Thrombin generation testing for monitoring hemophilia treatment: a clinical perspective

Thrombin generation is a key process that determines the extent of a hemostatic plug or a thrombotic process. The ensuing thrombin burst is crucial for the formation of a stable fibrin clot. During its active life, thrombin exerts a multitude of highly regulated actions on the blood and the vessel wall, among which is the clotting of fibrinogen. The inappropriate generation of thrombin may lead to pathological processes, foremost of which are hemorrhagic or thrombotic diseases. The coagulation system is usually investigated by means of two in vitro classical clotting tests, the activated partial thromboplastin time and prothrombin time. These assays assess only the time taken to form a clot and do not entirely reflect global hemostatic balance. They permit identification of connectivity between the component activities identified as required for plasma coagulation and define the concept of intrinsic and extrinsic coagulation pathways, which converge at the step of formation of the prothrombinase complex. However, the mechanisms established by in vitro tests are not always mirrored in the human pathologies associated with bleeding or thrombosis. The recent development of newer tests based on the continuous registration of thrombin generation (TG) under in vitro conditions that mimic more closely what occurs in vivo prompted us to reinvestigate the balance between procoagulants and anticoagulants in patients. Thrombin generation assays (TGA) not only provide an overall assessment of hemostasis, but they also target potential extrahemostatic effects of the generated thrombin, a potent agonist of a multitude of cellular activation pathways. Moreover, estimation of an individual's thrombin generation potential may correlate more closely with a hyper- or hypocoagulable phenotype, compared with traditional coagulation tests. In this review, we discuss to what extent TG can be expected to reflect the clotting function of blood, the development and use of different TGA systems suitable for detecting changes in the kinetics of thrombin generation, and the test's clinical utility for patients with hemophilia or von Willebrand disease.