Platelets: bridging thrombosis and inflammation

Recent advances in the fields of thromboinflammation and immunothrombosis induced a paradigm shift integrating platelets as key components of the immune system, independent of their hemostatic functions. Platelets constitutively express a plethora of immune receptors such as toll-like receptors (TLRs), complement receptors, antibody receptors (FcR), and intracellular NOD-like receptors (NLRs) and, upon activation, can also upregulate and secrete an arsenal of immunomodulatory molecules, regulating both the innate and adaptive immune responses [1,2]. Although platelets were initially shown to promote a proinflammatory and prothrombotic state in sterile and infectious injuries, recent studies have shown protective roles for platelets during inflammation, in particular in the maintenance of vascular integrity, resolution of inflammation, and promotion of tissue repair [3,4]. More recently, platelet microvesicles have emerged as novel regulators of thrombo-inflammatory diseases, which, unto themselves, can regulate both innate and adaptive immunity [5,6]. Inflammatory/immune alteration of platelet function does not occur solely in periphery, but might also result from transcriptional and translational alteration in the genetic profile of megakaryocytes. The pro- or anti-inflammatory functions of platelets are highly dynamic with distinct receptors engaged in different vascular beds during the course of the inflammatory response. Likewise, the composition and structure of thrombi under inflammatory conditions is highly heterogeneous, dictated directly by the specific nature of the insult and the characteristics of the target vascular bed/organ. Moreover, recent studies have shown significant changes in the composition of the thrombi within the same organ during disease progression, increasing the complexity of successful treatment under thromboinflammatory conditions without global alteration of the hemostatic balance. Therefore, the success of novel anti-thrombotic drugs or the strategic repurposing of existing therapies will need to be tailored to each stimulus, organ, and disease state in an effort to limit both thrombosis and inflammation while simultaneously preserving vascular integrity and organ function.

In this Platelets review series, experts in the field of immunothrombosis and thromboinflammation present and discuss both established and newly emerging roles for platelets beyond hemostasis, emphasizing their function, and dysfunction, within these challenging conditions. These reviews focus on the role of platelets, their progenitors, and descendent microvesicles in the regulation of innate and adaptive immune cells while maintaining perspective on the potential hemorrhagic and thrombotic complications.

Marcoux et al. [7] discuss the role of platelets and megakaryocytes in the regulation of innate and adaptive immunity including antigen uptake and presentation, the establishment of an adaptive response, and antibody production. The authors focus on the role of the platelet ITAM-coupled antibody receptor FcγRIIa in the adaptive response and highlight possible implications in COVID-19 patients.

Vulliamy et al. [8] outline what is known about platelet reactivity after an initial traumatic injury and hemorrhage. This review focuses on the shift from a hyporeactive to a hyperreactive state in platelets following recovery from the initial insult. This review also highlights the mechanisms by which changes in platelet reactivity alter coagulation and inflammation in trauma patients and discusses the potential of platelet-based therapies in trauma patients. In the last decade, there is also increasing evidence showing the heterogeneous composition of thrombi in different thrombo-inflammatory diseases. Staessens & De Meyer [9] present and discuss the evidences for the presence of different molecular and cellular patterns of thrombi in ischemic stroke patients. These studies forge the path toward personalized anti-thrombotic therapies to reduce stroke in patients.

One of the principle non-hemostatic functions of platelets is to regulate immunothrombosis. Martinod and Deppermann [10] review the role of platelets in immunothrombosis, focusing on the interaction between platelets and innate immune cells in sterile and infectious diseases. The authors review novel roles for the platelet receptors CLEC-2, GPVI, and GPIb in the development of deep vein thrombosis associated with infections. In addition to direct interaction with immune cells, platelets also cooperate with endothelial cells and the coagulation cascade to regulate immunothrombosis. Building upon this concept, Mackman and Antoniak [11] highlight the role of tissue factor, thrombin, and platelets in the host immune response to viral infections. The role of platelets in immunothrombosis does not depend exclusively on direct platelet activation and release of anti-microbial or immunomodulatory molecules. Often platelet participation in immunothrombosis is initiated by and regulated through their interactions with the coagulation cascade, immune cells, and the endothelium. Gomez et al. [12] discuss the contribution and molecular mechanisms involved in platelet-mediated release of neutrophil extracellular traps (NETs) during bacterial and viral infection. Importantly, this relationship is not simply unidirectional; NETs feedback onto the platelet, regulating activation and aggregation, shaping the thromboinflammatory phenotype throughout the infection. As such, NETs potentially represent a new therapeutic target for the treatment of excessive inflammation and coagulation associated with infection.

This review series highlights the multifaceted role of platelets in sterile and infectious injuries. Whereas the function of these small, anuclear cellular fragments was once thought to be limited primarily to hemostasis, we now are beginning to better understand the central role platelets play in infection, inflammation, tissue injury, and repair. Continued work will further clarify the function of platelets in thromboinflammation and immunothrombosis, identifying new therapeutic possibilities tailored to specific disease states and affected organs, in an effort to improve patient outcomes while preserving the critical hemostatic functions of platelets.

Declaration of Interest Statement

The authors report no conflict of interest.