Review article: Coagulation and fibrinolysis in diabetes

Abstract

Atherothrombotic complications are the main cause of mortality in subjects with diabetes. Premature atherosclerosis, increased platelet reactivity and activation of coagulation factors with associated hypofibrinolysis all contribute to increased cardiovascular risk in this population. Blood clot formation represents the last step in the atherothrombotic process, and the structure of the fibrin network has a role in determining predisposition to cardiovascular disease. In this review, we discuss alterations in coagulation factor plasma levels and/or activity in diabetes and clarify their role in predisposition to cardiovascular events. The effect of diabetes on fibrin network structure/fibrinolysis is reviewed and potential mechanisms that modify clot properties are discussed. Finally, modulation of clotting potential by the various therapeutic agents used in diabetes is examined. Understanding the mechanisms by which diabetes influences the coagulation pathway will help to develop more effective treatment strategies to reduce thrombotic events in subjects with this condition. KeywordsAtherothrombosis, clot structure, coagulation factors, coronary artery disease, diabetes, fibrinogen Clot formation and lysisFibrin clot formation, leading to vessel occlusion, represents the final step in the atherothrombotic process and involves multiple interactions between coagulation factors and platelets.6 Rupture or fissuring in atherosclerotic plaques exposes a prothrombotic core that comes into contact with platelets and coagulation factors. Initially, platelets adhere to the site of the break and become partially activated. Factor VII (FVII) binds to exposed tissue factor (TF) and forms a complex, which subsequently activates FIX and FX, resulting in FV activation. Activated FX and FV cleave prothrombin to generate limited amounts of thrombin, enough to maintain platelet activation but insufficient to sustain thrombus formation. Platelet stimulation by thrombin and exposed collagen results in full activation and degranulation, followed by FV release and activation by both FXa and thrombin. Thrombin also activates FVIII and this can form an active complex with FIXa, further enhancing the coagulation process. Subsequently, enough Diabetes and thrombosis riskCardiovascular disease (CVD) remains the main cause of morbidity and mortality in individuals with diabetes. Up to 80% of diabetes subjects die as a result of cardiovascular complications, and the risk of atherothrombotic events in this population is similar to non-diabetic individuals with a history of ischaemic heart disease (IHD).1 Moreover, the prognosis in these individuals following an event remains poor, despite major advances in treatment.2 Increased atherothrombosis risk is even evident in the pre-diabetes stage, as subjects with insulin resistance and normoglycaemia are at risk of cardiovascular events secondary to clustering of risk factors. 3The underlying mechanisms for increased thrombosis risk in diabetes are complex and involve multiple pathways. S...

Low-grade risk of hypercoagulable state in patients suffering from diabetes mellitus type 2

“…This study has demonstrated that not only the plasma levels of TF but also TFPI were higher in type 2 diabetes mellitus (T2DM) patients; however, only uncontrolled with microalbuminuria. The TF expression by endothelial cells is found in trace amounts in the resting state; however, that synthesis is upregulated in the presence of inflammation, which is commonly associated with diabetes type 2 (Alzahrani and Ajjan, 2010;Breitenstein et al, 2010). The TF level does not always correlate with the activity of TF, it is probably related to the simultaneous synthesis of the TFPI by the endothelial cells (Steffel et al, 2006).…”

“…Mechanisms for altered clot structure in diabetes are multifactorial: firstly, high plasma glucose can lead to increased glycations of fibrinogen and fibrin, which is associated with a more massive clot structure, which, in turn, favors resistance to lysis; secondly, elevated plasminogen activator inhibitor (PAI)-1 level reduces the fibrinolytic potential; thirdly, the non-enzymatic glycations of plasminogen and decreased activities of protein C act as the inhibitors of PAI-1 (Alzahrani and Ajjan, 2010). This study has demonstrated that not only the plasma levels of TF but also TFPI were higher in type 2 diabetes mellitus (T2DM) patients; however, only uncontrolled with microalbuminuria.…”

“…It is considered that 80% of diabetic patients die from thrombotic episodes and 75% from the results of cardiovascular complications (Boden et al, 2007;Alzahrani and Ajjan, 2010;Chu, 2011;Kota et al, 2012). Diabetic patients without previous cardiovascular disease show a similar rate of myocardial infarction (MI), as compared with non-diabetic subjects who suffered from previous MI events (Alzahrani and Ajjan, 2010;Hess and Grant, 2011). Diabetes is also the most significant cause of end-stage renal failure worldwide.…”

“…Diabetes mellitus, including type 1 and type 2, is associated with the hypercoagulable state through increased thrombotic tendencies due to platelet hyperreactivity and an increased activation of prothrombotic coagulation factors, such as VII, VIII, X, XI, and XII, simultaneously with a decreased anticoagulant protein C level and the deterioration of the fibrinolysis process (Boden et al, 2007;Alzahrani and Ajjan, 2010;Breitenstein et al, 2010;Chu, 2011). These abnormalities, together with low-grade inflammation, lead to changes in the vessel architecture and the composition of the extracellular matrix (ECM) (Kota et al, 2012).…”

Hypoglycaemia, thrombosis and vascular events in diabetes

“…It is well recognized that chronic hyperglycemia promotes the development of atherothrombosis in diabetes by a concatenation of events that leads to increased atherosclerotic plaque formation and rupture, enhanced platelet activation, and increased thrombus formation [20,21]. Mechanisms for increased thrombosis risk include increased platelet activation as well as quantitative and qualitative changes in coagulation proteins such as plasminogen activator inhibitor-1 (PAI-1), fibrinogen, and plasminogen generating a denser fibrin clots that are resistant to fibrinolysis [22][23][24][25][26].…”