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

心血管疾病（CVD）和相关的血栓性疾病导致显著的发病率和死亡率，全球每年夺去1710万人的生命。CVD（包括心脏病和中风）占英国死亡人数的十分之四左右。心血管疾病的发病率随着年龄的增长而明显增加，在社会贫困地区往往更高。在CVD中，内皮和血管损伤的过程以及凝血级联的激活导致异常凝块，通常具有过度交联的纤维蛋白网络。这种凝块通常被临床医生称为不良凝块。据称，更紧密的纤维蛋白网络导致身体有效消化这些凝块（溶解）的能力降低。然而，全血凝块微观结构和溶解之间的关系仍然存在争议。这部分是由于缺乏流变学技术来表征凝块微观结构和适当地测量凝块溶解。能够表征凝块微观结构和测量凝块溶解的能力将形成新的血液流变学装置的基础，所述血液流变学装置可用于诊断疾病状态（例如CVD）、监测抗凝治疗、指导治疗干预和评估各种药物的效率。人们普遍认为，最初的凝块微观结构是随后凝块发展的模板，因此将最终控制用于溶解凝块的纤维蛋白溶解剂的可及性。计划通过在全血凝固过程中进行适当的流变学测量来检验该假设。然而，凝块溶解的测量由于其与血小板介导的凝块收缩同时存在的事实而变得复杂，所述血小板介导的凝块收缩具有凝块从流变仪的测量板拉离的效果。这项工作的一个新的方面是进行全血凝块的粘弹性测量，同时保持流变仪的测量板之间的法向力为零。这具有期望的效果，即在凝块收缩期间，纤维蛋白网络起到将板朝向彼此拉动的作用，因此有助于收缩凝块的适当粘弹性测量。这些测量将允许更好地理解凝块微观结构和凝块溶解之间的关系。总的来说，研究的最终目标是开发一种新的血液流变学工具，该工具有可能用于临床环境中，以使患者受益。

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.