Abstract
Atherosclerotic cardiovascular disease is the major cause of morbidity and mortality in patients with type 1 diabetes mellitus (T1DM). Enhanced platelet reactivity is considered a main determinant of the increased atherothrombotic risk of diabetic patients. Thrombopoietin (THPO), a humoral growth factor able to stimulate megakaryocyte proliferation and differentiation, also modulates the response of mature platelets by enhancing both activation and binding to leukocytes in response to different agonists. Increased THPO levels have been reported in different clinical conditions characterized by a generalized pro-thrombotic state, from acute coronary syndromes to sepsis/septic shock, and associated with elevated indices of platelet activation. To investigate the potential contribution of elevated THPO levels in platelet activation in T1DM patients, we studied 28 T1DM patients and 28 healthy subjects. We measured plasma levels of THPO, as well as platelet-leukocyte binding, P-selectin, and THPO receptor (THPOR) platelet expression. The priming activity of plasma from diabetic patients or healthy subjects on platelet–leukocyte binding and the role of THPO on this effect was also studied in vitro. T1DM patients had higher circulating THPO levels and increased platelet–monocyte and platelet–granulocyte binding, as well as platelet P-selectin expression, compared to healthy subjects, whereas platelet expression of THPOR did not differ between the two groups. THPO concentrations correlated with platelet–leukocyte binding, as well as with fasting glucose and Hb1Ac. In vitro, plasma from diabetic patients, but not from healthy subjects, primed platelet–leukocyte binding and platelet P-selectin expression. Blocking THPO biological activity using a specific inhibitor prevented the priming effect induced by plasma from diabetic patients. In conclusion, augmented THPO may enhance platelet activation in patients with T1DM, potentially participating in increasing atherosclerotic risk.
Highlights
Cardiovascular disease (CVD) is the major cause of morbidity and mortality in patients with type 1 diabetes mellitus (T1DM) [1]
The results of our study suggest that THPO may participate in the pathophysiology of enhanced platelet activation in patients with type 1 diabetes mellitus
That higher concentrations of circulating THPO were associated with increased indices of platelet activation in vivo in type 1 diabetic patients
Summary
Cardiovascular disease (CVD) is the major cause of morbidity and mortality in patients with type 1 diabetes mellitus (T1DM) [1]. The rising global incidence of T1DM with an even earlier age of onset leads to a longer exposure to the disease and a greater risk of premature CVD with microvascular and macrovascular complications that accelerate the process of atherosclerosis [2,3]. Together with endothelial dysfunction, increased levels of coagulation factors, and impaired fibrinolysis, has been associated with the elevated atherothrombotic risk of diabetic patients, and oral antiplatelet therapy has become a key treatment for reducing the long-term risk of ischemic events in DM patients [6,7,8]. The use of more potent and prolonged antiplatelet therapies reduces the rates of drug resistance and the recurrence of ischemic events, but the increase in bleeding complications represents a major concern [9]
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