We propose to develop a novel device for the measurement of blood clot elasticity with improved accuracy and speed, and requiring smaller sample volumes. In the long term, this may enable better point- of-care management and diagnoses of coagulopathies arising from a wide array of cardiovascular disorders including myocardial infarction, stroke, coronary artery disease, venous thromboembolism, and hyperglycemia. This expectation arises from the fact that the clot elastic modulus (CEM) or related clot structural properties have been shown to be strongly correlated with hypofibrinolysis (decreased ability to break up clots) in these diseases. We hypothesize that a more accurate device will provide a better predictive ability for CEM as a relevant diagnostic parameter, that the increased speed of analysis may be especially important for preoperative monitoring of anti-coagulant therapies, and that the decreased sample volume will enable studies of genetic murine animal models for cardiovascular disease. Our proposal entails the development of an emerging technique for small sample elasticity measurement based upon resonant acoustic spectroscopy with optical vibrometry-based detection (RASOV). In RASOV, the fundamental acoustic resonance modes of a blood sample are measured by sweeping the excitation frequency on a microbead transducer that imparts negligible inertia to the sample. Because the resonance modes are an intrinsic property of the specimen directly related to the CEM, the measurement requires no calibration procedures. Furthermore, there is no limitation to sample size, and measurement speeds <0.2s are anticipated. While preliminary data indicates the utility of RASOV for fibrin clot analysis, resources are needed for further improvements in order to position this technology for clinical translation.
Our first aim i s to incorporate several hardware improvements into the RASOV, including a smaller optical interferometer for improved displacement sensitivity, and a microbead transducer with smaller inertial mass. Also, we will validate CEM measurements with a commercial mechanical analyzer.
Our second aim i s to apply the robust RASOV technology to the analysis of whole blood samples from healthy donors. To investigate the capabilities of RASOV, additional fibrinogen or antibodies will be added to blood to simulate hyperfibrinogenemia and hemophilia, respectively, which we expect to result in increased and decreased CEM, respectively. Furthermore, we will compare the time-dependent CEM results during coagulation with that from a commercial clot analyzer, to understand the particular strengths of RASOV. By the conclusion of this study the RASOV technology will have been tested over the physiological range of expected CEM in whole blood and fully validated against a standard mechanical analyzer. This will poise the technology for clinical trials in a wide variety of cardiovascular diseases to establish the diagnostic relevance of CEM, and will lead to rapid clinical translation.
This proposal entails the construction of a novel device for more accurate, rapid, and smaller sample volume assessment of blood clot stiffness. This may provide better diagnostics and risk management for a wide range of cardiovascular diseases including coronary artery disease, stroke, venous thromboembolism, myocardial infarction, and diabetes. It may also lead to better management of blood coagulation properties and dosing of anti-coagulant drugs during surgery.
