Thrombosis and Haemostasis 112.4/2014 © Schattauer 2014 1 Theme Issue Article Infections and the role of plasma proteins and platelets Immune functions of platelets Daniel Duerschmied; Christoph Bode; Ingo Ahrens Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany Summary This review collects evidence about immune and inflammatory func- tions of platelets from a clinician’s point of view. A focus on clinically relevant immune functions aims at stimulating further research, be- cause the complexity of platelet immunity is incompletely understood and not yet translated into patient care. Platelets promote chronic in- flammatory reactions (e.g. in atherosclerosis), modulate acute inflam- matory disorders such as sepsis and other infections (participating in the host defense against pathogens), and contribute to exacerbations of autoimmune conditions (like asthma or arthritis). It would hence be obsolete to restrict a description of platelet functions to thrombosis and haemostasis – platelets clearly are the most abundant cells with immune functions in the circulation. Keywords Platelet immunology, sepsis, leukocyte function / activation Correspondence to: Daniel Duerschmied, MD Department of Cardiology and Angiology I Heart Center, University of Freiburg Hugstetter Str. 55, 79106 Freiburg, Germany Tel.: +49 761 207 34410, Fax: +49 761 270 37855 E-mail: daniel.duerschmied@universitaets-herzzentrum.de Received: February 17, 2014 Accepted after major revision: September 3, 2014 Epub ahead of print: September 11, 2014 http://dx.doi.org/10.1160/TH14-02-0146 Thromb Haemost 2014; 112: 678–691 Introduction The primary mission of platelets is haemostatic, because they me- diate primary haemostasis and atherothrombotic events (reviewed in [1]). Platelets also promote venous thromboembolism (2, 3). But platelets not only build thrombi, they are also highly active in the host defense against pathogens and have hence been recog- nized as cells with immune functions. They are involved in sepsis and other acute inflammatory responses to infection as well as in chronic inflammatory diseases like atherosclerosis or arthritis (re- viewed in [4–8]). Platelets circulate in large numbers through the vasculature (several hundred thousand per microliter), patrolling the endothelium and are able to rapidly release an array of immu- nomodulatory cytokines, chemokines, and other mediators (9, re- viewed in [10]). Platelets express several immune receptors on the cell surface, such as Toll-like receptors, immunoglobulin receptors or the co-stimulatory proteins CD40 and CD40L. Another feature that platelets have in common with other immune cells is the pres- ence of granules in the cytoplasm that can be exocytosed following specific stimulation. This allows the targeted release of mediators and the instantaneous upregulation of surface receptors at sites of inflammation. Platelets are able to modulate leukocyte functions such as phagocytosis or extravasation directly or in cooperation with endothelial cells of inflamed vessels. Surprisingly, increasing evidence shows that platelets are even able to capture and neutra- lise pathogens directly. Here we summarise observations of im- mune and inflammatory platelet components and functions. Clinical and experimental evidence of immune functions of platelets Every clinician has experienced marked changes in platelet count of patients with inflammatory diseases and many may have specu- lated about the role that platelets play in immunity. Whether long- term antiplatelet therapy, especially with the newer, more potent agents, influences inflammatory or immune responses has not been examined systematically. However, several studies have de- ciphered relevant contributions of platelets to the pathophysiology of inflammatory or immune disorders in animals or humans. Infections Thrombocytopenia is a common feature of severe bacterial or viral infection and a marker of poor outcome (reviewed in [11]). This suggests that platelets actively participate in the struggle against pathogens. Interestingly, recovery is often associated with reactive thrombocytosis (12). Platelet consumption in microthrombotic re- sponses to infection is a possible complication, such as in dissemi- nated intravascular coagulation (DIC), but does not explain these frequent findings in milder clinical courses. Thrombocytopenia and reactive thrombocytosis are hence not only collateral damage, but most likely constitute an active part of the host defense against infection. Curiously, direct antimicrobial activity of platelets has been discovered in animal models. In murine malaria, platelets were shown to eradicate intra-erythrocytic parasites and have hence an impact on survival, an effect that could be reproduced in ex vivo models with human blood cells (13). When platelet bind- ing to hepatic Kupffer cells via glycoprotein (GP)Ibα was imaged For personal or educational use only. No other uses without permission. All rights reserved. Note: Uncorrected proof, epub ahead of print online Downloaded from www.thrombosis-online.com on 2014-09-18 | ID: 1000495621 | IP: 193.196.237.20