Automatic depletion with Spectra Optia allows a safe 16% reduction of red blood cell pack consumption in exchanged sickle cell anemia patients.

BACKGROUND: Chronic red blood cell exchanges (RBCXs) are frequently used to prevent complications in patients with sickle cell anemia, but the scarcity of matched red blood cell packs (RBCPs) is a serious concern. The main goal of this study was to compare the number of RBCPs used during RBCXs between the Spectra Optia (SO) device (with the automatic depletion step) and the former Cobe Spectra (CSP) device. STUDY DESIGN AND METHODS: The performances and safety of 300 SO sessions using the automatic depletion step (SO/DE) in 50 patients with sickle cell anemia under a chronic transfusion program over a 1-year period were prospectively analyzed. The numbers of RBCPs saved using this protocol compared to the SO device without depletion and to the CSP device were determined. RESULTS: The SO/DE protocol appeared to be safe, as only 5% and 17% of the sessions were characterized by a significant decrease in blood pressure and increase in heart rate (grade 2 adverse events), respectively. Postapheresis hematocrit and fraction of cells remaining reached expected values. The SO/DE protocol required 16% fewer RBCPs compared to SO without depletion, allowing a mean saving of 12 RBCPs per patient and per year and 13% fewer compared to CSP device. Interestingly, the saving was more important for patients with high total blood volume and/or high preapheresis hematocrit. CONCLUSION: The SO/DE protocol is an efficient, safe and cost-effective procedure for patients with sickle cell anemia under a chronic transfusion program.

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.

Independent evaluation of tolerance of therapeutic plasma inactivated by amotosalen-HCl-UVA (Intercept ™) over a 5-year period of extensive delivery.

Amotosalen-HCl-UVA (AI) is a process to inactivate pathogens in therapeutic plasma (FFP). Tolerance is the main residual issue in FFP transfusion, and only large series observations are powered enough to identify significantly elevated levels of hazards. We report here on 15,133 new transfusions of AI-FFP, over the previously published 36,035, which in all represents one of the largest series observed by means of a highly standardized surveillance (51.168 observations). There is no noticeable difference in terms of tolerance of AI-FFP compared to 5875 transfusions of Quarantine (Q)-FFP. There was no significant difference in terms of advance events, between the two types of FFP (P = 0.98); further, no difference was recorded either when the total number of AI-FFP (51,168) was compared to the corresponding number of Q-FFP (5875; P = 0.62).

Monitoring of sprint and change of direction velocity, vertical jump height, and repeated sprint ability in sub-elite female football players throughout their menstrual cycle.

AIMS: The aim of this study was to investigate the associations between the early follicular (EF, i.e., menstruation), late follicular (LF), and middle luteal (ML) phases of the menstrual cycle and different factors that may influence football performance. METHODS: To this end, 11 eumenorrheic sub-elite female football players underwent field tests to assess sprint speed, lower extremity power, repeated sprint ability, velocity on change of direction, and technical skills at each cycle phase. RESULTS: Performance during the 15-m change of direction ability test, 15-m ball dribbling test, squat jump height, total sprint time [sum of 7 sprints] and decrement score [(mean sprint time/best sprint time × 100) - 100], maximum and mean heart rate, and perceived exertion did not significantly differ among menstrual cycle phases. Conversely, the linear sprint velocity over 10, 20, 30-m distances was decreased in EF vs LF (10-, 20- and 30-m) and in ML vs LF (10- and 20-m) (p < 0.05). The 40-m sprint velocity did not change in the different menstrual cycle phases. CONCLUSION: Overall, our study suggests that sex hormone fluctuations during the menstrual cycle are not associated with vertical jump, velocity on change of direction, and repeated sprint ability, but may influence linear sprint velocity over short distances (10, 20, and 30 m).

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.

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.

In vitro assessment of apheresis and pooled buffy coat platelet components suspended in plasma and SSP+ photochemically treated with amotosalen and UVA for pathogen inactivation (INTERCEPT Blood System™).

BACKGROUND AND OBJECTIVES: INTERCEPT Blood System™ is a pathogen inactivation system for blood components. The initial approval required a platelet component to be suspended in a combination of plasma and Platelet additive Solution/PAS-III. Improved platelet storage has been reported with Mg++ and K+ supplementation (PAS-IIIM). This study validated the use of INTERCEPT™/PAS-IIIM for apheresis and pooled buffy-coat platelet components. MATERIALS AND METHODS: The platelet dose and pH throughout 5 days of storage met the European and French requirements for quality standards. RESULTS AND CONCLUSION: Additional metabolic and activation assessments of the treated platelets confirmed the previously reported superiority of PAS-IIIM over PAS-III, but extended it to the INTERCEPT™ process.

[Platelet immunology and the immune response]. / Immunologie plaquettaire et réponse immune.

Platelets exert not only hemostatic activities, but also pro-inflammatory effects. Platelet-linked inflammation seems essentially related to their capacity of secreting cytokines, chemokines and related molecules. This activity is important in terms of concentration of secreted products. This secretory function confers to platelets a regulatory role in immunity. Besides, platelets do exhibit non-self infectious danger detection molecules on their surfaces, belonging in particular to the "Toll-like receptor family"; through this property, platelets can bind infectious agents but also deliver differential signals for the secretion of cytokines and chemokines. Platelets, which are non-nucleated cells deprived of nuclear DNA, possess however some cellular machinery which permits intracellular signalling and even the production of RNA transcripts for certain cytokines. Last, platelets express variant surface determinants of hemostatic molecules (referred to as HPA antigens) along with HLA class I variant molecules, the function of which on platelets is still unknown. An intriguing question is to reconcile those diverse properties and to understand whether the pro-inflammatory secretory process can affect the immunogenicity of transfused, allogeneic, platelet components.

Cytokines and related molecules, and adverse reactions related to platelet concentrate transfusions.

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.

[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.

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.

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.

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 cytokines and their effects on platelet transfusion]. / Les cytokines des plaquettes et leurs effets lors des transfusions de concentrés de plaquettes.

Platelets have long been confined to haemostasis only. However, novel functions for platelets have been identified recently. Those non-nucleated cells indeed participate to inflammation and also they produce and release numerous factors with known immunomodulatory functions. Among those factors are cytokines and chemokines and the like, such as soluble CD40-Ligand (CD154), which are key molecules in that they bridge innate and adaptative immunity; sCD40L is active on T cells, B cells, monocytes and macrophages, dendritic cells and endothelial cells lining the blood vessels. This means that when a platelet concentrate is transfused to a recipient, a huge amount of cytokines and chemokines is also infused. In this state of the art review, we will present arguments on the role of platelet secretory products in modulating cellular parameters of immunity, and--very likely--in altering functions of those immune cells upon encounters while infusing platelets in blood recipients. We aimed at summarizing data that have been made available on the issue of cytokines/chemokines released by stored platelets prior to delivery. We will focus on the suspected role of the CD40/CD40L tandem in postplatelet transfusion reactions or incidents. We will present recent data on the role of pathogen inactivators on the docking and/or release of cytokines/chemokines by platelets.

Determination of predictors of severity for recipient adverse reactions during platelet product transfusions.

The introduction of allogeneic cells is not a natural process, even if the transfusion is therapeutic and - when no alternative exists, as is often the case - essential. Transfusion of cellular products creates some level of danger sensed by recipients. Danger may manifest itself clinically or biologically, in which case we are dealing with recipient adverse reactions. Platelet concentrate transfusion in particular may be responsible for notable adverse reactions. Some appear to be inevitable, while others are tied to recipient factors: either health or genetic characteristics. The authors' research is specifically focused on platelet storage lesion and stress factors, and the means of controlling them to ensure greater recipient tolerance.

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.

Transfusion as an Inflammation Hit: Knowns and Unknowns.

Transfusion of blood cell components is frequent in the therapeutic arsenal; it is globally safe or even very safe. At present, residual clinical manifestations are principally inflammatory in nature. If some rare clinical hazards manifest as acute inflammation symptoms of various origin, most of them linked with conflicting and undesirable biological material accompanying the therapeutic component (infectious pathogen, pathogenic antibody, unwanted antigen, or allergen), the general feature is subtler and less visible, and essentially consists of alloimmunization or febrile non-hemolytic transfusion reaction. The present essay aims to present updates in hematology and immunology that help understand how, when, and why subclinical inflammation underlies alloimmunization and circumstances characteristic of red blood cells and - even more frequently - platelets that contribute inflammatory mediators. Modern transfusion medicine makes sustained efforts to limit such inflammatory hazards; efforts can be successful only if one has a clear view of each element's role.

Differential downstream effects of CD40 ligation mediated by membrane or soluble CD40L and agonistic Ab: a study on purified human B cells.

With the addition of various cytokines, the CD40-CD40 ligand (CD40L) system can act as a T-helper cell surrogate to permit B lymphocytes to produce large amounts of polyclonal Ig. In the present study, we tested six CD40-CD40L stimulation models: (i, ii) soluble agonistic 89 and G28.5 mAbs ; (iii, iv) 89 and G28.5 bound via their Fc fragments on CDw32-transfected mouse fibroblasts; (v) purified, soluble, trimeric human CD40L molecules (sCD40L); and (vi) human CD40L expressed by a CD40L-transfected mouse fibroblastic cell line (LCD40L). Target B cells consisted of purified blood and tonsillar CD19+ lymphocytes cultured in the presence of CD40 stimuli and IL-2 and IL-10, added at the onset of each B cell culture. A) There was differential expression of CD69, CD80 and CD86 exposure to sCD40L and LCD40L was ensued by the strongest % MFI changes over control. B) In blood B cells, mAbs and sCD40L induced IgA, IgM and IgG production almost equally well; LCD40L proved less efficient. In contrast, in tonsil B cells, LCD40L induced significantly more IgA, IgG1, IgG3 and IgM production than other signals. Using certain CD40/CD40L stimuli to model in vitro Ig production, a system used regularly in many laboratories, may affect the interpretation based on the cell type and on the CD40/CD40L system used.

[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.