Hypersensitivity transfusion reactions to fresh frozen plasma: a retrospective analysis of the French hemovigilance network.

Few data are currently available on hypersensitivity transfusion reactions (HTRs) after exposure to fresh frozen plasma (FFP). Between 2000 and 2018, three different FFP production strategies have been used in France, leading to the concomitant use of different types of FFP. The objective of this study was to describe the rate of FFP-related HTRs and to assess the relative risk of each type of FFP. HTR following FFP transfusion between 2000 and 2018 were retrospectively extracted from the national hemovigilance database of the French National Agency for Medicines and Health Products Safety (ANSM). Temporal evolution of the incidence of reactions was modeled using logistic regression. During the study period, the overall rate of FFP-related HTRs was 52.0 (95% CI 50.2-53.9) reactions per 100,000 units of FFP issued. The rate of FFP-related HTRs progressively increased over the study period, from 28.7 (95% CI 22.8-36.0) in 2000 to 88.9 (78.8-100.3) reactions per 100,000 units of FFP issued in 2018 (OR 1.08 [1.07 - 1.09], P < .001), whereas the rate of other types of adverse transfusion reactions (ATRs) decreased. Between 2000 and 2014, its period of use, Solvent-Detergent-treated Apheresis FFP (SD-APH) was associated with the lowest risk of HTR. Our results indicate that although the rate of HTRs to FFP is low in France, the risk of having such a reaction has steadily increased between 2000 and 2018. A declarative bias is unlikely as the rate of other type of FFP-related ATRs decreased over the same period. The risk of HTRs to FFP is suggested to differ according to the processing of the FFP with a lower risk for SD-APH.

Hypersensitivity transfusion reactions to platelet concentrate: a retrospective analysis of the French hemovigilance network.

BACKGROUND: Among labile blood products, platelet concentrates (PCs) are the leading cause of hypersensitivity transfusion reactions (HTRs). These reactions often lead to interruption of PC transfusion and can result in a prolonged transfusion process leading to significant morbidity and use of premedication and close monitoring for patients with a history of allergic transfusion reactions. The French hemovigilance database is one of the largest standardized databases providing information on HTRs following administration of labile blood products. In this study, we analyzed this database to assess the relative risk of HTR for each type of PC. STUDY DESIGN AND METHODS: HTRs following PC transfusion were retrospectively extracted from the e-Fit Hemovigilance database of the French National Agency for Medicines and Health Products Safety (ANSM). Frequencies were calculated using the number of specific PCs transfused. RESULTS: Between 2008 and 2014, the overall estimated incidence of HTRs following PC administration was calculated at 232 HTRs per 100,000 PCs transfused. The rate of HTRs was significantly higher with apheresis PC (337/100,000) than with buffy-coat PC (94/100,000). Platelets in additive solutions (PAS) were associated with a significantly lower frequency of HTRs when compared with PCs in native plasma. Amotosalen/UVA- PCs (APCs and BCPCs) which are always in PAS in France, exhibited the lowest frequency of HTRs when compared with their corresponding PCs in native plasma or in PAS (p < 10-7 in all comparisons). CONCLUSION: Our results showed that the type of PC and its processing may have an impact on the risk of HTR.

Analysis of Transfusion-Related Acute Lung Injury and Possible Transfusion-Related Acute Lung Injury Reported to the French Hemovigilance Network From 2007 to 2013.

Using the French Hemovigilance Network database from 2007 to 2013, we provide information on demographics, incidence, and risk factors of reported transfusion-related acute lung injury (TRALI) and possible TRALI, analyze TRALI mitigation efforts for fresh frozen plasma and platelet concentrates, and consider the impact of platelet additive solutions on TRALI incidence. We applied the Toronto consensus conference definitions for TRALI and possible TRALI. Two TRALI subgroups were considered: "antibody positive" when a donor has human leukocyte antigen (class I or II) and/or human neutrophil antigen antibodies and the recipient has cognate antigen, and "antibody negative" when immunological investigation is negative or not done. The analysis targeted 378 cases, divided into antibody-positive TRALI (n=75), antibody-negative TRALI (n=100), and possible TRALI (n=203). TRALI patients were younger and received more blood components than the general population of transfused patients. Moreover, we identified the following clinical conditions where patients seemed to be at higher risk to develop TRALI: postpartum hemorrhage, acute myeloid leukemia, liver transplantation, allogeneic and autologous hematopoietic stem cells transplantation, polytrauma, and thrombotic microangiopathy. Policy measures intended to reduce antibody-positive TRALI were found effective for apheresis platelet concentrates and fresh frozen plasma but not for whole blood-derived platelet concentrates. The use of platelet additive solutions was associated with a significant reduction in the incidence of TRALI following transfusion of buffy coat-derived platelet concentrates but not following transfusion of apheresis platelets. Our data reinforce the concept that possible TRALI and TRALI, as defined in the Canadian consensus conference, share many characteristics. No specific policy measures are currently directed at mitigation of possible TRALI despite its impact on transfusion safety. Despite TRALI mitigation measures, the overall incidence of TRALI cases reported to the French Hemovigilance system was not significantly reduced. Therefore, additional research is needed to reduce, if not eradicate, all TRALI categories.

[Blood components and good practices in transfusion]. / Du bon usage des produits sanguins.

Each year, more than three millions of blood components are transfused to more than five hundred thousand patients in France. The optimal use of blood components requires that physicians prescribing blood components master the clinical indications of red blood cells concentrates, platelet concentrates and fresh frozen plasma. In addition, physicians in charge of blood component prescription should provide adequate pre- and post-transfusion information to their patients. Compliance of blood components administration in patients with safety guidelines contributes as well to their optimal use. In addition, for each blood component transfused, a proper evaluation of its safety and its efficacy should be done. Finally, a regular evaluation of transfusion practice in hospital services were blood components are used, through audits made in cooperation with their blood component provider, either blood transfusion centre or the hospital blood bank, enables to appreciate the level of compliance with safety and clinical guidelines, and more globally how the transfusion process is mastered.

Banking of pluripotent adult stem cells as an unlimited source for red blood cell production: potential applications for alloimmunized patients and rare blood challenges.

The transfusion of red blood cells (RBCs) is now considered a well-settled and essential therapy. However, some difficulties and constraints still occur, such as long-term blood product shortage, blood donor population aging, known and yet unknown transfusion-transmitted infectious agents, growing cost of the transfusion supply chain management, and the inescapable blood group polymorphism barrier. Red blood cells can be now cultured in vitro from human hematopoietic, human embryonic, or human-induced pluripotent stem cells (hiPSCs). The highly promising hiPSC technology represents a potentially unlimited source of RBCs and opens the door to the revolutionary development of a new generation of allogeneic transfusion products. Assuming that in vitro large-scale cultured RBC production efficiently operates in the near future, we draw here some futuristic but realistic scenarios regarding potential applications for alloimmunized patients and those with a rare blood group. We retrospectively studied a cohort of 16,486 consecutive alloimmunized patients (10-year period), showing 1 to 7 alloantibodies with 361 different antibody combinations. We showed that only 3 hiPSC clones would be sufficient to match more than 99% of the 16,486 patients in need of RBC transfusions. The study of the French National Registry of People with a Rare Blood Phenotype/Genotype (10-year period) shows that 15 hiPSC clones would cover 100% of the needs in patients of white ancestry. In addition, one single hiPSC clone would meet 73% of the needs in alloimmunized patients with sickle cell disease for whom rare cryopreserved RBC units were required. As a result, we consider that a very limited number of RBC clones would be able to not only provide for the need for most alloimmunized patients and those with a rare blood group but also efficiently allow for a policy for alloimmunization prevention in multiply transfused patients.

Red blood cell generation from human induced pluripotent stem cells: perspectives for transfusion medicine.

BACKGROUND: Ex vivo manufacture of red blood cells from stem cells is a potential means to ensure an adequate and safe supply of blood cell products. Advances in somatic cell reprogramming of human induced pluripotent stem cells have opened the door to generating specific cells for cell therapy. Human induced pluripotent stem cells represent a potentially unlimited source of stem cells for erythroid generation for transfusion medicine. DESIGN AND METHODS: We characterized the erythroid differentiation and maturation of human induced pluripotent stem cell lines obtained from human fetal (IMR90) and adult fibroblasts (FD-136) compared to those of a human embryonic stem cell line (H1). Our protocol comprises two steps: (i) differentiation of human induced pluripotent stem cells by formation of embryoid bodies with indispensable conditioning in the presence of cytokines and human plasma to obtain early erythroid commitment, and (ii) differentiation/maturation to the stage of cultured red blood cells in the presence of cytokines. The protocol dispenses with major constraints such as an obligatory passage through a hematopoietic progenitor, co-culture on a cellular stroma and use of proteins of animal origin. RESULTS: We report for the first time the complete differentiation of human induced pluripotent stem cells into definitive erythrocytes capable of maturation up to enucleated red blood cells containing fetal hemoglobin in a functional tetrameric form. CONCLUSIONS: Red blood cells generated from human induced pluripotent stem cells pave the way for future development of allogeneic transfusion products. This could be done by banking a very limited number of red cell phenotype combinations enabling the safe transfusion of a great number of immunized patients.

[Trends in blood transfusion indications]. / Comment évolue la prescription des produits sanguins?

Blood components prescription has been greatly modified in the recent years. From 1986 to 2002, the consciousness rising of diseases transmission by blood transfusion led to a reduction of their indications, and for accepted indications, to establish specific thresholds and choice of components in order to reduce donor exposure as much as possible. Since 2003 and more significantly since 2006, we observed a constant increase (3 to 5%/year) of their use. Improvement of blood transfusion safety by many measures taken from collection to delivery including expansion of pathogen reduction technology to cellular blood components, population ageing (as the proportion of transfused people increases exponentially with age) and evidence of under-transfusion risks are the main key factors for such an evolution of practices.

Erythrocytapheresis: Do Not Forget a Useful Therapy!

SUMMARY: In patients with pathologically altered erythrocytes, red blood cell exchange is a very efficient therapeutic measure without important side effects. With increasing migration more patients with e.g. severe malaria or sickle cell anemia have to be treated. In minor or bidirectional ABO-mismatched stem cell transplantations after reduced intensity conditioning, hemolysis can be prevented by prophylactic erythrocytapheresis. Other rare indications for red blood cell exchange are advanced erythropoietic protoporphyria and babesiosis. Sickle cell anemia can be treated with hydroxyurea. Transfusions are administered when necessary, but this results in iron overload in the long term. An expensive but safe and very efficient treatment alternative is red blood cell exchange. In cases with stroke, acute chest syndrome and other severe complications, erythrocytapheresis reproducibly breaks the vicious circle of sickling and increasing oxygen deficiency. At the same time one can aim at an exact end hematocrit. In severe malaria, erythrocytapheresis both reduces parasite load to the designated extent and reconstitutes reduced oxygen transport capacity without serious adverse effects. Here we describe our experience of erythrocytapheresis in long-term prophylaxis of complications in sickle cell anemia and sickle cell thalassemia patients. The documentation of improved iron balance was carried out by liver susceptometry.

[Evaluation of the professional practices of physicians in transfusion technology and medicine]. / L'évaluation des pratiques professionnelles des médecins en technologie et médecine transfusionnelles.

The evaluation of the professional practices (EPP) is obligatory for all the physicians since July 1, 2005 for a first five-year period. It represents one of the components of the continuous medical training (CMT). The French Society of Blood Transfusion and National Institute of Blood Transfusion are the promoters of the EPP in transfusion technology and medicine. Initially, the programs of EPP will be conceived and controlled by experts and will relate to their basic activities. During a five years cycle, the physician taking part in a program must validate a specific action and take part in a rolling programme. At the end of the programme, the physician will receive a certificate issued by National Institute of Blood Transfusion and will have to submit it to a committee placed under the responsibility of the regional physicians' committee.

[Introduction of platelet additive solutions in transfusion practice. Advantages, disadvantages and benefit for patients]. / Introduction en pratique transfusionnelle des concentrés de plaquettes en solution de conservation. Avantages, inconvénients, et intérêt pour les patients.

Platelet additive solutions (PAS) have been developed since the years 1980. However, decisive improvements have been made in the last five years, leading nowadays to several PAS available for transfusion practice. Few compounds are present in PAS, with the intention of controlling platelet metabolic alterations and activation that occur during storage: acetate, which is a substrate for the tricarboxylic acid cycle, enables to maintain oxidative metabolism, is present in all PAS; a buffer effect is required to prevent the progressive pH fall during storage, and is obtained either with sodium phosphate or gluconate; platelet activation is controlled by citrate, and in the latest PAS, by magnesium and potassium. It is important to note that whatever the PAS used, it is mandatory to maintain a final concentration of 20-40% of plasma, mainly in order to ensure glucose availability. The use of PAS leads to a more rationalized blood processing, as it provides an additional volume of plasma available for plasma fractionation, it contributes to standardization of blood components, and it is part of at least one pathogen reduction process. The expected benefit for patient is the reduction of adverse reactions related to plasma. There is already evidence that the incidence of allergic adverse reactions is reduced. In the case of other less frequent adverse reactions such as transfusion related acute lung injury (TRALI) or haemolytic reaction due to minor ABO incompatibility, only a long-term follow-up through haemovigilance organization will be informative.

Ex vivo production of human red blood cells from hematopoietic stem cells: what is the future in transfusion?

There is difficulty in obtaining adequate supplies of blood components, as well as disappointing performance of stabilized or recombinant hemoglobins, limited indications of oxygen transporters (perfluorocarbons), and slow development of "universal" red blood cells (RBCs). There is, therefore, a need for complementary sources of RBCs for transfusion. Thus, an attempt to generate erythroid cells in vitro makes good sense. We describe in this article a methodology permitting the massive ex vivo production of mature human RBCs having all the characteristics of native adult RBCs from hematopoietic stem cells of diverse origins: blood, bone marrow, or cord blood. This protocol allows both the massive expansion of hematopoietic stem cells/progenitors and their complete differentiation to the stage of perfectly functional mature RBCs. The levels of amplification obtained (10(5) to 2 x 10(6)) are compatible with an eventual transfusion application. We discuss in this article the state of the art of this new concept and evoke possible obstacles that need to be overcome to pass from a laboratory model to clinical practice. We analyze its possible indications in the medium and long term, discuss the economic aspects, and raise the question: Can we afford the luxury of developing this approach, one that could represent a considerable advance in blood transfusion?

The influence of methylene blue light treatment and methylene blue removal filter on fibrinogen activity states and fibrin polymerisation indices.

BACKGROUND/OBJECTIVE: Methylene blue light treatment (MBLT) is efficient in inactivating viruses in plasma. However, it may cause alterations in clotting factors, especially fibrinogen (Fg). The true mechanism of such a selective alteration is poorly understood, The effects of MBLT and MB removal filters (MBRF) on Fg concentration, functional activity and fibrin polymerisation were studied. DESIGN: Apheresis plasma collected by Haemonetic MCS Plus (n=10) was split into two equal aliquots. Both were leukofiltered and virally inactivated in a standardized fashion, using Theraflex MB-Plasma Photodynamic viral inactivation Macopharma method. One of the pair was subsequently processed, using Blueflex MBRF to remove residual MB and its by-products. Control plasma samples were obtained after filtration but before MBLT. Samples were also obtained after MBLT and MBRF. All samples were analyzed for the Fg activity, Fg antigen, thrombin clotting time (TT), and alterations fibrin polymerisation indices. RESULTS: After MBLT, mean Fg concentration increased slightly (2%) whereas functional activity decreased by 31%, as compared to control samples. Mean TT prolonged by 6s after MBLT, with no further changes after MBRF. A similar trend was observed using RT. Both thrombin and reptilase triggered fibrin polymerisation were delayed and the polymerisation curves slopes were decreased slightly, with concomitant changes in fibrin opacity in samples from MBLT and MBRF as compared to control. Comparison is made for the first time with a similar changes observed in dysfibrinogenemia. CONCLUSION: MBLT resulted in about 30% decrease in Fg activity but a slight modification in fibrin polymerisation indices, with no additional alteration subsequent to MBRF. These in vitro changes are similar to those seen in plasma from patients with dysfibrinogenemia, which are usually without clinical significance.

The French Haemovigilance System: organization and results for 2003.

In 1993 by law, in France, haemovigilance became a national system of surveillance and alert, from blood collection to the follow-up of the recipients, gathering and analysing all adverse events of blood transfusion in order to prevent their recurrences. In 2003, 2911 incidents with strong imputability have been specially analysed, among them seven confirmed cases of bacterial contamination, 137 incorrect blood components transfused with 12 cases of ABO incompatibility, 15 adverse reactions diagnosed as TRALI and 12 deaths. The analysis of information provided by haemovigilance has led to the implementation of new guidelines.

Hemovigilance network in France: organization and analysis of immediate transfusion incident reports from 1994 to 1998.

BACKGROUND: Hemovigilance networks have been introduced in several countries to improve knowledge of blood transfusion-related morbidity and mortality. The general organization of the French network and its results from 1994 through March 1999 are presented here. STUDY DESIGN AND METHODS: The hemovigilance network relies on blood transfusion centers and hospital correspondents, who analyze unexpected and untoward blood transfusion-related effects and transmit a Transfusion Incident Report (TIR) to a national database (Transfusion Incident Reports Electronic Data Management [GIFIT]). RESULTS: As of March 1, 1999, the GIFIT database contained 24,234 TIRs related to incidents that occurred from the start of the hemovigilance network until December 31, 1998. The network was not fully implemented until 1996; but the reporting rate seems to have since stabilized at approximately 7000 per year (2.5 reports per 1000 blood components). The highest reporting rate is observed with platelet concentrates (4.02/1000), followed by RBCs (1.71/1000) and FFP (0.34/1000). Bacterial contamination quickly appeared as a major cause of morbidity and mortality (185 cases and 18 fatalities). However, a general trend of reduction in this type of incident was observed over time, which can be attributed to adoption of several preventive measures. In contrast, major ABO mismatchings during RBC transfusion remained at a constant rate throughout this period and accounted for six fatalities. After the implementation of universal WBC reduction, some incidents known to be related to WBCs, such as nonhemolytic febrile transfusion reactions (NHFTR) and HLA immunization, were dramatically reduced. CONCLUSION: Hemovigilance is an important tool not only to analyze blood transfusion incidents, but also to measure the effects of new processes or corrective actions at a national level.

Hemovigilance in France

In this work the organization of the hemovigilancesystem in France, the alert system related to undesirabletransfusion effects and the search for seropositive blooddonors is discussed.

No relato são apresentados aspectos daorganização da hemovigilância na França, osistema de alerta relacionado com reaçõestransfusionais indesejáveis e a busca dereceptores sorologicamente positivos.