[The role of platelets in atherosclerosis, diabetes mellitus, and chronic kidney disease. An attempt at explaining the TREAT study results]

Abstract

Erythropoiesis-stimulating agents (ESA) are used to treat renal anemia. The TREAT study (Trial to Reduce Cardiovascular Events with Aranesp Ther- apy) of diabetic patients with chronic kidney disease (CKD) found that the risk of stroke was significantly higher than in the control arm. This raises the question as to what causes this phenomenon. Platelets may play a crucial role in this context. Atherogenesis involves complex interactions between platelets and monocytes (platelet-monocyte crosstalk) and with endothelial cells. Platelets are activated in cases of diabetes mellitus, especially. During atherogenesis, partial functions of platelets other than those inhibited by aspirin, as a cyclooxygenase inhibitor, or by adenosine diphosphate receptor P2Y(12)antagonists, such as thienopyridines, are of relevance. During platelet-monocyte crosstalk, specifically, an important role is played by adhesion receptors such as selectins and integrins. In addition, ESA cause platelet activation by direct and indirect mechanisms. Antagonistic thereto is a renal bleeding tendency in cases of severe CKD, due to platelet dysfunction, which can be remedied with appropriate renal replacement therapy and administration of ESA in order to reach a hemoglobin (Hb) level of 10 g/dl. However, if the Hb level exceeds 10 g/dl, the even stronger platelet activation caused by ESA, combined with the activation caused by diabetes, leads to a prothrombotic state, which in patients with severe atherosclerosis can result in acute atherothrombotic complications, in the genesis of which platelets play a key role. This would be one hypothesis for explaining the increased incidence of strokes in the TREAT study.