DOAC-associated bleeding, hemostatic strategies, and thrombin generation assays - a review of the literature

Direct oral anticoagulants (DOACs) account for most oral anticoagulant use. DOAC-associated bleeding events are commonly encountered in clinical practice and are associated with substantial morbidity and mortality. Both specific reversal agents and nonspecific hemostatic therapies, such as prothrombin complex concentrates, are used in the management of DOAC-associated bleeding. Measuring hemostatic efficacy and demonstrating a clinical impact from these therapies among studies of bleeding patients is challenging. Thrombin generation assays provide information on the total hemostatic potential of plasma, and have emerged as a promising modality to both measure the impact of DOACs on coagulation and to evaluate the effects of hemostatic therapies among patients with DOAC-associated bleeding. The mechanisms by which nonspecific hemostatic agents impact coagulation and thrombin generation in the context of DOAC therapy are unclear. As a result, we undertook a review of the literature using a systematic search strategy with the goal of summarizing the effects of DOACs on thrombin generation and the effects of both specific reversal agents and nonspecific hemostatic therapies on DOAC-altered thrombin generation parameters. We sought to identify clinical studies focusing on whether altered thrombin generation is associated with clinical bleeding and whether correction of altered thrombin generation parameters predicts improvements in clinical hemostasis. Lastly, we sought to outline future directions for the application of thrombin generation assays toward anticoagulation therapies and the question of anticoagulation reversal.