Hypofibrinolysis in diabetes: a therapeutic target for the reduction of cardiovascular risk

An enhanced thrombotic environment and premature atherosclerosis are key factors for the increased cardiovascular risk in diabetes. The occlusive vascular thrombus, formed secondary to interactions between platelets and coagulation proteins, is composed of a skeleton of fibrin fibres with cellular elements embedded in this network. Diabetes is characterised by quantitative and qualitative changes in coagulation proteins, which collectively increase resistance to fibrinolysis, consequently augmenting thrombosis risk. Current long-term therapies to prevent arterial occlusion in diabetes are focussed on anti-platelet agents, a strategy that fails to address the contribution of coagulation proteins to the enhanced thrombotic milieu. Moreover, antiplatelet treatment is associated with bleeding complications, particularly with newer agents and more aggressive combination therapies, questioning the safety of this approach. Therefore, to safely control thrombosis risk in diabetes, an alternative approach is required with the fibrin network representing a credible therapeutic target. In the current review, we address diabetes-specific mechanistic pathways responsible for hypofibrinolysis including the role of clot structure, defects in the fibrinolytic system and increased incorporation of anti-fibrinolytic proteins into the clot. Future anti-thrombotic therapeutic options are discussed with special emphasis on the potential advantages of modulating incorporation of the anti-fibrinolytic proteins into fibrin networks. This latter approach carries theoretical advantages, including specificity for diabetes, ability to target a particular protein with a possible favourable risk of bleeding. The development of alternative treatment strategies to better control residual thrombosis risk in diabetes will help to reduce vascular events, which remain the main cause of mortality in this condition

Plasma fibrinogen in NIDDM - The Rotterdam Study

OBJECTIVE - To compare plasma fibrinogen levels across groups of subjects with and without NIDDM with respect to diabetes therapy and to evaluate the influence of metabolic control and other selected factors. RESEARCH DESIGN AND METHODS - In a cross-sectional study, plasma fibrinogen was measured in 2,971 elderly subjects aged 55 years and older (mean age 70.8 years). This was part of the baseline examination of the Rotterdam Study, a population-based study of chronic diseases in the elderly. RESULTS - Plasma fibrinogen levels did not differ among subjects with and without NIDDM (2.84 vs. 2.81 g/l, P = 0.5). After adjustment for age, sex, smoking, BMI, and waist-to-hip ratio, the plasma fibrinogen levels were higher in subjects receiving insulin therapy. In those without diabetes (n = 2,640), with diabetes but not taking antidiabetes medication (n = 196), taking oral medication (n = 99), and taking insulin (n = 36), the age- and sex-adjusted fibrinogen levels were 2.82 (SE 0.01), 2.79 (0.05), 2.79 (0.07), and 3.23 (0.11) g/l, respectively (P <0.005). Adjustment for leukocyte count or serum creatinine level did not affect the observed association, while adjustment for fructosamine decreased the differences. CONCLUSIONS - Plasma fibrinogen levels are elevated in insulin-treated NIDDM patients, which may reflect worse metabolic control in this subgroup

Plasma fibrinogen in NIDDM - The Rotterdam Study

OBJECTIVE - To compare plasma fibrinogen levels across groups of subjects with and without NIDDM with respect to diabetes therapy and to evaluate the influence of metabolic control and other selected factors. RESEARCH DESIGN AND METHODS - In a cross-sectional study, plasma fibrinogen was measured in 2,971 elderly subjects aged 55 years and older (mean age 70.8 years). This was part of the baseline examination of the Rotterdam Study, a population-based study of chronic diseases in the elderly. RESULTS - Plasma fibrinogen levels did not differ among subjects with and without NIDDM (2.84 vs. 2.81 g/l, P = 0.5). After adjustment for age, sex, smoking, BMI, and waist-to-hip ratio, the plasma fibrinogen levels were higher in subjects receiving insulin therapy. In those without diabetes (n = 2,640), with diabetes but not taking antidiabetes medication (n = 196), taking oral medication (n = 99), and taking insulin (n = 36), the age- and sex-adjusted fibrinogen levels were 2.82 (SE 0.01), 2.79 (0.05), 2.79 (0.07), and 3.23 (0.11) g/l, respectively (P <0.005). Adjustment for leukocyte count or serum creatinine level did not affect the observed association, while adjustment for fructosamine decreased the differences. CONCLUSIONS - Plasma fibrinogen levels are elevated in insulin-treated NIDDM patients, which may reflect worse metabolic control in this subgroup