Platelet Dysfunction in Type 1 Diabetes: Stressing the Thromboxanes

Overall death from cardiovascular disease (CVD) has declined over the past 20 years; yet, the population with diabetes has seen minimal benefit (1,2). When broken out by diabetes type, individuals with type 1 diabetes mellitus (T1DM) have approximately a 10-fold age-adjusted increased risk of CVD, even higher than that observed in those with type 2 diabetes mellitus (T2DM), with women being more affected then men (3,4). This is in the face of drastically improved insulin therapy regimens over the past decades, suggesting that hyperglycemia itself may not explain this increased CVD. Paradoxically, though, high-quality clinical studies regarding the risks of CVD in T1DM and the potential mechanisms underlying this pathophysiology remain woefully underrepresented as compared with similar studies related to individuals with T2DM, who are known to have persistently elevated platelet reactivity and a depressed inhibitory response to aspirin (5,6). Furthermore, the published studies that do exist are performed variably on pediatric and adult T1DM patients and show highly conflicting results (7–14). Taken together, the current state of the field is a hindrance to the proper care and treatment of individuals with T1DM. A number of risk factors have been proposed to elevate CVD risk in T1DM patients, including hyperglycemia, dyslipidemia, inflammation, oxidative stress, and genetics, among others (3). A significant contributing factor to the diabetic prothrombotic state is the aberrant regulation of antiplatelet-activating mechanisms that normally maintain high levels of inhibitory cAMP to prevent aggregation (1). Molecules directly affecting platelet cAMP production are the arachidonic acid metabolites thromboxane A2 (TXA2) and prostacyclin (PGI2). TXA2 …