Abstract
Platelets play an essential role in maintaining homeostasis in the circulatory system after an injury by forming a platelet thrombus, but they also occupy a central node in the intravascular innate immune system. This concept is supported by their extensive interactions with immune cells and the cascade systems of the blood. In this review we discuss the close relationship between platelets and the complement system and the role of these interactions during thromboinflammation. Platelets are protected from complement-mediated damage by soluble and membrane-expressed complement regulators, but they bind several complement components on their surfaces and trigger complement activation in the fluid phase. Furthermore, localized complement activation may enhance the procoagulant responses of platelets through the generation of procoagulant microparticles by insertion of sublytic amounts of C5b9 into the platelet membrane. We also highlight the role of post-translational protein modifications in regulating the complement system and the critical role of platelets in driving these reactions. In particular, modification of disulfide bonds by thiol isomerases and protein phosphorylation by extracellular kinases have emerged as important mechanisms to fine-tune complement activity in the platelet microenvironment. Lastly, we describe disorders with perturbed complement activation where part of the clinical presentation includes uncontrolled platelet activation that results in thrombocytopenia, and illustrate how complement-targeting drugs are alleviating the prothrombotic phenotype in these patients. Based on these clinical observations, we discuss the role of limited complement activation in enhancing platelet activation and consider how these drugs may provide opportunities for further dissecting the complex interactions between complement and platelets.
Highlights
The Complement SystemThe complement system functions as an intravascular surveillance system and constitutes one of the branches of the innate immune system
The classical and lectin pathways are triggered by pattern-recognition molecules (PRMs) that bind to foreign targets or altered self surfaces, whereas the alternative pathway is continuously activated at a low level in the fluid phase and can be rapidly amplified when an activating foreign surface is present
Platelets interact with the cascade systems of blood in a highly controlled fashion, with complement mediating platelet-leukocyte interactions, contributing to platelet activation, and helping to mount a pro-inflammatory response, all while preserving host cell integrity and avoiding complementmediated damage to healthy cells
Summary
The Complement SystemThe complement system functions as an intravascular surveillance system and constitutes one of the branches of the innate immune system. C3(H2O) bound to activated platelets could potentially combine with factor B to form an alternative pathway C3 convertase to initiate the events leading to MAC formation, a model that has received experimental support [26].
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