Platelets are anucleated blood components with a pivotal role in hemostasis and also other functions in the biology and pathophysiology of complex diseases [1]. Beyond hemostasis and thrombosis, contemporary knowledge ascribes to platelets a key role also in inflammation and innate immunity [2,3,4,5]. Therefore, platelets may be considered as immune cells [6]. Quantitative and qualitative platelet derangements represent a shortcoming in cardiac surgery and extracorporeal life supports (ECLS). Thrombocytopenia, indeed, is an intrinsic drawback of cardiac surgery with a prevalence > 30% [7,8]. It is not a trivial event but rather a clinically relevant entity independently associated with increased postoperative morbidity and mortality [7,8]. A conclusive knowledge about the causes of the phenomenon is lacking whereas certainty of its clinical implications exists [9].

Therefore, beyond the role of platelets in hemostasis and thrombosis, the present review aims to give a comprehensive analysis of platelet behavior in the cardiac surgery setting (Figure 1).

Multiple sides of platelet biology greatly impact on heart procedures because cardiac surgery enhances a systemic immuno-inflammation response, platelet activation and the coagulation cascade [10].

Platelets undergo both quantitative and qualitative alterations throughout a cardiopulmonary bypass (CPB), the extracorporeal circulation applied to cardiac surgery procedures. The interaction between blood and artificial surfaces of the CPB triggers damage to several cells, the release of various inflammatory cytokines and the activation of the complement and coagulation-fibrinolysis systems [11,12]. During a CPB, platelet changes are caused by hypothermia, shear stress, extensive exposure to artificial surfaces and the use of exogenous drugs (heparin and protamine) [11,12]. Moreover, the coagulation cascade also begins with the activation of factor XII. Clotting factor activation occurs and initiates the subsequent activation of kallikrein, the kinin-bradykinin system and the fibrinolytic and complement cascades [11,12]. All of these mechanisms lead to increased postoperative outcomes such as mortality, major complications (e.g., stroke, acute kidney injury, postoperative infections) and a prolonged in-hospital length of stay [7]. Moreover, the hemodilution related to a CPB contributes to increasing the rate of thrombocytopenia [10,11,12]. Therefore, cardiac surgery and a CPB lead to a complex homeostatic alteration that enhances the so-called “thromboinflammation”, a complex mechanism involving inflammation, thrombosis and innate immunity [10,11]. The same scenario occurs also as a response to other triggers such as veno-arterial (V-A) and veno-venous (V-V) extracorporeal membrane oxygenation (ECMO) and cardiac prosthetic devices [1,13,14].

Moreover, a major role is attributed to the direct platelet-leucocyte interaction that bidirectionally boosts their reciprocal activation [15]. This cross-talk is fundamental in the multistep pathway of neutrophil extravasation (i.e., margination, rolling, extravasation and migration) that occurs in the systemic inflammatory response syndrome in patients on a CPB [16,17]. This process causes the activation of the endothelial cells and of several cellular adhesion molecules (CAMs) resulting lastly in tissue metabolic impairments and an ischemia-reperfusion injury (IRI) [16,17]. Moreover, the interplay between platelets and neutrophils was reported as a prerequisite for the release of neutrophil extracellular traps (NETs), which further triggers platelet activation and aggregation [18,19]. Furthermore, the binding of platelets’ integrin αIIbβ3 to neutrophils’ macrophage-1 antigen (Mac-1) stimulates the signaling leading to the formation of NETs. This interaction activates an inflammatory response mediated by the nuclear factor-kB (NF-kB) [20,21,22,23].

Platelets also modulate the immunoactivity of monocytes/macrophages by NF-kB activation. Moreover, the synthesis of proinflammatory mediators is stimulated. Platelets promote monocytes’ chemokines synthesis via P-selectin/P-selectin glycoprotein ligand (PSGL)-1 axis mediated “regulated on activation, normal T cell expressed and secreted” (RANTES) activation [24]. Furthermore, platelet α-granules (their most abundant storage granules) contain a diverse range of cytokines and chemokines among which are CXCL1, platelet factor 4 (PF4; CXCL4), CXCL5, interleukin-8 (IL-8) and RANTES [25]. Platelets have also been shown to independently enhance the inflammatory cascade in innate immune cells in vivo, thus contributing to the release of IL-1 cytokines [26].

In addition to these direct and indirect biological mechanisms, platelets also interact with the classical and the alternative pathways of the complement system [27]. The release of chondroitin sulfate modulates complement activity promoting anaphylatoxins and membrane attack-complex (MAC) generation, thus inducing further platelet activation [28,29]. The interplay between platelets and the complement system seems to involve platelet microparticles containing complement components such as C5b-9 at their surface [30,31].

Furthermore, platelets are the main source of microparticles in the bloodstream [32]. Extracellular vesicles composition varies and includes chemokines, cytokines and CAMs as well as small non-coding RNAs called microRNA (miRNA) [33,34]. MiRNA are involved in gene expression via negative post-transcriptional regulation [33,34]. Circulating miRNAs (i.e., miR-223 and miR-499) were detected following thrombin stimulation [34,35]. Even if the underlying mechanism is still to be cleared, miRNAs could transfer genetic material to recipient cells (among which are endothelial and immune cells) impacting the biological functions of recipient cells (i.e., regulating CAMs expression) [34,35]. Indeed, plasma exosomal miR-223 concentration was found to increase after CPB onset and to downregulate the inflammatory response reducing IL-6 and NLRP3 expression in monocytes [36]. A few studies have suggested that platelet microparticles may also be a source of a circulating tissue factor, explaining the activation of the extrinsic coagulation cascade and again linking hemostasis with immuno-inflammation via platelet activity [37].

Therefore, platelets contain abundant RNAs even if they lack a nucleus. Intraplatelet miRNA alterations may influence platelet messenger RNAs and consequently their proteome. Platelet protein expression impairment may further contribute to postoperative platelet dysfunction. A platelet qualitative impairment such as a reduced surface GPIb expression was found to be associated with the overexpression of some miRNAs (i.e., mir-10b and mir-96) and also with enhanced platelet Bax apoptotic signaling in cardiac surgery cohorts [38,39]. Microcirculatory impairment is another factor associated with platelet dysfunction following heart procedures. It consists of the loss of capillary density and increased flow heterogeneity and reflects how endothelial activation and glycocalyx degradation are both a consequence and a determinant of the systemic inflammatory response [40,41,42]. Furthermore, a recent investigation showed how perivascular mast cells were activated through the release of the lipid mediator platelet activating factor (PAF) from gut microvascular endothelial-adherent platelets to explain the inflammatory mediated tissue damage and organ injury following a CPB [43]. This mechanism might highlight platelets as a direct determinant of IRI related tissue damage.