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

点击翻译按钮获取中文摘要

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.