of hypercoagulability associated with this disorder. Existing evidence suggests that antithrombin may exert an anti-inflammatory effect.Aims: This case-control study of inherited antithrombin deficiency aimed to 1) characterise the clinical and biochemical phenotypes; 2) expand the molecular analysis; 3) investigate the utility of a thrombin generation in the management of this disorder; 3) test the hypothesis that inherited antithrombin deficiency may be associated with inflammatory states.
Methods: After obtaining consent, a one-time blood sample was collected from each participant. Clinical, biochemical and extended molecular characterisation studies were performed. Thrombin generation potential was measured by STG-ThromboScreen on ST-Genesia analyser. Seven inflammatory markers were tested, including VCAM-1, ICAM-1, C-reactive protein, Complement-C3a, circulating nucleosomes, fibrinogen and von Willebrand factor.
Results: This study characterised a large cohort of patients with inherited antithrombin deficiency. The results showed significant heterogeneity, further complicated by the presence of coexisting genetic mutations in 14% of the entire cohort. Antithrombin activity assays show variable diagnostic effectiveness; the Biophen factor Xa-based assay showed greater sensitivity when compared to the Berichrom thrombin-based assay, which failed to detect most type 2 antithrombin variants.
There was a significantly increased endogenous thrombin potential, start tail and peak height between non-anticoagulated ATD and healthy controls, suggesting a hypercoagulable state. Negative correlations were observed between antithrombin activity and endogenous thrombin potential and start tail. Positive correlations existed between D-dimer and velocity index, and between prothrombin fragment 1+2 and endogenous thrombin potential, velocity index and peak height. Individual results showed a high variability between different anticoagulants.
Antithrombin deficiency did not exhibit an altered inflammatory state, as measured by a group of biomarkers. The increased circulating nucleosomes and VCAM-1 observed in participants with antithrombin deficiency compared to paired healthy controls may be attributed to a previous history of venous thromboembolism.
| Date of Award | 20 Mar 2026 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Graham Mills (Supervisor) & Gavin Knight (Supervisor) |
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