Results of a recent in silico study suggest that for patients with hemophilia A, the use of a therapy targeted against antithrombin has the potential to restore thrombin generation, but with a high rate of variation between patients. The study’s results were published in the journal Scientific Reports.
In patients with hemophilia A, factor VIII (FVIII) deficiency leads to reduced thrombin synthesis from prothrombin conversion, which impacts the ability of blood to clot. The condition becomes marked by an imbalance between procoagulant and anticoagulant processes. The study authors explained in their report that fitusiran is a new ribonucleic acid interference (RNAi)-based agent designed to reduce the synthesis of antithrombin and thereby improve the balance of procoagulants and anticoagulants in patients with hemophilia A.
This study evaluated dynamics of prothrombin conversion and thrombin inactivation processes in patients with different levels of severity of hemophilia A (mild, moderate, and severe) and in control individuals without hemophilia. In silico analysis was used to model the influence of reductions in antithrombin levels on thrombin generation and hemostatic balance in patients with hemophilia A. Antithrombin reductions that were tested in silico ranged from 90% to 2.5% of the original plasma level.
A total of 26 patients with hemophilia A and 27 control individuals, matched for age and sex, were evaluated for thrombin generation and dynamics. Across all participants, the mean age was 49 years. The mean FVIII level in patients with hemophilia A was 0.083 IU/mL, and in healthy control participants it was 1.41 IU/mL, and results of thrombin generation tests reflected significant differences between patients and control individuals in the capacity for thrombin generation.
Average prothrombin conversion curves were lower for patients with hemophilia A than in the control population. Other analyses suggested a higher capacity for thrombin inactivation in individuals who had higher levels of FVIII.
In all patients, in silico experimentation showed a partial, dose-dependent normalization of the thrombin generation curve as the antithrombin level was reduced. In patients with hemophilia A, a 50% reduction in the antithrombin level had potential to restore the thrombin generation profile to a mean peak height of 69 nM + 37 nM, compared with a mean peak height of 41 nm + 24 nM when the antithrombin level was not reduced. When the antithrombin level was reduced to 5%, the mean peak height was 93 nM + 48 nM.
“To conclude, we found a disturbed balance between prothrombin conversion and thrombin inactivation in patients with haemophilia A,” the study authors wrote in their report, noting an association between a low rate of prothrombin conversion and low thrombin generation in patients with hemophilia A. They also concluded that in silico results indicated the potential for reduction of antithrombin levels to increase thrombin generation, with this possibly serving as an individualized therapeutic approach to balancing coagulation in patients with hemophilia A.
Disclosures: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.
de Laat-Kremers RMW, Ninivaggi M, van Moort I, de Maat M, de Laat B. Tailoring the effect of antithrombin‑targeting therapy in haemophilia A using in silico thrombin generation. Sci Rep. 2021;11(1):15572. doi:10.1038/s41598-021-95066-8