title: Hypofibrinolysis in diabetes: a therapeutic target for the reduction of cardiovascular risk.
abstract: 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.
authors.affiliation: Division of Cardiovascular & Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM), University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Katherine
authors.initials: K
authors.lastname: Kearney
authors.affiliation: Biomedical Health Research Centre, Astbury Building, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Darren
authors.initials: D
authors.lastname: Tomlinson
authors.affiliation: Division of Cardiovascular & Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM), University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Kerrie
authors.initials: K
authors.lastname: Smith
authors.affiliation: Division of Cardiovascular & Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM), University of Leeds, Leeds, LS2 9JT, UK. R.Ajjan@leeds.ac.uk.
authors.forename: Ramzi
authors.initials: R
authors.lastname: Ajjan
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D003920:Diabetes Mellitus / Q000097:blood*; D005340:Fibrinogen / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects*; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D018570:Risk Assessment; D012307:Risk Factors; D013927:Thrombosis / Q000097:blood* / Q000188:drug therapy* / Q000209:etiology
chemical_list: D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D005340:Fibrinogen
keywords: Diabetes; Fibrinogen; Fibrinolysis