Adenosine diphosphate and thromboxane A2 platelet activation in type II diabetes mellitus

Abstract

Type II diabetes mellitus is associated with various co-morbidities and has become a global health concern. Patients suffering from type II diabetes mellitus have an increased risk for thrombotic events such as myocardial infarction and stroke. Platelets play an important role in the development of a thrombus through activation, aggregation and the formation of a fibrin network by providing surface area for thrombin generation. Platelet activators and its receptors are of significant interest, because these molecules are responsible for the initiation of coagulation and the subsequent development of the thrombus through continued platelet activation and recruitment. Adenosine diphosphate and thromboxane A2 are two potent platelet activators and signalling through their pathways are often targeted in antiplatelet therapy. Platelet reactivity in response to these agonists and increased receptors for adenosine diphosphate (P2Y1 and P2Y12) or thromboxane A2 (TP) as a possible mechanism of action for platelet hyperactivity in the type II diabetes mellitus population has not been well defined.

The aim of this study was to elucidate whether type II diabetes mellitus platelets are more reactive towards adenosine diphosphate or thromboxane A2, and whether they express more receptors for these agonists, compared to healthy platelets. This was done by analysing receptor expression on platelet surfaces (P2Y1, P2Y12, TP) using flow cytometry and laser scanning confocal microscopy and assessing platelet activation in response to adenosine diphosphate and thromboxane A2 by using Thromboelastography platelet mappingTM. Morphological differences between platelets from healthy individuals and patients with type II diabetes mellitus were also visualised in order to determine whether type II diabetes mellitus platelets are more activated using laser scanning confocal microscopy.

The results showed that type II diabetes mellitus platelets are more sensitive to adenosine diphosphate -mediated signalling compared to the platelets from healthy individuals. In line with previous findings, the present study demonstrated augmented adenosine diphosphate induced aggregation through significantly higher adenosine diphosphate Thromboelastography platelet mappingTM parameters (MAADP, GADP and percentage aggregation) compared to healthy individuals, while thromboxane A2 parameters were normal. In addition, flow cytometric analysis indicated an increase in P2Y12 expression in unstimulated platelets. The Thromboelastography platelet mappingTM parameters for thrombin and fibrin was also significantly higher in patients suffering from type II diabetes mellitus while microscopic analyses revealed that type II diabetes mellitus platelets have more activated morphology and form more aggregates.

The results obtained potentially support the hypothesis that type II diabetes mellitus platelets are more reactive towards adenosine diphosphate as a result of increased pathway sensitivity and an increase in the number of P2Y12 receptors in an unstimulated state (constitutive expression of receptors). Furthermore, the findings of higher fibrin and thrombin parameters in type II diabetes mellitus corroborate previous results of augmented fibrin formation and enhanced thrombin generation. The results of this study could aid in the development of future strategies to treat or prevent thrombotic events in patients suffering from type II diabetes mellitus especially in the context of resistance to conventional antiplatelets.