Aspirin and P2Y12 Inhibitors in platelet-mediated activation of neutrophils and monocytes

Abstract

Platelets are key players in haemostasis and represent a pivotal link between inflammation, immunity and atherogenesis. Depending on the (patho)physiological environment platelets modulate various leukocyte functions via release of inflammatory mediators and direct cell-cell interactions. Elevated levels of circulating platelet-leukocyte aggregates are found in patients suffering from several thrombotic or inflammatory conditions. Platelet-monocyte and platelet-neutrophil interaction can trigger pro- and anti-inflammatory responses and modulate effector functions of all leukocyte subpopulations. These platelet-mediated immune responses have implications for the progression of cardiovascular diseases and also play a crucial role during infections, cancer, transplantations and other inflammatory diseases of several organs. Antiplatelet therapy including the COX inhibitor aspirin and/or ADP receptor P2Y12 inhibitors such as clopidogrel, prasugrel and ticagrelor are the therapy of choice for various cardiovascular complications. Both aspirin and P2Y12 inhibitors attenuate platelet-leukocyte interactions, thereby also modulating immune responses. This may have beneficial effects in some pathological conditions, while it might be detrimental in others. This review aims to summarise the current knowledge on platelet-leukocyte interactions and the impact of aspirin and P2Y12 inhibition on platelet-mediated immune responses and to give an overview on the effects of antiplatelet therapy on platelet-leukocyte interplay in various diseases.

Ticagrelor Protects the Heart Against Reperfusion Injury and Improves Remodeling After Myocardial Infarction

“…Also in addition to ticagrelor, the other P2Y 12 antagonists, clopidogrel and prasugrel, can attenuate platelet-leukocyte interactions and modulate inflammatory response. 54 Yet, in our model, ticagrelor, but not clopidogrel, limited IS and improved postinfarction remodeling, despite similar platelet inhibition by both drugs. No data are available for prasugrel in this regard.…”

Measuring and interpreting platelet-leukocyte aggregates

“…Emerging studies suggest associations between PLAs and pro-inflammatory effects in numerous pathological conditions, including CVD, rheumatoid arthritis, inflammatory bowel disease and autoimmune cerebral inflammation, which were previously reviewed (1,79,80). In this review we focus on platelet-leukocyte interactions in acute ischemic stroke, renal diseases, and hepatic as well as lung inflammation and infection, and give an overview on the leukocyte types involved (Figure 2).…”

“…Due to their high sensitivity to thrombotic and immunologic factors, platelets further represent susceptible sentinels that are ready to launch immediate and potent immune responses. Platelet activation and concomitant degranulation enables platelets to engage with leukocytes via soluble factors and physical interaction facilitated by a variety of receptors (1). Most importantly receptors involved in direct interactions include platelet P-selectin (CD62P) and CD40 ligand (CD40L), as well as PSGL-1, CD40 and Mac-1 (integrin α M β 2 , CD11b/CD18) on leukocytes (2–4).…”

“…Most importantly receptors involved in direct interactions include platelet P-selectin (CD62P) and CD40 ligand (CD40L), as well as PSGL-1, CD40 and Mac-1 (integrin α M β 2 , CD11b/CD18) on leukocytes (2–4). Platelet-leukocyte interactions are further stabilised by crosstalk of numerous additional receptor/ligand pairs that were reviewed previously (1,5) and trigger mutual activation and release of granular content by both platelets and leukocytes, thereby modulating leukocyte function and fine-tuning immune responses (5). Importantly, platelet-leukocyte interactions facilitate leukocyte recruitment and extravasation to sites of inflammation (6,7), promote leukocyte release of pro-inflammatory mediators (8,9), oxidative burst, phagocytosis, release of neutrophil extracellular traps (NETs) (10,11), and may also dampen inflammation under some pathological conditions (12–14).…”

Platelets: an outlook from biology through evidence-based achievements in critical care

“…Today these are well-described by the NETosis processes represented in Figure 6. The pathophysiological consequences of these interactions in various diseases such as liver, renal, and skin disease, rheumatoid arthritis, lupus, transplantation, respiratory disorders, viral and bacterial infections, and cancer are discussed by Schrottmaier et al in a remarkable review (49). Furthermore, platelets have been involved when the basal barrier of the alveolar capillary endothelium loses its integrity in order to repair and remodel in pulmonary, alveolar and bronchial vessels.…”