Supplementary funding (360G-Wellcome-077078_Z_05_G)
Elevated plasma levels of fibrinogen have been shown to be an independent risk factor for ischaemic heart disease and have also been associated with other thrombotic disorders such as stroke, peripheral arterial disease and venous thrombosis. This risk may be mediated in part via altered fibrin structure as we have demonstrated in myocardial infection (MI) patients and their first-degree relatives (Mills et al, Circulation, in press 2002). The fibrinogen gene transcript is processed by alternative mRNA splicing resulting in a variant of the gA/gA chain of fibrinogen denoted gA/g'. This gA/g' variant has 4 amino acids deleted from the carboxy-terminus of the gA/gA chain of fibrinogen which is substituted with a 20 amino acid extension. It has recently been shown that g' binds factor XIII (FXIII) and thrombin and also enhances activation of FXIII by thrombin. Activated FXIII cross-links fibrin polymers to form fibrin clot structures that are more stable physically and chemically, and it has been demonstrated that clots prepared using gA/g' rather than gA/gA fibrinogen have greater resistance to fibrinolysis. The presence of gA/g' is thought to occur as approximately 10-15% of total fibrinogen within normal individuals. Most recently it has been possible to measure gA/g' levels in plasma and it has been shown that patients with coronary artery disease have elevated gA/g' levels, independent of total fibrinogen level. The variation of gA/g' plasma levels in subjects with other thrombotic disorders is unknown. We will therefore develop and characterise an ELISA specific for gA/g' fibrinogen and using this ELISA determine gA/g' levels in patients with various thrombotic disorders (i.e. patients that have had myocardial infarction, stroke, venous thromboembolism and first-degree relatives of MI patients). We will also use a family study of 539 subjects of which there are 89 pedigrees to assess heritability of gA/g' levels using genetic model fitting techniques. Furthermore we will study the effect of varying gA/g' levels on ex-vivo fibrin structure.
£55,000 29 Mar 2010