Detection of procoagulant imbalance

Coagulation has been historically investigated by the basic and time-honored tests prothrombin and activated partial thromboplastin times (PT and APTT). These tests have been instrumental for improving our understanding of the coagulation mechanisms and for the diagnosis of congenital hemorrhagic diseases such as hemophilia and allied disorders, conditions in which they are abnormally prolonged. PT and APTT are however much less suitable to investigate the other face of the coin (i. e. thrombosis). They are in fact within normal limits in patients with congenital deficiency of the naturally occurring anticoagulants [antithrombin, protein C (PC) and protein S (PS)], conditions in which they should be shorter than normal as thrombin production in these conditions is heightened because of the deficiency of the anticoagulants. It should therefore be concluded that PT and APTT are responsive to the procoagulant factors, but much less to their anticoagulant counterpart. Possible explanations for this conclusion rest on the design of the two assays. PT and APTT are static tests in which plasma clots soon after 5 % of the total amount of thrombin is generated (1), thus leaving the remaining 95 % unnoticed. Furthermore, owing to the relatively short time interval between coagulation ignition and clot formation (a few seconds) the most important naturally occurring anticoagulant systems cannot express their full anticoagulant potential and cannot therefore contribute to downregulate thrombin generation. This is valid for both the antithrombin and PC systems that require conformational changes brought about by heparin-like substances and activation by thrombomodulin (TM), respectively (2, 3). These moieties are located on endothelial cells and much less in plasma. A procedure based on the continuous registration of thrombin generation (mediated by the procoagulants) and decay (mediated by the anticoagulants) was described in the 1950s by Macfarlane and Biggs (4) and was later modified by Hemker et al. (5) to generate the so-called thrombogram, which is described by various parameters. Among them, the endogenous thrombin potential (ETP) defines the area under the thrombin generation (and decay) curve recorded upon activation of coagulation with small amounts of tissue factor and negatively charged phospholipids. The ETP represents the net amount of thrombin that can be generated by the test plasma under the experimental conditions and is driven by the balance between the proand anticoagulants. Other parameters of Detection of procoagulant imbalance