Platelets are the smallest blood cells, and yet their total volume and surface area exceed those of all types of leukocytes combined. Platelets are produced by the bone marrow megakaryocytes and megakaryocytes in the lung microvessels. Approximately 50% of all platelets are produced in the lungs, which makes it possible to characterize them as the main site for the production of platelets. In small circuit of blood circulation, there are approximately 30% more platelets than in large circuit. This “excess” of platelets is necessary for the stabilization of the endothelial barrier of the lung vessels regulated by the platelet mediator sphingosine-1-phosphate, a regulator of tight junctions of endothelial cells. The circulating platelets have an amazing ability to “bud” new pro- and pre-platelets, giving rise to new platelets. The removal of platelets from circulation proceeds via their phagocytosis by spleen macrophages (if platelets are covered with IgG or are bound to immune complexes), or Kupffer liver cells and hepatocytes (if platelets have incomplete glycans or desialated proteins). In homeostatic conditions, most of the platelets are removed in liver. Platelet clearance in bacterial infections and sepsis is accelerated because of the activity of bacterial sialidases. Recognition of desialized platelet structures is carried out by the liver cells through the Asgr receptor. Despite DNA absence, the platelets are able to synthesize proteins at mRNAs that are present in majority of platelets. Activation of platelets leads to aggregation and exocytosis of the granule contents, and production of immunomodulating molecules. However, activation of platelets may be incomplete and has various consequences. In a non-classical activation model, platelets can release microparticles that contain about 600 different proteins. About 75% of microparticles in the blood of healthy donors are derived from platelets. Like as immune system cells, platelets are activated by numerous endogenous ligands (alarms), including ADP and ATP, which bind to purinergic receptors P2Y1, P2Y12 andP2X1. Platelets accumulate and retain 99% of the serotonin stored in the body. The platelets contribute to induction of inflammation by releasing proinflammatory cytokines, chemokines, and lipid mediators. In addition, platelets are the source of enzymes that accomplish the capacities of neutrophils and endothelium for production of anti-inflammatory lipid mediators that contribute to tissue repair following acute phase of inflammation.

Резюме Abstract In recent years, a critical mass of information has accumulated, which has made it possible to equate platelets to the cells of innate immunity, which ensures the initiation of inflammation and the reactions of innate immunity. In the presented review platelets were examined from the point of view of antibacterial immune reactions. Mechanisms that allow platelets to recognize bacteria and their soluble products as characteristic of immune cells (via TLR2, TLR4, TLR7 and TLR9, FcγRIIa and receptors for complement components), as well as the mechanisms involved in the hemostasis process (GPIb, GPIIb-IIIa)

Thrombocytes keep a leading role in conjugating thrombosis, inflammation and congenital immune responses. The platelets provide stable adhesion and interaction with immune cells. Activated platelets express CD40L (CD154), a membrane glycoprotein of tumor necrosis factor (TNF) family. Hence, the platelets are the main source of sCD40L in blood plasma. Platelet CD154 may interact with CD40 receptor on endothelial cells, causing an inflammatory response, and enhancing production of immunoglobulins by B-lymphocytes. Membrane and soluble CD154 of platelets combined with other signals can induce maturation and activation of dendritic cells (DC). The platelets possess functional receptors, e.g., TLR2, TLR4, TLR7 and TLR9 they also bear Fc-receptors, including FcγRIIA, FcεRI and FcαRIA. FcγRIIA on platelets mediate protection against bacteria. Cross-linking of FcαRI on platelets results in production of prothrombotic and pro-inflammatory mediators such as tissue factor and IL-1β. Activation of platelets via FcεR1 causes release of chemokine RANTES and serotonin, which contribute to the pro-inflammatory response of other immune cells. Platelets possess receptors for activated complement components and its fragments (CR2, CR3, CR4, C1q, C1 inhibitor and factors D and H). Activated platelets trigger the complement system through the release of protein kinases and ATP, and also by phosphorylation of C3 and C3b. α-granules of platelets contain chemokines which represent the most numerous group of antimicrobial proteins of platelets (kinocidins), and there is an antimicrobial protein of the defensin family – hBD-1 in the cytoplasm of platelets. Ligand and receptor of the TNF superfamily (TRAIL and LIGHT), the SDF-1 chemokine (CXCL12), the IL-1βinterleukins, IL-8 and the soluble IL-6 receptor (sRIL-6) are recognized as platelet products belonging to the family of cytokines and their receptors. The HMGB-1 protein classified as an inflammatory cytokine, is expressed by activated platelets and causes formation of the extracellular traps by neutrophils. Platelets produce numerous growth factors, including EGF-α and EGF-β1, EGF-β2, TGF-α and TGF-β1, TGF-β2, PDGF, HGF, FGF-β, IGF, pro- and antiangiogenic factors, e.g., VEGF-F and angiopoietins Ang-1 and Ang-2. Fulfillment of immune functions by the platelets is carried out by their interaction with leukocytes, which are attracted to the site of infection and inflammation and retained during the development of an “immune thrombus” under conditions of high shear stress. Platelets can not only maintain and guide the immune response, but also initiate these events. They are able to present the antigen in the context of MHC class I molecules, and activate naїve CD8+T lymphocytes. Potential consequences of platelet interaction with neutrophils, monocytes, dendritic cells and lymphocytes are discussed in the review article.

Participation of blood platelets in the development of sepsis is clearly illustrated by hemocoagulation disorders and frequently observed thrombocytopenia. In the patients with sepsis, thrombocytopenia develops rapidly, with minimal platelet counts registered on the fourth day of observation, after which the platelet counts usually rise. Continuous thrombocytopenia and absence of a relative increase in platelets are considered predictors of patient death. The mechanisms of thrombocytopenia developing in sepsis are quite diverse, but the processes in periphery are prevailing, e.g., the so-called “platelet consumption” which is determined by their activation, chemotaxis and isolation in the microvasculature. Recently, a mechanism has been identified for the accelerated removal of platelets with desialized surface glycoproteins from the circulation. Sialidases, also known as neuraminidases, are widely present in viruses and bacteria, and pharmacological inhibition of sialidases is able to withstand thrombocytopenia in the infectious process. The key role of platelets in the development of septic shock was revealed. Sequestration of platelets in the microvessels of the lungs and brain (manifesting as thrombocytopenia) is accompanied by rapid serotonin release, thus underlying the main clinical manifestations, e.g., decreased blood pressure, heart rate and increased capillary permeability. To counteract sharp release of this mediator, pharmacological attempts are made to inhibit the SERT transporter by means of selective serotonin reuptake inhibitors. Blood platelets are key participants in the pathogenesis of multiple organ failure syndromes, such as acute renal damage, acute respiratory distress syndrome, myocardial dysfunction, and sepsis-associated encephalopathy. To restore impaired vascular permeability in these conditions, in particular, sepsis-associated encephalopathy, a pharmacological S1P receptor mimetic is under study. The review specifies possible pathogenetically significant targets that can be used to perform pharmacological correction of conditions associated with sepsis and concomitant thrombocytopenia.

Invasive aspergillosis (IA) is a serious disease, with mortality rate up to 80%. A. fumigatus is an angiovasive pathogen, fragments of its hyphae can detach and circulate in the bloodstream. Platelets are activated by surface structures, metabolites and soluble fungal complexes, resulting in adhesion to conidia and fungal hyphae. The melanin and hydrophobin contained in the conidia, as well as the galactosaminogalactan contained in the hyphae and the glyphotoxin secreted by the hyphae, suppress phagocytic cells, but activate the platelets. Activated platelets show direct antifungal activity by releasing microbicidal proteins and serotonin. In addition to direct antifungal effect, platelets form an interactive network with cellular components of the immune system and a complement system, increasing the response of neutrophils and monocytes. In the presence of platelets, the efficacy of antimycotics is greatly enhanced. The adverse effects of platelet activation in IA are associated with clinical conditions such as hemoptysis, pulmonary hemorrhage and infarctions of various organs. Another danger associated with IA is the development of thrombocytopenia. Thrombocytopenia is defined as an independent risk factor of mortality in IA in oncohematological patients after allogeneic transplantation of hematopoietic stem cells. Numerous evidences of the important role of platelets in protection from A. fumigatus suggest that the study of the number and functional state of platelets will provide a new data, which will help develop new methods for prediction and treatment of IA.