Good clot? Bad clot? Rheological and microstructural studies of abnormal blood clots from incipiency to breakdown

Cardiovascular disease (CVD) and associated thrombotic disorders cause significant morbidity and mortality claiming 17.1 Million lives a year worldwide. CVD (including heart disease and stroke) accounts for around four out of ten of deaths in the UK. The incidence of CVD increases markedly with age and is often higher in socially deprived areas. In CVD, the processes of endothelial and vascular damage and activation of the coagulation cascade result in abnormal clots, often with excessively cross-linked fibrin networks. Such clots are often referred to as bad clots by the clinician. It has been claimed that tighter fibrin networks lead to a decreased ability of the body to effectively digest these clots (lysis). However, the relationships between whole blood clot microstructure and lysis remains contentious. This is in part due to the lack of rheological techniques to characterise clot microstructure and to appropriately measure clot lysis. The ability to characterise clot microstructure and measure clot lysis will form the basis of a new haemorheometrical device which can be used to diagnose disease states (such as CVD), to monitor anticoagulant therapy, to guide therapeutic interventions and to assess the efficiency of various drugs.This Application will address the hypothesis that measurement of incipient clot microstructure can provide the basis for a new biomarker of clot lysis. It is widely assumed that the incipient clot microstructure is a template for ensuing clot development, and will therefore ultimately control the accessibility of fibrinolytic agents that serve to lyse the clot. It is planned to test this hypothesis by conducting appropriate rheological measurements during whole blood coagulation. However, measurement of clot lysis has been complicated by the fact that it exists simultaneously with platelet mediated clot retraction which has the effect of the clot pulling away from the rheometer's measuring plates. A novel aspect of this work is to perform viscoelastic measurements of whole blood clots whilst maintaining a zero normal force between the rheometer's measuring plates. This has the desired effect that, during clot retraction, the fibrin network acts to pull the plates towards each other therefore facilitating appropriate viscoelastic measurements of the contracted clot. These measurements will allow a greater understanding of the relationships between clot microstructures and clot lysis. Overall, the ultimate goal of the research is to develop a new haemorheometrical tool which has the potential to be used in a clinical setting for patient benefit.

Who might benefit from this research? How might they benefit from this research? A short term beneficiary of this research is industry (including medical diagnostic, bioengineering and pharmaceutical firms). The impact of the applicant's research has already been demonstrated at Swansea University in the form of a spin in medical device company, Haemair Ltd. and a collaborative project with Calon Cardio Technologies Ltd. It is envisaged that continued research within the area of haemorheology will attract further investment in these companies and the possibility of the formulation (spinning in or spinning out) of new companies who wish to make commercial use of this research leading to the the creation of jobs and wealth within the biomedical sector. Furthermore, the pharmaceutical industry may be interested in the potential of the Applicant's haemorheological techniques as a tool for measuring the efficiency of various clot busting drugs and anticoagulants. This may lead to investment in research and development at Swansea University by global companies. The ultimate beneficiary in the long term will be patients and the general public as the research develops into novel techniques used in hospitals for disease screening. These include members of the general public who may be at risk of cardiovascular disease due to various genetic factors (e.g. familial hypercholesterolemia) or patients who have had previous cardiovascular events (e.g. deep vein thrombosis, stroke, or a heart attack). Furthermore, the Applicant's research into haemorheological techniques has already shown significant potential as a tool for anticoagulant monitoring. This will have enormous benefit to patients undergoing anticoagulant therapy (e.g. warfarin) as they will have an more rigorous measure of their anticoagulant status allowing a more appropriate dose to be administered by the doctor. In addition to enhancing the quality of life, health and well being of the patient this work has wider implications in the economy and NHS. Costs associated with patients regularly visiting hospitals and clinics will be substantially reduced as technologies are geared more towards a near patient or point of care (POC) setting. The Applicant's research into haemorheological techniques lends itself to the possibility of a development of a POC device, saving time and costs for both the NHS and the patient.