Giuseppina Facco

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.

Human T-lymphotropic virus and transfusion safety: does one size fit all?

Human T‐cell leukemia viruses (HTLV‐1 and HTLV‐2) are associated with a variety of human diseases, including some severe ones. Transfusion transmission of HTLV through cellular blood components is undeniable. HTLV screening of blood donations became mandatory in different countries to improve the safety of blood supplies. In Japan and Europe, most HTLV‐infected donors are HTLV‐1 positive, whereas in the United States a higher prevalence of HTLV‐2 is reported. Many industrialized countries have also introduced universal leukoreduction of blood components, and pathogen inactivation technologies might be another effective preventive strategy, especially if and when generalized to all blood cellular products. Considering all measures available to minimize HTLV blood transmission, the question is what would be the most suitable and cost‐effective strategy to ensure a high level of blood safety regarding these viruses, considering that there is no solution that can be deemed optimal for all countries.

Leucoreduction of blood components: an effective way to increase blood safety?

Over the past 30 years, it has been demonstrated that removal of white blood cells from blood components is effective in preventing some adverse reactions such as febrile non-haemolytic transfusion reactions, immunisation against human leucocyte antigens and human platelet antigens, and transmission of cytomegalovirus. In this review we discuss indications for leucoreduction and classify them into three categories: evidence-based indications for which the clinical efficacy is proven, indications based on the analysis of observational clinical studies with very consistent results and indications for which the clinical efficacy is partial or unproven.

Convalescent plasma: new evidence for an old therapeutic tool?

Passive immunisation for the prevention and treatment of human infectious diseases can be traced back to the 20(th) century. The recent Ebola virus outbreak in West Africa has turned the spotlight onto the possible use of convalescent whole blood and convalescent plasma in the treatment of infectious diseases because they are the only therapeutic strategy available in some cases, given the unavailability of vaccines, drugs or other specific treatments. Convalescent blood products could be a valid option in the treatment/prophylaxis of several infectious diseases both in association with other drugs/preventive measures and as the only therapy when a specific treatment is not available. However, there are still some issues to consider in determining the advisability of implementing a large-scale convalescent plasma transfusion programme.

Health Technology Assessment of pathogen reduction technologies applied to plasma for clinical use.

Although existing clinical evidence shows that the transfusion of blood components is becoming increasingly safe, the risk of transmission of known and unknown pathogens, new pathogens or re-emerging pathogens still persists. Pathogen reduction technologies may offer a new approach to increase blood safety. The study is the output of collaboration between the Italian National Blood Centre and the Post-Graduate School of Health Economics and Management, Catholic University of the Sacred Heart, Rome, Italy. A large, multidisciplinary team was created and divided into six groups, each of which addressed one or more HTA domains.Plasma treated with amotosalen + UV light, riboflavin + UV light, methylene blue or a solvent/detergent process was compared to fresh-frozen plasma with regards to current use, technical features, effectiveness, safety, economic and organisational impact, and ethical, social and legal implications. The available evidence is not sufficient to state which of the techniques compared is superior in terms of efficacy, safety and cost-effectiveness. Evidence on efficacy is only available for the solvent/detergent method, which proved to be non-inferior to untreated fresh-frozen plasma in the treatment of a wide range of congenital and acquired bleeding disorders. With regards to safety, the solvent/detergent technique apparently has the most favourable risk-benefit profile. Further research is needed to provide a comprehensive overview of the cost-effectiveness profile of the different pathogen-reduction techniques. The wide heterogeneity of results and the lack of comparative evidence are reasons why more comparative studies need to be performed.

AISF-SIMTI Position Paper: The appropriate use of albumin in patients with liver cirrhosis

The use of human albumin is common in hepatology since international scientific societies support its administration to treat or prevent severe complications of cirrhosis, such as the prevention of post-paracentesis circulatory dysfunction after large-volume paracentesis and renal failure induced by spontaneous bacterial peritonitis, and the treatment of hepatorenal syndrome in association with vasoconstrictors. However, these indications are often disregarded, mainly because the high cost of human albumin leads health authorities and hospital administrations to restrict its use. On the other hand, physicians often prescribe human albumin in patients with advanced cirrhosis for indications that are not supported by solid scientific evidence and/or are still under investigation in clinical trials. In order to implement appropriate prescription of human albumin and to avoid its futile use, the Italian Association for the Study of the Liver (AISF) and the Italian Society of Transfusion Medicine and Immunohaematology (SIMTI) nominated a panel of experts, who reviewed the available clinical literature and produced practical clinical recommendations for the use of human albumin in patients with cirrhosis.

Prioritizing of bacterial infections transmitted through substances of human origin in Europe

Bacteria are the pathogens most frequently transmitted through substances of human origin (SoHO). The European Centre for Disease Prevention and Control (ECDC) organized an expert consultation, with the objective of developing a priority list of bacterial pathogens transmissible via SoHO. The list will be used to further assess risks and determine appropriate preventive measures.

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.

Clinical use and the Italian demand for antithrombin

Antithrombin (AT) is a single-stranded glycoprotein synthesised in the liver with a plasma concentration of approximately 150 μg/mL and a molecular weight of approximately 59,000 Da1. It is a complex molecule with multiple biologically important properties. It is a serine protease inhibitor (serpin) that inactivates many enzymes in the coagulation cascade2,3. Indeed, it is the key inhibitor of the coagulation system and is estimated to provide 80% of the inhibitory activity against thrombin but it also inhibits activated factors X, IX, VII, XI, and XII. AT has a great affinity for thrombin and is also known as heparin cofactor as it is responsible for the anticoagulant effect of heparin. Heparins markedly accelerate the rate of complex formation between AT and the serine proteases thus increasing AT inhibitory activity 5,000–40,000-fold4. AT also has remarkable anti-inflammatory properties, several of which result from its actions in the coagulation cascade. Other anti-inflammatory properties of AT involve direct interactions with endothelial cells, leading to the release of prostacyclin, which also mediates its anti-platelet effect3. In addition, recent evidence of interactions of the endothelial cell growth factors bFGF (basic fibroblast growth factor) and VEGF (vascular endothelial cell growth factor) with a heparin-like molecule in matrix provide the rationale for further investigation into the possible role of AT as a potent anti-angiogenic factor5. Normal values of AT activity in the plasma range from 80% to 120%. In normal conditions, its biological half-life is 1.5–2.5 days. In conditions of acquired deficiency and in the presence of heparin, the half-life of AT can be notably shorter, being reduced to only a few hours6.