PB1226 - Hyperglycaemia enhances platelet degranulation and microparticle shedding: a novel mechanism underlying thrombotic complications in diabetes patients.

Background: Platelet hyperactivity and increased thrombosis risk are typical of type 2 diabetes mellitus patients, for whom cardiovascular diseases represent the most common cause of death. The cellular and molecular causes for the increased thrombotic risk in diabetes remain to be elucidated, although platelet hyperactivity has been observed in these patients.

Aims: In order to understand the effect of diabetes on platelets, we studied the effect of hyperglycaemia on platelet responsiveness in vitro. Platelet phenotypes and underlying molecular mechanisms identified in vitro were validated in clinical samples from diabetes patients.

Methods: In vitro studies were performed on peripheral blood from healthy volunteers treated for up to 48 hours with different concentrations of glucose. Clinical samples from diabetes patients were obtained from the University Medical Center Eppendorf (Hamburg) and were selected based on glycated haemoglobin (HbA1c): healthy control with HbA1c < 6.0%, diabetes patients with HbA1c > 7.0%. Further patient stratification was applied based on age, sex, cardiovascular comorbidity, and renal comorbidity. Platelet activation, secretion, procoagulant activity, microparticle release and leukocyte complexation were assessed by flow cytometry. The intracellular signalling underlying platelet phenotypes was investigated by immunochemistry and in vitro pharmacology.

Results: Supraphysiological glucose concentrations in vitro increased basal and primary agonist-induced platelet degranulation. The increased degranulation was not associated with an increase in integrin activation and platelet aggregation, which suggested a selective glucose-dependent control of granule secretion rather than a generalised effect on platelet responsiveness. Platelet degranulation in supraphysiological glucose was accompanied by a release of platelet-derived microparticles and procoagulant microparticles , which was confirmed in the plasma of diabetes patients. The microparticles from diabetes patients enhanced platelet responses and coagulation cascade in vitro.

Conclusion(s): In this study, we describe a potential new mechanism linking the secretory properties of platelets with the increase cardiovascular risk of diabetes mellitus patients.