**3.2 Aggregation**

In DM, platelets exhibit hyperactivity and increased sensitivity to agonists such as ADP, AA, collagen, and epinephrine [26], which augments successive increased secretion of and response to prostaglandins [21, 27]. Specifically, there is greater platelet reactivity in T1DM compared with T2DM and healthy controls as evaluated by light transmission aggregometry (LTA) and platelet function analyzer-100 (PFA-100) [28, 29]. Notably, aggregation curves are biphasic at low agonist concentrations showing greater augmentation of second wave [26] indicating increased secretion of and response to prostaglandins [27]. The mechanism for the biphasic wave response is due to altered ATP/ADP metabolism [30], nucleotide and thromboxane secretion [31], and calcium fluxes [32]. These are because, upon agonist stimulation, there is an initial phase characterized by glycogenolysis with minimal ATP synthesis causing translocation of alpha granule-containing glucose transporter 3 (Glut-3) to the surface, followed by a second phase of enhanced Glut-3 glucose entry, glycolysis, and ATP synthesis leading to both alpha and delta granule translocation and degranulation [33]. These processes are exaggerated in the presence of high vWF, cholesterol and poor glycemic control in T1DM [24].

In contrast, others have found no change in ADP-induced platelet aggregation in T1DM [34, 35]. The lack of consistency with other studies probably suggests loss of adhesive molecules into platelet microparticles [36] or modulation by factors extrinsic to the platelets such as magnesium ions [37], insulin [38], and acidosis [39].
