Integrated Coagulation Sensing to Predict Hemorrhage and Guide Transfusions

Massachusetts General Hospital, Boston MA

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Abstract

ABSTRACT In this continuing renewal RO1 project, we will advance a novel hemostasis profiler, iCoagLAB as a companion diagnostic during extracorporeal membrane oxygenation (ECMO) and conduct prospective clinical studies in ECMO patients to evaluate risk of bleeding and thrombosis. Heart failure (HF) is a common consequence of heart disease affects millions of patients worldwide. Patients with HF have a high risk of cardiogenic shock (CGS), which in severe cases, requires ECMO to fully support cardiac and pulmonary function. ECMO is life- saving in hundreds of thousands of patients world-wide; yet, over 40% of ECMO patients experience life- threatening hemorrhage. Multiple factors including underlying coagulopathies, clotting factor consumption, shear stresses created by mechanical pumping, hemolysis, platelet impairments and fibrinolytic activation increase bleeding risk, further exacerbated by heparin administered to prevent clotting in the ECMO circuit. Impaired coagulation can lead to hemorrhage that may cause severe anemia, shock, and multiple organ failure, and on the other hand coagulation defects may manifest as ‘hypercoagulable’ states resulting in potentially fatal stroke and pulmonary embolism. Therefore, during ECMO intervention, clinicians are tasked with maintaining the delicate balance between bleeding and coagulation. As a result, ECMO patients undergo frequent blood draws for coagulation testing further leading to large iatrogenic blood loss. Unfortunately, despite frequent blood testing, conventional laboratory tests take too long, are ineffective in the context of rapidly changing coagulation during ECMO and are poorly correlated with bleeding events resulting in hemostasis management that is often imprecise with devastating consequences. Consequently, due to the lack of tools to precisely and comprehensively assess coagulation at the point of care, bleeding and thrombosis due to impaired coagulation, remain the leading causes of death in patients on ECMO. Our project directly addresses this barrier. During the prior RO1 period we developed iCoagLAB, a novel hemostasis profiler that quantifies several relevant coagulation parameters rapidly with 50µL of whole blood. Our studies in cardiac surgical patients on cardiopulmonary bypass demonstrated the feasibility of obtaining iCoagLAB parameters during mechanical circulatory support (MCS). Although iCoagLAB opens the opportunity to provide actionable coagulation parameters, the existing technology has not been adapted for use during long-term MCS, such as in ECMO, where the risk of hemorrhage is the greatest and the need for actionable and rapid coagulation profiling is the most severe. This is because, current iCoagLAB disposables and assays are not sufficiently tailored for point of care use during ECMO and are unable to detect hemolysis, a common occurrence in ECMO patients. Therefore, in this next phase of our RO1 project we refine, adapt and advance the iCoagLAB technology for multiplexed measurement of anticoagulant, antiplatelet and hemolytic response and obtain actionable bleeding risk scores in patients on ECMO. We will further conduct multi-center clinical studies at 3 high-volume ECMO sites (Brigham and Women’s Hospital, Massachusetts General Hospital and Mayo Clinic, Rochester) in 150 patients to determine whether iCoagLab risk scores can accurately predict hemorrhagic or thrombotic events in ECMO patients. The major impact of our work will be in ultimately preventing serious complications and mortality associated with severe bleeding in patients on ECMO.