1. Introduction

Anaemia is very common condition in human pathology that may result from a wide variety of causes, either congenital or acquired. It is always the manifestation of an underlying disease, and never a disease by itself. Haemoglobin concentration (Hb) is the most reliable indicator of anaemia, but since its normal distribution at population level varies with age, sex, and physiological status, the Word Health Organization (WHO) has defined the existence of anaemia when Hb is less than 110 g/L in children and pregnant women, 120 g/L in non-pregnant women and 130 g/L in men. Moreover, measuring Hb is relatively easy and inexpensive, and currently, all automated and semi-automated haematology analysers measure Hb with great precision and accuracy. It is well known that iron deficiency in children and women and chronic diseases in adults and elderly, is the most frequent cause of mild to moderate anaemia worldwide [1, 2].

In general, there are three primary causes of anaemia: (1) Bone marrow erythropoietic defects associated with or without reduced haemoglobin synthesis. (2) Haemolysis or excessive destruction of mature red blood cells (RBCs), and (3) blood loss or bleeding. Anaemia can be the consequence of a single disease (e.g. haemoglobinopathy, enzyme deficiency, etc.), but it can be also the expression of external factors such as nutritional deficiencies, parasitic or viral infection, and other. However, there is a group of anaemias that is considered rare because their frequency in our population is less than 5 cases for 10,000 individuals. These are the so-called rare anaemias (RA), mostly of congenital origin [3]. RA are an important, and relatively homogeneous group of rare diseases (RD), where anaemia is the first and most relevant clinical manifestation of the disease. This importance was recognized, for first time, by the European Commission (EC) that in 2002 approved the co-financing of the DG-SANCO Project: "European Network for rare and congenital diseases" (ENERCA; www.enerca.org). Interestingly, this Project started shortly before the creation of the High Level Group (HLG) in 2004 that brought together experts from all the Member States (MS) in several areas of RD expertise. For RA, this was a great advantage, because it facilitated the progressive development of ENERCA Project in parallel to the development of the different HLG areas of action: (a) Patient safety and quality of care, (b) Health impact assessment and health systems, (c) Health technology assessment, (d) European workforce for health professionals, e) European reference networks, (f) Information and e-health and more recently, (g) Cross-border healthcare purchasing and provision [4].

Before ENERCA, RA were almost unknown in Europe, including some health professionals, because in many cases, the cause of the anaemia was not known and/ or there is no treatment available. Moreover, for many years, anaemias, in general, have been underestimated by public health providers, due to its frequent misdiagnosis with iron deficiency anaemia, the most frequent cause of anaemia worldwide. ENERCA changed definitively this situation by developing three consecutive phases with a total duration of 15 years (www.enerca.org). The first ENERCA Project (ENERCA 1), starting in 2003, dedicated to congenital RA, only, allowed the establishment of the necessary background for a sustainable coordination in the area of health information, collection of epidemiological data, comparability issues, exchange of data and information within and between MS. At this time, it also facilitated a rapid reaction to RA diagnosis and treatment. The second ENERCA Project (ENERCA 2) starting in 2005, covered, in addition, to congenital anaemias, other rare causes of anaemia, either hereditary or acquired, and dedicated more and stronger activities to health Information, patient's data collection, education and training and quality assessment for special RA diagnostic procedures. This has provided a first and unique approach for prevention, diagnosis and treatment of RA in the word. The third ENERCA Project (ENERCA 3), starting in 2009, was co-financed by the EC through its Executive Agency for Health and Consumers (EAHC) and its objectives were parallel to the strategic objectives of the EU Health Programme 2008–2013 consistent in the creation of a European Reference Network (ERN) of Centres of Expertise (CEs) in Rare Anaemias (Figure 1).

After 2013, the EC has approved co-financing ENERCA Project for an additional 3 years period (2014–2016), with the aim of developing and implementing the new e-health information and communication technologies (ICT) for assuring the same access to health services in RAs across Europe, independently from the place of residence. This new and last, but not least, ENERCA Project, called e-ENERCA, was based, in part, on previous ENERCA projects achievements, but adapted to the Directive 2011/24/EU of 9 March 2011 on the application of patients' rights in crossborder healthcare has become a very important tool for the promotion of Rare Diseases (RD) European Reference Networks (ERN) that, within that general framework, have provided the following benefits:


#### Figure 1. European Network for Rare and Congenital Anaemias Map.


For maintaining its sustainability, in March 2016, ENERCA applied for the ERN European Commission (EC) Call, by expanding the rare anaemias to all the other rare haematological diseases (RHD), including oncological and non-oncological diseases [5].

Currently, the ERN for Rare Haematological Diseases (RHD), called EuroBloodNet (www.eurobloodnet.eu), is one of the 24 recognized ERNs, and after its second year of life, can be considered an acceptable tool for the improvement RHD diagnosis and for the provision of high-quality healthcare to all patients who have conditions requiring a particular concentration of resources or expertise. In brief, EuroBloodNet will also provide focal points for medical training and research, information dissemination and evaluation, and will contribute to the establishment of national contact points for RHD. Up to now, however, only 66 Centres in Europe are recognized as Health Care Providers (HCP) for RHD, a situation created by the extremely different endorsement decisions of individual Members States (MS). So, we have arrived to the astonishing situation in that many of the ENERCA experts, well recognized by the state of the art and ENERCA White Book recommendations, are not included as EuroBloodNet experts because they do not belong to an national recognized Healthcare Provider (HCP) and cannot take participate in the Network activities and/or take profit from their advantages. In order to overcome this restraint, a new EC call for membership application to the existing European Reference Networks (ERNs) has been launched on September 30, 2019.


#### Table 1.

General classification of rare anaemias.
