DEVELOPMENT OF A NOVEL WHOLE BLOOD COAGULATION ASSAY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Over the last 40 years, our understanding of blood coagulation has changed significantly. Newer, more potent antiplatelet and anticoagulant medications have been introduced. Despite the innovation of drug therapy, our standard laboratory assays of hemostasis do not reflect our new insights into the clotting mechanism, and do not serve as adequate laboratory monitors for these new drugs. Current clinical laboratory assays are performed on plasma samples that do not contain platelets. It is becoming increasingly apparent that whole blood is the most appropriate patient sample for analyzing coagulation. The Hemodyne Hemostasis Analysis System (H.A.S.) analyzes whole blood samples using quantitative physical techniques. Previous investigations have shown that the parameters measured by the H.A.S. reflect not only the structural qualities of the blood clot, but also platelet function during clot formation. The H.A.S. is the first ex vivo system to quantitatively assess platelet function during clot formation. Due to the recent introduction of very potent antiplatelet and anticoagulant medications, the ability to monitor their effects is increasingly important. These potent drugs have a very narrow therapeutic window between efficacy and toxicity. Although they effectively control thrombosis in hypercoagulable conditions, their relative potency increases the risk of major hemorrhage. Unfortunately conventional monitoring parameters (i.e., PT, aPTT, INR) cannot measure or predict efficacy or toxicity. Thus, clinicians cannot adequately (or safely) monitor these new drug therapies for safety or efficacy. While the routine monitoring of some anticoagulants (such as low molecular weight heparin (LMWH)) may not be necessary in normal patients, the importance of documenting adequate and safe clinical response is critical in complex patients with concurrent risk factors for hemorrhage (e.g., patients with hepatic or renal dysfunction). We have compelling preliminary data conducted in end-stage renal disease (ESRD) subjects that demonstrate an enhanced anticoagulant response following exposure to the LMWH enoxaparin. For these special populations, clinicians desperately need an inexpensive assay that can quickly measure efficacy and predict risk of toxicity. We believe the H.A.S. can serve this role, and improve the care to these special populations with coagulation disorders. By doing so, this would allow clinicians to tailor anticoagulant therapy to achieve successful outcomes while preventing adverse bleeding events. These outcomes should result in reduced healthcare costs. This study has two specific aims. The first involves using the Hemodyne Hemostasis Analysis System , to define the in vivo relationship of antifactor Xa activity to thrombin generation time (TGT) following increasing doses of enoxaparin (0.25, 0.50 and 1.0 mg/kg) in two groups of subjects: 1) normal, healthy subjects without renal dysfunction; and 2) subjects with end-stage renal disease (ESRD; creatinine clearance < 10 mL/min) on maintenance hemodialysis. The second goal is to determine the ability of the Hemodyne Hemostasis Analysis System to characterize intergroup (control versus ESRD) differences in thrombin generation time over 12 hours following single dose enoxaparin 1 mg/kg. All previous and current measures of platelet function must be performed with clotting by characterizing these important clotting parameters, the H.A.S. is a sensitive, novel, whole blood assay that monitors coagulation status in various disease states and in patients on anticoagulant therapy.