A research grant of £117,081 has been awarded to Dr Alan Stewart and Prof Ramzi Ajjan (University of Leeds) from British Heart Foundation to carry out a new 36-month study entitled “Zinc-mediated effects on the fibrin network and its importance in thrombotic disease”.
Diabetes affects nearly half a billion people worldwide with cardiovascular disease representing the major cause of morbidity and mortality. An enhanced thrombotic environment is a key mechanism for the adverse vascular outcome in diabetes; obstructive blood clots (leading to myocardial infarction and cerebrovascular events) are formed secondary to complex interactions between platelets and coagulation proteins. Both the cellular and protein arms of coagulation are activated in diabetes leading to the formation of compact fibrin networks and impaired fibrinolysis.
We have identified a new mechanism for increased thrombosis risk in diabetes caused by the displacement of zinc from its primary circulatory buffering/transport protein, albumin through elevated levels of non-esterified fatty acid (NEFA). NEFAs are also transported by albumin and their binding causes a structural change that disrupts zinc binding allowing other molecules to bind available zinc. Raised plasma NEFAs, as observed in diabetes, are associated with zinc-dependent aberrations in fibrin clot formation and platelet functioning through zinc-dependent pathways.
In this project we will explore the mechanisms by which zinc impacts upon the fibrin network both through direct co-ordination to the fibrinogen molecule and through modulation of interactions between the fibrin network with activated platelets and other haemostatic molecules.