Abstract

The discovery that platelets possess cell membrane, cytoplasmic, and secreted forms of the co-stimulatory molecule CD40 ligand (CD40L, also known as CD154) has led to a revolution in the view of this anucleate, differentiated cell fragment, previously thought only to be involved in blood clotting (hemostasis). During the last decade, it has become clear that platelets function in innate and adaptive immunity and possess pro-inflammatory, as well as pro-thrombotic properties. They interact not only with other platelets and endothelial cells, but also with lymphocytes, dendritic cells, and structural cells such as fibroblasts. Soluble forms of CD40L (sCD40L) in the human circulation are almost entirely derived from platelets. Elevated levels of CD40L are associated with clinically important conditions, such as vascular disease, abnormal clotting (thrombosis), lung injury, and autoimmune disease. Each year millions of platelet transfusions are given to patients that contain large amounts of sCD40L. sCD40L in the supernatant of stored platelets can induce cytokines, chemokines, and lipid mediators by activating CD40 bearing cells. Increased levels of sCD40L in transfused blood are associated with transfusion-related acute lung injury, a potentially fatal complication, as well as more common, milder transfusion reactions such as fever and rigors. These effects come under the rubric of transfusion immunomodulation, which postulates that transfusion recipient biology, particularly immune function, is dramatically altered by transfusion of stored allogeneic blood.