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, including the clotting of
fibrinogen. The inappropriate generation of
thrombin may lead to
pathologic processes, foremost of which are hemorrhagic or thrombotic diseases. The coagulation system is usually investigated by means of two in vitro classic clotting tests, the activated partial thromboplastin time (APTT) and prothrombin time (PT), which assess only time to initiation of clot formation and do not entirely reflect global
hemostatic balance. The APTT and PT 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 point 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 under in vitro conditions that mimic more closely what occurs in vivo prompt a reinvestigation of the balance between procoagulants and
anticoagulants in patients with various
hemostatic disorders.
Thrombin-generation assays not only provide an overall assessment of hemostasis but 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 hypercoagulable or hypocoagulable phenotype when compared with traditional coagulation tests. In this review, we discuss to what extent
thrombin generation can be expected to reflect the clotting function of blood, the development and use of different
thrombin-generation assay systems suitable for detecting changes in the kinetics of
thrombin generation, and the clinical utility of
thrombin generation.