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Cytokines and related molecules, and adverse reactions related to platelet concentrate transfusions
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Cytokines and related molecules, and adverse reactions related to platelet concentrate transfusions Cytokines/molécules apparentées et événements indésirables receveurs liés aux transfusions de concentrés plaquettaires F. Cognasse a,∗ , O. Garraud b,c,d a
The Rhône-Alpes-Auvergne Regional Branch of the French National Blood System EFS, 42000 Saint-Étienne, France EA3064, Faculty of Medicine, University of Lyon, 42023 Saint-Étienne, France c Palliative Care Unit, the Ruffec Hospital, 16700 Ruffec, France d Institut National de la Transfusion Sanguine, 75015 Paris, France b
a r t i c l e
i n f o
Article history: Available online xxx Keywords: Transfusion Platelets Inflammation Adverse reactions Biological response modifier
a b s t r a c t Platelet transfusion is a safe process, but during or after the process the recipient may experience an adverse reaction and occasionally a serious adverse reaction (SAR). Platelet concentrate transfusion may be liable for significant absence of beneficial response. Danger may manifest clinically or biologically; in the latter case, manifestations are frequently an absence of the expected response to the blood component by the recipient. Blood platelets exert roles in inflammation, especially through the immunomodulator complex CD40/CD40L (sCD40L). In this review, we concentrate on the inflammatory potential of platelets and their participation to SARs in transfusion. ´ e´ franc¸aise de transfusion sanguine © 2019 Published by Elsevier Masson SAS on behalf of Societ (SFTS).
r é s u m é Mots clés : Transfusion Plaquettes Inflammation Effets indésirables receveurs Modificateurs du comportement biologique
La transfusion de plaquettes est un processus sûr, mais pendant ou après le processus, le receveur peut subir un effet indésirable receveur (EIR) plus ou moins grave. La transfusion de concentré plaquettaire peut être responsable d’une absence significative de réponse bénéfique. Le danger peut se manifester cliniquement ou biologiquement. Les plaquettes sanguines jouent un rôle dans l’inflammation, en particulier par le biais du complexe immunomodulateur CD40/CD40L (sCD40L). Dans cette revue, nous nous concentrons sur le potentiel inflammatoire des plaquettes et leur participation aux EIRs en transfusion. ´ e´ franc¸aise de transfusion sanguine (SFTS). © 2019 Publie´ par Elsevier Masson SAS au nom de Societ
Although rare, recipients of blood transfusions can experience serious adverse reactions (SARs). Clinical signs of SARs appear either during the transfusion or within hours (or days) following the procedure. The responsibility of PCs in inducing SARs could be related to the inflammatory function of platelets. Indeed, besides their contribution to the haemostatic response, platelets are innate immune cells that lead to pro-inflammatory reactions [1–4]. Our recent research showed that SARs are related to an elevated soluble CD40-Ligand (sCD40L) level in the transfused PC; however,
∗ Corresponding author. E-mail address: [email protected] (F. Cognasse).
other molecules are potentially co-inducer of SARs (IL-13, MIP-1␣); those inflammatory molecules may dictate the occurrence and the clinical form of the SAR (in particular, febrile haemolytic transfusion reaction or allergy); in that way, they may even be predictive, allowing to the establishment of models and decision trees [5]. The national SAR reporting rate is 235.7 per 100,000 transfused labile blood products (LBP) in France [6]. The lowest incidence rate is associated with therapeutic plasma, and the highest with PC. The main five SAR diagnoses are isolated alloimmunization, febrile nonhemolytic reaction (FNHR), allergy, overload pulmonary oedema and immunological incompatibility [6]. The platelet products in SAR may be related to the inflammatory function of platelets. Blood platelets are non-nucleated
https://doi.org/10.1016/j.tracli.2019.06.324 ´ e´ franc¸aise de transfusion sanguine (SFTS). 1246-7820/© 2019 Published by Elsevier Masson SAS on behalf of Societ
Please cite this article in press as: Cognasse F, Garraud O. Cytokines and related molecules, and adverse reactions related to platelet concentrate transfusions. Transfusion Clinique et Biologique (2019), https://doi.org/10.1016/j.tracli.2019.06.324
G Model TRACLI-3076; No. of Pages 3 2
ARTICLE IN PRESS F. Cognasse, O. Garraud / Transfusion Clinique et Biologique xxx (2019) xxx–xxx
cellular elements that contribute to the haemostatic response. They are also innate immune cells that can lead to pro-inflammatory events [7–9]. Platelets release a wide variety of growth factors, cytokines, chemokines and related substances, including histamine, bradykinins, serotonin, activated complement (C3a, C5a), PF-4,  thromboglobulin, RANTES, MIP-1␣, INF␥, sCD40L, etc. These molecules modulate vascular endothelial cell and leukocyte functions. Platelets have a short life span of approximately ten days. Platelets collected and prepared for transfusion purposes may be stored for five days after preparation in France before transfusion (now seven days provided that a safety process is applied to reduce or inactivate pathogens). They are likely to release large quantities of bioactive and pro-inflammatory products during storage that may accumulate in the storage medium, indicating a certain level of activation and the possibility of storage lesions, which are defined alterations of the biological or physico-chemical characteristics of the PC content [10]. Platelets may also release microvesicles or particles, which are likely to contain a high concentration of these secretory and membrane products. The physiological and pathophysiological role of these platelet microparticles is not well understood, but it is likely major [11]. FNHR is characterized by an hyperthermia resulting from the effects of potentially ‘endogenous’ pyrogenic cytokines produced by patients themselves and/or by ‘exogenous’ pyrogenic cytokines from the LBP that accumulate in the transfused product during storage [5,12–20]. The pathophysiology of transfusion allergic reactions [21] often involves factors relating to the donor, the LBP, or the recipient. In a research project of ours, we aim to examine SARs related to the transfusion of apheresis and pooled PC (APC and PPC, respectively), capable of bringing inflammatory elements and which occur independently from an antigen or antibody interaction. Indeed, inflammatory SARs are mainly related to donation (donor) or product characteristics and cannot be avoided by currently available measures other than leucoreduction and dilution of the inflammatory products with additive solutions [22]. By crossreferencing data: • from the database of a regional setting of the national blood establishment database, i.e. EFS-Auvergne-Rhône-Alpes (AuRa), and particularly information related to PC production and quality parameters; • from the research unit (EA3064-GIMAP) database that characterize the inflammatory potential of each transfused PC, we analyse the presence and accumulation of inflammatory factors in PC according to their production processes and storage times. Over the last few years, we have consolidated preliminary results and gathered samples as part of a multi-site collaboration between the EFS-AuRa and the main EFS-AuRa distribution/delivery centres Saint-Étienne, St-Priest en Jarez, and Clermont-Ferrand to collect and analyse all prepared platelet products, including those that resulted in a SAR. The project’s regional scope enabled us to approach working hypothesis with a high degree of statistical power. We collected 8992 blood samples on the day they were collected from the donor (6247 samples) and the day they were delivered (2745 samples); one hundred and forty of them were related to a SAR. The level of two inflammatory molecules, sCD40L and sCD62P, were assessed in all samples. This workflow represents the largest collection of platelet products, SAR-related platelet products and inflammatory content data ever assembled to our knowledge. Platelet products are still ongoing and observational study continues to be supplemented by in vitro analysis of the content and functional roles of sCD40L and sCD62P along with other Biological Response Modifier (BRMs: cytokines and other related molecules). This work has entered the next stage of data acquisition
and mining. In-depth analysis will also be pursued with increasing acquisition of clinical-biological data. Some intermediate data have already been communicated at least in part [5,9,12–16,23–28]. The first achievement of this global study [29] did not aim to confirm previous data, but instead to provide new information on the link between sCD40L and SARs, namely, to determine whether high levels of sCD40L are consistently associated with SARs in transfused patients. It demonstrated that PC storage duration is associated with the secretion of sCD40L [30] and the occurrence of sCD40L-associated SARs. Thus, we sought to further examine the relationship of sCD40L values and SARs in the context of PC storage time. We plotted the supernatant sCD40L levels of PCs associated with the 140 reported SARs against controls after various storage durations. The results are particularly suggestive of an “all-or-nothing” threshold phenomenon, which has been previously proposed in case studies. They suggest a second trigger is required in addition to higher sCD40L levels. Such a trigger has yet to be identified, but this notion fits well with both the “2-hit” and “threshold” models of TRALI and various clinical conditions. In all, platelet transfusion is usually secure and instrumental to patients. SARs (which cannot be avoided by present interventions) happen on rare occasions with clinical presentation of acute inflammation. BRMs (which consist mainly of cytokines and chemokines and associated molecules such as sCD40L) are discovered to be in close connection in all instances studied to date, either on the basis of clinical findings or experimentally tested. Again, transfusionlinked inflammation is probably the consequence of a mixture of donor, BC and recipient-related variables. Transfusion medicine may become one of the first medical specialties where personalized medicine comes into effect: “How can a person receive the BC most suitable for his or her situation?” Funding This work was supported by grants from the French Blood Establishment, France; the Agence Nationale de la Sécurité et du Médicament et des Produits de Santé (ANSM - AAP-2012-011, Reference 2012S055), and the Association “Les Amis de Rémi” Savigneux, France. Disclosure of interest The authors declare that they have no competing interest. References [1] Adam F, Kauskot A, Nurden P, Sulpice E, Hoylaerts MF, Davis RJ, et al. Platelet JNK1 is involved in secretion and thrombus formation. Blood 2010;115:4083–92. [2] Sandrock K, Nakamura L, Vraetz T, Beutel K, Ehl S, Zieger B. Platelet secretion defect in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL-5). Blood 2010;116:6148–50. [3] Garraud O, Berthet J, Hamzeh-Cognasse H, Cognasse F. Pathogen sensing, subsequent signalling, and signalosome in human platelets. Thromb Res 2011;127:283–6. [4] Garraud O, Cognasse F. Platelet Toll-like receptor expression: the link between “danger” ligands and inflammation. Inflamm Allergy Drug Targets 2010;9:322–33. [5] Nguyen KA, Hamzeh-Cognasse H, Sebban M, Fromont E, Chavarin P, Absi L, et al. A computerized prediction model of hazardous inflammatory platelet transfusion outcomes. PLoS One 2014;9:e97082 [Research Support, Non-U.S. Gov’t]. [6] ANSM. Rapport d’activité hémovigilance 2015. Agence nationale de sécurité du médicament et des produits de santé (ANSM); 2016. p. 1–91. [7] Garraud O, Tariket S, Sut C, Haddad A, Aloui C, Chakroun T, et al. Transfusion as an inflammation hit: knowns and unknowns. Front Immunol 2016. [8] Cognasse F, Garraud O, Pozzetto B, Laradi S, Hamzeh-Cognasse H. How can non-nucleated platelets be so smart? J Thromb Haemost 2016;14:794–6. [9] Garraud O, Cognasse F. Are platelets cells? And if yes, are they immune cells? Front Immunol 2015;6 [Review. Article 70]. [10] Devine DV, Serrano K. The platelet storage lesion. Clin Lab Med 2010;30:475–87.
Please cite this article in press as: Cognasse F, Garraud O. Cytokines and related molecules, and adverse reactions related to platelet concentrate transfusions. Transfusion Clinique et Biologique (2019), https://doi.org/10.1016/j.tracli.2019.06.324
G Model TRACLI-3076; No. of Pages 3
ARTICLE IN PRESS F. Cognasse, O. Garraud / Transfusion Clinique et Biologique xxx (2019) xxx–xxx
[11] Marcoux G, Duchez AC, Rousseau M, Levesque T, Boudreau LH, Thibault L, et al. Microparticle and mitochondrial release during extended storage of different types of platelet concentrates. Platelets 2017;28:272–80. [12] Nguyen KA, Hamzeh-Cognasse H, Laradi S, Pozzetto B, Garraud O, Cognasse F. Specific activation, signalling and secretion profiles of human platelets following PAR-1 and PAR-4 stimulation. Platelets 2015;26:795–8 [Research Support, Non-U.S. Gov’t]. [13] Hamzeh-Cognasse H, Laradi S, Osselaer JC, Cognasse F, Garraud O. AmotosalenHCl-UVA pathogen reduction does not alter poststorage metabolism of soluble CD40 ligand, Ox40 ligand and interkeukin-27, the cytokines that generally associate with serious adverse events. Vox Sang 2015;108:205–7. [14] Cognasse F, Aloui C, Anh Nguyen K, Hamzeh-Cognasse H, Fagan J, Arthaud CA, et al. Platelet components associated with adverse reactions: predictive value of mitochondrial DNA relative to biological response modifiers. Transfusion 2015. [15] Hamzeh-Cognasse H, Damien P, Nguyen KA, Arthaud CA, Eyraud MA, Chavarin P, 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;54:613–25. [16] 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;54:2583 [Comment Letter]. [17] Cognasse F, Hamzeh-Cognasse H, Lafarge S, Acquart S, Chavarin P, Courbil R, et al. Donor platelets stored for at least 3 days can elicit activation marker expression by the recipient’s blood mononuclear cells: an in vitro study. Transfusion 2009;49:91–8. [18] Cognasse F, Payrat JM, Corash L, Osselaer JC, Garraud O. Platelet components associated with acute transfusion reactions: the role of platelet-derived soluble CD40 ligand. Blood 2008;112:4779–80. [19] Cognasse F, Osselaer JC, Payrat JM, Chavarin P, Corash L, Garraud O. Release of immune modulation factors from platelet concentrates during storage after photochemical pathogen inactivation treatment. Transfusion 2008;48:809–13. [20] Cognasse F, Boussoulade F, Chavarin P, Acquart S, Fabrigli P, Lamy B, et al. Release of potential immunomodulatory factors during platelet storage. Transfusion 2006;46:1184–9.
3
[21] Savage WJ, Tobian AA, Savage JH, Wood RA, Schroeder JT, Ness PM. Scratching the surface of allergic transfusion reactions. Transfusion 2013;53: 1361–71. [22] Garraud O, Cognasse F, Laradi S, Hamzeh-Cognasse H, Peyrard T, Tissot JD, et al. How to mitigate the risk of inducing transfusion-associated adverse reactions. Transfus Clin Biol 2018;25:262–8. [23] Chabert A, Hamzeh-Cognasse H, Pozzetto B, Cognasse F, Schattner M, Gomez RM, et al. Human platelets and their capacity of binding viruses: meaning and challenges? BMC Immunol 2015;16:26. [24] Cognasse F, Hamzeh-Cognasse H, Laradi S, Chou ML, Seghatchian J, Burnouf T, et al. The role of microparticles in inflammation and transfusion: a concise review. Transfus Apher Sci 2015;53:159–67 [Review]. [25] 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 Apher Sci 2015;53:137–45 [Review]. [26] Bost V, Chavarin P, Boussoulade F, Fabrigli P, Chabre C, Benamara H, et al. Independent evaluation of tolerance of therapeutic plasma inactivated by ® amotosalen-HCl-UVA (Intercept ) over a 5-year period of extensive delivery. Vox Sang 2015;109:414–6. [27] Boudreau LH, Duchez AC, Cloutier N, Soulet D, Martin N, Bollinger J, et al. Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation. Blood 2014;124:2173–83. [28] Aloui C, Sut C, Prigent A, Fagan J, Cognasse F, Granados-Herbepin V, et al. Are polymorphisms of the immunoregulatory factor CD40LG implicated in acute transfusion reactions? Sci Rep 2014;4:7239 [Research Support, Non-U.S. Gov’t]. [29] 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;130:1380–3 [Letter Multicenter Study/Research Support, Non-U.S. Gov’t]. [30] Sut C, Tariket S, Aubron C, Aloui C, Hamzeh-Cognasse H, Berthelot P, et al. The non-hemostatic aspects of transfused platelets. Front Med (Lausanne) 2018;5:42 [Review].
Please cite this article in press as: Cognasse F, Garraud O. Cytokines and related molecules, and adverse reactions related to platelet concentrate transfusions. Transfusion Clinique et Biologique (2019), https://doi.org/10.1016/j.tracli.2019.06.324
ARTICLE IN PRESS
TRACLI-3076; No. of Pages 3
Transfusion Clinique et Biologique xxx (2019) xxx–xxx
Disponible en ligne sur
ScienceDirect www.sciencedirect.com
Update article
Cytokines and related molecules, and adverse reactions related to platelet concentrate transfusions Cytokines/molécules apparentées et événements indésirables receveurs liés aux transfusions de concentrés plaquettaires F. Cognasse a,∗ , O. Garraud b,c,d a
The Rhône-Alpes-Auvergne Regional Branch of the French National Blood System EFS, 42000 Saint-Étienne, France EA3064, Faculty of Medicine, University of Lyon, 42023 Saint-Étienne, France c Palliative Care Unit, the Ruffec Hospital, 16700 Ruffec, France d Institut National de la Transfusion Sanguine, 75015 Paris, France b
a r t i c l e
i n f o
Article history: Available online xxx Keywords: Transfusion Platelets Inflammation Adverse reactions Biological response modifier
a b s t r a c t Platelet transfusion is a safe process, but during or after the process the recipient may experience an adverse reaction and occasionally a serious adverse reaction (SAR). Platelet concentrate transfusion may be liable for significant absence of beneficial response. Danger may manifest clinically or biologically; in the latter case, manifestations are frequently an absence of the expected response to the blood component by the recipient. Blood platelets exert roles in inflammation, especially through the immunomodulator complex CD40/CD40L (sCD40L). In this review, we concentrate on the inflammatory potential of platelets and their participation to SARs in transfusion. ´ e´ franc¸aise de transfusion sanguine © 2019 Published by Elsevier Masson SAS on behalf of Societ (SFTS).
r é s u m é Mots clés : Transfusion Plaquettes Inflammation Effets indésirables receveurs Modificateurs du comportement biologique
La transfusion de plaquettes est un processus sûr, mais pendant ou après le processus, le receveur peut subir un effet indésirable receveur (EIR) plus ou moins grave. La transfusion de concentré plaquettaire peut être responsable d’une absence significative de réponse bénéfique. Le danger peut se manifester cliniquement ou biologiquement. Les plaquettes sanguines jouent un rôle dans l’inflammation, en particulier par le biais du complexe immunomodulateur CD40/CD40L (sCD40L). Dans cette revue, nous nous concentrons sur le potentiel inflammatoire des plaquettes et leur participation aux EIRs en transfusion. ´ e´ franc¸aise de transfusion sanguine (SFTS). © 2019 Publie´ par Elsevier Masson SAS au nom de Societ
Although rare, recipients of blood transfusions can experience serious adverse reactions (SARs). Clinical signs of SARs appear either during the transfusion or within hours (or days) following the procedure. The responsibility of PCs in inducing SARs could be related to the inflammatory function of platelets. Indeed, besides their contribution to the haemostatic response, platelets are innate immune cells that lead to pro-inflammatory reactions [1–4]. Our recent research showed that SARs are related to an elevated soluble CD40-Ligand (sCD40L) level in the transfused PC; however,
∗ Corresponding author. E-mail address: [email protected] (F. Cognasse).
other molecules are potentially co-inducer of SARs (IL-13, MIP-1␣); those inflammatory molecules may dictate the occurrence and the clinical form of the SAR (in particular, febrile haemolytic transfusion reaction or allergy); in that way, they may even be predictive, allowing to the establishment of models and decision trees [5]. The national SAR reporting rate is 235.7 per 100,000 transfused labile blood products (LBP) in France [6]. The lowest incidence rate is associated with therapeutic plasma, and the highest with PC. The main five SAR diagnoses are isolated alloimmunization, febrile nonhemolytic reaction (FNHR), allergy, overload pulmonary oedema and immunological incompatibility [6]. The platelet products in SAR may be related to the inflammatory function of platelets. Blood platelets are non-nucleated
https://doi.org/10.1016/j.tracli.2019.06.324 ´ e´ franc¸aise de transfusion sanguine (SFTS). 1246-7820/© 2019 Published by Elsevier Masson SAS on behalf of Societ
Please cite this article in press as: Cognasse F, Garraud O. Cytokines and related molecules, and adverse reactions related to platelet concentrate transfusions. Transfusion Clinique et Biologique (2019), https://doi.org/10.1016/j.tracli.2019.06.324
G Model TRACLI-3076; No. of Pages 3 2
ARTICLE IN PRESS F. Cognasse, O. Garraud / Transfusion Clinique et Biologique xxx (2019) xxx–xxx
cellular elements that contribute to the haemostatic response. They are also innate immune cells that can lead to pro-inflammatory events [7–9]. Platelets release a wide variety of growth factors, cytokines, chemokines and related substances, including histamine, bradykinins, serotonin, activated complement (C3a, C5a), PF-4,  thromboglobulin, RANTES, MIP-1␣, INF␥, sCD40L, etc. These molecules modulate vascular endothelial cell and leukocyte functions. Platelets have a short life span of approximately ten days. Platelets collected and prepared for transfusion purposes may be stored for five days after preparation in France before transfusion (now seven days provided that a safety process is applied to reduce or inactivate pathogens). They are likely to release large quantities of bioactive and pro-inflammatory products during storage that may accumulate in the storage medium, indicating a certain level of activation and the possibility of storage lesions, which are defined alterations of the biological or physico-chemical characteristics of the PC content [10]. Platelets may also release microvesicles or particles, which are likely to contain a high concentration of these secretory and membrane products. The physiological and pathophysiological role of these platelet microparticles is not well understood, but it is likely major [11]. FNHR is characterized by an hyperthermia resulting from the effects of potentially ‘endogenous’ pyrogenic cytokines produced by patients themselves and/or by ‘exogenous’ pyrogenic cytokines from the LBP that accumulate in the transfused product during storage [5,12–20]. The pathophysiology of transfusion allergic reactions [21] often involves factors relating to the donor, the LBP, or the recipient. In a research project of ours, we aim to examine SARs related to the transfusion of apheresis and pooled PC (APC and PPC, respectively), capable of bringing inflammatory elements and which occur independently from an antigen or antibody interaction. Indeed, inflammatory SARs are mainly related to donation (donor) or product characteristics and cannot be avoided by currently available measures other than leucoreduction and dilution of the inflammatory products with additive solutions [22]. By crossreferencing data: • from the database of a regional setting of the national blood establishment database, i.e. EFS-Auvergne-Rhône-Alpes (AuRa), and particularly information related to PC production and quality parameters; • from the research unit (EA3064-GIMAP) database that characterize the inflammatory potential of each transfused PC, we analyse the presence and accumulation of inflammatory factors in PC according to their production processes and storage times. Over the last few years, we have consolidated preliminary results and gathered samples as part of a multi-site collaboration between the EFS-AuRa and the main EFS-AuRa distribution/delivery centres Saint-Étienne, St-Priest en Jarez, and Clermont-Ferrand to collect and analyse all prepared platelet products, including those that resulted in a SAR. The project’s regional scope enabled us to approach working hypothesis with a high degree of statistical power. We collected 8992 blood samples on the day they were collected from the donor (6247 samples) and the day they were delivered (2745 samples); one hundred and forty of them were related to a SAR. The level of two inflammatory molecules, sCD40L and sCD62P, were assessed in all samples. This workflow represents the largest collection of platelet products, SAR-related platelet products and inflammatory content data ever assembled to our knowledge. Platelet products are still ongoing and observational study continues to be supplemented by in vitro analysis of the content and functional roles of sCD40L and sCD62P along with other Biological Response Modifier (BRMs: cytokines and other related molecules). This work has entered the next stage of data acquisition
and mining. In-depth analysis will also be pursued with increasing acquisition of clinical-biological data. Some intermediate data have already been communicated at least in part [5,9,12–16,23–28]. The first achievement of this global study [29] did not aim to confirm previous data, but instead to provide new information on the link between sCD40L and SARs, namely, to determine whether high levels of sCD40L are consistently associated with SARs in transfused patients. It demonstrated that PC storage duration is associated with the secretion of sCD40L [30] and the occurrence of sCD40L-associated SARs. Thus, we sought to further examine the relationship of sCD40L values and SARs in the context of PC storage time. We plotted the supernatant sCD40L levels of PCs associated with the 140 reported SARs against controls after various storage durations. The results are particularly suggestive of an “all-or-nothing” threshold phenomenon, which has been previously proposed in case studies. They suggest a second trigger is required in addition to higher sCD40L levels. Such a trigger has yet to be identified, but this notion fits well with both the “2-hit” and “threshold” models of TRALI and various clinical conditions. In all, platelet transfusion is usually secure and instrumental to patients. SARs (which cannot be avoided by present interventions) happen on rare occasions with clinical presentation of acute inflammation. BRMs (which consist mainly of cytokines and chemokines and associated molecules such as sCD40L) are discovered to be in close connection in all instances studied to date, either on the basis of clinical findings or experimentally tested. Again, transfusionlinked inflammation is probably the consequence of a mixture of donor, BC and recipient-related variables. Transfusion medicine may become one of the first medical specialties where personalized medicine comes into effect: “How can a person receive the BC most suitable for his or her situation?” Funding This work was supported by grants from the French Blood Establishment, France; the Agence Nationale de la Sécurité et du Médicament et des Produits de Santé (ANSM - AAP-2012-011, Reference 2012S055), and the Association “Les Amis de Rémi” Savigneux, France. Disclosure of interest The authors declare that they have no competing interest. References [1] Adam F, Kauskot A, Nurden P, Sulpice E, Hoylaerts MF, Davis RJ, et al. Platelet JNK1 is involved in secretion and thrombus formation. Blood 2010;115:4083–92. [2] Sandrock K, Nakamura L, Vraetz T, Beutel K, Ehl S, Zieger B. Platelet secretion defect in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL-5). Blood 2010;116:6148–50. [3] Garraud O, Berthet J, Hamzeh-Cognasse H, Cognasse F. Pathogen sensing, subsequent signalling, and signalosome in human platelets. Thromb Res 2011;127:283–6. [4] Garraud O, Cognasse F. Platelet Toll-like receptor expression: the link between “danger” ligands and inflammation. Inflamm Allergy Drug Targets 2010;9:322–33. [5] Nguyen KA, Hamzeh-Cognasse H, Sebban M, Fromont E, Chavarin P, Absi L, et al. A computerized prediction model of hazardous inflammatory platelet transfusion outcomes. PLoS One 2014;9:e97082 [Research Support, Non-U.S. Gov’t]. [6] ANSM. Rapport d’activité hémovigilance 2015. Agence nationale de sécurité du médicament et des produits de santé (ANSM); 2016. p. 1–91. [7] Garraud O, Tariket S, Sut C, Haddad A, Aloui C, Chakroun T, et al. Transfusion as an inflammation hit: knowns and unknowns. Front Immunol 2016. [8] Cognasse F, Garraud O, Pozzetto B, Laradi S, Hamzeh-Cognasse H. How can non-nucleated platelets be so smart? J Thromb Haemost 2016;14:794–6. [9] Garraud O, Cognasse F. Are platelets cells? And if yes, are they immune cells? Front Immunol 2015;6 [Review. Article 70]. [10] Devine DV, Serrano K. The platelet storage lesion. Clin Lab Med 2010;30:475–87.
Please cite this article in press as: Cognasse F, Garraud O. Cytokines and related molecules, and adverse reactions related to platelet concentrate transfusions. Transfusion Clinique et Biologique (2019), https://doi.org/10.1016/j.tracli.2019.06.324
G Model TRACLI-3076; No. of Pages 3
ARTICLE IN PRESS F. Cognasse, O. Garraud / Transfusion Clinique et Biologique xxx (2019) xxx–xxx
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Please cite this article in press as: Cognasse F, Garraud O. Cytokines and related molecules, and adverse reactions related to platelet concentrate transfusions. Transfusion Clinique et Biologique (2019), https://doi.org/10.1016/j.tracli.2019.06.324