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Reticulated platelets in poorly controlled diabetes: A new era in the management of residual risk?

Diabetes is characterized by a higher risk of occlusive, thrombotic cardiovascular disease with poorer outcomes than is seen in subjects without diabetes. Evidence indicates that diabetes-related alterations in clotting may contribute to this risk and that the platelet has a critical role. These observations have led to antiplatelet therapy becoming the cornerstone of the prevention and management of acute coronary syndromes (ACS) in high-risk individuals. However, although intensive management of cardiovascular risk, including dual antiplatelet therapy, improves outcome post-ACS in both diabetes and non-diabetes subjects, there remains a worse outcome in diabetes after ACS, a difference which is commonly referred to as ‘residual risk’. High glucose levels have been implicated in the increased thrombotic environment in diabetes through various mechanisms. Glycation of coagulation proteins in poorly controlled diabetes interferes with normal function leading to altered fibrin clot formation1 and decreased ability to break down the fibrin network,2 the backbone of the vascular obstructive blood clot. This fibrin mesh provides an important scaffold on which the platelet binds, creating the platelet-rich fibrin mesh characteristic of arterial thrombus. It has been recognized for decades that subjects with poorly controlled diabetes have increased platelet size and a more rapid turnover of bone marrow platelet production. This situation occurs through the generation of immature platelets, also known as reticulated platelets, which maintains the platelet pool in the circulation. In recent years, the failure of conventional antiplatelet therapy to close the residual risk gap has led to attention being directed towards understanding the potential role in ACS outcomes of the small fraction of the platelet pool represented by reticulated platelets. These immature platelets circulate in a relatively activated form compared to mature platelets and there is evidence to suggest that they exhibit resistance to both clopidogrel3 and aspirin.4 Clinical studies have indicated that the percentage of reticulated platelets is an indicator of outcome post ACS5 and of cardiovascular events after non-cardiac surgery.6 A recent, important, paper from Monash University in Melbourne has demonstrated that diabetes with suboptimal glycaemic control creates an environment whereby increased immature platelets are released into the circulation.7 In this in vivo study, hyperglycaemia led to increased hepatic Kupffer cell production of interleukin (IL)-6 which in turn increased thrombopoietin production and the generation of bone marrow–derived reticulated platelets. A number of interventions blocked this process, but most notably, from a clinical perspective, lowering blood glucose with a sodium-glucose cotransporter-2 (SGLT2) inhibitor. These findings finally bring the issue of reticulated platelets into the diabetes space and indicate that the generation of reticulated platelets in poorly controlled diabetes produces a reversible pro-thrombotic environment to go along with the reversible effects of glycation on fibrin structure1 and clot lysis2 processes. Further work to understand the significance of these findings in diabetes patients and particularly the implications for future antiplatelet strategies may help to produce therapies that narrow the residual risk gap in diabetes that continues to contribute to increased vascular morbidity and mortality in this highrisk population.