Fabio Candura

Human Parvovirus B19 and blood product safety: a tale of twenty years of improvements

The establishment of systems to ensure a safe and sufficient supply of blood and blood products for all patients requiring transfusion is a core issue of every blood programme. A spectrum of blood infectious agents is transmitted through transfusion of infected blood donated by apparently healthy and asymptomatic blood donors. Recent emerging-infectious-disease threats include West Nile virus1,2, chikungunya3, babesia4, dengue5, hepatitis E virus6, and variant of Creutzfeldt-Jakob disease7. Parvovirus B19 (B19V), long known to be the causative agent of erythema infectiosum (fifth disease), is not a newly emerging agent. However, it deserves discussion because it may be present in blood and in plasma products, can circulate at extraordinarily high titres, can infect recipients, and, in some cases, can cause severe disease8. Its potentially severe pathological effects have become more apparent in the past decade with the widespread use of (pooled) plasma-derived medicinal products and are the main reason for the uneasy relationship between transfusion medicine specialists and B19V9. The aim of this review is to analyse the role played by this virus in compromising safety in transfusion medicine and the progressive measures to reduce the risks associated with the virus.

Hepatitis E: an old infection with new implications.

The availability of safe blood and blood products is an important public health issue. Improvements in donor screening and testing, pathogen inactivation1 and removal methods, the use of serological tests with greater diagnostic efficacy and the introduction of nucleic acid testing (NAT) have resulted in a substantial drop in transfusion-transmitted infections over the last two decades2. Nonetheless, blood supplies remain vulnerable to emerging and re-emerging infections. In recent years, numerous infectious agents found worldwide have been identified or reconsidered as potential threats to blood supplies3–5. Hepatitis E virus (HEV) has long been considered an enterically transmitted virus causing self-limiting acute viral hepatitis. The disease is endemic in many developing countries, but in recent years an increasing number of autochthonous and sporadic HEV infections have been described in developed countries6. This virus usually causes an acute self-limiting hepatitis, but in some cases fulminant hepatic failure resulting in morbidity and mortality may occur, especially in at-risk groups such as the elderly, pregnant women and patients with pre-existing liver disease or those who are immunocompromised. Furthermore, recent seroprevalence studies are questioning the concept of the low circulation of HEV in developed countries7. This narrative review aims at providing a comprehensive view of HEV and its possible “role” in transfusion medicine.

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.

Plasma-derived medicinal products in Italy: information sources and flows.

For the purpose of a systematic analysis of the manufacturing, marketing and usage of plasma-derived medicinal products (PMPs), it is essential to define all stages of the medicinal product life-cycle and to properly identify all information sources suitable for detecting and quantifying the information related to the assessment of each stage. The PMPs present some peculiarities. Their biological active substances are obtained by an industrial extraction process of human plasma derived from voluntary donations, instead of chemical synthesis. As a raw material, plasma can be a vehicle of blood born infectious diseases. Therefore, the Italian and European legislations identified several measures aimed at reducing the risk of infection, such as: donor selection, biological validation tests, methods of pathogen removal and inactivation; moreover, the adoption of prescriptive measures is envisaged in order to guarantee both traceability and pharmacovigilance of all PMPs1–11. Another peculiar feature of PMPs is related to the ownership of the raw material and of the derived medicinal products. In Italy, as regards the national plasma collected by Regional Blood Transfusion Services, Regions and Autonomous Provinces (henceforth referred to as ‘Regions’) retain the ownership of both of them within the toll fractionation agreements with the authorised manufacturer. On the contrary, the commercial product ownership is assigned to pharmaceutical companies, which obtain the raw material from blood establishments in all other countries where plasma provision for commercial use is allowed. The aim of this manuscript is to provide an exhaustive critical description of all data sources available in Italy for the study and monitoring of the entire medicinal product life-cycle and then to highlight the degree of overlap of various information sources and to demonstrate the feasible analyses that might be developed using each of them.

Clinical use and the Italian demand for activated prothrombin complex and activated recombinant factor VII concentrates

The activated prothrombin complex concentrate (aPCC, Factor Eight Inhibitor Bypassing Activity, FEIBA, Baxter, Deerfield, IL, USA) and the recombinant activated factor VII concentrate (rFVIIa, NovoSeven, Novo Nordisk A/S, Bagsvaerd, Denmark) are the so-called “by-passing agents”, i.e. products able to promote haemostasis through mechanisms alternative to the physiological tenase complex, in which a phospholipid-dependent reaction occurs with factor (F) X as the substrate, activated (a) FIX as the enzyme and FVIIIa as a cofactor1. The mechanism(s) of action of these agents are still not completely elucidated. The aPCC, which contains activated FII, FIX, FX and small amounts of FVII, is thought to facilitate thrombin generation on the platelet surface. This product was first introduced in clinical practice in 1975, as a therapeutic agent for haemophilia B when specific FIX concentrates were not available, and in the current vapour-heated formulation in 19852. The rFVIIa concentrate was specifically developed to provide a therapeutic approach in haemophilia with inhibitors, being able at high concentrations to enhance platelet-surface FXa generation, irrespective of the presence of FVIII or FIX3. The first use of rFVIIa was reported in 1988, and the product was registered in Europe in 1996 and in the United States in 1999. aPCC and rFVIIa are the mainstay of treatment of patients with congenital and acquired haemophilia (AH) with inhibitors4–6, in whom efficacy and safety of such agents have been documented over more than three and two decades of clinical use, respectively. As a specific replacement agent, rFVIIa is indicated in patients with factor VII deficiency7 and, as an alternative haemostatic agent, in patients with Glanzmann’s thrombasthenia (GT) and alloantibodies and/or platelet transfusion refractoriness8. Because of the rarity of the other recognised indications for treatment, most clinical and literature data regarding bypassing agents have been generated in the setting of congenital haemophilia with inhibitors. Before presenting the Italian demand for aPCC and rFVIIa in this 5-yr analysis, the clinical use of bypassing agents in the management of patients with bleeding disorders, in particular in those with congenital haemophilia and inhibitors, with the numerous challenges and open issues, will be concisely reviewed.

The demand for human albumin in Italy.

Human albumin (HA) is a blood plasma protein produced in the liver. It constitutes about 60% of plasma proteins and is a physiological plasma-expander. However, its limited availability and high cost make it essential to define recommendations for its appropriate use, as an alternative to other therapeutic strategies including solutions of crystalloids and non-protein colloids. According to all official recommendations, the choice to use albumin rather than an artificial colloid strictly depends on the clinical situation of the patient1–6. HA is also used in all cases in which there is a contraindication to the use of non-protein colloids7. Based on clinical evidence, the 2009 guidance document of the Italian Society of Transfusion Medicine and Immunohaematology (SIMTI)7 recommends the use of HA in acute conditions, which call for blood volume expansion and maintenance of adequate blood flow, as well as in some chronic conditions of low serum albumin levels. “There are some widely shared and fully agreed indications for the appropriate use of human albumin and indications that are occasionally appropriate, that is, when other criteria are fulfilled”7. In addition, in haemorrhagic shock HA should only be used as a second choice [i.e. when solutions of crystalloids or non-protein colloids (first choice treatment) have already been used at maximum doses without having produced a clinically adequate response] and in cases in which non-protein colloids are contraindicated7.

Recommendations for factor VIII product source to treat patients with haemophilia A

Dear Sir, We appreciate that Coppola, together with the whole Executive Committee of the Italian Association of Haemophilia Centres (AICE)1, agreed with us2 on the reasons underlying the increased consumption of plasma-derived factor VIII products recorded in Italy between 2011 and 2014. We also agree with them that previously-untreated patients with severe haemophilia A are unlikely to have contributed to the observed increase, not only because very few of them are born in Italy each year (15-20 cases) but also because being infants of small body weight they cannot be large consumers of factor VIII in absolute terms. Even though being a previously-untreated patient is by definition a short-lasting condition, these are the people with haemophilia who are at the highest risk of developing inhibitors. Thus, it is to be hoped that the forthcoming new Principles of Treatment from AICE will provide meaningful, specific recommendations on how to choose factor VIII products for this critical category of patients. We also agree with Coppola et al.1 that the forthcoming AICE recommendations should emphasise once more and forever that the choice of the source of factor VIII products by haemophilia doctors should be based upon shared decision-making involving patients and their families. This principle of shared decision-making was illustrated by Mannucci et al.3 in an article published in 2012 with one of Coppolas co-authors (ES). In that article on how to choose factor VIII products, the authors stated that the informed choice should take into account the perception that recombinant factor VIII products are safer from the point of view of the theoretical risk of transmission of infections. The perception that plasma factor VIII products are safer from the point of view of inhibitor risk was also mentioned in the frame of shared decision-making3. The striking current novelty is that the results of SIPPET (Survey of Inhibitors in Plasma-Products Exposed Toddlers), a study with a randomised design4 (thus providing the highest level of clinical evidence), have transformed the aforementioned perception into evidence, and that this new information should be now conveyed without ambiguity to patients during the decision-making process. Disclaimer of conflicts of interest The Authors declare no conflicts of interest, with the exception of PMM who declares having received in the past 12 months honoraria for lectures as a speaker or for chairing symposia organised by Alexion, Bayer, BaxaltaShire, Grifols, Kedrion, LFB, and Novo Nordisk. He has also acted as a scientific consultant for Bayer and Kedrion.

Clinical use and the Italian demand for prothrombin complex concentrates

Prothrombin complex concentrates (PCCs) are an important plasma-derived therapeutic option for the rapid correction of deficiency of vitamin-K dependent clotting factors1. PCCs are produced by ion-exchange chromatography from the cryoprecipitate supernatant of large plasma pools after removal of antithrombin and factor (F) XI2. Different processing techniques involving ion exchangers permit the production of either three- (i.e., FII, FIX and FX) or four-factor (i.e., FII, FVII, FIX and FX) concentrates with a final overall clotting factor concentration approximately 25 times higher than in normal plasma (Tables I and ​andIIII)3. To prevent activation of these factors, most PCCs contain heparin. In addition, they may also contain the physiological inhibitors of coagulation protein C and protein S. PCCs are standardised according to their FIX content and are subjected to viral inactivation processes, both by physical (vapour, heating) and chemical (solvent detergent treatment) methods. Table I Three-factors prothrombin complex concentrates brief fact sheet. Table II Four-factors prothrombin complex concentrates brief fact sheet. Various preparations are commercially available in Italy, as reported in Tables III4 and ​andIVIV4. Table III Products containing three-factors prothrombin complex concentrates currently available on the Italian market. Table IV Products containing four-factors prothrombin complex concentrates currently available on the Italian market. Clinical indications of prothrombin complex concentrates PCCs were originally developed for the treatment of haemophilia B patients; however, due to the availability in recent years of plasma-derived high purity FIX concentrates and, more recently, of a recombinant FIX product, they have progressively shifted from this clinical indication towards the replacement of vitamin K-dependent clotting factors. The current indications for the clinical use of PCCs are mostly based on retrospective or observational studies, as very few controlled randomised clinical trials have been conducted so far in this setting3. Therefore, PCCs are used for prophylaxis or treatment of bleeding in patients with a documented inherited deficiency of FII or FX; if PCCs are not available, fresh frozen plasma (FFP) can be used as an alternative. However, solvent/detergent plasma should be preferred in patients with inherited coagulation disorders who need replacement therapy when virus-inactivated single-factor concentrates are not available5. Similarly, in patients with congenital deficiency of FVII or FIX, PCCs can be used only when the specific clotting factor concentrate is not available. In patients with acquired deficiencies of factors of the prothrombin complex (due to severe liver disease, blood loss or dilution), PCCs could be administered, as a second choice alternative to FFP, taking into account that the potential utility of PCCs in (bleeding) patients not being treated with vitamin K antagonist (VKA) is only based on limited evidence from retrospective studies involving few patients6 and that the risk of thrombosis is higher with PCC than with plasma7–10. Thus, the current clinical indications for PCC use include: - patients on VKA therapy requiring emergency reversal in case of bleeding or need for urgent surgery (grade of recommendation: 1B)7,9,11–19. PCCs are able to completely reverse the warfarin-induced anticoagulation within 10 minutes but the infused clotting factors have a finite half-life. Therefore, intravenous vitamin K (10 mg) should be given with the PCC. The recently published ACCP (American College of Chest Physicians) guidelines suggest, for patients with VKA-associated major bleeding, rapid reversal of anticoagulation with four-factor PCCs, due to the presence of FVII (Grade of recommendation: 2C)19; - prophylaxis or treatment of bleeding in patients with a documented inherited deficiency of FII or FX (grade of recommendation: 2C)7,9,20,21; - prophylaxis or treatment of bleeding in patients with congenital deficiency of FVII or FIX if the specific clotting factor concentrate is not available (grade of recommendation: 2C)7,9,20,21; - patients with acquired deficiencies of factors of the PCCs and limitations to the use of FFP, such as those at a risk of circulatory overload or with the need for urgent restoration of normal haemostasis (grade of recommendation: 2C)6,7,9,22. Quantification and characterisation of the three-factors prothrombin complex concentrates demand Tables V and ​andVIVI show both the absolute and standardised demand (expressed in I.U. and per capita I.U., respectively) for three-factors PCCs in the period 2007–2011, at the national and regional level, according to medicinal products traceability data23. Table V Quantification of total (public and private) demand for three-factors prothrombin complex concentrates (expressed in international units) in Italy and Italian regions, from 2007 to 2011. Table VI Quantification of total (public and private) standardised demand for three-factors prothrombin complex concentrates (expressed in per capita international units) in Italy and Italian regions, from 2007 to 2011. The three-factors PCCs national demand showed an increase of about 65%, from 15,645,100 I.U. in 2007 to 25,782,200 I.U. in 2011 (Table V), with a per capita consumption of 0.4 I.U. in 2011 (Table VI). Regions with the highest per capita demand are Aosta Valley and Emilia-Romagna, as well as the Autonomous Province (AP) of Bolzano with about 2 and 1 I.U., respectively (Figure 1), with a percentage change from the national mean demand of +313%, +84%, and +156%, respectively (Figure 2). Figure 1 Quantification of total (public and private) standardised demand for three-factors prothrombin complex concentrates (in per capita international units), in Italy and Italian regions, year 2011. Figure 2 Percentage change from the national mean value of standardised regional demand of prothrombin complex concentrates (per capita international units) in 2011. Regions with the lowest observed demand are Calabria, Latium and Abruzzo with 0.1, 0.2, and 0.3 per capita I.U., with a percentage departure of −71%, −46%, and −42% from the national mean value (Figure 2). The distribution of PCCs takes place almost exclusively through the public health facilities distribution channel23. Aosta Valley, the AP of Bolzano and Emilia-Romagna have the largest demand through this channel, i.e. about 2 per capita I.U. for the first Region and about 1 I.U. for the latter two, respectively (Figure 3). Figure 3 Demand for three-factors prothrombin complex concentrates (per capita international units), in Italy and Italian regions, by public health facilities channel, year 2011. It is also necessary to underline the use of the pharmacies open to the public channel in Latium and Campania, which represents on average of about 6% of the total demand of both Regions (data reported elsewhere)24.

The demand for polyvalent immunoglobulins in Italy.

Polyvalent immunoglobulins (IG) for subcutaneous administration (SCIG) and for intravascular administration (IVIG) are used in the replacement therapy of the immunodeficiencies and in the treatment of autoimmune pathologies or systemic inflammatory processes (Tables I and ​andIIII)1,2. However, in the clinical practice IGs are often used more extensively than what the authorised indications allow (“off-label” use) even if, in this case, the use is not always supported by available scientific evidence1–4. Table I Polyvalent immunoglobulins, for subcutaneous administration, brief fact sheet. Table II Polyvalent immunoglobulins, for intravascular administration, brief fact sheet IGs are isolated from pooled plasma that has been donated by 1,000–100,000 people. With such large pools of donors, the entire spectrum of antibodies produced by the population is represented in the final product. IVIG contains 8–15 g/dL of protein, of which >90% is IgG. IVIG is further purified to remove or inactivate infectious agents and prevent aggregates1,3–5.

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.