Platelets as Central Mediators of Systemic Inflammatory Responses

Abstract

Systemic inflammatory responses are associated with high morbidity and mortality and represent a diverse and clinically challenging group of diseases. Platelets are increasingly linked to inflammation, in addition to their well-known roles in hemostasis and thrombosis. There is agreement that traditional functions of platelets, including adherence, aggregation, and secretion of preformed mediators, contribute to systemic inflammatory responses. However, emerging evidence indicates that platelets function in non-traditional ways. In this review, we focus on new functions of platelets that may be involved in the host response to infection.

Introduction

The role of platelets in the host response to infection is increasingly appreciated. Platelet function is often compromised in diseases as diverse as human immunodeficiency virus (HIV), dengue and sepsis and disease severity and mortality correlate with the degree of thrombocytopenia that is clinically observed [1], [2], [3]. The etiology of thrombocytopenia in infectious diseases is complex but is typically due to decreased production of platelets and/or increased sequestration and clearance of activated platelets in the periphery. In regards to production, platelets are formed from megakaryocytes, which typically reside in the bone marrow but have also been observed in the circulation and lungs [4]. Several studies have shown that megakaryopoiesis and/or thrombopoiesis become disrupted during infection, contributing to reduced platelet counts [5]. There is also evidence that platelets continue to develop in the circulation [6]. In this regard, our group recently reported that circulating platelets themselves have the ability to divide and form functional progeny [7]. Whether or not the formation of progeny contributes to circulating platelet counts is unknown. However, when platelets encounter thrombin or E. coli they fail to produce progeny raising the possibility that this new function of platelets may contribute to the thrombocytopenia observed in infectious situations [7].

Although the production of platelets is unquestionably affected as the host encounters pathogens, it is more recognized that systemic infections are associated with increased platelet activation in the bloodstream. Activated platelets bind other platelets and leukocytes in the bloodstream setting off a cascade of events that contribute to the development, evolution, and resolution of the systemic inflammatory response (Fig. 1). Abnormal sequestration of platelets in the microcirculation induces thrombocytopenia and often leads to disseminated intravascular coagulation (DIC). In critically ill patients, DIC participates in the development of multiple organ failure and often death. Understanding how platelets become activated and the downstream consequences of platelet activation will contribute to the treatment of infectious diseases and the development of new therapeutics. In this review, we briefly focus on mechanisms by which platelets become activated during infectious states, paying particular attention to the emerging role of toll-like receptors (TLRs) in this process. We then discuss downstream consequences of platelet activation, focusing on recently identified prolonged actions of platelets that are turned on during the host response to infection.