Platelet transfusion in adults: An update.

Many patients worldwide receive platelet components (PCs) through the transfusion of diverse types of blood components. PC transfusions are essential for the treatment of central thrombocytopenia of diverse causes, and such treatment is beneficial in patients at risk of severe bleeding. PC transfusions account for almost 10% of all the blood components supplied by blood services, but they are associated with about 3.25 times as many severe reactions (attributable to transfusion) than red blood cell transfusions after stringent in-process leukoreduction to less than 106 residual cells per blood component. PCs are not homogeneous, due to the considerable differences between donors. Furthermore, the modes of PC collection and preparation, the safety precautions taken to limit either the most common (allergic-type reactions and febrile non-hemolytic reactions) or the most severe (bacterial contamination, pulmonary lesions) adverse reactions, and storage and conservation methods can all result in so-called PC "storage lesions". Some storage lesions affect PC quality, with implications for patient outcome. Good transfusion practices should result in higher levels of platelet recovery and efficacy, and lower complication rates. These practices include a matching of tissue ABH antigens whenever possible, and of platelet HLA (and, to a lesser extent, HPA) antigens in immunization situations. This review provides an overview of all the available information relating to platelet transfusion, from donor and donation to bedside transfusion, and considers the impact of the measures applied to increase transfusion efficacy while improving safety and preventing transfusion inefficacy and refractoriness. It also considers alternatives to platelet component (PC) transfusion.

How to mitigate the risk of inducing transfusion-associated adverse reactions.

Transfusion has become extremely safe but can still be associated with adverse reactions. Some adverse reactions can be mitigated by applying measures to donor selection, the process of separating blood components as well as hospital-based procedures consisting in matching the donor and the recipient; special attention is given to optimizing the best fit between the component and the beneficiary, which is not only an immuno-hematological challenge (fresh versus old blood, testing for certain viruses such as CMV, parvovirus B19, etc.). Considerable progress has also been achieved to strengthen the overall quality and safety of the whole transfusion chain. Guidelines and recommendations have resulted in substantial progress, and the recent revisiting of patients as part of a more holistic approach has enabled blood management programs to be created. Such programs, when wisely applied in a context of optimal blood use, reinforce patient safety; they enhance hospital recognition of transfusion and hemovigilance specialists as useful players acting in the interests of patients in full compliance with hospital budgets. This review considers the step-by-step processes that reinforce transfusion safety and identifies hurdles that cannot yet be properly addressed; it proposes steps for further progress, in light of personalized medicine.

Platelet and TRALI: From blood component to organism.

Even though used systematically with leukocyte reduction, platelet transfusions still cause adverse reactions in recipients. They include Transfusion-Related Acute Lung Injury (TRALI), respiratory distress that occurs within six hours of the transfusion. The pathophysiology of this transfusion complication brings complex cellular communication into play. The role, particularly inflammatory, played by blood platelets in TRALI pathophysiology has been demonstrated, but is still under debate. Blood platelets play a role in inflammation, particularly via the CD40/CD40L (sCD40L) immunomodulator complex. In this study, we examine in particular the specific involvement of the CD40/CD40L (sCD40L) complex in the inflammatory pathogenesis of TRALI. This molecular complex could be a major target in a TRALI prevention strategy. Improving the conditions in which the platelet concentrates (PC) are prepared and stored would contribute to controlling partly the risks of non-immune TRALI.

Transfusion-associated hazards: A revisit of their presentation.

As a therapy or a support to other therapies, despite being largely beneficial to patients in general, transfusion it is not devoid of some risks. In a moderate number of cases, patients may manifest adverse reactions, otherwise referred to as transfusion-associated hazards (TAHs). The latest French 2016 haemovigilance report indicates that 93% of TAHs are minor (grade 1), 5.5% are moderate (grade 2) and 1.6% are severe (grade 3), with only five deaths (grade 4) being attributed to transfusion with relative certainty (imputability of level [or grade] 1 to 3). Health-care providers need to be well aware of the benefits and potential risks (to best evaluate and discuss the benefit-risk ratio), how to prevent TAHs, the overall costs and the availability of alternative therapeutic options. In high-income countries, most blood establishments (BEs) and hospital blood banks (HBBs) have developed tools for reporting and analysing at least severe transfusion reactions. With nearly two decades of haemovigilance, transfusion reaction databases should be quite informative, though there are four main caveats that prevent it from being fully efficient: (ai) reporting is mainly declarative and is thus barely exhaustive even in countries where it is mandatory by law; (aii) it is often difficult to differentiate between the different complications related to transfusion, diseases, comorbidities and other types of therapies in patients suffering from debilitating conditions; (aiii) there is a lack of consistency in the definitions used to describe and report some transfusion reactions, their severity and their likelihood of being related to transfusion; and (aiv) it is difficult to assess the imputability of a particular BC given to a patient who has previously received many BCs over a relatively short period of time. When compiling all available information published so far, it appears that TAHs can be analysed using different approaches: (bi) their pathophysiological nature; (bii) their severity; (biii) the onset scheme; (biv) a quality assessment (preventable or non-preventable); (bv) their impact on ongoing therapy. Moreover, TAHs can be reported either in a non-integrative or in an integrative way; in the latter case, presentation may also differ when issued by a blood establishment or a treating ward. At some point, a recapitulative document would be useful to gain a better understanding of TAHs in order to decrease their occurrence and severity and allow decision makers to determine action plans: this is what this review attempts to make. This review attempts to merge the different aspects, with a focus on the hospital side, i.e., how the most frequent TAHs can be avoided or mitigated.

Platelets and immunity: From physiology to pathology.

Blood platelets are cells acting during primary haemostasis. The thrombocytopenia observed in many different types of infectious processes begs the question of the relationship between cells and infectious pathogens and the role of platelets in the detection of biological hazards. This in turn brings us back to the role of platelets - via their molecular, membrane and secretory arsenal - in the detection and repair of vascular hazards. The common denominator between a breakdown of haemostasis and the risk of infection has been shown to be a cutoff point in the inflammatory continuum between physiology and physiopathology. The trophic role of platelets - as topical factor and as platelet transfusions - and their inflammatory complexities appear to correlate this proposed model, as reported in this short review.

[Blood transfusion and inflammation as of yesterday, today and tomorrow]. / Transfusion et inflammation : hier - aujourd'hui - demain.

Blood transfusion is made possible principally by use of donated homologous components that - in turn - can be perceived as sources of danger by recipients. This may create an innate immune response dominated by inflammation, especially when transfusion is repeated. Residual leukocytes in blood components can source inflammatory lesions but considerably less than used to be prior to systematic, early and stringent - in process - leukoreduction. Every blood component can cause inflammation, though barely in the case of therapeutic plasma (in such a case, this is mainly restricted to allergy). Iron that may be freed by red blood cells but also processing and storage lesions such as the emission of microparticles can reveal themselves as pro-inflammatory. Platelets in platelet components represent the main source of inflammatory and/or allergic hazards in transfusion; this is linked with processing and storage lesions but also with the platelet physiology itself. It is of utmost importance to avoid inflammatory adverse events in patients that are fragile because of their primary condition and/or treatment; this stands for their safety, as inflammation can be extremely severe and even lethal, and also for their comfort; this increases efficacy of transfusion programs while reducing the overall costs.

Amotosalen-HCl-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.

Platelets in therapeutic platelet concentrates are commonly acknowledged to release biologically active constituents during storage. This study examined the influence of photochemical pathogen reduction treatment (PRT) using amotosalen-HCl and UVA light vs. untreated control platelet components, on three factors recently reported to be associated with serious adverse events associated with platelet component (PC) transfusions: sCD40L, IL-27 and sOX40 ligand. Levels of such cytokine-like factors increased significantly during storage, but no significant difference was detected between PRT- and control PCs. This suggests that occurrences of AEs are not directly influenced by PRT but rather may depend on alternate determinants.

[Blood transfusion and inflammation]. / Transfusion sanguine et inflammation.

Transfusion of labile blood products (LBPs) generates occasional inflammatory : type, hazards; for a large part of these, no antigen/antibody conflict is thus, detected. Residual leucocytes used to account for a large part of such incidents - rarely accidents. Since, however, the systematic leukoreduction of LBPs, leucocytes are the less and less incriminated in adverse events. Platelets themselves proved capable of secreting copious amounts of inflammatory mediators, even in the absence of any deliberated stimulation. Meanwhile, even though exceptionally, inflammation can be observed after red blood cell transfusion. It has been noticed that the collection mode of cellular compounds, as well as the preparation and storage conditions are capable of inflicting lesions to the cell membranes and to activate those cells, and thus promoting inflammatory responses. Storage lesions as well as ageing of the stored cells alongside with cell apoptosis contribute to inflammatory responses. This present 'State of the Art' paper aims at encompassing the primary and secondary components of the LBPs, along with the various types of molecules displaying pro-inflammatory properties that can be encountered in transfusion. A better knowledge of causes of inflammatory transfusion-linked hazards is indeed instrumental to the implementation of safety measures aimed at reducing or suppressing these unwanted effects.

Platelets and cytokines: How and why?

For patients with platelet deficiencies, platelet components are therapeutic products for which there is no substitute. However, transfusion complications are more frequent with this labile blood product than with others. This is attributable to products secreted by the platelets themselves, including a variety of cytokines, chemokines, and biological response modifiers, some of which are secreted in large quantities following platelet activation. Why platelets are activated and prone to releasing these molecules during certain inflammatory and innate immune responses is not yet fully understood, but it could be due to several parameters including incompatibilities between blood donors and recipients, the process of platelet preparation and preservation, and the ability of the donor's immune system to sense danger presented by external stimuli during the blood donation process. This review presents our current knowledge of how the platelets that constitute the platelet component for transfusion are sources of cytokines and biological response modifiers and discusses methods to improve the quality of blood transfusion products and safety for patients.

Complexes between nuclear factor-κB p65 and signal transducer and activator of transcription 3 are key actors in inducing activation-induced cytidine deaminase expression and immunoglobulin A production in CD40L plus interleukin-10-treated human blood B cells.

The signal transducer and activator of transcription 3 (STAT3) transcription factor pathway plays an important role in many biological phenomena. STAT3 transcription is triggered by cytokine-associated signals. Here, we use isolated human B cells to analyse the role of STAT3 in interleukin (IL)-10 induced terminal B cell differentiation and in immunoglobulin (Ig)A production as a characteristic readout of IL-10 signalling. We identified optimal conditions for inducing in-vitro IgA production by purified blood naive B cells using IL-10 and soluble CD40L. We show that soluble CD40L consistently induces the phosphorylation of nuclear factor (NF)-κB p65 but not of STAT3, while IL-10 induces the phosphorylation of STAT3 but not of NF-κB p65. Interestingly, while soluble CD40L and IL-10 were synergistic in driving the terminal maturation of B cells into IgA-producing plasma cells, they did not co-operate earlier in the pathway with regard to the transcription factors NF-κB p65 or STAT3. Blocking either NF-κB p65 or STAT3 profoundly altered the production of IgA and mRNA for activation-induced cytidine deaminase (AID), an enzyme strictly necessary for Ig heavy chain recombination. Finally, the STAT3 pathway was directly activated by IL-10, while IL-6, the main cytokine otherwise known for activating the STAT3 pathway, did not appear to be involved in IL-10-induced-STAT3 activation. Our results suggest that STAT3 and NF-κB pathways co-operate in IgA production, with soluble CD40L rapidly activating the NF-κB pathway, probably rendering STAT3 probably more reactive to IL-10 signalling. This novel role for STAT3 in B cell development reveals a potential therapeutic or vaccine target for eliciting IgA humoral responses at mucosal interfaces.

Streptococcus sanguinis-induced cytokine release from platelets.

BACKGROUND: There is increasing evidence that both chronic and acute infections play a role in the development and progression of atherothrombotic disorders. One potential mechanism is the direct activation of platelets by bacteria. A wide range of bacterial species activate platelets through heterogeneous mechanisms. The oral micro-organism S. sanguinis stimulates platelet aggregation in vitro in a strain-dependent manner, although there are no reports of associated cytokine production. OBJECTIVE: The aim of the present study was to determine whether platelet activation by S. sanguinis involved the release of pro-inflammatory and immune modulating factors, and whether activation was enhanced by epinephrine. METHODS AND RESULTS: Four strains of S. sanguinis and one of S. gordonii stimulated the release of RANTES, PF4, sCD40L and PDGF-AB, whereas only one S. sanguinis strain caused the release of sCD62p. Epinephrine enhanced S. sanguinis-induced platelet aggregation and phosphorylation of phospholipase Cγ2 and Erk, but inhibited RANTES, PF4, sCD40L and PDGF-AB release. Wortmannin inhibited S. sanguinis-induced aggregation and release; however, only aggregation was partially reversed by epinephrine. CONCLUSIONS: The present study demonstrates that platelets respond to S. sanguinis with both prothrombotic and pro-inflammatory/immune-modulating responses. Epinephrine, potentially released in response to infection and/or stress, can significantly enhance the prothrombotic response, thereby providing a putative link between bacteraemia and acute coronary events during stress. In contrast, epinephrine inhibited the pro-inflammatory/immune-modulating response by an undetermined mechanism.

[Blood platelets and biological response to 'danger' signals and subsequent inflammation: towards a new paradigm?]. / Plaquettes sanguines, réponses aux signaux de danger infectieux et inflammation: vers un nouveau paradigme?

Blood platelets are cellular elements of primary haemostasis. During the last decade research on platelets has been subsequently based on this paradigm, with separate observations on issues such as the ability for platelets to bind infectious agents or even engulf them, to drop in counts in case of evolving infectious processes, etc. More recently, novel work has set up bases for novel functions for platelets, as members of functional immune cells, principally in innate immunity but capable of influencing adaptive immunity. Platelets are thus essential to haemostasis and to inflammation, questioning their essential functionality and the set up of a novel paradigm: could platelets be tissue-repairing cells? Such an assumption would open an entire new field of investigations. The present "State of the Art" essay attempts to discuss the main arguments on this.

[Platelets "Toll-like receptor" engagement stimulates the release of immunomodulating molecules]. / L'engagement des Toll-like receptors stimule la libération de facteurs plaquettaires à capacité immunomodulatrice.

Platelets are nonnucleated cellular elements that play a role in the process of haemostasis, and also in various ways in innate immunity and in inflammation. Platelets also contain numerous secretory products and can exert critical roles in several aspects of haemostasis. In addition, they house and secrete a variety of cytokines, chemokines and associated molecules which behave as ligands for receptors/counterparts displayed by endothelial cells lining tissue vessels and most leukocyte subsets. These latter studies show that platelets have an important role in innate as well as adaptive immunity; thus platelets can take part in an immune directive response. Moreover, platelets display receptors for several types of cytokines/chemokines along with FcgammaRII receptors. Finally, platelets not only express a variety of Toll-like receptors, with recently identified functions or not as-yet fully identified, but have also been demonstrated to express the key tandem pair of inflammatory and antigen presentation molecules (CD40 and CD40-ligand/CD154), this latter function making them the major purveyors of soluble CD40L in the plasma. It appears that platelets may be regarded as one of the neglected components of immune cell regulators, and platelets contribute to some interesting aspects in bridging innate and adaptive immunity. We propose that platelets discriminate danger signals and adapt the subsequent responses, with polarized cytokine secretion. Platelets may recognize several types of infectious pathogens and limit microbial colonization by sequestering these pathogens and releasing immunomodulatory factors. This review allows us to re-explore indications that platelets exert direct anti-infection immunity and we will present experimentally-driven arguments in favour of a role of platelet TLR in regulating certain immune activities.