Development of a novel whole blood coagulation assay

The inability to adequately monitor the effects of newer, potent anticoagulants is increasingly apparent. These powerful drugs have a very narrow therapeutic window. This is especially true in high-risk populations such as those with hepatic and renal dysfunction. Conventional monitoring parameters (i.e., PT, aPTT, INR) do not adequately measure or predict efficacy or toxicity for many of these newer agents, in part because they are performed in the absence of platelets. It is now understood that platelets are a critical step in the production of the thrombin burst. We have developed a novel assay that tests platelet function during clotting of whole blood. This platelet assay determines the thrombin generation time (TGT). TGT correlates with thrombin's appearance in the clotting sample. TGT is short in disease states associated with thrombosis, is prolonged in diseases associated with bleeding, is prolonged by anticoagulants (and some antiplatelet agents), and is shortened by hemostatic agents. This raises the possibility of that TGT might serve as a broad spectrum drug monitor. We have performed pilot investigations that support this possibility. Most recently we demonstrated altered hemostatic function in patients with end stage renal disease (ESRD). The ex vivo response of ESRD blood to a low molecular weight heparin was also noted to differ significantly from normal. The studies outlined in this proposal build on these very encouraging results and, if our hypotheses are supported, will serve as the foundation for Phase II studies of TGT as a monitor of multiple agents. Clinicians need a simple, inexpensive assay that can quickly measure efficacy and predict risk of toxicity. We believe the TGT can serve this role, and improve the care to these special populations with coagulation disorders. This assay can allow clinicians to tailor anticoagulant therapy to achieve successful outcomes while preventing adverse bleeding events. These outcomes should result in reduced healthcare costs.