Labile Blood Products Research Articles

Le point sur la réglementation et la procédure d’autorisation

Patients receiving blood transfusion must benefit from the same quality of care, no matter where they are treated. In an effort to enhance transfusion safety, regulations applicable to blood depot facilities have been considerably reinforced over the last few years. At the present time, facilities authorized to store and distribute labile blood products are subject to the same principles of good practice as transfusion centers. A series of regulations published in 2007 established the duties and responsibilities of depot facilities according to category (emergency, intermediary or distribution) and set out the conditions for certification.

Exemple d’un incident de délivrance à l’EFS Alpes-Méditerranée

The Alps-Mediterranean division of the French blood establishment (EFS Alpes-Mediterranée) has implemented a risk management program. Within this framework, the labile blood product distribution process was assessed to identify critical steps. Subsequently, safety measures were instituted including computer-assisted decision support, detailed written instructions and control checks at each step. Failure of these measures to prevent an incident underlines the vulnerability of the process to the human factor. Indeed root cause analysis showed that the incident was due to underestimation of the danger by one individual. Elimination of this type of risk will require continuous training, testing and updating of personnel. Identification and reporting of nonconformities will allow personnel at all levels (local, regional, and national) to share lessons and implement appropriate risk mitigation strategies.

Le livre blanc

It is necessary for European countries to have references and guidelines to cope with the wide field of blood transfusion. It is the institutions and professionals’ role to provide for technical specifications linked to the collection, qualification, preparation, storage and distribution of labile blood products. In this context, EuroNet-TMS publishes every five year (2005, 2010…) a White Book meant to issue statements on the current situation, activities in progress in Europe and future developments.

La diminution de l’autotransfusion programmée en France ne s’est pas accompagnée d’une augmentation de consommation de concentrés de globules rouges homologues

The use of preoperative autologous blood transfusion has dramatically decreased in France. The aim of this study was to evaluate the evolution of practice both of autologous and homologous Red Blood Cells (RBC) concentrates transfusion between 2002 and 2005, and to asses the consequences of the highlighted changes.Data on blood transfusion are collected and validated nationwide by a network of regional coordinators of haemovigilance. For each hospital, from 2002 to 2005, the annual changes in the number of transfused homologous and autologous RBC have been evaluated. The ratio of preoperative autologous RBC, number of autologous RBC divided by the number of all RBC, has also been calculated. Hospitals have been split into three cohorts, according to their 2005 autologous RBC ratio. For each cohort, correlations between the variations of the number of autologous, homologous and total RBC in each hospital have been studied.Data have been validated for 22 French regions that performed 71.8% of the total French transfusion in 2004. In 2005, 1,831,544 labile blood products have been transfused in 1197 hospitals and clinics among which 379 have used preoperative autologous transfusion. A total of 37,289 autologous RBC have been transfused in 2003, 28,689 in 2004 (-23.1%) and 17,758 in 2005 (-38.1%). The first cohort of 269 hospitals had a ratio of autologous RBC under 3%, the second cohort of 38 hospitals, a ratio between 3 and 6%, while the third cohort of 72 hospitals had transfused 6% or more of autologous RBC. In the two first cohorts, non-surgical activities were so large that it was impossible to assess the changes in surgical use of transfusion. The third cohort, with a ratio of 6% or more, was essentially devoted to surgery (88% of beds). These hospitals and clinics have transfused 13,076 autologous RBC in 2002 and 8583 in 2005 (-34.4%). In this group, there was a statistical correlation between the decrease of autologous RBC and the decrease of total RBC (r(2)=0.36), and no increase in the transfusion of homologous RBC has been observed. During the same period, neither hospitals nor clinics showed any decrease of their surgical activity. The drop of autologous RBC transfusion led to a decrease of the total number of RBC transfused and thus, to a decrease of the global exposure to transfusion hazard.The present results confirmed a decline of preoperative autologous transfusion in France, between 2002 and 2005. Meanwhile no supplementary need of homologous RBC has been observed among hospitals, performing surgery that formerly had a high ratio of autologous RBC.

French Haemovigilance Data on Platelet Transfusion

The Agence Française de Sécurité Sanitaire des Produits de Santé (Afssaps; French Health Products Safety Agency) is responsible, through its hemovigilance unit, for the organization and the functioning of the national hemovigilance network. In accordance with the French law, it receives all data on adverse transfusion reactions regardless of their severity. With the aim of evaluating the tolerance of two kinds of labile blood products (LBP), pooled platelet concentrates (PP) and apheresis platelet concentrates (APC), we screened the French national database from January 1, 2000 to December 31, 2006. We observed that the number of transfusion incident reports is more than twice as high with APC (8.61:1,000 LBP) than with PP (4.21:1,000 LBP). The difference between these two ratios is statistically significant as shown by chi-square test (e = 21.00 with α= 5%). The risk to suffer adverse reactions of any type, except for alloimmunization, is higher with APC, and the major type of diagnosis related to APC is allergic reaction (1:200 APC issued) even if those allergic reactions are rarely serious. The new French National Hemovigilance Commission should impel a working group evaluating this topic and above all the impact of additive solutions which have been used since 2005 to put forward preventives measures.

Blood components: Current challenges

Labile blood products are still here to stay for quite a long time. All European surveys come in agreement to reveal that indications, extremely heterogeneous from one country to another, are not fully under control. Both the EuroNet-TMS network and Euro'SAT congresses aim at improving the use of such products within an evidence-based medicine perspective.

The Declining Risk of ABO Incompatibilities: Twelve Years of Hemovigilance in France.

Background: ABO incompatibilities (ABOi) usually result from the failure to comply with Standard Operating Procedures (SOP). Continuous training (CT) is the main way to ensure their proper use in ultra-high security systems like civil aviation but little is known for transfusion. In France, SOP include a Beth-Vincent test at the bedside before the transfusion of Packed Red Cells (PRC). At the hospitals, Hemovigilance Officers (HO) are in charge of transfusion safety along with the settlement of traceability and the notification of all Adverse Effects (AE). If SOP and CT are requested by Law since 1993 for blood banks, they are only advised for hospitals even though the bedside Beth-Vincent test requires a special training. However, HO have more and more transposed the model of blood banks in hospitals especially since 2000. Objective: to describe time-trends of ABOi observed in e-fit, the French Hemovigilance database. Population and methods: All AE with “acute ABOi” as the final diagnostic were considered. Time-trends were studied according to the Box and Jenkins model (ARMA).Results: From 07/01/1994 to 12/31/2005, 79 106 AE were registered in e-fit, corresponding to about 30,000,000 Labile Blood Products (LBP) transfused. 304 (0.4%) were ABOi (1/107,850 LBP transfused). There were 183 men and 121 women with 81.3% of whom more than 40 years old. 205 patients (67.4%) received only PRC, 73 (24.0%) Platelet Concentrates (PC), 22 (7.2%) Fresh Frozen Plasma (FFP) and 4 (1.3%) more than a single LBP. 18 ABOi were fatal, possibly (4 cases) probably (4 cases) or definitely (9 cases) associated with a PRC, and 1 doubtfully with a FFP. Time-trends displayed 3 periods: (1) from 1994 to 1997 ABOi increased concurrently with the frequency of all AE notifications, (2) from 1997 to 2000 they reached a steady-state with 35 ABOi/year on average (1/70,000 LBP), (3) since 2001 they regularly decreased of 14%/year on average (13 ABOi for 2005 = 1/198,450 LBP). The localization of the failure to comply with SOP (i.e. hospital, blood bank or both) was studied for PRC. From 1997 to 2005, the liability of blood banks alone or along with hospitals remained stable (resp 0.42 and 2.58/year on average) whereas those of hospitals dramatically decreased (16.25/year from 1997 to 2000 and 8.6/year from 2001 to 2005).Conclusion: (1) ABOi are now 3 times less frequent than in 2000 ; (2) a notification bias is unlikely because both hospitals and blood banks are aware of traceability data that include the ABO phenotype for both the recipient and the LBP issued ; (3) CT applied on a nationwide basis seems to be the main factor to reduce ABOi in hospitals ; (4) a residual risk related to human errors seems to exist ; (5) the way to overcome that risk remains a matter of debate.

The Canadian Blood Donor Health Assessment Questionnaire: Lessons From History, Application of Cognitive Science Principles, and Recommendations for Change

Over the last 20 years, the Canadian Blood Services' (CBS) Donor Health Assessment Questionnaire (DHAQ), used to screen prospective blood donors to determine their eligibility, has grown in complexity and length. Its growth is inextricably linked to the evolution of the environment within which CBS operates from unregulated collection and distribution of labile blood products to a fully regulated environment and to the need to satisfy both Health Canada and US Food and Drug Administration (FDA) requirements. Within this context, the development of the CBS DHAQ has been characterized by addition of questions and items without any periodic reevaluation of the need for retaining existing questions and/or items. In this review, we apply principles from cognitive science relating to how people think when answering questionnaires to the situation of blood donors completing the DHAQ. We show that some items that were added at different times in separate questions, for reasons that were historically relevant, could be now asked more simply with a single question. The historical development of the DHAQ, resulting in the condensing of many items into lists, the use of complex wording, and the sheer number of items included in the questionnaire make accurate retrieval of information from the donor's memory difficult. Thus, we believe that redesigning the DHAQ will improve the quality and accuracy of the donors' answers to screening questions.

H5N1 influenza virus and the safety of plasma products

The ever-increasing number of human H5N1 influenza virus infections may enable these viruses to acquire the ability to spread effectively among humans and potentially to cause a pandemic. Recently, more systemic virus dissemination was reported during H5N1 virus infection of humans, resulting in significant virus concentrations also in the blood. The observation has raised concerns about the safety of labile blood products for transfusion and consequentially also for plasma derivatives. To confirm the safety margins of plasma products, dedicated virus inactivation processes used during their production were investigated for their effectiveness in inactivating this virus of recent concern. Virus inactivation by steps commonly used during the manufacture of plasma derivatives, such as pasteurization for human albumin, solvent/detergent treatment for intravenous immunoglobulin (IVIG), vapor heating for factor VIII inhibitor bypassing activity, and incubation at low pH for IVIG, were investigated with a reassortant strain of H5N1 influenza virus. The results show that H5N1 influenza behaves as expected for lipid-enveloped viruses; that is, the virus is effectively inactivated by all the commonly used virus inactivation procedures tested. The safety margins of plasma derivatives against the theoretical transmission of H5N1 influenza virus are very substantial.

Epidemiology of Transfusion Related Acute Lung Injury in e-FIT, the French Hemovigilance Database: 1994 to 2006. A Study of the French Hemovigilance Network.

Background: Transfusion Related Acute Lung Injury (TRALI) is a life-threatening complication of allogenic blood transfusion, manifested typically by a non-cardiogenic pulmonary edema. However, the magnitude of the risk of TRALI remains unknown at this time, all the more so as a variety of other clinically similar respiratory complications can be associated with transfusion. Hemovigilance had been implemented in France since 1994. All adverse effects (AE) regardless of their severity should be notified on a normalized form to AFSSaPS, the French health products safety agency, as required by the French law.Objective : to describe TRALI observed in e-FIT, the French hemovigilance database.Population and methods: AE possibly, probably or definitely associated with transfusion were considered for inclusion. As the item “ TRALI” was explicitly present since 09/01/2001, we screened the database from 07/01/1994 to 09/01/2001 with “ pulmonary edema AND fluid overload excluded” , or with free comments including the words “TRALI ” , “ anti-granulocyte antibodies ”, “ non-cardiogenic pulmonary edema ” , “ white lung syndrome ” . The subsequent AE were considered for inclusion only if TRALI was the final diagnostic.Results: From 07/01/1994 to 06/01/2006, 82,436 AE were registered in e-FIT, corresponding to about 30,000,000 labile blood products (LBP) transfused. 117 AE fulfilled the above criteria (3.9/1,000,000 LBP transfused). There were 59 men and 58 women, age = 0 to 86 (median 58); 34 men and 21 women were 60 years old or more. 107 patients presented with pulmonary symptoms, 93 with dyspnea, 63 with chills and/or hyperthermia and 53 with a typical pulmonary edema. 13 TRALI were fatal, 85 were life-threatening and 19 were benign. 42 patients received only packed red cells, 4 only fresh frozen plasma and 40 only platelet concentrates ; among the 31 remainders, 14 received platelets concentrates associated with an other LBP.Conclusion:Although the initial French database was not adapted to detect TRALI cases until 2001, the dynamics of notification is of interest ;TRALI is more frequent in elderly patients, as noted in other reports ;Platelets concentrates remains the more frequently LBP involved, but packed red cells also contribute to nearly half of the TRALI reported ;Besides the classical life-threatening presentation, a benign form of TRALI seems to exist ;A national working party is implementing new ways to define and investigate TRALI, which will provide more accurate information on TRALI in France.

Épidémiologie de la variante de la maladie de Creutzfeldt-Jakob en France

Variant Creutzfeldt-Jakob disease (vCJD) is the only form of prion diseases linked to bovine spongiform encephalopathy (BSE). The disease was first described in the United-Kingdom (UK) and France is the second affected country with 21 cases. Clinical, genetic and neuropathological features are the same in both countries. Comparison of the total number of cases in France and in the UK, according to dates of onset, shows that, in France, the maximum incidence seems to be five years delayed and that, in the UK, the number of vCJD cases regularly decreases since 1999. Delayed exposure to contaminated beef products in France compared to the UK could explain this temporal gap. Three cases of vCJD after transfusion of labile blood products were observed in the UK. No such of cases were observed in France but three patients developing signs of vCJD in 2004 were blood donors. A total of 42 recipients were identified with 17 recipients still alive.

Évaluation du risque transfusionnel vis-à-vis de la variante de la maladie de Creutzfeldt-Jakob en France

The latest updates (February 2004 and February 2005) of the analysis of the risk of transmission of the agent of Creutzfeldt-Jakob disease (CJD) by blood and blood products in France firstly reported in 2000, were triggered by the two cases of probable transmission of variant CJD (vCJD) by transfusion reported in the UK, and the notification of two French cases of vCJD who had been blood donors on several occasions before clinical onset. Even though some figures of the quantitative assumption used in the risk analysis have been modified since 2000, the conclusion as regards the risk for blood cellular component is considered unchanged: it can be assumed that one unit of labile blood products will contain more than one infectious unit if the donor is incubating the disease. Therefore, the residual risk of receiving by transfusion one infectious blood unit is depending on the prevalence of subjects incubating the disease in the blood donor population. For this particular aspect, the expected number of clinical vCJD cases to occur in France has been lowered since 2000. However, the worst-case scenario of 300 cases in the next 60 years has been maintained in the risk analysis, leading to the hypothesis that one blood donor per 120,000 could be infectious. In conclusion, the risk of getting one infectious blood unit is considered probable to a level of 1/120,000, but the benefit outweighs the risk if the use of transfusion is restricted to well justified indications and if patients are informed a priori and a posteriori.

Mechanisms of transfusion-linked parasite infection

Besides bacteriae and viruses, parasite infections can be transmitted by blood as a consequence of blood transfusion. To be transmitted by blood transfusion, parasites must: -i) circulate in the blood stream of donors, -ii) comprise of certain physical characteristics and resist processing steps leading to the preparation of labile blood products (packed red blood cells, therapeutic frozen plasma, or platelet concentrates), -iii) survive conservation; further, to generate infection in the blood receiver, such parasites must retain infectivity. In this Forum, the main characteristics of parasites—with respect to transmissibility by blood exposure—are recalled. This forum will further discuss each of these topics and try to make an issue with possible risks in transfusion, in countries that are either non-endemic for the given parasite or which can afford implementation of preventive measures.

Acute transfusion reactions in the pediatric intensive care unit

Acute transfusion reactions (ATRs) are probably underdiagnosed in critically ill children because associated symptoms can frequently be attributed to the patient's underlying disease. This study was undertaken to determine the incidence, type, imputability, and severity of ATRs observed in a tertiary care pediatric intensive care unit (PICU). All transfusions of labile blood product administered to consecutive patients admitted to our PICU, between February 2002 and February 2004, were prospectively recorded. For each transfusion, the bedside nurse recorded the patient's status before, during, and up to 4 hours after the transfusion, as well as the presence of any new sign or symptom suggesting an ATR. Three independent experts retrospectively reviewed all transfusion event reports and hospital charts. The presence, type, imputability, and severity of ATRs were adjudicated by consensus of two of three experts (Delphi method), with predefined criteria. A total of 2509 transfusions were administered to 305 patients during the study. Forty transfusion events (1.6%) were confirmed to be ATRs by expert consensus: 24 febrile nonhemolytic, 6 minor allergic, 4 isolated hypotension, 3 bacterial contamination, 1 major allergic (anaphylactic shock), 1 TRALI, and 1 hemolytic reaction. Imputability of ATRs was probable or possible in 35 cases (88%). ATRs led to an immediate vital threat in 15 percent of cases. Improved surveillance of transfusions given to PICU patients and better knowledge of these reactions by health care professionals should improve the safety of transfusions in the PICU.

Inactivation des agents pathogènes dans les produits sanguins labiles : sécurité transfusionnelle et impact économique

The safety of labile blood products (red blood cell concentrates, platelet concentrates and plasma) is currently ensured by medical and biological donor selection measures. Nonetheless, in addition to the residual risk of bacterial injection of platelet concentrates and parasitic infection of red cell concentrates, there is the emerging danger associated with new viruses. Pathogen inactivation based on chemical or photochemical genomic modifications is a broad-spectrum approach. These techniques are already used to inactivate plasma, and are being developed or application to platelet and erythrocyte concentrates. Universal inactivation of all labile blood products should be possible in a few years' time, but clinical and hemovigilance studies must first show that the biological properties and therapeutic efficacy of these products are not markedly affected, and that the methods used do not lead to long-term toxicity.

Haemovigilance in developing countries

The word haemovigilance is derived from the word pharmacovigilance, which covers activities and systems to collect information in medicinal products, especially for adverse drug reactions in humans. Haemovigilance, initially created in France in the begining of 90s has Greek and Latin roots: ‘‘haema’’: blood and ‘‘vigilans’’: paying special attention. Haemovigilance concerns blood components. Pharmacovigilance concerns plasma derivatives such as clotting factor oncentrates, immunoglobulins, albumin and other fractionated products. Since 1993, in European legislation plasma derivatives are considered to be pharmaceuticals, and the manufactures have to comply with the European regulations on pharmacovigilance. Transfusion reports from US and United Kingdom showed that most of the incidents were caused by clerical errors. Not only identification but also administrative errors also plays an important role. In France, by a law in 1994, the first definition of hemovigilance was introduced. Various number of definitions have been written since then. In the European Blood Directive, it is defined as a group of organized surveillance procedures relating to serious, adverse or unexpected events or reactions in donors or recipients, and the epidemiological follow-up of donors. The definition given by the European Haemovigilance Network (EHN) is the one most widely used. ‘‘Haemovigilance is a set of surveillance procedures covering the entire transfusion chain (from the donation of blood and its components to the follow-up of recipients of transfusions), intended to collect and assess information on unexpected or undesirable effects resulting from the therapeutic use of labile blood products, and to prevent the occurrence or recurrence of such incidents’’ [1]. Haemovigilance and the European Blood Directive

Évaluation de l'organisation du dépistage sérologique pré- et post-transfusionnel en France en 2001

In France, data collection related to blood recipient's viral infectious disease markers pre and post-transfusion is a legal requirement for hospitals. Our study aimed to evaluate the actual modalities of this extensive screening in 2001, six years after the Ministry of health issued recommendations. A questionnaire was sent to the haemovigilance correspondents in hospitals having transfused labile blood products (LBP) in 2001. A total of 1463 hospitals having transfused 85% of LBP in France responded. 82,4% of hospitals have written guidelines for pre-transfusion screening of viral markers, mainly for HIV and hepatitis C. A frozen repository storage is held by 23,9% of hospitals with storage durations between 1 to 40 years. 84% of hospitals have written guidelines for post-transfusion screening. The test prescriptions are mostly done by physicians from clinical services and they include in more than 80% of cases, HIV and HCV markers. Only 12% of hospitals recontact the patient in case of a no show. Even though 77,5% of responding hospitals have labile blood products recipients follow up processes, their effectiveness remains quite low, only 16% of recipients having test results available at the hospital.

Évaluation des hypertransaminasémies lors du bilan post-transfusionnel

Dosage of post transfusion ALT has been performed since a government recommendation was issued in 1996. Yet, the advantage of this analysis during the post transfusion tests has not been determined. The aims of this study were to estimate: a) the incidence of hypertransaminasemia, b) the causes of hypertransaminasemia and c) the advantage of an etiologic investigation. Patients and methods. – At the University Hospital of Brest, follow-up of the labile blood products recipients was initiated in June 1993. Since 1997, a visit in the hepatogastroenterology unit was systematically proposed to patients having post transfusion hypertransaminasemia. Results. – Since November 1997 to July 2003, ALT increase was detected in 235 patients (4%). Among them, 108 patients consulted a hepatologist. Diagnosis was certain for 46 patients (46%). A drug reaction or alcoholic disease was the cause of ALT elevation in the majority of cases (80%). The diagnosis was probable for 42 patients (39%) due to medications in 81% of cases. The diagnosis remained undetermined in 20 patients (18%). Conclusion. – Our study shows that alcohol or drug hepatotoxicity explained the majority of post transfusion hypertransaminasemia. We could not demonstrate a viral cause. We have decided to continue the follow-up of post transfusion hypertransaminasemia during two more years and to reevaluate the usefulness of the etiologic investigation.

Satisfaction survey in general hospital personnel involved in blood transfusion: implementation of the ISO 9001: 2000 standard

As part of its policy of constant quality improvement, Établissement français du sang (EFS) des pays de la Loire (Pays de la Loire Regional Blood Transfusion Centre) carried out a satisfaction survey among the hospital personnel involved in prescribing and using immunohaematological tests and labile blood products (LBP). The polling tool selected by agreement between the Saint Nazaire’s hospital management and Quality Assurance (QA) Department was a questionnaire that permitted item rating and free commentary. It addressed the personnel’s perception of the quality of erythrocyte immunohaematological (EIH) testing and of the products administered, as well as their perception of the quality of communications with the local EFS. The questionnaire was sent to 26 physicians and 32 senior nurses in 15 hospital departments. The reply rate was 60% and expressed an 85% overall satisfaction level. Dissatisfaction causes were more specifically analysed, the main one involving LBP distribution in emergency situations. A joint undertaking by the EFS and the hospital led to the implementation of corrective measures, including the writing and implementation of a common standard operating procedure for emergency transfusion management. The results obtained demonstrated the feasibility of this type of survey and the interest, to a blood transfusion centre and the hospital personnel involved in transfusion, of assessing their very own perception of service quality.

Évaluation du dépistage sérologique pré- et post-transfusionnel en France en 2001

Screening of labile blood products recipients for HIV and HCV has been performed in France since a government recommendation was issued in 1996. It has been designed to get transfusion related contamination of recipients through pre- and post-transfusion serological tests. Since then, residual risk has decreased dramatically and it was suspected that recommendations might sometimes be ignored. A nationwide survey has been done to measure the real screening rate and its cost efficacy ratio. In addition accuracy of tracability and recipients mortality has also been evaluated. A random sample of 1115 labile blood products among all the 1203 378 distributed during first semester of 2001 in France has been drawn. They have been matched with test results obtained in hospital files. Tracability has been considered accurate if name, surname and birth date of recipients were exactly the same both in hospital file and in the file of the Etablissement Français du Sang. A total of 1092 hospital files has been retrieved. Pre transfusion HIV and HCV tests have been performed in 58.5 % of cases, 95 % CI [55.6-61.5], and post-transfusion tests in 30.5 % [28.5–35.5] of cases. Only 19.5% [16.6–22.6] of recipients, not known to be dead 6 months after transfusion, have had both pre and post-transfusion tests. No HIV or HCV contamination has been notified by the Haemovigilance network during the same period. Accuracy rate of tracability was 96.25% [94.9–97.3]. Furthermore 35.8% [33–38.7] of recipients were found dead within 6 months after transfusion. A logistic regression analysis showed that the hospital area, the hospital size (more than 300 beds) and the annual amount of blood bags transfused in it (less than 5000) were factors independently associated with having a full pre and post-transfusion screening. Currently, the screening program may detect 0.14 cases of HIV and 0.05 HCV transfusion related contamination of recipient every year. The total cost of this program is about 20 million € and the cost per case exceeds 110 million €. The program will be of no use in case of an emerging transmitable disease. This program does not comply to any evaluation criteria of screening programs and its cost efficacy ratio is very poor.