Effects and Side Effects of Platelet Transfusion

Abstract

Aside from their canonical role in hemostasis, it is increasingly recognized that platelets have inflammatory functions and can regulate both adaptive and innate immune responses. The main topic this review aims to cover is the proinflammatory effects and side effects of platelet transfusion. Platelets prepared for transfusion are subject to stress injury upon collection, preparation, and storage. With these types of stress, they undergo morphologic, metabolic, and functional modulations which are likely to induce platelet activation and the release of biological response modifiers (BRMs). As a consequence, platelet concentrates (PCs) accumulate BRMs during processing and storage, and these BRMs are ultimately transfused alongside platelets. It has been shown that BRMs present in PCs can induce immune responses and posttransfusion reactions in the transfusion recipient. Several recent reports within the transfusion literature have investigated the concept of platelets as immune cells. Nevertheless, current and future investigations will face the challenge of encompassing the immunological role of platelets in the scope of transfusion.

Keywords

platelet physiology - transfusion medicine - inflammatory mediators

The primary role of platelets is to maintain hemostasis.[1] However, platelets can also be actively involved in the inflammatory response by interacting with endothelial cells and circulating leukocytes.[2] [3] Either through direct interactions or the release of soluble mediators, platelets can influence both innate (neutrophils, monocytes, and macrophages) and adaptive immune cells (lymphocytes). Platelets communicate with the immune system to recruit and initiate an inflammatory response[4] [5] [6] and, also by virtue of their number in circulation, can therefore be considered the primary sentinels of the bloodstream.[2] Aside from initiation, platelets also have a recently appreciated role in resolving inflammation. Platelets contribute to this resolution in several ways, including interaction and modification of immune (T cells, neutrophils, and macrophages) and nonimmune cells (endothelial cells). Aside from their earlier-described role in in vivo inflammation, many biochemical and functional modifications occur during the process of storing platelets for transfusion. These changes, called “storage lesions,” include acidification of the storage medium secondary to anaerobic platelet metabolism, platelet activation, and an increase in biological response modifiers (BRMs) and lipids level in platelet concentrates (PCs). These storage lesions can compromise the viability and change the functionality of the platelets to a more proinflammatory phenotype, which ultimately reduces efficacy of the transfusion. In recipients, these changes can also contribute to transfusion reactions.[7] Below, we discuss how platelet-related inflammation can influence the composition, and ultimately the clinical utility, of PCs.

Inflammatory Roles of Blood Platelets

The role of platelets in inflammation includes the recognition of pathogens, due mainly to the expression of receptors from the Sialic acid–binding immunoglobulin-like lectins (SIGLEC)[8] [9] or toll-like receptor (TLR) families.[10] [11] [12] [13] These are transmembrane receptors which recognize bacterial, viral, or parasite patterns and induce the release of proinflammatory cytokines by immune cells, including platelets. For example, platelets primarily hold TLR-2, TLR-4, and TLR-9 functional receptors, which are capable of stimulating platelet activation, while TLR-3 and TLR-7 are more heavily involved in platelet–viral interactions.[14] [15] [16] The presence of TLRs on and within platelets suggests that they are immune effector cells, that they play a role in surveillance and pathogen detection, and that they are able to transfer information to other immune cells.

Aside from receptor expression, activated platelets secrete or express more than 5,000 proteins or lipids that play a role in hemostasis as well as the platelet's inflammatory function.[17] [18] [19] These mediators are primarily contained in α or dense granules and are mostly preformed and stored. Through these various molecules, blood platelets can be described as tremendously diverse in terms of function and are able to respond to a wide range of inflammatory scenarios by their diversity in secretion mechanisms and diversity of cellular targets.

To speak to the diverse function of platelet secretory products, some of these molecules promote the interaction of platelets with leukocytes, plasma proteins, and endothelial cells (e.g., CD62P [P-selectin]). Others promote the recruitment and activation of immune cells at the site of inflammation such as PF4 (platelet factor 4), RANTES (regulated upon activation, normal T cell expressed and secreted), or platelet-derived microparticles (PMPs). This is not to mention soluble CD40L (sCD40L), which plays a pivotal role between innate and adaptive immunity.[3] [20] [21] [22] This list ([Table 1]) is nonexhaustive, and we will define a few of these factors later. Given the importance of these secretory mediators for the immune function of platelets, it is incredibly useful to understand how these platelet-derived components can modulate the composition of PCs during storage. In the following section, we also highlight specific examples where these mediators have been investigated in the context of transfusion products.

• One of the essential platelet receptors for direct contact with myeloid cells and stimulated T lymphocytes is CD62P.[23] [24] [25] [26] CD62P is stored in the membrane of platelet α-granules and is then exposed on the membrane surface during platelet activation. Exposure of CD62P on the platelet membrane is used as a marker for degranulation and activation. When exposed on the membrane, CD62P is able to bind to its receptor, PSGL-1 ligand (P-selectin glycoprotein ligand 1), and primarily expressed on the surface of neutrophils, monocytes, and dendritic cells. This CD62P/PSGL-1 bond enables the recruitment of immune cells to the site of injury, the formation of platelet–leukocyte aggregates, and the activation of myeloid cells and stimulated T lymphocytes via PSGL-1 intracellular signaling. Furthermore, once blood platelets are activated, CD62P can be cleaved and becomes soluble. Soluble CD62P is one of the characteristic markers of platelet activation. Soluble CD62P concentrations differ in apheresis PCs (APCs) and buffy coat–derived PCs.[27]

• PF4 (CXCL4), contained in α-granules,[28] [29] [30] is one of the most abundant chemokines in the platelet. Belonging to the family of CXC chemokines, CXCL4 is recognized by the CXCR3A and CXCR3B receptors, as well as by glycosaminoglycans present on target cells.[31] [32] CXCL4 is heavily involved in inflammation. In vitro, it is a chemotactic molecule for neutrophils and monocytes[28] and also promotes the survival of monocytes and supports macrophage differentiation.[31] CXCL4 also plays an anti-inflammatory role, as it inhibits T-lymphocyte proliferation and guides their differentiation to a TH2 phenotype.[33] Furthermore, CXCL4 is capable of activating endothelial cells and inducing the expression of E-selectin in human umbilical vein endothelial cells.[34] Apelseth et al[35] demonstrated CXCL4 was detected within PC and showed a significant increase during storage.

• RANTES, also stored in α-granules, is released in soluble form during platelet activation.[36] [37] It has been shown that RANTES acts in synergy with P-selectin expressed on the platelet surface to induce the synthesis of monocyte chemoattractant protein-1 (MCP-1) by monocytes.[38] RANTES released by platelets can also immobilize on the surface of the activated endothelium and thus promote the recruitment of monocytes.[39] As a factor released by platelets, RANTES accumulates in PCs during storage even after leukoreduction.[40] We know that, like sCD40L, RANTES is the cause of several transfusion reactions.[41] [42] Nogawa et al showed that sCD40L and RANTES concentrations increased more slowly in SSP+ platelet additive solution (PAS), Composol, and M-Sol compared with Intersol. This suggests that the accumulation behavior of platelet-derived bioactive substances like RANTES or sCD40L depends on the PAS used.[43]

• Platelet microparticles are the most abundant microparticles in the bloodstream.[44] They are involved in maintaining vascular homoeostasis by preserving endothelial function but may also initiate a harmful process if they are excessively released or if they express inflammatory components. In fact, PMPs expose a procoagulant surface[45] and act as transporters for bioactive molecules, namely, growth factors, signaling molecules, and genetic material, including messenger RNA (mRNA), microRNA, and mitochondrial DNA (mtDNA).[45] PMPs can transfer their contents to vascular endothelial cells and regulate the expression and function of recipient cell genes.[45] During inflammation, PMPs can activate antigen-presenting cells, modulate dendritic cell activation, increase T-cell responses, induce immunoglobulin G (IgG) production by B cells, and improve formation of the germinal center in cooperation with T cells.[45] [46] [47] Marcoux et al suggest that PMPs, such as those which carry mitochondrial damage-associated molecular patterns (mtDAMPs), may be a useful biomarker for predicting the potential risk of transfusion reactions.[48] In addition, this work implies that further research is needed to determine if mtDAMPs encapsulated in PMPs are associated with a causal pathogenic role compared with mtDAMPs in solution.[49]

Table 1 Characteristics and physiological roles of platelet-released major biological response modifiers (this list is nonexhaustive)

	Source	Ligand	Function	Refs.
CD62P (P-selectin)	• Endothelial cells • Platelets	• P-selectin glycoprotein ligand-1 • Heparan sulfate • Fucoidans	• Initial recruitment of leukocytes • Recruitment and aggregation • Helps cancer cells invade into the bloodstream for metastasis • Contribute to the seeding of tumor microemboli in distant organs • Inflammatory reaction	[113] [114] [115] [116] [117] [118]
PF4 (CXCL4)	• Platelets	• CXCR3B	• Promotes inflammatory fibrosis • Promotes blood coagulation by moderating the effects of heparin-like molecules • Play a role in wound repair and inflammation • Strong chemoattractant for neutrophils, monocyte, and fibroblasts	[119] [120] [121] [122]
RANTES (CCL5)	• Platelets • T cells		• Chemotactic for T cells, eosinophils, and basophils, and plays an active role in recruiting leukocytes into inflammatory sites • Induces the proliferation and activation of certain natural-killer (NK) cells to form CHAK (CC-chemokine-activated killer) cells • Natural HIV-suppressive factor	[123] [124] [125] [126]
Platelet microparticles (PMPs)	• Platelets		• Transport and delivery system for bioactive molecules • Participating in:  i. Hemostasis and thrombosis  ii. Inflammation  iii. Malignancy infection transfer  iv. Angiogenesis  v. Immunity	[45] [127] [128] [129] [130] [131]
CD154 (sCD40L)	• T cells • Platelets • Mast cells • Macrophages • Basophils • NK cells • B lymphocytes • Smooth muscle cells • Endothelial cells • Epithelial cells	• CD40 • α5β1 integrin • αIIbβ3	• Promotes B-cell maturation • Costimulation and regulation of the immune response • Activation of endothelial cells by CD40L leads to reactive oxygen species production, as well as chemokine and cytokine production, and expression of adhesion molecules such as E-selectin, ICAM-1, and VCAM-1. • Promotes recruitment of leukocytes to lesions and may potentially promote atherogenesis	[132] [133] [134] [135] [136] [137]

On their surface, activated platelets express CD40L, which is also found in soluble form (sCD40L) in the bloodstream.[50] [51] The endothelium is a key target of platelet CD40L, but CD40L also plays both direct and indirect roles in the inflammatory response, coagulation, tissue remodeling, and defense against infections, with all of these processes overlapping at several levels. At the endothelium, platelet CD40L induces the expression of proinflammatory and chemotactic molecules and the expression of adhesion molecules (e.g., CD62E, CD54, and CD106), leading to the recruitment and activation of leukocytes.[25] [52] [53] Once activated, these target cells can recruit and, in turn, activate other cells. Several amplification loops are thus generated, including platelet activation by soluble CD40L itself.[3] [25] The detrimental role of platelet CD40L has been demonstrated in inflammatory pathological conditions like atherosclerosis[37] [54] and systemic lupus erythematosus.[55] [56] sCD40L is described as being partly responsible for certain transfusion reactions following platelet transfusions,[7] [52] [57] [58] and levels of this molecule are widely thought to be modulated according to processing and storage of PCs.

In conclusion, the mediators released by activated platelets increase the recruitment of blood cells at the vascular wall, thus participating in inflammation, immune processes, vessel repair, and regeneration after injury. Therefore, blood platelets from PCs used in blood transfusions should also be considered to have these inflammatory properties described earlier.

PC Preparation and Storage Lesions Promote Secretion of Biological Response Modifiers

Platelet transfusions are crucial due to thrombocytopenia, but they can be associated with both immediate and delayed transfusion reactions. There is a great deal of literature concerning the characterization and the nature of these transfusion reactions.[22] [59] [60] [61] [62] The most frequent complications associated with PC transfusions are allergic reactions and febrile nonhemolytic transfusion reaction (FNHTR), while other (e.g., transfusion-associated circulatory overload, bacterial sepsis, transfusion-related acute lung injury, and posttransfusion purpura) occur less frequently.

PCs, like other blood products, are living cellular products with a limited life span. As such, platelets prepared for transfusion suffer stress-induced lesions during collection, preparation, and storage.[7] [63] [64] Platelet storage lesions are defined as alterations that occur at any point in the process from drawing blood to transfusion. Thus, the secretion of BRMs during ex vivo processing of platelets[7] [27] [63] [64] [65] [66] [67] is an example of a platelet storage lesion that modifies the platelet structure and function.

As mentioned in the previous section, many platelet-derived secretory mediators are released during PC storage. An increase in the general inflammatory milieu of PCs is likely to play a direct role in triggering transfusion reactions. For example, our previous study provides new information on the link between sCD40L and transfusion reactions: the level of sCD40L was significantly elevated in PCs that triggered transfusion reactions, and the storage duration of PCs is associated with an increase in secretion of sCD40L.[57]

Some studies have shown that platelets were able to change morphologically based on the methods used to prepare PCs.[68] [69] [70] [71] [72] These different preparation techniques differentially affect platelet physiology because they do not expose the platelets to the same stresses.[73] [74] During the preparation of PCs, platelets are subjected to numerous types of stress, especially in relation to the shear stress inflicted by centrifugation, as well as the way the packs are processed, for example, leukoreduction (by filtration), the use of different preservative/additive solutions, irradiation, and/or the use of pathogen inactivation/reduction treatments. Furthermore, it has been demonstrated that platelet degranulation and vesiculation are influenced by preparation techniques.[75] [76] In fact, Noulsri et al have shown that PMP secretion varies based on the different preparation processes used.[77] In this study, the authors show that the type of apheresis employed activates platelets differently. This was particularly evident with apheresis using the Amicus instrument, where the percentage of both platelet and PMP activation was significantly higher than in other PCs.[77] Amicus apheresis seems to activate platelets more so than when compared with the other types of apheresis, namely, Trima.[78] Another study showed that the PMP content in PCs is predicted by the PMPs present in the donors,[79] indicating the potential for the donor's inflammatory status to influence that of the recipients posttransfusion. The way PCs are processed also has a direct impact on the production of platelet cytokines and chemokines. For example, one study showed that the reduction of pathogens using UVC light increases cytokine accumulation.[80]

Platelet storage lesions include the appearance of platelet activation markers, morphological changes, mitochondrial dysfunction, loss of glycoprotein Ibα expression, and secretion of α-granules.[58] [81] This may be linked to transfusion reactions incidence, which has been observed to increase as storage time lengthens. To lessen this incidence, we can suggest that PCs should be transfused as soon as possible taking into account the specificities of PCs stock and therapeutic indications. However, this conclusion should be considered relative to both the constraint of production and delivery of PCs and based on the demand for products from healthcare facilities. Our team showed that the concentration of these BRMs—sCD40L in particular—increases significantly starting on the third day of PC storage.[82] Furthermore, sCD40L induces the production of reactive oxygen species (ROS) during PC storage, causing an increase in production and release of proinflammatory molecules.[83] These observations suggest that storage lesions have a major effect on PC-induced inflammation.

How PCs are processed during preparation and storage may affect platelet activation. Leitner et al showed that the extent of initial platelet activation—as reflected in CD62P expression—was significantly greater when platelets were stored in Intersol than when other additive solutions (Composol and SSP + ) were used.[84] Nevertheless, platelet storage in an additive solution has some benefits, including a reduction in the incidence of transfusion reactions,[69] [85] compared with retaining the plasma as the supernatant. To date, pooled PCs (PPCs) and APCs are comparable in quality, but Daurat et al showed transfusion reactions to be associated with PPCs less frequently than with APCs.[86] These findings suggest that APCs, currently in widespread use, should be limited to specific indications. For any given medical indication, a risk–benefit evaluation considering each kind of PC should allow prescription of the best product. Storage lesions triggered by extrinsic factors (preparation methods) or intrinsic factors (plasma and platelet factors, residual leukocytes) might be largely responsible for a reduction not only in the therapeutic efficacy of PC transfusion but also in the increase in the rate of transfusion reactions.[87] [88] [89] [90]

Numerous studies have shown that sCD40L is involved in reactions following PC transfusion.[3] [21] [64] [65] [91] [92] [93] We have also shown that other soluble factors, such as IL-27 and sOX40L, are involved in FNHTRs.[94] Mathematical models using machine learning have shown transfusion reactions to be very reliably predicted by several other soluble factors, including sCD40L, IL-13, and macrophage inflammatory protein (MIP)-1α.[95] Indeed, this study showed that the concentration of sCD40L and IL-13 is correlated with the occurrence of transfusion reactions. In addition, the concentration of MIP-1α in supernatants associated with transfusion reactions appears to determine the type of transfusion reactions that occurs: FNHTRs or allergic reaction.

PCs also contain mtDNA, which has been linked to transfusion reactions.[49] [96] [97] [98] In fact, Boudreau et al showed that activated platelets release mitochondria, both in encapsulated microparticles and as free organelles. The levels of extracellular mitochondria found in transfused PCs are higher in those having caused transfusion reactions (FNHTR cutaneous and cardiovascular symptoms) in transfusion patients.[99]

In addition to cytokines and chemokines, PMPs, which are important mediators of inflammation and immune response regulation, also seem to be involved in the occurrence of transfusion reactions.[3] [65] [100] [101] PMPs containing microRNA may also be involved in a pathophysiological response following a PC transfusion. Furthermore, studies have shown that pathogen reduction technologies, which are designed to reduce the potential risk of transfusion-transmitted infections, induce platelet activation and alter mRNA and microRNA levels.[102] [103] These changes in RNA are correlated with an increase in PMP concentration. Consequently, it seems likely that pathogen reduction technologies may also increase the formation of PMPs in PCs.

We recently showed that soluble high mobility group box 1 (HMGB1) levels are also heavily associated with transfusion reactions.[104] It is worth noting that HMGB1 present in PCs is a RAGE (Receptor for Advanced Glycation End-Products), TLR-2, TLR-4, and TLR-9 ligand.[105] [106] [107] [108] As such, HMGB1 is considered a DAMP. Receptors such as TLRs, expressed on and within platelets, can recognize various ligands including HMGB1 and, in turn, induce a receptor-dependent response. A single TLR can recognize several PAMPs and DAMPs, and the structural and molecular mechanisms acting as mediators have so far not been extensively studied. Simultaneous signaling within platelets can modulate the response following the involvement of TLRs. Accordingly, this level of complexity makes studying the platelet inflammatory responses induced by PAMPs and DAMPs difficult, though no less fascinating. As platelets are effectors of hemostasis, inflammation, and the immune continuum,[109] it is also interesting to consider the platelet response in situations where infectious (sepsis, HIV, COVID, etc.) and noninfectious (transfusion, vascular inflammation, autoimmune disease, etc.) contexts meet.

Donor factors possibly affect BRM content, particularly microparticles, in PCs, although this point remains generally uninvestigated. To highlight this point, Highton et al[110] suggested that acute exercise can increase circulating PMP counts, but regular exercise training can diminish this effect and eventually reduce overall resting MP counts, partially preventing their pathophysiological effects. We can extrapolate these observations to blood donors and evaluate how exercise affects the number and function of microparticles after blood donation. As mentioned earlier, the PMP content in PCs is correlated with the levels of PMPs present in the donors,[78] which may adversely affect the inflammatory status of the recipient. Melki et al[111] elegantly suggest that cell-derived extracellular vesicles are not restricted to pathological onset. In fact, MPs circulate in variable concentrations, also with variable half-times in blood vasculature at a steady state. The physiological functions of PMPs in healthy individuals, and with extrapolation to blood donors, are still not completely understood. Finally, Vafeiadou et al assessed the evidence for the effects of total dietary fat and individual fatty acids on vascular function, cellular microparticles, and endothelial progenitor cells.[112] Ultimately, the authors suggest that diet before donation could influence the content of inflammatory mediators in blood products.

Conclusion/Outlook

The various data found in the literature consolidate the hypothesis that activation of the platelets in PCs may directly play a role in an inflammatory response within the recipient posttransfusion. To minimize the risk of transfusion reactions, consideration should be given to reducing the concentration of sCD40L and other BRMs identified as being involved in such reactions, especially those that accumulate in storage.

A transfusion of labile blood products involves elements related to the donor, the product, and the recipient. The systematic—not individual—study of these three elements in transfusion medicine will lead to personalized medicine, that is, the ability to select a PC (and more generally a labile blood product) for transfusion based on its composition (including BRM levels) and the recipient's disease. By taking into account the characteristics of the three “actors” in transfusion (donors, products, and patients) and analyzing databases using machine-learning type biomathematics tools, we will be able to optimize the delivery of the best product to treat each patient in a precise and personalized manner.

Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgments

We would like to thank the medical staff and personnel of the Etablissement Français du Sang Auvergne-Rhone-Alpes, Saint-Etienne, France, for technical support throughout our studies. We thank the blood donors for taking part in this study. This work was supported by grants from the French National Blood Service – EFS (Grant APR) and the Association “Les Amis de Rémi” Savigneux, France.

• References

• 1 Clemetson KJ. Platelets and primary haemostasis. Thromb Res 2012; 129 (03) 220-224
• 2 Hally K, Fauteux-Daniel S, Hamzeh-Cognasse H, Larsen P, Cognasse F. Revisiting platelets and toll-like receptors (TLRs): at the interface of vascular immunity and thrombosis. Int J Mol Sci 2020; 21 (17) E6150
• 3 Cognasse F, Laradi S, Berthelot P. et al. Platelet inflammatory response to stress. Front Immunol 2019; 10: 1478
• 4 Deppermann C, Kubes P. Start a fire, kill the bug: the role of platelets in inflammation and infection. Innate Immun 2018; 24 (06) 335-348
• 5 Margraf A, Zarbock A. Platelets in inflammation and resolution. J Immunol 2019; 203 (09) 2357-2367
• 6 Rossaint J, Margraf A, Zarbock A. Role of platelets in leukocyte recruitment and resolution of inflammation. Front Immunol 2018; 9: 2712
• 7 Sut C, Tariket S, Aubron C. et al. The non-hemostatic aspects of transfused platelets. Front Med (Lausanne) 2018; 5: 42
• 8 Nguyen KA, Hamzeh-Cognasse H, Palle S. et al. Role of Siglec-7 in apoptosis in human platelets. PLoS One 2014; 9 (09) e106239
• 9 Cognasse F, Nguyen KA, Damien P. et al. The inflammatory role of platelets via their TLRs and Siglec receptors. Front Immunol 2015; 6: 83
• 10 Shiraki R, Inoue N, Kawasaki S. et al. Expression of toll-like receptors on human platelets. Thromb Res 2004; 113 (06) 379-385
• 11 Andonegui G, Kerfoot SM, McNagny K, Ebbert KV, Patel KD, Kubes P. Platelets express functional Toll-like receptor-4. Blood 2005; 106 (07) 2417-2423
• 12 Cognasse F, Hamzeh H, Chavarin P, Acquart S, Genin C, Garraud O. Evidence of Toll-like receptor molecules on human platelets. Immunol Cell Biol 2005; 83 (02) 196-198
• 13 Aslam R, Speck ER, Kim M. et al. Platelet toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-alpha production in vivo. Blood 2006; 107 (02) 637-641
• 14 D'Atri LP, Schattner M. Platelet toll-like receptors in thromboinflammation. Front Biosci 2017; 22: 1867-1883
• 15 Hamzeh-Cognasse H, Berthelot P, Tardy B. et al. Platelet toll-like receptors are crucial sensors of infectious danger moieties. Platelets 2018; 29 (06) 533-540
• 16 Alonso AL, Cox D. Platelet interactions with viruses and parasites. Platelets 2015; 26 (04) 317-323
• 17 Burkhart JM, Vaudel M, Gambaryan S. et al. The first comprehensive and quantitative analysis of human platelet protein composition allows the comparative analysis of structural and functional pathways. Blood 2012; 120 (15) e73-e82
• 18 Burkhart JM, Gambaryan S, Watson SP. et al. What can proteomics tell us about platelets?. Circ Res 2014; 114 (07) 1204-1219
• 19 Aloui C, Barlier C, Claverol S. et al. Differential protein expression of blood platelet components associated with adverse transfusion reactions. J Proteomics 2019; 194: 25-36
• 20 Refaai MA, Phipps RP, Spinelli SL, Blumberg N. Platelet transfusions: impact on hemostasis, thrombosis, inflammation and clinical outcomes. Thromb Res 2011; 127 (04) 287-291
• 21 Sahler J, Spinelli S, Phipps R, Blumberg N. CD40 ligand (CD154) involvement in platelet transfusion reactions. Transfus Clin Biol 2012; 19 (03) 98-103
• 22 Stolla M, Refaai MA, Heal JM. et al. Platelet transfusion - the new immunology of an old therapy. Front Immunol 2015; 6: 28
• 23 Chen C, Li Y, Yu Z. et al. Platelet activity in the pathophysiology of inflammatory bowel diseases. Curr Drug Targets 2015; 16 (03) 219-225
• 24 Algahtani M, Heptinstall S. Novel strategies for assessing platelet reactivity. Future Cardiol 2017; 13 (01) 33-47
• 25 Au AE, Josefsson EC. Regulation of platelet membrane protein shedding in health and disease. Platelets 2017; 28 (04) 342-353
• 26 van Velzen JF, Laros-van Gorkom BA, Pop GA, van Heerde WL. Multicolor flow cytometry for evaluation of platelet surface antigens and activation markers. Thromb Res 2012; 130 (01) 92-98
• 27 Sut C, Tariket S, Aloui C. et al. Soluble CD40L and CD62P levels differ in single-donor apheresis platelet concentrates and buffy coat-derived pooled platelet concentrates. Transfusion 2019; 59 (01) 16-20
• 28 Brandt E, Ludwig A, Petersen F, Flad HD. Platelet-derived CXC chemokines: old players in new games. Immunol Rev 2000; 177: 204-216
• 29 Fleischer J, Grage-Griebenow E, Kasper B. et al. Platelet factor 4 inhibits proliferation and cytokine release of activated human T cells. J Immunol 2002; 169 (02) 770-777
• 30 von Hundelshausen P, Petersen F, Brandt E. Platelet-derived chemokines in vascular biology. Thromb Haemost 2007; 97 (05) 704-713
• 31 Petersen F, Bock L, Flad HD, Brandt E. Platelet factor 4-induced neutrophil-endothelial cell interaction: involvement of mechanisms and functional consequences different from those elicited by interleukin-8. Blood 1999; 94 (12) 4020-4028
• 32 Petersen F, Spillmann D, Scheuerer B, Fleischer J, Flad HD, Brandt E. Is platelet factor-4 a chemokine?. Eur Cytokine Netw 2000; 11 (03) 506-507
• 33 Romagnani P, Maggi L, Mazzinghi B. et al. CXCR3-mediated opposite effects of CXCL10 and CXCL4 on TH1 or TH2 cytokine production. J Allergy Clin Immunol 2005; 116 (06) 1372-1379
• 34 Yu G, Rux AH, Ma P, Bdeir K, Sachais BS. Endothelial expression of E-selectin is induced by the platelet-specific chemokine platelet factor 4 through LRP in an NF-kappaB-dependent manner. Blood 2005; 105 (09) 3545-3551
• 35 Apelseth TO, Hervig TA, Wentzel-Larsen T, Bruserud O. Cytokine accumulation in photochemically treated and gamma-irradiated platelet concentrates during storage. Transfusion 2006; 46 (05) 800-810
• 36 Karshovska E, Weber C, von Hundelshausen P. Platelet chemokines in health and disease. Thromb Haemost 2013; 110 (05) 894-902
• 37 von Hundelshausen P, Schmitt MM. Platelets and their chemokines in atherosclerosis-clinical applications. Front Physiol 2014; 5: 294
• 38 Weyrich AS, Elstad MR, McEver RP. et al. Activated platelets signal chemokine synthesis by human monocytes. J Clin Invest 1996; 97 (06) 1525-1534
• 39 Gear AR, Camerini D. Platelet chemokines and chemokine receptors: linking hemostasis, inflammation, and host defense. Microcirculation 2003; 10 (3-4): 335-350
• 40 Fujihara M, Ikebuchi K, Wakamoto S, Sekiguchi S. Effects of filtration and gamma radiation on the accumulation of RANTES and transforming growth factor-beta1 in apheresis platelet concentrates during storage. Transfusion 1999; 39 (05) 498-505
• 41 Wakamoto S, Fujihara M, Kuzuma K. et al. Biologic activity of RANTES in apheresis PLT concentrates and its involvement in nonhemolytic transfusion reactions. Transfusion 2003; 43 (08) 1038-1046
• 42 Savage WJ, Savage JH, Tobian AA. et al. Allergic agonists in apheresis platelet products are associated with allergic transfusion reactions. Transfusion 2012; 52 (03) 575-581
• 43 Nogawa M, Naito Y, Chatani M. et al. Parallel comparison of apheresis-collected platelet concentrates stored in four different additive solutions. Vox Sang 2013; 105 (04) 305-312
• 44 Lannan KL, Sahler J, Kim N. et al. Breaking the mold: transcription factors in the anucleate platelet and platelet-derived microparticles. Front Immunol 2015; 6: 48
• 45 Boilard E, Duchez AC, Brisson A. The diversity of platelet microparticles. Curr Opin Hematol 2015; 22 (05) 437-444
• 46 Nomura S, Fujita S, Nakanishi T. et al. Platelet-derived microparticles cause CD154-dependent activation of dendritic cells. Platelets 2012; 23 (01) 81-82
• 47 Dong JF. Platelet microparticles are not created equal. Blood 2014; 124 (14) 2161-2162
• 48 Marcoux G, Magron A, Sut C. et al. Platelet-derived extracellular vesicles convey mitochondrial DAMPs in platelet concentrates and their levels are associated with adverse reactions. Transfusion 2019; 59 (07) 2403-2414
• 49 Cognasse F, Aloui C, Anh Nguyen K. et al. Platelet components associated with adverse reactions: predictive value of mitochondrial DNA relative to biological response modifiers. Transfusion 2016; 56 (02) 497-504
• 50 Elzey BD, Ratliff TL, Sowa JM, Crist SA. Platelet CD40L at the interface of adaptive immunity. Thromb Res 2011; 127 (03) 180-183
• 51 Davì G, Ferroni P. CD40-CD40L interactions in platelet activation. Thromb Haemost 2005; 93 (06) 1011-1012
• 52 Tariket S, Sut C, Hamzeh-Cognasse H, Laradi S, Garraud O, Cognasse F. Platelet and TRALI: from blood component to organism. Transfus Clin Biol 2018; 25 (03) 204-209
• 53 Iannacone M. Platelet-mediated modulation of adaptive immunity. Semin Immunol 2016; 28 (06) 555-560
• 54 Pamukcu B, Lip GY, Snezhitskiy V, Shantsila E. The CD40-CD40L system in cardiovascular disease. Ann Med 2011; 43 (05) 331-340
• 55 Duffau P, Seneschal J, Nicco C. et al. Platelet CD154 potentiates interferon-alpha secretion by plasmacytoid dendritic cells in systemic lupus erythematosus. Sci Transl Med 2010; 2 (47) 47ra63
• 56 Yazdany J, Davis J. The role of CD40 ligand in systemic lupus erythematosus. Lupus 2004; 13 (05) 377-380
• 57 Cognasse F, Sut C, Fromont E, Laradi S, Hamzeh-Cognasse H, Garraud O. Platelet soluble CD40-ligand level is associated with transfusion adverse reactions in a mixed threshold-and-hit model. Blood 2017; 130 (11) 1380-1383
• 58 Garraud O, Tariket S, Sut C. et al. Transfusion as an inflammation hit: knowns and unknowns. Front Immunol 2016; 7: 534
• 59 Garraud O, Cognasse F, Tissot JD. et al. Improving platelet transfusion safety: biomedical and technical considerations. Blood Transfus 2016; 14 (02) 109-122
• 60 Savage WJ. Transfusion reactions. Hematol Oncol Clin North Am 2016; 30 (03) 619-634
• 61 Frazier SK, Higgins J, Bugajski A, Jones AR, Brown MR. Adverse reactions to transfusion of blood products and best practices for prevention. Crit Care Nurs Clin North Am 2017; 29 (03) 271-290
• 62 Kreuger AL, Caram-Deelder C, Jacobse J, Kerkhoffs JL, van der Bom JG, Middelburg RA. Effect of storage time of platelet products on clinical outcomes after transfusion: a systematic review and meta-analyses. Vox Sang 2017; 112 (04) 291-300
• 63 Edelstein SB. Blood product storage: does age really matter?. Semin Cardiothorac Vasc Anesth 2012; 16 (03) 160-165
• 64 Morrell CN. Immunomodulatory mediators in platelet transfusion reactions. Hematology (Am Soc Hematol Educ Program) 2011; 2011: 470-474
• 65 Ng MSY, Tung JP, Fraser JF. Platelet storage lesions: What more do we know now?. Transfus Med Rev 2018; 32 (03) 144-154
• 66 Adams F, Bellairs G, Bird AR, Oguntibeju OO. Biochemical storage lesions occurring in nonirradiated and irradiated red blood cells: a brief review. [Review] BioMed Res Int 2015; 2015: 968302
• 67 Devine DV, Serrano K. The platelet storage lesion. Clin Lab Med 2010; 30 (02) 475-487
• 68 Jain A, Marwaha N, Sharma RR, Kaur J, Thakur M, Dhawan HK. Serial changes in morphology and biochemical markers in platelet preparations with storage. Asian J Transfus Sci 2015; 9 (01) 41-47
• 69 van der Meer PF, de Korte D. Platelet additive solutions: a review of the latest developments and their clinical implications. Transfus Med Hemother 2018; 45 (02) 98-102
• 70 Schubert P, Johnson L, Marks DC, Devine DV. Ultraviolet-based pathogen inactivation systems: untangling the molecular targets activated in platelets. Front Med (Lausanne) 2018; 5: 129
• 71 Prudent M, D'Alessandro A, Cazenave JP. et al. Proteome changes in platelets after pathogen inactivation--an interlaboratory consensus. Transfus Med Rev 2014; 28 (02) 72-83
• 72 Feys HB, Van Aelst B, Compernolle V. Biomolecular consequences of platelet pathogen inactivation methods. Transfus Med Rev 2019; 33 (01) 29-34
• 73 Nguyen KA, Chavarin P, Arthaud CA, Cognasse F, Garraud O. Do manual and automated processes with distinct additive solutions affect whole blood-derived platelet components differently?. Blood Transfus 2013; 11 (01) 152-153
• 74 Macher S, Sipurzynski-Budrass S, Rosskopf K. et al. Function and activation state of platelets in vitro depend on apheresis modality. Vox Sang 2010; 99 (04) 332-340
• 75 Black A, Orsó E, Kelsch R. et al. Analysis of platelet-derived extracellular vesicles in plateletpheresis concentrates: a multicenter study. Transfusion 2017; 57 (06) 1459-1469
• 76 Kamhieh-Milz J, Mustafa SA, Sterzer V. et al. Secretome profiling of apheresis platelet supernatants during routine storage via antibody-based microarray. J Proteomics 2017; 150: 74-85
• 77 Noulsri E, Udomwinijsilp P, Lerdwana S, Chongkolwatana V, Permpikul P. Differences in levels of platelet-derived microparticles in platelet components prepared using the platelet rich plasma, buffy coat, and apheresis procedures. Transfus Apheresis Sci 2017; 56 (02) 135-140
• 78 Maurer-Spurej E, Larsen R, Labrie A, Heaton A, Chipperfield K. Microparticle content of platelet concentrates is predicted by donor microparticles and is altered by production methods and stress. Transfus Apheresis Sci 2016; 55 (01) 35-43
• 79 Sandgren P, Berlin G, Tynngård N. Treatment of platelet concentrates with ultraviolet C light for pathogen reduction increases cytokine accumulation. Transfusion 2016; 56 (06) 1377-1383
• 80 Wadhwa M, Krailadsiri P, Dilger P, Gaines Das R, Seghatchian MJ, Thorpe R. Cytokine levels as performance indicators for white blood cell reduction of platelet concentrates. Vox Sang 2002; 83 (02) 125-136
• 81 Garraud O, Sut C, Haddad A. et al. Transfusion-associated hazards: a revisit of their presentation. Transfus Clin Biol 2018; 25 (02) 118-135
• 82 Cognasse F, Boussoulade F, Chavarin P. et al. Release of potential immunomodulatory factors during platelet storage. Transfusion 2006; 46 (07) 1184-1189
• 83 Aloui C, Prigent A, Sut C. et al. The signaling role of CD40 ligand in platelet biology and in platelet component transfusion. Int J Mol Sci 2014; 15 (12) 22342-22364
• 84 Leitner GC, List J, Horvath M, Eichelberger B, Panzer S, Jilma-Stohlawetz P. Additive solutions differentially affect metabolic and functional parameters of platelet concentrates. Vox Sang 2016; 110 (01) 20-26
• 85 van der Meer PF. PAS or plasma for storage of platelets? A concise review. Transfus Med 2016; 26 (05) 339-342
• 86 Daurat A, Roger C, Gris J. et al. Apheresis platelets are more frequently associated with adverse reactions than pooled platelets both in recipients and in donors: a study from French hemovigilance data. Transfusion 2016; 56 (06) 1295-1303
• 87 Vassallo RR, Adamson JW, Gottschall JL. et al. In vitro and in vivo evaluation of apheresis platelets stored for 5 days in 65% platelet additive solution/35% plasma. Transfusion 2010; 50 (11) 2376-2385
• 88 Diedrich B, Sandgren P, Jansson B, Gulliksson H, Svensson L, Shanwell A. In vitro and in vivo effects of potassium and magnesium on storage up to 7 days of apheresis platelet concentrates in platelet additive solution. Vox Sang 2008; 94 (02) 96-102
• 89 Shanwell A, Diedrich B, Falker C. et al. Paired in vitro and in vivo comparison of apheresis platelet concentrates stored in platelet additive solution for 1 versus 7 days. Transfusion 2006; 46 (06) 973-979
• 90 Phipps RP, Kaufman J, Blumberg N. Platelet derived CD154 (CD40 ligand) and febrile responses to transfusion. Lancet 2001; 357 (9273): 2023-2024
• 91 Blumberg N, Heal JM, Phillips GL, Phipps RP. Platelets--to transfuse or not to transfuse. Lancet 2012; 380 (9850): 1287-1289
• 92 Garraud O, Cognasse F, Hamzeh-Cognasse H, Spinelli S, Phipps RP, Blumberg N. Removal of biologic response modifiers associated with platelet transfusion reactions: strategies worth considering?. Transfusion 2014; 54 (10) 2583
• 93 Blumberg N, Cholette JM, Cahill C. et al. Transfusion medicine: a research agenda for the coming years. Transfus Apheresis Sci 2019; 58 (05) 698-700
• 94 Hamzeh-Cognasse H, Damien P, Nguyen KA. et al. Immune-reactive soluble OX40 ligand, soluble CD40 ligand, and interleukin-27 are simultaneously oversecreted in platelet components associated with acute transfusion reactions. Transfusion 2014; 54 (03) 613-625
• 95 Nguyen KA, Hamzeh-Cognasse H, Sebban M. et al. A computerized prediction model of hazardous inflammatory platelet transfusion outcomes. PLoS One 2014; 9 (05) e97082
• 96 Yasui K, Matsuyama N, Kuroishi A, Tani Y, Furuta RA, Hirayama F. Mitochondrial damage-associated molecular patterns as potential proinflammatory mediators in post-platelet transfusion adverse effects. Transfusion 2016; 56 (05) 1201-1212
• 97 Yang L, Yang D, Yang Q, Cheng F, Huang Y. Extracellular DNA in blood products and its potential effects on transfusion. Biosci Rep 2020; 40 (03) BSR20192770
• 98 Li H, Liu D, Lu J, Bai Y. Physiology and pathophysiology of mitochondrial DNA. Adv Exp Med Biol 2012; 942: 39-51
• 99 Boudreau LH, Duchez AC, Cloutier N. et al. Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation. Blood 2014; 124 (14) 2173-2183
• 100 Burnouf T, Chou ML, Goubran H, Cognasse F, Garraud O, Seghatchian J. An overview of the role of microparticles/microvesicles in blood components: Are they clinically beneficial or harmful?. Transfus Apheresis Sci 2015; 53 (02) 137-145
• 101 Goubran H, Sheridan D, Radosevic J, Burnouf T, Seghatchian J. Transfusion-related immunomodulation and cancer. Transfus Apheresis Sci 2017; 56 (03) 336-340
• 102 Osman A, Hitzler WE, Meyer CU. et al. Effects of pathogen reduction systems on platelet microRNAs, mRNAs, activation, and function. Platelets 2015; 26 (02) 154-163
• 103 Diallo I, Benmoussa A, Laugier J, Osman A, Hitzler WE, Provost P. Platelet pathogen reduction technologies alter the microRNA profile of platelet-derived microparticles. Front Cardiovasc Med 2020; 7: 31
• 104 Cognasse F, Sut C, Hamzeh-Cognasse H, Garraud O. Platelet-derived HMGB1: critical mediator of SARs related to transfusion. Ann Transl Med 2020; 8 (04) 140
• 105 Kwak MS, Kim HS, Lee B, Kim YH, Son M, Shin JS. Immunological significance of HMGB1 post-translational modification and redox biology. Front Immunol 2020; 11: 1189
• 106 Raucci A, Di Maggio S, Scavello F, D'Ambrosio A, Bianchi ME, Capogrossi MC. The Janus face of HMGB1 in heart disease: a necessary update. Cell Mol Life Sci 2019; 76 (02) 211-229
• 107 Andersson U, Yang H, Harris H. High-mobility group box 1 protein (HMGB1) operates as an alarmin outside as well as inside cells. Semin Immunol 2018; 38: 40-48
• 108 Klune JR, Dhupar R, Cardinal J, Billiar TR, Tsung A. HMGB1: endogenous danger signaling. Mol Med 2008; 14 (7-8): 476-484
• 109 Vieira-de-Abreu A, Campbell RA, Weyrich AS, Zimmerman GA. Platelets: versatile effector cells in hemostasis, inflammation, and the immune continuum. Semin Immunopathol 2012; 34 (01) 5-30
• 110 Highton PJ, Martin N, Smith AC, Burton JO, Bishop NC. Microparticles and Exercise in Clinical Populations. Exerc Immunol Rev 2018; 24: 46-58
• 111 Melki I, Tessandier N, Zufferey A, Boilard E. Platelet microvesicles in health and disease. Platelets 2017; 28 (03) 214-221
• 112 Vafeiadou K, Weech M, Sharma V. et al. A review of the evidence for the effects of total dietary fat, saturated, monounsaturated and n-6 polyunsaturated fatty acids on vascular function, endothelial progenitor cells and microparticles. Br J Nutr 2012; 107 (03) 303-324
• 113 André P. P-selectin in haemostasis. Br J Haematol 2004; 126 (03) 298-306
• 114 Vandendries ER, Furie BC, Furie B. Role of P-selectin and PSGL-1 in coagulation and thrombosis. Thromb Haemost 2004; 92 (03) 459-466
• 115 Woollard KJ, Chin-Dusting J. P-selectin antagonism in inflammatory disease. Curr Pharm Des 2010; 16 (37) 4113-4118
• 116 Antonopoulos CN, Sfyroeras GS, Kakisis JD, Moulakakis KG, Liapis CD. The role of soluble P selectin in the diagnosis of venous thromboembolism. Thromb Res 2014; 133 (01) 17-24
• 117 Kutlar A, Embury SH. Cellular adhesion and the endothelium: P-selectin. Hematol Oncol Clin North Am 2014; 28 (02) 323-339
• 118 Abadier M, Ley K. P-selectin glycoprotein ligand-1 in T cells. Curr Opin Hematol 2017; 24 (03) 265-273
• 119 Mattioli AV. Prevalence of anti-PF4/heparin antibodies and the HIT syndrome in cardiovascular medicine. Semin Thromb Hemost 2004; 30 (03) 291-295
• 120 Aidoudi S, Bikfalvi A. Interaction of PF4 (CXCL4) with the vasculature: a role in atherosclerosis and angiogenesis. Thromb Haemost 2010; 104 (05) 941-948
• 121 Kowalska MA, Rauova L, Poncz M. Role of the platelet chemokine platelet factor 4 (PF4) in hemostasis and thrombosis. Thromb Res 2010; 125 (04) 292-296
• 122 Pilatova K, Greplova K, Demlova R, Bencsikova B, Klement GL, Zdrazilova-Dubska L. Role of platelet chemokines, PF-4 and CTAP-III, in cancer biology. J Hematol Oncol 2013; 6: 42
• 123 Appay V, Rowland-Jones SL. RANTES: a versatile and controversial chemokine. Trends Immunol 2001; 22 (02) 83-87
• 124 Conti P, DiGioacchino M. MCP-1 and RANTES are mediators of acute and chronic inflammation. Allergy Asthma Proc 2001; 22 (03) 133-137
• 125 Vangelista L, Secchi M, Lusso P. Rational design of novel HIV-1 entry inhibitors by RANTES engineering. Vaccine 2008; 26 (24) 3008-3015
• 126 Levy JA. The unexpected pleiotropic activities of RANTES. J Immunol 2009; 182 (07) 3945-3946
• 127 Morel O, Morel N, Freyssinet JM, Toti F. Platelet microparticles and vascular cells interactions: a checkpoint between the haemostatic and thrombotic responses. Platelets 2008; 19 (01) 9-23
• 128 Burnouf T, Goubran HA, Chou ML, Devos D, Radosevic M. Platelet microparticles: detection and assessment of their paradoxical functional roles in disease and regenerative medicine. Blood Rev 2014; 28 (04) 155-166
• 129 Johnson L, Raynel S, Seghatchian J, Marks DC. Platelet microparticles in cryopreserved platelets: potential mediators of haemostasis. Transfus Apheresis Sci 2015; 53 (02) 146-152
• 130 Żmigrodzka M, Guzera M, Miśkiewicz A, Jagielski D, Winnicka A. The biology of extracellular vesicles with focus on platelet microparticles and their role in cancer development and progression. Tumour Biol 2016; 37 (11) 14391-14401
• 131 Chen F, Liao Z, Peng D, Han L. Role of platelet microparticles in blood diseases: future clinical perspectives. Ann Clin Lab Sci 2019; 49 (02) 161-170
• 132 Zhang B, Wu T, Chen M, Zhou Y, Yi D, Guo R. The CD40/CD40L system: a new therapeutic target for disease. Immunol Lett 2013; 153 (1-2): 58-61
• 133 Laman JD, Claassen E, Noelle RJ. Functions of CD40 and its ligand, gp39 (CD40L). Crit Rev Immunol 2017; 37 (2-6): 371-420
• 134 Michel NA, Zirlik A, Wolf D. CD40L and its receptors in atherothrombosis-an update. Front Cardiovasc Med 2017; 4: 40
• 135 Karnell JL, Rieder SA, Ettinger R, Kolbeck R. Targeting the CD40-CD40L pathway in autoimmune diseases: humoral immunity and beyond. Adv Drug Deliv Rev 2019; 141: 92-103
• 136 Bosmans LA, Bosch L, Kusters PJH, Lutgens E, Seijkens TTP. The CD40-CD40L dyad as immunotherapeutic target in cardiovascular disease. J Cardiovasc Transl Res 2020; ; (epub ahead of print) DOI: 10.1007/s12265-020-09994-3.
• 137 Daub S, Lutgens E, Münzel T, Daiber A. CD40/CD40L and related signaling pathways in cardiovascular health and disease-the pros and cons for cardioprotection. Int J Mol Sci 2020; 21 (22) E8533

Publication History

Received: 15 September 2020

Accepted: 07 January 2021

Article published online:
12 March 2021