Tailoring the effect of antithrombin-targeting therapy in haemophilia A using in silico thrombin generation

Factor (F) VIII deficiency causes bleeding in haemophilia A patients because of the reduced formation of procoagulant enzyme thrombin, which is needed to make the blood clot. We measured the dynamics of coagulation in haemophilia A patients by measuring thrombin generation (TG). Additionally, we quantified the procoagulant process of prothrombin conversion and anticoagulant process of thrombin inhibitor complex formation. In haemophilia A, prothrombin conversion is severely reduced, causing TG to be low. Nevertheless, the thrombin inactivation capacity of these patients is comparable to that in healthy subjects, leading to a severe imbalance between procoagulant and anticoagulant processes and a subsequent increased bleeding risk. A novel therapy in haemophilia A is the targeting of anticoagulant pathway, e.g. thrombin inhibitor antithrombin (AT), to restore the haemostatic balance. We simulated the effect of AT reduction on TG in silico. Lowering AT levels restored TG dose-dependently and an AT reduction of 90-95% led to almost normal TG in most patients . However, the variation in response to AT reduction was large between patients, indicating that this approach should be tailored to each individual patients. Ideally, TG and thrombin dynamics simulation could in the future contribute to the management of patients undergoing AT targeting therapy.

Automated summary

Factor (F) VIII deficiency in haemophilia A patients leads to reduced thrombin generation and a severe imbalance between procoagulant and anticoagulant processes, increasing the risk of bleeding. Targeting the anticoagulant pathway, such as with thrombin inhibitor antithrombin (AT), could restore the haemostatic balance, but individual variations in response to AT reduction suggest a need for personalized treatment. In silico simulations showed that lowering AT levels dose-dependently restored thrombin generation, indicating the potential future use of modeling thrombin dynamics in managing patients undergoing AT targeting therapy.