Blood clotting activation causes an increased thrombin generation. The direct measurement of plasma thrombin is not feasible due to the absence of reliable methods. Thus, only indirect approaches are possible. Different markers of thrombin generation have been proposed in the past years. Some methods are nowadays of historical interest. Among various methods reported the 'gold standard' is fibrinopeptide A assay, while thrombin-antithrombin complexes assay needs further validation to be employed as a reliable index of increased thrombin generation, and more recent methods (such as those for F1+2 fragment and for protein C activation peptide) are not available for routine use.