Platelet Measurements and Type 2 Diabetes: Investigations in Two Population-Based Cohorts

Abstract

Type 2 diabetes is a major risk factor for cardiovascular disease. Given the contribution of platelets to atherothrombosis-which in turn is a major contributor to cardiac events, there may be cause to consider platelet function in management of diabetes. Despite the large body of research concerning the role of platelets in cardiovascular complications of type 2 diabetes, evidence from population-based studies of platelet aggregation in diabetes is limited. Mean Platelet Volume (MPV), a cell trait partially associated with markers of platelet activity, is more commonly available. We investigated the association of metabolic syndrome and diabetes with platelet aggregation to three physiological agonists, ADP, collagen, and epinephrine, in the Framingham Heart Study Offspring cohort. We further examined the relationship between MPV measured with Beckman Coulter LH750 instruments and self-reported diabetes as well as MPV and diabetes medication in the UK BioBank cohort, performing the largest such analysis to date. Increased platelet aggregation associated with prevalent diabetes was observed for low concentration epinephrine (0.1 µM) alone and only in analyses of participants stratified either by male sex and/or having metabolic syndrome. Other agonists and concentrations were not significant for prevalent diabetes, or in opposite direction to the main hypothesis (i.e., they showed lower platelet aggregation associated with diabetes). After a median of 18.1 years follow-up, no platelet aggregation trait was associated with increased risk of diabetes (n = 344 cases). As expected, increased MPV was significantly associated with diabetes (β = 0.0976; P = 8.62 × 10 −33). Interestingly, sex-stratified analyses indicated the association of MPV with diabetes is markedly stronger in males (β = 0.1232; P = 1.00 × 10 −31) than females (β = 0.0514; P = 7.37 × 10 −5). Among diabetes medications increased MPV was associated with Insulin (β = 0.1341; P = 1.38 × 10 −11) and decreased MPV with both Metformin (β = 0.0763; P = 1.99 × 10 −6) as well as the sulphonylureas (β = 0.0559; P = 0.0034). Each drug showed the same direction of effect in both sexes, however, the association with MPV was nearly twice as great or more in women compared to men. In conclusion, platelet function as measured by aggregation to ADP, collagen, or epinephrine does not appear to be consistently associated with diabetes, however, MPV is robustly associated suggesting future work may focus on how MPV segments pre-diabetics and diabetics for risk prediction.

Dapagliflozin reduces thrombin generation and platelet activation: implications for cardiovascular risk reduction in type 2 diabetes mellitus

“…It is well known that platelet function changes under diabetic conditions and the risk of thrombotic events is increased. While results from studies in diabetic volunteers are in part controversial [14,15,44], we show here that dapagliflozin affects resting platelets in diabetic mice. However, this is in contrast to healthy humans, in whom an effect was only detectable after agonist stimulation.…”

“…Clearly, translation to volunteers with diabetes is required in further studies, dapagliflozin decreases thrombin-mediated platelet activation and alpha granule secretion via both direct effects and HDL-mediated effects on thrombin formation. Decreased platelet-leucocyte aggregates and subsequent diminished monocyte-macrophage-recruitment to the vascular wall contribute to atheroprotection by dapagliflozin treatment particularly against the background that clinical studies have shown controversial results regarding platelet activation under diabetic conditions [14,15]. Activated platelets facilitate leucocyte adhesion to the endothelium and subsequent immune cell recruitment to the vascular wall [46].…”

“…It might be suggested that platelet pre-activation, as in obesity and insulin resistance, is needed to see dapagliflozin’s effects [ 45 ]. Clearly, translation to volunteers with diabetes is required in further studies, particularly against the background that clinical studies have shown controversial results regarding platelet activation under diabetic conditions [ 14 , 15 ].…”

“…In this context conflicting results have been reported [ 14 , 15 ], but nevertheless this topic is of specific importance for people with diabetes: patients with poorly controlled diabetes have increased platelet-dependent thrombin generation and higher plasma levels of important markers of coagulation [ 16 – 18 ]. Elevated coagulation and platelet activation are known drivers of atherogenesis and atheroprogression [ 19 ], leading to cardiovascular events such as myocardial infarction and heart failure.…”

Association between Neutrophilic Granulocyte Percentage and Diabetes Mellitus in Cushing’s Syndrome Patients: A Cross-Sectional Study

“…Several hematological markers have already been reported to be associated with diabetes mellitus. These included red blood cell distribution width (RDW) [ 12 ], mean platelet volume (MPV) [ 13 ], neutrophil count to lymphocyte count ratio (NLR) [ 14 ], platelet count to lymphocyte count ratio (PLR) [ 15 ], and MPV to lymphocyte count ratio (MLR) [ 16 ]. The association between these indicators and diabetes has been well established.…”