Transfusion at the border of the "intention-to-treat", in the very aged person and in palliative care: A debate.

In both palliative care and in the very aged person i.e. at the end of life, transfusion aims at bringing supportive care; it has indeed no intention to treat. It can occasionally be compassionate as to bring oxygen to a patient or a resident in nursing home wishing to enjoy some exercise or entertainment. Transfusion in this condition is not consensual, for reasons that are medical and/or societal. The present essay aims at discussing the main options to provide transfusion in such extreme, though non-exceptional, conditions.

Blood, perceptions, resource and ownership: When transfusion illustrates the complexity.

Blood is apart from the rest of the tissues as this fluid is overseen by basic and applied life and humanistic sciences. Blood is the essence of human functioning. It is the object of one of the most commonly known cancers, leukemia. It is life-saving in transfusion - a property that also gives blood a special credit and questions blood as a valuable merchandise or as no ones' property but common good. But blood is also scandalous after the tainted blood affair in the 1980s and 1990s. Blood is further inseparable from most religious practices, both forefront and hidden (magic cults). It is frightening as it is versed in legitimate and illegitimate combats; it is poured to compensate offenses or debts in many civilizations. Any time blood comes forefront, rationale science leaves it to irrational digressions. Even the very same life-saving transfusion, is beaten by groups of opponents on religious grounds. Further, at a time blood cells and molecules are scrutinized, no one can claim having a complete understanding of what blood is, off the vasculature, as - to study it - one has to alter it. The study of blood is fascinating for all colleges of an academy and not many topics can share this property: chemists, physicists, geneticists, physiologists, medical doctors, philosophers, ethicists, theologians, artists, historicists, anthropologists, sociologists, etc. have all contributed to depict different, specific, aspects of blood. The present review aims at merging different aspects of blood to give pathophysiologists a platform to better understand fears and hopes related to this special tissue, when dealing with patients of theirs.

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.

How to reposition the benefice-risk balance to safely transfuse patients in non-vital situations?

It appears that the vast majority of review articles on transfusion deal with complications rather than benefits of this supportive therapy. However, deduced from reports compiled by hemovigilance systems, the majority of transfusion procedures do not lead to complications; rather, the majority of prescriptions of blood components generate measurable benefits in the transfused patient. This short review attempts to analyze the causes for such a discrepancy between benefits and complications in the literature and in the everyday life in wards and introduces the role of Patient Blood Management in this understanding.

Plasma for direct therapeutic use, for today and tomorrow: A short critical overview.

Plasma for direct therapeutic use is a fast-evolving blood component in terms of its production and presentation. More than a dozen forms are available worldwide, which is often overlooked since most countries apply policies making only one or very few forms available for treating patients in need. It is most often reserved for the same three clinical indications, i.e. overall clotting-factor deficiency, reversal of vitamin K antagonists in the context of active bleeding or prior to urgent surgery, and therapeutic plasma exchange. The level of evidence is often less robust than generally acknowledged for such major indications while novel indications are tending to emerge in medical and trauma settings. This short review explores classical views and new prospects opened up by novel presentations and statuses for therapeutic plasma.

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.

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.

[Emergent viral threats in blood transfusion]. / Risques viraux émergents en transfusion sanguine.

During the last 20 years, the safety of blood products increased dramatically with regard to the infectious risk and notably to that represented by retroviruses (HIV and HTLV) and hepatitis B and C viruses. The aim of this review is to identify the residual and emergent viral threats that could be responsible for the occurring of new contaminations in the receivers of blood products. Beside many other viruses (HHV-8, erythrovirus B19, hepatitis A and E viruses...), a special attention has been paid to emerging arbovirus diseases (West Nile virus infection, dengue, chikungunya) that threaten to occur in the French metropolitan area following the implantation in Europe of the mosquito Aedes albopictus, the main vector of dengue and chikungunya in temperate regions. Another blood-linked risk, notably in United Kingdom and France, is the prion agent responsible for the variant form of the Creutzfeldt-Jakob disease. The review is concluded by a brief overview of the measures aimed to control these emergences, including the exclusion of at-risk donors, the diagnostic tests able to detect a specific agent, the leukocyte reduction of labile blood products, and the physical or chemical treatments aiming the nonspecific inactivation of infectious agents potentially present in blood without impairing significantly the physiological properties of blood compounds. The ability to control prospectively the new viral risks linked to blood products is a challenge for the preservation of the confidence of both clinicians and receivers in the safety of blood transfusion.

[Analysis of a severe septic transfusion reaction with standard platelet concentrate]. / Analyse d'un incident bactérien grave transmis par transfusion d'un concentré plaquettaire.

We recently observed a near fatal case of transfusion-transmitted infection with standard platelet concentrate. Streptococcus dysgalactiae subspecies equisimilis was isolated both from donor, residual component container and cultures of the patient's blood. This should question the usefulness of systematic bacterial detection in platelet concentrates, however a lethal accident has occurred recently which escaped bacterial detection. This observation calls for implementation of pathogen inactivation procedures for platelets concentrates.

[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.

[Guide for the organisation of ceremonies for delivering pins and certificates of recognition to volunteer blood donors. Etablissement français du sang Auvergne-Loire. Associations pour le don du sang bénévole]. / Guide d'organisation des cérémonies de remises des diplômes et des insignes de reconnaissance en faveur des donneurs de sang bénévoles. Etablissement français du sang Auvergne-Loire. Associations pour le don du sang bénévole.

Award ceremonies constitute an important means of promotion among the blood donor population, and also the general population. They contribute to the development of blood donation loyalty. Even so, their organization must be rigorously and perfectly codified. With this aim, the Etablissement français du sang Auvergne-Loire, in partnership with the departmental representation of the blood donors national federation, worked out a guide for their associations.

[Identitovigilance and its impact on the results ensuring the transfusion security]. / Identitovigilance et son impact sur les résultats d'immuno-hématologie érythrocytaire assurant la sécurité transfusionnelle.

Errors on identity of patients during their registration may lead to non-compliance with a transfusion procedure, a non-issue adjusted blood and thus a transfusion risk. The main mistake is the misknowledge of an antibody, secondarily a loss of transfusion information and a redundancy of examinations. The creation of a working group "identitovigilance" helped sensitize the staff of health establishments and clinical chemistry laboratories. In this area of computerization of medical and transfusion records, shared folders and networking, identification of patients is a real issue of risk management hospital.

An active haemovigilance programme characterizing the safety profile of 7437 platelet transfusions prepared with amotosalen photochemical treatment.

BACKGROUND: An active haemovigilance programme was implemented to survey adverse events (AE) associated with transfusion of platelets photochemically treated with amotosalen and ultraviolet A (PCT-PLT). The results of 5106 transfusions have already been reported. Here we report the results of an additional 7437 PCT-PLT transfusions. METHODS: The focus of this ongoing haemovigilance programme is to document all AEs associated with PCT-PLT transfusion. Data collected for AEs include: time of event after starting transfusion, clinical descriptions, vital signs, results from radiographs and bacterial cultures, event severity (Grade 0-4) and causal relationship to PCT-PLT transfusion. RESULTS: One thousand four hundred patients (mean 60 years, range 1-96) received PCT-PLT transfusions. The majority of the patients (53.4%) had haematology-oncology diseases and required conventional chemotherapy (44.8%) or stem cell transplantation (8.6%). Sixty-eight PCT-PLT transfusions were associated with AE. Acute transfusion reactions (ATR), classified as an AE possibly related, probably related, or related to PCT-PLT transfusions were infrequent (n = 55, 55/7437 = 0.7%) and most were of Grade 1 severity. Thirty-nine patients (39/1400 = 2.8%) experienced one or more ATRs. The most frequently reported signs/symptoms were chills, fever, urticaria, dyspnoea, nausea and vomiting. Five AEs were considered severe (> or = Grade 2); however, no causal relationship to PCT-PLT transfusion was found. Repeated exposure to PCT-PLT did not increase the likelihood of an ATR. No cases of transfusion-related acute lung injury and no deaths due to PCT-PLT transfusions were reported. CONCLUSIONS: Routine transfusion of PCT-PLT is well-tolerated in a wide range of patients. ATRs related to PCT-PLT transfusion were infrequent and most were of mild severity.

[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.

[Blood safety: malaria and blood donation in Africa]. / Sécurité transfusionnelle: paludisme et don de sang en Afrique.

Malaria is a principal cause of mortality in Africa and represents a major blood-borne disease. The studies made on the continent show that transfusion-associated malaria is highly prevalent in blood donors groups and that some risk factors and clinical manifestations are frequently observed. The disease is mostly asymptomatic and the signs are mild, which reduces significantly an efficient selection of the blood donors during the predonation interview and a secure supply of blood products. Furthermore, the lack of appropriate screening assays of the malaria in blood banks on the continent limit the diagnosis of the disease and hamper the blood safety. However, the prevention of transfusion-associated malaria is a frequently asked question. The destruction of the parasite in the blood bag and the recipient anti-malarial prophylaxis are the described possibilities, added to local programs against the vectors of the disease.

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.

[Post-transfusion malaria: is the risk irreconciliable with biological silence?]. / Le risque de paludisme transfusionnel confronté à celui de la mutité biologique: deux données irréconciliables?

Despite the relatively high frequency of imported malaria in metropolitan France, the transmission of malaria by transfusion is exceptional. The screening of donations to determine those at risk is performed by an interview, and by the testing of serology for defined groups of donors. However, the exclusion of a candidate 'at risk' as a blood donor, by a pre-donation interview, is not completely mastered and the discrimination by biological examination lacks sensitivity, as much for methodological reasons as for reasons linked to the complex parasitic pathogenic agent (Plasmodium ssp.), as for the specific host defence system. The risk of introducing an unsafe-potentially dangerous (transfusion-transmitted malaria is often lethal)-element into the transfusional circuit is not completely covered. Is serology testing the most adequate test to avoid the risk of infected donations, in particular by Plasmodium falciparum; what are the alternatives and what will be the eventual added-costs of the biological qualification of such donations? The transfusional risk linked to Plasmodium seems, however, to be reduced to a minimum, concerning the circulation of plasma, which could represent an alternative for donors at real risk (rare) and those with a supposed risk (relatively numerous).

Schistosomiasis co-infection in humans influences inflammatory markers in uncomplicated Plasmodium falciparum malaria.

Malaria and schistosomiasis are the two major parasite diseases present in developing countries. The epidemiological co-infection with schistosomiasis could influence the development of the physiological reaction associated with Plasmodium falciparum infection in human. Most studies have demonstrated the association of circulating levels of interferon-gamma (IFN-gamma), tumour necrosis factor-a (TNF-alpha), interleukin-10 (IL-10), transforming growth factor (TGF-beta) and soluble Tumour Necrosis Factor Receptors (sTNF-RI and sTNF-RII) with the morbidity of malaria. In the present study, we showed that Schistosoma haematobium co-infection influences, in an age-dependent manner, the unbalance between pro- and anti-inflammatory circulating cytokines that play a key role during malaria infection. Indeed, children co-infected by S. haematobium have higher levels of IFN-gamma and sTNF-RII than children infected only by P. falciparum. In contrast, co-infected adults presented a significant increase of IFN-gamma, IL-10, TGF-beta, sTNF-RI and sTNF-RII rates and IL-10/TNF-alpha ratio. Taken together, this study indicates that schistosomiasis co-infection can unbalance the regulation of inflammatory factors in uncomplicated P. falciparum malaria. The possible consequences of the schistosomiasis co-infection for age-dependent malaria morbidity are discussed.