The role of fibrin clots in cardiovascular disease and infection control

Coagulation plays an important role in the haemostatic process, forming a blood clot to prevent blood loss. Changes in formation, structure or breakdown of these clots can result in the pathogenesis of thrombotic disorders. These imbalances can be caused by changes to the fibrin(ogen) molecule, inflammation and levels of other plasma proteins. This thesis focusses on different mechanisms that effect clot structure, and how these prevent or promote disease, with the aim of uncovering new pathways to target therapeutically. This study revealed the vast range of physiological fibrinogen γ’ levels present in 1164 patients, fluctuating between 0.8 % and 39.5 % of total fibrinogen. Furthermore, it demonstrated that changes of fibrinogen γ’ levels within this physiological range plays an important role in modulating clot structure, with fibrinogen γ’ significantly increasing height and volume of clots under flow. It also found that the FXIII-B Arg95 variant is associated with an increased risk of AAA, suggesting a possible role for FXIII in AAA pathogenesis. It showed how PNH patients with increased clone size have a more thrombotic phenotype, with faster forming, more stable clots, but these changes do not appear to be caused by changes in the fibrin clot. In addition, it showed that the antithrombotic effects of eculizumab treatment appear to function in part due to a reduction in fibrinogen and thrombin levels. And finally the discovery of a remarkable aspect of blood clotting in which fibrin forms a protective film at the air-blood interface covering the external surface of the clot, retaining blood cells and providing an instant barrier against microbial invasion. Together these data provide new insight into some of the main modulators of clot structure, providing previously unknown mechanisms of haemostasis and possible new pathways to target in the prevention and treatment of thrombosis and infection.