Thrombin Generation as a Potential Surrogate Marker of Hemostatic Status in the Era of Novel Therapies for Hemophilia

The hemophilia treatment landscape has been profoundly reshaped by non-factor therapies (NFT), which provide effective prophylaxis regardless of inhibitor status while reducing treatment burden through subcutaneous administration. However, their hemostatic effect cannot be reliably assessed using routine laboratory assays. This limitation creates a growing need for tools capable of evaluating the global hemostatic status in patients receiving these agents. Monitoring remains essential, as interindividual variability necessitates personalized management to ensure adequate hemostatic control during bleeding episodes or surgery while minimizing the risk of thrombotic complications. Currently, no validated assay accurately reflects the global hemostatic status of patients receiving NFTs, leaving clinicians to rely on empirical decisions that may entail significant risk. The thrombin generation assay (TGA) is the most promising candidate to address this gap, although its correlation with clinical phenotype varies according to assay conditions and clinical context. Establishing standardized, clinically validated monitoring strategies—particularly TGA-based approaches—is therefore crucial for safe therapeutic guidance and reflects a paradigm shift from factor replacement toward optimization of thrombin generation in modern hemophilia care.