PB0547 - Antithrombin deficiency is associated with more compact plasma fibrin clot structure and impaired susceptibility to fibrinolysis

Background: Inherited antithrombin deficiency is associated with increased risk of venous thromboembolism (VTE), largely due to insufficient thrombin inhibition. We hypothesized that antithrombin deficiency affects fibrin clot structure and function.

Aims: To evaluate plasma fibrin clot phenotype and factors affecting it in antithrombin-deficient patients.

Methods: We assessed 37 VTE patients with genetically confirmed antithrombin deficiency (aged 40±15 years) and 37 age- and sex-matched VTE patients with normal antithrombin activity. Clot permeability in a thrombin-based assay (Ks), clot lysis time (CLT), clot microstructure on scanning electron microscopy, along with thrombin generation, fibrinogen were assessed after >3 months since the VTE episode un blood samples obtained 24 hours since the last dose of direct oral anticoagulants (DOACs). The study was approved by the Ethical Committee and conducted in accordance with the Declaration of Helsinki. Patients provided written informed consent.

Results: Patients with antithrombin deficiency (median factor FIIa-based antithrombin activity: 63%, range 55-69%) had 21% reduced Ks (p < 0.001) in association with 30% thinner fibrin fibers and 27% prolonged CLT (p < 0.001) compared to controls. As expected, patients with antithrombin deficiency had 57% higher peak thrombin concentrations and 44% higher endogenous thrombin potential (ETP), while fibrinogen was similar. Type I (n=22, 59.5%) compared to type II antithrombin-deficient patients were characterized by lower Ks and longer CLT, along with higher thrombin generation (all p< 0.05). Ks (r=0.38, p=0.0083), CLT (r=-0.44, p=0.016), and ETP (r=-0.37, p=0.017) correlated with antithrombin activity in antithrombin-deficient patients. ETP was not associated with fibrin clot properties. Addition of human antithrombin to deficient plasma to reach 100% resulted in thrombin generation inhibition, while Ks increased by 8% and CLT by 14%, but they were still lower than in controls.

Conclusion(s): Apart from increased thrombin generation, denser fibrin clot structure and poorly lysable clots might contribute to increased risk of VTE observed in antithrombin-deficient patients.