Role of global assays in thrombosis and thrombophilia

Hemostasis is a complex process and is difficult to monitor in its entirety. Many laboratory tests have been developed to discern specific parts of the coag-ulation process in an attempt to diagnose disorders such as a tendency toward bleeding or clotting abnormally, and/or to predict clinical outcomes in these disorders. Because an in vitro test is simply a model of an in vivo process, it is important to under-stand what each test is measuring and its limitations. Traditional clotting assays such as the prothrombin time (PT) and activated partial thromboplastin time (APTT) measure the time for initiation of clot for-mation when, following initiation of coagulation in plasma via differing activators (PT: –thromboplas-tin,— comprised of tissue factor and phospholipid; APTT: –partial thromboplastin,— comprised of phospholipid without tissue factor), thrombin medi-ates the conversion of fibrinogen to fibrin. The end-point of the PT and APTT occurs when only approximately 5% of thrombin has been produced [1]. PT and APTT also do not provide information regarding the rate and extent of clot formation, nor lytic function. As for other global tests, they are non-specific assays and, for abnormal test results, further testing is generally warranted to evaluate causality. Specific testing may include factor assays to evaluate for a factor deficiency or antibody testing to assess for inhibitory antibodies. The need for improved testing of hemostasis has been long recognized but an accepted standardized test is not yet widely available.Thrombophilic states and the propensity toward thrombosis are difficult to diagnose/predict with laboratory assays. Testing for thrombophilia can be cumbersome, generally requiring testing for individual abnormalities, and may be difficult with smallerpatients due to the amount of blood required for comprehensive testing. There is a need for improved thrombophilia/thrombosis testing and monitoring. Global assays attempt to better define the complete course of clot formation and breakdown through avenues such as the measurement of thrombin gen-eration, fibrin formation, plasmin generation, and clot dissolution. Through a more complete picture of the hemostatic process, global assays may fill the gaps in knowledge regarding hemostatic abnormalities.The two most commonly employed global assay methodologies in both clinical practice and applied research are thrombin generation assays (TGA) and thromboelastography, which measure thrombin gen-eration and fibrin clot formation over time in a clot-ting plasma or whole blood sample, respectively. Both assays have been used in the broad evaluation of hemostatic abnormalities, including both bleeding and thrombotic disorders. Despite limitations of methods standardization and result interpretation, these global assays offer an approach to the evaluation of hemostatic balance that may allow for more indi-vidualized management. The use of global assays in the evaluation of pediatric thrombophilia, thrombosis, and thrombotic complications is an ongoing field of study. In addition to TGA and thromboelastography, there are a multitude of additional global assays in use, most commonly in research laboratories and in varying stages of development and practice. In this chapter, we describe the common global assays as well as a few of the less common assays, highlighting how they may contribute to the understanding of the complex process of blood clot formation and breakdown. We also describe the current use of these assays in the field of pediatric thrombosis.