Plasma collection and supply in Europe: Proceedings of an International Plasma and Fractionation Association and European Blood Alliance symposium.

At the symposium organized by the International Plasma and Fractionation Association and European Blood Alliance, experts presented their views and experiences showing that the public sector and its blood establishments may strengthen the collection and increase the supply of plasma using the right strategies in plasma donor recruitment, retention and protection, scaling-up collection by increasing the number of donors within improved/new infrastructure, supportive funding, policies and legislation as well as harmonization of clinical guidelines and the collaboration of all stakeholders. Such approaches should contribute to increased plasma collection in Europe to meet patients' needs for plasma-derived medicinal products, notably immunoglobulins and avoid shortages. Overall, presentations and discussions confirmed that European non-profit transfusion institutions are committed to increasing the collection of plasma for fractionation from unpaid donors through dedicated programmes as well as novel strategies and research.

Hyperimmune Globulins for the Management of Infectious Diseases.

This review is focused on the use of hyperimmune globulin therapy to treat some infectious diseases of viral or bacterial origin. Despite the introduction of antibiotics and vaccines, plasma immunoglobulin therapy from whole blood donation can still play a key role. These treatments provide passive transfer of high-titer antibodies that either reduces the risk or the severity of the infection and offer immediate but short-term protection against specific diseases. Antibody preparations derived from immunized human donors are commonly used for the prophylaxis and treatment of rabies, hepatitis A and B viruses, varicella-zoster virus, and pneumonia caused by respiratory syncytial virus, Clostridium tetani, Clostridium botulinum. The use of hyperimmune globulin therapy is a promising challenge, especially for the treatment of emerging viral infections for which there are no specific therapies or licensed vaccines.

Detection of antibodies against SARS-CoV-2 both in plasma pools for fractionation and in commercial intravenous immunoglobulins produced from plasma collected in Italy during the pandemic.

BACKGROUND: We investigated the presence of anti-SARS-CoV-2 antibodies in Italian plasma pools and intravenous immunoglobulins sent to our Institute (Italian National Institute of Health - Istituto Superiore di Sanità) in the context of the Official Control Authority Batch Release. The plasma pools were made up from donations collected in several different Italian regions from May 2017 to October 2020, i.e. in the pre-pandemic and pandemic periods. MATERIALS AND METHODS: All plasma pools were initially tested for the qualitative detection of anti-SARS-CoV-2 antibodies against the nucleocapsid protein using the Roche Elecsys® Anti-SARS-CoV-2 test kit. Plasma pools positive for these antibodies were further tested using the Roche Elecsys® Anti-SARS-CoV-2 S test kit for the quantitative detection of antibodies against SARS-CoV-2 spike receptor binding domain. All plasma pools showing reactivity to these antibodies were tested undiluted for the presence of SARS-CoV-2 RNA using the Grifols Procleix SARS-CoV-2 transcription-mediated amplification assay. Intravenous immunoglobulins were tested using both test kits to determine the presence of anti-SARS-CoV-2 antibodies. RESULTS: All plasma pools made up from donations collected in the pre-pandemic period were negative for anti-SARS-CoV-2 antibodies against the nucleocapsid protein. Of the plasma pools made up from donations collected from December 2018 to March 2020, only 1 pool out of 68 (1.4%), that was made up from donations from the Lombardy region, was reactive for these antibodies. Interestingly, 105 out of 174 (60.3%) of the plasma pools made up from donations collected from November 2018 to October 2020 showed the presence of these antibodies. All plasma pools positive for these antibodies were tested for antibodies against SARS-CoV-2 spike receptor binding domain and were confirmed positive. DISCUSSION: None of these plasma pools tested were reactive for SARS-CoV-2 RNA. In the case of intravenous immunoglobulins, 20 out of 25 (80%) batches showed the presence of both anti-SARS-CoV-2 antibodies, reflecting the concentration in the plasma pools used for their production.

ABO blood group and COVID-19: an updated systematic literature review and meta-analysis.

BACKGROUND: Following the first reports in the literature, the association between the ABO blood group and SARS-CoV-2 infection has been investigated by a number of studies, although with varying results. The main object of this systematic review was to assess the relationship between the ABO blood group and the occurrence and severity of COVID-19. MATERIALS AND METHODS: A systematic literature search using appropriate MeSH terms was performed through Medline and PubMed. The outcomes considered were the prevalence of the blood group O vs non-O types in SARS-CoV-2 infected and non-infected subjects, and the severity of SARS-CoV-2 infection according to ABO group. The methodological quality of the studies included in the analysis was assessed with the Newcastle-Ottawa Scale, and the overall quality of the available evidence using the GRADE system. Benchmarks used to evaluate the effect size were odd ratios (ORs) for case control studies and risk ratios (RRs) for cohort studies. RESULTS: Twenty-one studies were included in the analysis. Overall, individuals with group O had a lower infection rate compared to individuals of non-O group (OR: 0.81; 95% CI: 0.75, 0.86). However, the difference in the effect size was significantly lower in cohort studies compared to case control studies. No evidence was found indicating an effect of the O type on the disease severity in the infected patients. DISCUSSION: We have found low/very low evidence that group O individuals are less susceptible to SARS-CoV-2 infection compared to those in the non-O group. No evidence was found indicating an effect of the O type on disease severity in SARS-CoV-2 infection.

The growing importance of achieving national self-sufficiency in immunoglobulin in Italy. The emergence of a national imperative.

Since the inception of industrial plasma fractionation during the Second World War, a succession of protein therapies isolated from plasma have determined the volume of plasma requiring collection, and have also shaped the economics of the industry. These so-called plasma drivers have successively included albumin, coagulation Factor VIII (FVIII) and, for the past thirty years, intravenously (IV) and subcutaneously (SC) administered immunoglobulin (IG) solutions. The sale of IG underpins the profitability of the industry and has experienced continuous growth over the past decades, as the result of growing clinical demand. Modelling this demand using decision analysis indicates that supplying the evidence-based indications for IG therapies will generate a need for IG which exceeds the current plasma collection capacity of most countries. A notable exception to this situation is the United States (US) of America, whose population of compensated plasma donors generates two thirds of the global supply of plasma for fractionation. The US is also the leading consumer of IG, and its health care providers pay the highest price for the product globally. Shortages of IG occur whenever the demand for the product outstrips the supply. Current shortages, following other historical periods of shortage, threaten the well-being of patients dependant on these products and incur heavy costs on health systems. In Italy, the national blood system, which is based on voluntary unpaid donors, reflects a policy of national self-sufficiency in blood-derived therapies (a strategic objective of the national blood system itself), based on solidarity as an ethical principle. This system has increased the collection of plasma for fractionation by 3.8% per annum over 2008-2017, in accordance to a plan for plasma procurement targeting a collection rate of 14.1 L of plasma per thousand (103) population by 2020. Over the same period, IG usage has increased by 8.5/per annum, to 89.2 g IG/103 population. In this paper, we review the factors which, increasingly, are causing an imbalance between the global supply and demand for IG, and we assess Italy's capacity to ensure that increasing this level of independence is no longer simply an ethical, but also an economic imperative, with implications for the security of Italy's health system.

Patient Blood Management: a revolutionary approach to transfusion medicine.

Patient Blood Management (PBM) is a multimodal, multidisciplinary approach adopted to limit the use and the need for allogeneic blood transfusion in all at-risk patients with the aim of improving their clinical outcomes. Although PBM usually refers to surgical patients, its clinical use has gradually evolved over the last few years and it now also refers to medical conditions. This review will critically analyse the current knowledge on the use of PBM programmes in surgical and non-surgical patients.

Emicizumab for the treatment of haemophilia A: a narrative review.

One of the most serious complications of the treatment of severe haemophilia A is the development of alloantibodies against exogenous factor VIII (FVIII). Inhibitors render factor replacement therapy ineffective, exposing patients to a remarkably high risk of morbidity and mortality. Besides the well-known bypassing agents (i.e. activated prothrombin complex concentrate and recombinant activated factor VII) used to treat or prevent bleeding in haemophilia patients with inhibitors, there is growing interest in newer haemostatic therapies that are not based on the replacement of the deficient FVIII. This review will focus on the most interesting among these innovative therapies, emicizumab, and will provide an update on its current stage of clinical development.

Factors affecting the quality, safety and marketing approval of clotting factor concentrates for haemophilia.

Selecting therapeutic products for the treatment of haemophilia follows the process of obtaining market approval of products submitted to the scrutiny of a regulatory agency. In well-resourced countries, key decisions on whether a product is sufficiently safe and of high quality are made by highly expert and well-resourced agencies, such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). In countries lacking such agencies, well-informed decisions can still be made through an appreciation of the key issues affecting the quality, safety and efficacy of haemophilia products. A number of well-established principles may then be applied in order to make a choice. In this review, reflecting principles outlined by the World Federation of Hemophilia, we outline the key features in determining the acceptability of therapeutic products for haemophilia in order to ensure an optimal choice in all the environments providing haemophilia care.

The methodology for defining the European standards for the certification of Haemophilia Centres in Europe.

INTRODUCTION: Work Package 4 Development of the standardisation criteria of the European Haemophilia Network project has the main objective of implementing a common and shared European strategy for a certification system for two levels of Haemophilia Centres: European Haemophilia Treatment Centres and European Haemophilia Comprehensive Care Centres in the Member States of the European Union. MATERIALS AND METHODS: An inclusive and participatory process for developing shared standards and criteria for the management of patients with inherited bleeding disorders has been carried out. The process has been implemented through four different consultation events involving the entire European community of stakeholders that significantly contributed in the drafting of the European Guidelines for the certification of Haemophilia Centres. RESULTS: The Guidelines set the standards for the designation of centres that provide specialised and multidisciplinary care (Haemophilia Comprehensive Care Centres) as well as local routine care (Haemophilia Treatment Centres). Standards cover several issues such as: general requirements; patient care; advisory services; laboratory; networking of clinical and specialised services. CONCLUSIONS: The drafting of the European Guidelines for the certification of Haemophilia Centres was performed adopting a rigorous methodological approach. In order to build the widest possible consensus to the quality standards, the main institutional and scientific stakeholders have been involved. The resulting document will significantly contribute in promoting standardisation in the quality of diagnosis and treatment in European Haemophilia Centres.

The European standards of Haemophilia Centres.

INTRODUCTION: The European haemophilia community of professionals and patients has agreed on the principles of haemophilia care to address comprehensive optimal delivery of care which is nowadays scattered throughout Europe. Many of the health facilities call themselves Haemophilia Centres despite their variation in size, expertise and services provided. Only a small number of countries have Haemophilia Centre accreditation systems in place. METHODS: In the framework of the European Haemophilia Network project, following an inclusive process of stakeholder involvement, the European Guidelines for the certification of haemophilia centres have been developed in order to set quality standards for European Haemophilia Centres and criteria for their certification. RESULTS: The Guidelines define the standards and criteria for the designation of two levels of care delivery: European Haemophilia Treatment Centres, providing local routine care, and European Haemophilia Comprehensive Care Centres, providing specialised and multi-disciplinary care and functioning as tertiary referral centres. Additionally, they define standards about general requirements, patient care, provision of an advisory service and establishment of network of clinical and specialised services. CONCLUSIONS: The implementation of the European Guidelines for the certification of Haemophilia Centres will contribute to the reduction of health inequalities through the standardisation of quality of care in European Union Member States and could represent a model to be taken into consideration for other rare disease groups.

The Italian institutional accreditation model for Haemophilia Centres.

BACKGROUND: In Italy, basic health needs of patients with inherited bleeding disorders are met by a network of 50 haemophilia centres belonging to the Italian Association of Haemophilia Centres. Further emerging needs, due to the increased life expectancy of this patient group, require a multi-professional clinical management of the disease and provide a challenge to the organisation of centres.In order to achieve harmonised quality standards of haemophilia care across Italian Regions, an institutional accreditation model for haemophilia centres has been developed. MATERIAL AND METHODS: To develop an accreditation scheme for haemophilia centres, a panel of experts representing medical and patient bodies, the Ministry of Health and Regional Health Authorities has been appointed by the National Blood Centre. Following a public consultation, a technical proposal in the form of recommendations for Regional Health Authorities has been formally submitted to the Ministry of Health and has formed the basis for a proposal of Agreement between the Government and the Regions. RESULTS: The institutional accreditation model for Haemophilia Centres was approved as an Agreement between the Government and the Regions in March 2013. It identified 23 organisational requirements for haemophilia centres covering different areas and activities. DISCUSSION: The Italian institutional accreditation model aims to achieve harmonised quality standards across Regions and to implement continuous improvement efforts, certified by regional inspection systems. The identified requirements are considered as necessary and appropriate in order to provide haemophilia services as "basic healthcare levels" under the umbrella of the National Health Service. This model provides Regions with a flexible institutional accreditation scheme that can be potentially extended to other rare diseases.

Definition of an organisational model for the prevention and reduction of health and social impacts of inherited bleeding disorders.

INTRODUCTION: Due to the increase in life expectancy, patients with haemophilia and other inherited bleeding disorders are experiencing age-related comorbidities that present new challenges. In order to meet current and emerging needs, a model for healthcare pathways was developed through a project funded by the Italian Ministry of Health. The project aimed to prevent or reduce the social-health burden of the disease and its complications. MATERIAL AND METHODS: The National Blood Centre appointed a panel of experts comprising clinicians, patients, National and Regional Health Authority representatives. Following an analysis of the scientific and regulatory references, the panel drafted a technical proposal containing recommendations for Regional Health Authorities, which has been formally submitted to the Ministry of Health. Finally, a set of indicators to monitor haemophilia care provision has been defined. RESULTS: In the technical document, the panel of experts proposed the adoption of health policy recommendations summarised in areas, such as: multidisciplinary integrated approach for optimal healthcare provision; networking and protocols for emergency care; home therapy; registries/databases; replacement therapy supply and distribution; recruitment and training of experts in bleeding disorders. The recommendations became the content of proposal of agreement between the Government and the Regions. Monitoring and evaluation of haemophilia care through the set of established indicators was partially performed due to limited available data. CONCLUSIONS: The project provided recommendations for the clinical and organisational management of patient with haemophilia. A particular concern was given to those areas that play a critical role in the comorbidities and complications prevention. Recommendations are expected to harmonise healthcare care delivery across regional networks and building the foundation for the national haemophilia network.

Public expenditure for plasma-derived and recombinant medicinal products in Italy.

BACKGROUND: In Italy, the supply of plasma-derived medicinal products funded by the National Health Service can be through public healthcare facilities, accredited pharmacies or toll fractionation agreements between Regions and the manufacturer. Pharmaceutical public expenditure includes the supply related to the first two channels and costs can significantly vary because of channel-specific price reductions. This paper describes 2011 public expenditure for plasma-derived medicinal products purchased on the market, as well as the cost analysis per active substance. MATERIALS AND METHODS: Analysis of the usage of plasma-derived medicinal products and of the related expenditure in public facilities has been carried out using medicinal product traceability data. The analysis related to the accredited pharmacies channel has been carried out using quantities for every medicinal package recorded by Pharmacy Associations and applying reference prices in force on March 1(st), 2012 as well as discounts for the accredited pharmaceutical expenditure imposed by law. RESULTS: At national and regional level, total and total per capita expenditures on plasma-derived medicinal products by market channel and funded by the National Health Service are shown. Analysis was conducted considering the active substances in three groups: substances included in toll fractionation agreements, recombinant coagulation factors, and other substances not included in toll fractionation agreements. In 2011, the national expenditure estimate for plasma-derived and recombinant medicinal product acquisition on the market was about € 535 million. DISCUSSION: The purchased volumes and mean purchased prices per unit of each substance have a significant influence on the observed regional variability of the pharmaceutical public expenditure. A strategy of regional comparison aimed at both sharing a national range of reference for purchase prices and evaluating modalities for centralised purchasing is desirable.