Donors with a rare pheno (geno) type - Wiley Online Library

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relevant blood group antigens was the most critical. Question 5. In 1999, testing ... patient (Lan–), we found one member of the family with the same rare phenotype ..... phenotype or lacking antigens like H, Kx, Lan and P are generally in short ...
Vox Sanguinis (2008) 95, 236–253 © 2008 The Author(s) Journal compilation © 2008 Blackwell Publishing Ltd. DOI: 10.1111/j.1423-0410.2008.01084.x

INTERNATIONAL FORUM

Donors with a rare pheno (geno) type INTERNATIONAL International International Forum ForumFORUM Blackwell Publishing XXX Ltd

H. W. Reesink, C. P. Engelfriet, H. Schennach, C. Gassner, S. Wendel, R. Fontão-Wendel, M. A. de Brito, P. Sistonen, J. Matilainen, T. Peyrard, B. N. Pham, P. Rouger, P. Y. Le Pennec, W. A. Flegel, I. von Zabern, C. K. Lin, W. C. Tsoi, I. Hoffer, K. Barotine-Toth, S. R. Joshi, K. Vasantha, V. Yahalom, O. Asher, C. Levene, M. A. Villa, N. Revelli, N. Greppi, M. Marconi, Y. Tani, C. C. Folman, M. de Haas, M. M. W. Koopman, E. Beckers, D. S. Gounder, P. Flanagan, L. Wall, E. Aranburu Urtasun, H. Hustinx, C. Niederhauser, E. Massey, A. Gray, M. Needs, G. Daniels, T. Callaghan, C. Flickinger, S. J. Nance & G. M. Meny The provision of compatible red blood cells (RBC) for patients who are negative for a high-frequency antigen and who have made alloantibodies against it, as well as for patients with a difficult combination of alloantibodies remains a challenge in transfusion medicine. National and international donor panels and banks of frozen units of RBCs from donors with a rare phenotype have been set up to facilitate the provision of compatible RBCs for the above patients. It seemed of interest to investigate how these facilities are used and which problems are still encountered. To obtain relevant information on the subject, the following questions were sent to the responsible authorities. Question 1. What is your definition of a rare donor? Question 2. Do you, in your country, have a national panel of rare donors and/or a national bank of frozen RBC units from such donors? If so, in which percentage of cases do you find compatible RBCs for the above patients? Which of the relevant phenotypes are lacking in your panel/bank? Question 3. If no compatible donor/RBCs are available from your national panel/bank, or if no such panel/bank exists, do you appeal to the World Health Organization (WHO) International Panel of Rare Donors and/or the Sanquin Bank of Frozen Red Cells or national panel/banks in other countries? If you do, could you indicate how many times you have appealed to these institutions in the past 5 years and in which percentage of cases compatible donors were obtained? Donors of which phenotype were the most difficult to find? Question 4. Could you mention any particular problems you encountered in finding compatible RBCs for your patients? Question 5. Are there restrictions in your country for the use of RBCs that were frozen at a time that not all tests required at present were performed and when no blood sample is available to do these tests? We obtained contributions from 17 countries/centres. The answers to the questions contain much interesting information that cannot be included in this survey. The reader is therefore strongly advised to read the individual answers. There is no complete consensus concerning the definition of a rare donor. However, in the vast majority of the countries, a donor who lacks a high-frequency antigen is considered to be rare, which means that the prevalence of such a donor in the population is 1 : 1000 or less (but 4 : 1000 in France and 1 : 100 to 1 : 1000 in Japan). In all countries/centres, a second

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category of rare donors are those who are negative for combinations of alloantigens, but the frequency at which such a combination is considered to be rare varies from 1 : 200 to 1 : 1000. In the USA, immunoglobulin A (IgA)-deficient subjects (< 0·05 mg/dl) are included in this category of donors. In the Netherlands, all donors with a phenotype with a frequency of less than 1% in the population are considered to be rare donors. In a letter, Dr Mary Lin from Taiwan mentions the complications that may arise from the fact that the frequency of some alloantigens may greatly differ in the various populations, for example, RhD is a high-frequency antigen in Taiwan and the South-East Asia in general (see also below). In nearly all countries, there is a national panel of donors with a rare phenotype, that is, the panel is located in the national transfusion centre. In some countries, however, there are several panels, divided over more than one centre, for example, three in Austria. In Italy, there is, so far, a panel and bank only in Lombardy (Milano), and in Spain, where there were two centres responsible for the provision of RBCs from donors with a rare phenotype, each serving half the country, there no longer is a centralised registry of rare donors since 2003. In France, not only donors but also patients with a rare phenotype are registered; the idea being that patients may become donors and vice versa. In most countries there also is a national bank of frozen units or local banks. The percentage of cases in which compatible RBCs could be provided by the national facilities is high; in some cases 100%, in spite of the fact that in all of them some of the rare phenotypes are lacking (see the individual answers for these phenotypes). As to be expected, RBCs with some of the rare phenotypes are much more difficult to find then others, for example, Ko, McLeod, U–, Vel–, Lan–, Bombay and p. It is general practice, when no compatible blood can be found via the national panel/bank, to appeal to the WHO International Panel of Rare Donors at Bristol, the Sanquin Bank of Frozen Blood at Amsterdam (previously the European Bank of Frozen Red Cells) and national panels/banks in other countries. Nearly all the units requested from these international and national organizations were obtained. Only a unit of RBCs with the following phenotypes could not be found: O positive, Ko, E–, Fy(a–), Jk(a–) and S–. From these requests, it appears that the phenotypes that are the most difficult to find internationally are Ko, McLeod, p, U–, Lan–, Vel– and

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Ge:–2–3. The total number of requests made in the last 5 years is not large, that is, 53 from 11 of the participating countries. Numerous possible problems in obtaining units of RBCs with a rare phenotype are mentioned. (i) The most important are logistic problems when units are sent from abroad. It may take up to 72 h before a unit arrives at its destination. Furthermore, when units have to be thawed in the centre of origin, the short preservation time of thawed RBCs may be a serious problem. (ii) Phenotypes with a very low frequency in a particular population may present a problem if there are only few donors from that population. (iii) The strict eligibility criteria for donors may reduce the number of donors with a rare phenotype. (iv) Some phenotypes, for example, Ko, are very difficult to find, even at the international level. The attitude towards the use of frozen units, on which not all the tests, now required, have been performed, varies. There is no problem if a serum sample from the donor is available to perform the necessary additional tests. If not, in some countries the decision whether to transfuse such a unit is left to the physician, that is, a risk–benefit decision. Sometimes a written consent from the physician is required and sometimes a consent from the patient as well. In Italy, such units are destroyed when no serum sample is available. In other countries, an official permit is required to use such a unit from, for example, The Medical Review Board (USA), the Ministry of Health (Austria), or a consultant in blood transfusion medicine working at the National Blood Service (UK). In France, such units are acceptable if on a later donation or serum sample from the same donor all necessary tests were done. In France, in emergency cases, it is allowed to take blood from a donor who is known to be infected [except with human immunodeficiency virus (HIV)], but to use the unit, a special permit from the Chief Executive of the National Institute of Blood Transfusion is required. Thus, it seems that, at least in the countries participating in this forum, compatible RBCs for patients with alloantibodies against a high-frequency antigen or a difficult combination of alloantibodies are virtually always obtained. In the vast majority of cases, they are found via the national donor panel or bank of frozen units. In the last 5 years, only 52 times RBCs had to be obtained from outside the country, with success except in one case. The most important problems encountered are logistic ones when blood has to be sent from abroad. H. W. Reesink Sanquin Consulting Services PO Box 9137 NL-1006 AC Amsterdam The Netherlands E-mail: [email protected] and Academic Medical Center Department of Gastroenterology and Hepatology Meibergdreef 9 NL-1105 AZ Amsterdam

The Netherlands E-mail: [email protected] C. P. Engelfriet Sanquin Research and Sanquin Diagnostic Services PO Box 9190 NL-1006 AD Amsterdam The Netherlands E-mail: [email protected]

H. Schennach & C. Gassner

Question 1 Our definition of this kind of donor conforms to the definition of the American Association of Blood Banks. We consider a person’s phenotype as rare if it differs from the majority of the population. The phenotype is ‘rare’, if it can only be found in one person out of 1000, that is, 0·1%; ‘very rare’, if this phenotype can only be found in one person out of 10 000, that is, 0·01%. But these definitions are also used for an infrequent combination of clinically relevant antigens. Individually, some of those antigens would not be ‘rare’. But the combined phenotype fits the above-mentioned definition.

Question 2 According to the fact that Austrian blood donor services are not centralized, we do not have a national panel or a national bank of frozen RBC units from rare donors. There are three centres that already store a rather small number of frozen RBC units, one additional centre is on the way to implement such a system. Most of the frozen units are reserved for autologous use, only a smaller part for allogeneic transfusion. The databases of the majority of the blood donor services give information about donors with rare phenotypes. If needed, these donors are invited to donate their blood, if possible by double dose red cell apheresis to obtain 2 RBC units, which are dedicated to a special patient. In some cases, these units are stored in a local bank for frozen RBCs. Although we do not have a national bank of frozen blood, no big problems have been reported so far with respect of providing compatible blood for patients with antibodies that are relevant for transfusion. This is a proof of the close cooperation between the different Austrian blood banks. Problems could arise concerning bombay blood, KEL4 (Kpb), KEL5 (Ku), 901001 Vel and p, but also combinations of high-frequency antigens with special Rh-phenotypes. Additionally, it must be mentioned that at least in two Austrian blood centres (Austrian Red Cross, Vienna and Central Institute for Blood Transfusion, Innsbruck) screening programmes are underway to DNA-type RBC donors for rare antigen carrier status. Although specificities applied are slightly different, both approaches include typing for KEL3/KEL4 (Kpa/Kpb), LU1/ LU2 (Lua/Lub), Y1/Y2 (Yta/Ytb), CO1/CO2 (Coa/Cob), and KN1/

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KN2 (Kna/Knb). With respect to one of these blood centres, approximately 1500 donor DNAs have been typed so far, which resulted in the identification of one Lu(a+b–), five Yt(a–b+), three Co(a–b+) and one Kn(a–b+) donors, respectively.

Question 3 In the last 5 years in Austria, only one case was reported, which led to a request to the European Bank of Frozen Red Cells, concerning a p–patient who needed 8 RBCs units. Four of these units were provided by the European Bank of Frozen Red Cells, the other units could be found in Austria. For another Austrian patient the badly needed RBCs came from the Finnish Red Cross Blood Transfusion Service. One patient who had a combination of antibodies against LU2 (Lub), FY1 (Fya) and MNS4 (s) was transfused with frozen RBCs of the Bavarian Red Cross blood bank and of the Red Cross blood bank of Vienna, respectively.

Question 4 In the majority of cases, the provision of compatible RBCs for patients with rare Rh-phenotypes combined with antibodies against high-frequency antigens and/or other clinically relevant blood group antigens was the most critical.

Question 5 In 1999, testing of blood donations for hepatitis C virus (HCV) by nucleic acids amplification technique (NAT) became mandatory. Frozen RBCs that were donated before this date and NAT testing cannot be performed from a back-up sample could only be used with the permission of the Austrian Ministry of Health. Most of the frozen allogeneic Austrian units were donated after 1999. From these donations blood samples are available for NAT testing of additional infectious diseases if required in the future. H. Schennach, C. Gassner Central Institute for Blood Transfusion University Clinics Anichstraße 35 A-6020 Innsbruck Austria E-mail: [email protected]

four; r ″r ″: four; and McLeod: two. In addition, we also have the following phenotypes in our frozen red cell bank: McLeod (14 units); Vel– (four); Di (b–) (four); Kp(b–) (18); KK (18); IgA-deficient (three), ryry (one); r′r′ (one); and r″r″ (five). Furthermore, we have a special stock of frozen RBCs typed for RH, K, FY, JK, and Ss, designated for patients with multiple antibodies. In the last 5 years, we had 10 patients with rare phenotype/antibodies (one McLeod; two anti-k; two anti-U, one anti-Lan, one anti-Ku, one anti-Dib, one anti-RH17 and one anti-Lub). We could provide blood from our stock for 4 (40%) of these patients (additionally, one of the patients also received further units from the International Blood Group Laboratory because of severe bleeding); one patient received blood from the International Blood Group Laboratory (Ko blood); one patient had a family member compatible for transfusion (Lan–); and the other four patients did not receive any blood transfusion (two anti-U, one anti-RH17 and one anti-Lub). Therefore, in the last 5 years, we transfused 39 rare RBCs from our stock whereas 26 frozen RBCs had a rare phenotype [seven McLeod, 17 KK and two Di(b–)] and 13 had special phenotypes for patients with multiple antibodies. One important phenotype that would be important for our panel is U-negative RBCs, since recently, we had two patients with anti-U with no available RBCs. Another important phenotype that would be interesting to have in our stock is RH29– and RH17–.

Question 3 When no compatible donor is available in our panel, we appeal to the International Blood Group Reference Laboratory, located in Bristol, UK. In the past 5 years, we appealed twice to this laboratory and we had a rate of 100% compatible donors. In these two events, we received a total of 5 units frozen RBCs (three McLeod and two Ko), which were thawed, deglycerolized and transfused successfully. In another situation when we did not find compatible blood in our inventory for a rare patient (Lan–), we found one member of the family with the same rare phenotype that could donate blood for this patient.

Question 4

S. Wendel, R. Fontão-Wendel & M. A. de Brito

Question 1 We consider a rare donor a donor with a phenol (geno) type with a frequency lower than 1 in 10 000 in our population.

The main problem for us is to receive compatible rare blood in a reasonable time for transfusion, especially when the blood is coming from a foreign centre. Our customs are very restricted and it is mandatory to present a number of documents and sometimes units might be held for days at the customs facility.

Question 5 Question 2 There is not a Brazilian national panel of rare donors, but there are few blood centres that have its own panel. Our rare donor panel has the following phenotypes: KK: 93; Kp(b–): four; Di(b–): nine; IgA-deficient donors: 28; Vel–: 13; r ′r ′:

Our legislation postulates that all blood components must be tested for hepatitis B and C, HIV 1 and 2, Chagas’ disease, syphilis, human T-cell lymphotrophic virus I and II. There is not a specific recommendation in our legislation concerning frozen RBC units.

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S. Wendel Blood Bank Hospital Sirio Libanês Rua Adma Jafet 91 São Paulo Brazil – 01308-050 E-mail: [email protected] R. Fontão-Wendel Blood Bank Hospital Sirio Libanês Rua Adma Jafet 91 São Paulo Brazil – 01308-050 E-mail: [email protected] M. A. de Brito Immunohematology Laboratory – Blood Bank Hospital Sirio Libanês Rua Adma Jafet 91 São Paulo Brazil – 01308-050 E-mail: [email protected]

P. Sistonen, J. Matilainen

Question 1 We consider a donor ‘rare’ when the donor is negative for one or more very common antigens in the population, for example, antigens or their combinations that have a frequency of 99.9% or more in the general population, and the owner of the phenotype is able to mount a clinically significant immune response against the missing antigen(s). Thus, a rare donor can be of a null phenotype, homozygote for an infrequent antithetical antigen, for example, Kpa, or a combination of antigens, for example, dCe/dCe.

Question 2 As the Red Cross Finland Blood Service is the sole provider of blood cell components to all hospitals in the country, we have a national panel of about 250 rare donors that is implemented into an in-house database application. No frozen blood units are available, although we are presently considering this option as closed systems have been made available. Most common examples of patients with a rare phenotype in Finland during recent years have been Jk:–3, LW(a–b+) and Pk. The percentage of finding compatible blood units for these patients (Finnish donors) has been so far 100%. The phenotypes that we are lacking at present and that have been relevant in the past are Vel– (one donor), Ge:–2,–3 (one donor), Knull (one donor) and Rh:–17 (one Rhnull donor). Although at present we have over 30 eligible Jk:–3 donors, we are also planning a new screening programme for the Jk:–3 phenotype in Finnish donors because of many requests of Jk:–3 RBCs for both Finnish and foreign patients in the past.

The Red Cross Finland Blood Service also functions as a serological blood group reference laboratory in Finland. The identification of the antibodies present and the corresponding rare phenotypes have in each case been carried out or, if new cases, will be referred to the reference laboratory. Therefore, all previous cases in this country are known to us, which greatly speeds their management and helps in designing a suitable cohort of rare donors with a given phenotype.

Question 3 If compatible donors are available in Finland, we do not appeal to other instances; if not, we may appeal to European Bank of Frozen Red Cells and/or to the WHO International Panel of Rare Cells. Depending on the case, we may also appeal directly to national panels/banks in other countries. In the past 5 years, we have only appealed directly to Umea Blood Bank (Sweden) in order to obtain Vel– units (twice) and Ge:–2–3 (once), but otherwise we have been able to find donors for rare phenotype patients from the Finnish donor population. An updated list of our eligible rare donors has been made available in the WHO International Panel in the beginning of this year.

Question 4 Same blood donation eligibility criteria are applied to rare donors as regular blood donors, and sometimes these strict criteria have unduly diminished the already small pool of potential donors. Question 5 While we do not have any RBCs for patient use that are stored frozen, and no official restrictions in this regard has been implemented, it is our opinion that the same restrictions should apply as they apply to routine use of RBCs at the moment of their use. This is a difficult question and obviously a requisite for its fulfilment is an archive plasma sample from the donor to be tested before the transfusion of the given RBC unit, if the time factors allow. The risks involved should be made known to the physician taking care of the patient. P. Sistonen, J. Matilainen Finnish Red Cross Blood Transfusion Service Kivihaantie 7 Helsinki FIN-00310 Finland E-mail: [email protected] E-mail: [email protected]

T. Peyrard, B. N. Pham, P. Rouger & P. Y. Le Pennec

Question 1 French regulations stipulate that a blood group phenotype is regarded as ‘rare’ if its prevalence is 4/1000 or less (i.e. ≤ 1/250)

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in the general population [1]. One hundred and twentyone rare blood specificities and 42 rare blood genotypes are currently defined at the National Reference Centre for Blood Groups (CNRGS – Paris) [2], a department of the National Institute of Blood Transfusion. This may concern either people lacking a high-prevalence antigen or several antigens within the same blood group system (e.g. Rh). Two important comments should be made on the legally admitted 4/1000 threshold characterizing rarity. 1. Every person with a blood group prevalence ≤ 4/1000 in the general population is enlisted into the National Registry of People with a rare blood phenotype or genotype. However, this prevalence threshold is not the only consideration for defining a rare blood donor in our country. The whole phenotype of the donor is indeed taken into account in order to assess the relevance of a RBC unit cryopreservation programme. For example, a k– donor will be considered as rare only if his/ her blood type is O, R1R1 or R2R2, or rr, with homozygous expressions for Fya/Fyb, Jka/Jkb and S/s antigens, in order to fill the maximum number of requests in multiply alloimmunized patients. 2. The prevalence of a rare blood group is closely linked to the ethnic background. A blood group may be quite frequent in a given population, but very rare if the whole population of a country is considered. As a result, the disparity between donors and patients’ origin, at a regional or national level, may dramatically increase the rarity and thus the subsequent shortage of corresponding RBC units. For historical reasons, the French population is composed of multiple ethnic backgrounds and several hundred thousand people are from African-Caribbean ancestry. Moreover, the prevalence of donors of African-Caribbean origin was often described to be lower than that of donors of Caucasian origin [3]. More than 6000 patients with sickle cell disease (SCD) are treated in our country and most of them are regularly transfused. These patients have specific phenotypes that are not encountered in the Caucasian population, for example, a Fy(a–b–), U–, Js(b–) and a distinctive prevalence of V, VS and Jsa antigens. For all the above reasons, a Fy(a–b–) donor may be considered as ‘rare’ in France, but a cryopreservation programme will be initiated only if the whole phenotype corresponds to the current restrictive inclusion criteria specified by the CNRGS. Finally, rare blood may also correspond to multiple negative ‘common’ antigens within several blood group systems. French regulations stipulate that the prevalence of such a phenotype has to be 4/100 000 or less (i.e. ≤ 1/25·000) in order to be considered as a rare blood group [4].

the National Registry of People with a rare blood phenotype or genotype. It is noteworthy that this database includes both donors and patients, as donors may become patients and vice versa. A national rare blood bank was set up in the early 1980s. This facility, located in Créteil (a few kilometres from Paris), is comanaged by the National Institute of Blood Transfusion (INTS – Paris) and the French Blood Establishment (EFS – Paris). Potential rare blood donors from the national database are highly encouraged to regularly donate blood for the National Rare Blood Bank, through 18 so-called ‘regional rare blood medical correspondents’ working for the EFS. The RBCs are cryopreserved with the high-glycerol technique and stored at a mean temperature of –80°C. The National Rare Blood Bank currently includes 5626 RBC units and 1650 active rare blood donors are enlisted in the national database. Rare blood type confirmation, registration of new people with a rare blood group within the national database, selection and delivery agreement of rare blood units are exclusively carried out by the CNRGS. Since 1994, 2082 rare blood units have been transfused for 324 patients and 874 transfusion episodes. During this 14year period, the 15 most required specificities for rare blood units were Fy(a–b–) (26·1%), k– (19·4%), Yt(a–) (12·7%), r ′r ′ (9·1%), U– (7·0%), Vel– (5·6%), r″r″ (3·5%), Lu(b–) (3·2%), D– – (1·1%), Lu:–13 (0·9%), Js(b–) (0·9%), Kp(b–) (0·9%), RZRZ (0·7%), I– (0·5%), Oh (0·4%) and Ge:–2,3 (0·3%). For patients with antibody(ies) corresponding to their rare phenotype and if transfusion support turns out to be absolutely necessary, we may consider that compatible blood was available in close to 100% of the cases. However, a few availability problems were encountered for rare blood types specifically found in the African-Caribbean population, for example, U– (especially if D–), HrS–, HrB–, Js(b-) and RN/RN, and also for exceptional phenotypes in the Caucasian population, for example, Rhnull, McLeod, Jr(a–) and Co(a–b–). Fortunately, we never had to cope with a life-threatening situation due to a severe shortage of rare blood. However, the supply and demand ratio of U- RBCs chronically proves to be the most challenging.

Question 3 To date, we never had to call on any external rare blood programme or bank of frozen RBCs in order to manage a transfusion support for a patient with a rare blood group. Besides, we happen to authorize the delivery of rare RBC units for foreign countries. From 2001 to 2005, 56 rare RBC units have been shipped abroad (Belgium, Canada, Germany, Switzerland and the Netherlands), accounting for 7·0% of all RBC units delivered within this 5-year period [5].

Question 2 A national database including both donors and patients has been implemented in our country in the late 1960s, in order to ensure transfusion and obstetrical safety of patients with a rare blood group. To date, 9803 persons are enlisted into

Question 4 As previously described, finding compatible blood for transfusion support of people of African-Caribbean origin turns out to be the most recurrent issue, especially for U– or

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Js(b–) patients with SCD. From 2001 to 2005, 33% of rare blood units have been delivered to patients with SCD [2,5]. A highly challenging context may also be encountered for people showing more than one rare phenotype [6]. Sixteen Caucasians are currently known in the national database with two rare blood specificities. As an example, one patient is k– and Vel–, and one patient is k– and Yt(a–) with anti-k, anti-Yta, anti-Fya and anti-Jkb. Both of them were transfused with their own blood, previously stored at the National Rare Blood Bank. Two African-Caribbean people are enlisted in the national database with two rare blood specificities, in addition to the Fy(a–b–) phenotype: one proband is Js(b–), Hy– and one is Lu(b–), Ge:–2,3 [6].

Question 5 First of all, no outdate period is applied in France for rare blood and the preservation time of rare frozen RBC units is considered virtually infinite. Nucleic acid testing for HIV and HCV was implemented in our country in July 2001. Previously drawn RBC units are considered fully valid if a blood donation or a blood sample has been subsequently tested for NAT. RBC units from donors who were never tested for NAT may also be used, provided there is no alternative solution [1]. However, our current policy is to progressively discard such RBC units, but this requires a very special care for exceedingly rare blood groups. French regulations allow for drawing blood from donors with positive infectious disease markers, except for HIV [1]. Such RBC units might be transfused only in a vital emergency context and if no alternative solution exists, with the informed consent of the patient (or of a family member if not possible) and with the agreement of the Chief Executive Officer of the National Institute of Blood Transfusion (or his representative) [1].

References 1 Arrêté du 28 décembre 1995 relatif aux conditions d’utilisation de prélèvements de sang ou de composants du sang correspondant à des groupes sanguins érythrocytaires rares, pris pour l’application de l’article D.666-4-2 du code de la santé publique (Journal Officiel, 13.01.1996) 2 Peyrard T, Pham BN, Le Pennec PY, Rouger P: The rare blood groups: a public health challenge. Transfus Clin Biol 2008;15: doi. 10.1016/j.tracli.2008.02.001 3 Boulware LE, Ratner LE, Ness PM, Cooper LA, Campbell-Lee S, LaVeist TA, Powe NR: The contribution of sociodemographic, medical, and attitudinal factors to blood donation among the general public. Transfusion 2002; 42:669– 678 4 Circulaire DGS/DH/AFS n°97/57 du 31 janvier 1997 relative à la transfusion autologue en chirurgie (Bulletin Officiel Santé, 23.03.1997) 5 Peyrard T, Fialaire-Legendre A, Noizat-Pirenne F, Bierling P, Rouger P, Le Pennec PY: A national file of individuals presenting a rare blood phenotype and a national blood bank for rare blood units: a five-year experience. Transfusion 2006; 46 Suppl:132A

6 Peyrard T, Fialaire-Legendre A, Noizat-Pirenne F, Bierling P, Rouger P, Le Pennec PY: Exceptional phenotypes in a national file of individuals presenting a rare blood group. Transfusion 2006; 46 Suppl:133A T. Peyrard, B. N. Pham, P. Rouger National Reference Centre for Blood Groups 20, rue Bouvier, BP79 75522 Paris Cedex 11 France E-mail: [email protected]; [email protected]; [email protected] and National Institute of Blood Transfusion 6, rue Alexandre Cabanel 75739 Paris Cedex 15 France and National Institute of Health and Medical Research, INSERM U665 6, rue Alexandre Cabanel 75739 Paris Cedex 15 France P. Y. Le Pennec National Reference Centre for Blood Groups 20, rue Bouvier, BP79 75522 Paris Cedex 11 France E-mail: [email protected] and National Institute of Blood Transfusion 6, rue Alexandre Cabanel 75739 Paris Cedex 15 France and National Institute of Health and Medical Research, INSERM U665 6, rue Alexandre Cabanel 75739 Paris Cedex 15 France and Deputy Chairman of the ‘Working Party on Rare Blood Donors' International Society of Blood Transfusion

W. A. Flegel & I. von Zabern

Question 1 The Working Party on Rare Donors [1] for the three Germanspeaking countries considers a donor as rare if he or she lacks a blood group phenotype that occurs at high prevalence in the population. One or more blood group antigens of one blood group system must be missing. Rare phenotypes have a prevalence of approximately 1 in 1000 donors or less. This cut-off is arbitrary and has receded in the past 15 years due to improved typing efforts, documentation and logistics. Donors who lack antigen k were formerly considered rare (1 in 500) until the supplies have become sufficient, while donors with CCddee phenotype still qualify easily (1 in 8300).

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Question 2 In Germany, the three blood centres in Hagen, Munich and Ulm maintain stocks of rare RBC units that are kept frozen. A deposit of frozen Swiss RBC units is kept at the The Sanquin Bank of Frozen Blood in the Netherlands and of Austrian RBC units in Vienna, Austria. An observational study originated in 2003 from the activities of the German Working Party on Rare Donors with the outcome that rare blood is most frequently needed in patients who are negative for the Kpb, Lub, Vel or Yta antigen [2]. Since then, resources have been allocated to identify such rare donors [3], and as a consequence these patients are often supplied with fresh RBC units today, provided that small numbers are needed in a planned fashion. However, the availability of fresh blood of the rarer blood groups or in emergencies will be accidental. For such patients stocks are therefore kept as frozen RBC units in liquid nitrogen for up to 10 years, and even stocks of frozen RBCs with the Rhnull phenotype or lacking antigens like H, Kx, Lan and P are generally in short supply.

Question 3 Red blood cell units were retrieved from and supplied to neighbouring countries utilizing the rare donor panel of the German-speaking countries during the past 5 years without formal tracking system. Within the last 3 years, we inquired at international panels and blood centres to explore the supply possibilities for patients with the Fy(a–b–) phenotype or lacking the antigens Inb, Ge2 or U who were, however, eventually not transfused. For the supply of rare RBC units and patient outcome, a systematic follow-up was initiated in 2005 in Germany using an adapted report form developed by the International Society Blood Transfusion (ISBT) Rare Donor Working Party. A preliminary analysis [4] including data of three blood centres documented the supply of 101 rare RBC units within 2·5 years. Out of these, one patient required the supply of 32 rare RBC unit transfusions.

1 day post-surgery. Surgery could have been performed several hours earlier, if the patient had no antibodies.

Question 5 According to the German transfusion law, a frozen RBC unit is subject to regulations that are applied to frozen plasma and may be released only once the donor has been retested and found negative for release-relevant parameters at least 4 months after donation. Frozen RBC units that do not conform to these regulations are kept separately and may be used only based on an individual risk–benefit decision, if the lack of a sufficient national blood supply is documented. This compassionate use has to be reported to state authorities.

References 1 Flegel WA: Arbeitsgruppe Seltene Blutgruppen – German Rare Donor Program. http://www.uni-ulm.de/~wflegel/RARE/ 2 Seltsam A, Wagner FF, Salama A, Flegel WA: Antibodies to highfrequency antigens may decrease the quality of transfusion support: an observational study. Transfusion 2003; 43:1563–1566 3 Wagner FF, Döscher A, Bittner R, Petershofen EK: Identifying donors with specific antigen combinations by multiplex PCR and pooled capillary electrophoresis [abstract]. Transfus Med Hemother 2007; 34:54 4 Flegel WA, von Zabern I, Kroll H, Just B: Rare blood utilization during a 2.5 years observation period in Germany [abstract]. Vox Sang 2008; 95 (Suppl 1):114–115 W. A. Flegel, I. von Zabern Institut für Transfusionsmedizin Universitätsklinikum Ulm DRK Blutspendedienst Baden-Württemberg – Hessen gemeinnützige GmbH Helmholtzstrasse 10 D-89081 Ulm Germany E-mail: [email protected]

C. K. Lin & W. C. Tsoi

Question 1 Question 4 Transfusion hazard analyses may consider adverse events related to an insufficient blood supply, because it may pose a serious hazard at least for the small and circumscribed group of patients carrying antibodies to high-prevalence antigens [2]. We find case reports in abstract form at congresses worthwhile, too: these reports may document limitations in transfusion support for this small but vulnerable group of patients who often lack advocacy. In March 2008, we supplied seven thawed RBC units for a 63-year-old woman with an anti-Lub and anti-Fya who needed surgery for a symptomatic aortic aneurysm complicated by a large mesenteric infarction. Although additional RBC units were supplied by other blood centres, the patient died

The Hong Kong Red Cross Blood Transfusion Service (HKRCBTS) adopts the definition of a rare donor as one who is negative for high-frequency blood group antigen or a combination of common blood groups with a frequency < 1 in 600 random donors of any ABO blood group.

Question 2 HKRCBTS maintains a territory-wide rare donor registry and a bank of frozen RBCs of rare blood groups. Currently, 1289 donors who meet the above definition have been registered in a special registry and our frozen bank contains 154 units of rare blood stored by the high glycerol technique at –70°C. Our satisfaction rates for the provision of compatible Hdeficient (0.006%)* and Jk(a–b–) (0.02%)* blood are at 100%.

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It is higher than 99% for cases with multiple alloantibodies against the common blood group antigens, for example, R2R2 Jk(a–b+) (1.5%)*; R2R2 Jk(a+b–) (1.3%)*. (*Figures in brackets indicated the frequency of RBC phenotypes in local population). However, we have only two Di(b–) donors in our registry and no Fy(a–b–) donor registered or blood in our frozen RBC bank. Rare blood issued in the past 5 years (2003–2007) are H-deficient units: 14 units; Jk(a–b–) units: nine units; and Fy(a–b+) units: 11 units.

Question 3 If no compatible donors or RBC units are obtained locally, we would firstly consider the possibility of autologous transfusion, then search and screen patient’s family members and discuss with the patient’s attending doctor to consider alternative treatment or pharmaceutical agents. In the past 5 years, we had not appealed for liquid RBCs from other countries. However, we had made appeals for Di(b–) RBCs and received supply from Japan in 1997 and another attempt for Fy(a–b–) RBCs from the USA in 1999. The required number of RBCs were fully filled in both cases. There was another episode of appeal for Jk(a–b–) blood for a patient in mainland China in which HKRCBTS mediated between the requestor in mainland China and Japanese Rare Donor Program in 2001.

informed about the risks and any alternative treatment modalities available. A written consent will be signed before issuing such ‘non-conforming’ products for clinical transfusion. C. K. Lin, W. C. Tsoi Hong Kong Red Cross Blood Transfusion Service 15 King’s Park Rise Yaumatei Kowloon Hong Kong E-mail: [email protected]; [email protected]

I. Hoffer & K. Barotine-Toth

Question 1 Rare donor is the negative of the high-frequency antigens.

Question 2 We have a national panel of rare donors but not a national stock or bank of frozen RBC units from such donors.

Question 3 We can appeal to the European Bank of Frozen Red Cells. In the last 5 years, we did that twice for two patients. In our practice, the most difficult to find are Cellano-negative donor, and other rare donor with other antigen-negative phenotypes.

Question 4 Question 4 Hong Kong is a cosmopolitan city where people of various races or ethnic groups are dwelling and visiting, although the great majority of the population is southern Chinese. In the event of encountering ethnic-related alloantibody(ies) against phenotypes that are of high incidence in the local population, difficulties in finding compatible RBCs can be anticipated. A possible scenario that could occur is a visitor of African origin who is RhD-negative and Fy(a–b–) and may have an episode of sickle cell crisis during his stay in Hong Kong. There is a high turnover rate of people living in Hong Kong, which may result in lost of contact with some registered donors.

Question 5 There is no restriction in Hong Kong prohibiting the use of RBCs that were not tested in accordance with the most updated blood screening policy. When a policy of implementing a new test is made, a clause to exempt products that are in the inventory prior to the implementation will usually be included. Moreover, problems associated with importing RBCs from foreign rare blood programme are that the incidence of infectious agents, the standard of screening for such markers and the residual risks linked to transfusion of such units may not be the same as the local pattern, practices and figures. Therefore, the attending doctors and their patients must be fully

We have not known any particular problems.

Question 5 Yes, we have got special restrictions. I. Hoffer, K. Barotine-Toth Hungarian National Blood Transfusion Service Budapest Hungary E-mail: [email protected]; [email protected]

S. R. Joshi & K. Vasantha

Question 1 A rare blood donor is one with a phenotype that is found in a frequency of 1 : 1000 in a given population. From the point of view of transfusion, a rare donor is one who lacks a highincidence antigen. Besides, a donor lacking multiple common antigens is also a rare donor since such a blood is useful for a recipient who possesses antibodies to corresponding antigens. Rare bloods encountered over a period in India include phenotypes like: Bombay (Oh), D– –/D– –, In(a+b–), Co(a–b–), a host of weaker variants of A, B, H, I–i–, CdE/CdE, and Mg (of the MNSs blood groups). Of these, rare donors with significance for transfusion are essentially four: ‘Bombay’ (Oh), D– –/D– –, In(a+b–), Co(a–b–) phenotypes and it has proven difficult to keep up their supply.

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Question 2 We, in our country, do not as yet have a national bank of frozen RBC units from such donors; however, a panel of rare donors for Bombay phenotype is listed at the National Institute of Immunohaematology, Mumbai. A request for this phenotype from in and around the city and sometimes from the neighbouring countries is met with from the donors’ list maintained at the institute. Other phenotypes like D– –/D– – [1,2], In(a+b–) [3] and Co(a–b–) [4] are sporadically requested in practice and we keep a track of these patients and their family members with these rare phenotypes as prospective donors.

a use of the blood product frozen at a time that not all test required at present were performed and when no blood sample is available to do these tests. It is therefore difficult to speculate and comment on the issues related to its restriction in our country. However, we presume that a use of such product may not be permitted by the regulating authority unless a so-called ‘saving clause’ is applicable! An establishment of a cryopreservation facility for storing rare blood units is of utmost importance to our country and efforts are being made in this direction. We hope that this is achieved in the coming years so that rare donor units can be frozen and used in times of need.

Question 3 We have never approached rare donor supplying registries such as the WHO International Panel of Rare Donors and/or the European Bank of Frozen Red Cells or national panel/ banks in other countries to obtain rare blood units. When encountering a recipient with a rare phenotype, our usual practice has been to screen the close family members, particularly the siblings of the recipients, with a hope to find the rare phenotype that the patient is in need of.

Question 4 In one such occasion [3], a patient with In(a+b–) phenotype with a high-titre anti-Inb, showing a remarkable prozone phenomenon, experienced a haemolytic transfusion reaction to a blood unit found to be compatible by the routine method used. One of her brothers was In(a+b–) and his blood unit was successfully used in a subsequent transfusion. As the patient required more units, we had to screen over 2000 random blood donors just to provide 2 units of this rare phenotype. In another occasion, an O, RhD negative recently delivered patient who was later typed as Co(a–b–) had a high-titre antiCo3 and the RBCs of neither any family members nor any of over 200 random donors were compatible with her serum. Luckily the baby did not require a transfusion to treat her mild haemolytic disease of the newborn (HDN). It becomes difficult to meet such emergency situation when we have no regular screening programme in place for rare phenotypes and no facility to preserve units of such rare blood in the frozen state. More often we were successful in our approach to screen and find the rare phenotype within the family members of the proband. Occasionally, we were left with no choice but to collect a blood unit from the mother with a rare phenotype, for example, D– –/D– –, to provide RBCs to her infant suffering from severe HDN [1]. However, a risk of transfusionassociated graft-versus-host disease would remain in the absence of a facility to irradiate the blood.

References 1 Badakare SS, Bhatia HM: Haemolytic disease of the newborn in a rare –D–/–D– Indian woman. Vox Sang 1973; 24:280 2 Vasantha K, Seema J, Swati K, Dipika M: Fetal Loss due to AntiHro in a lady having rare genotype of Rh (D– – / D– –). Transfus Med 2005; 15:78, abstract no.40 3 Joshi SR: Immediate haemolytic transfusion reaction due to antiInb. Vox Sang 1992; 63:232–233 4 Joshi SR, Wagner FF, Vasantha K, Panjwani SR, Flegel WA: An AQP1 null allele in an Indian woman with Co(a–b–) phenotype and high titer anti-Co3 associated with mild HDN. Transfusion 2001; 41:1273–1278 Sanmukh R. Joshi Institute of Health Sciences PO Box 3720 Ruwi Code 112 Muscat Oman E-mail: [email protected] K. Vasantha Institute of Immunohaematology 13th Floor NMS Building KEM Hospital Campus Parel Mumbai 400 012 India

V. Yahalom, O. Asher & C. Levene

Question 1 We define a rare donor as one that lacks a high-frequency antigen or shares a selected combination of antigens that can only be found in about 1 : 1000 donors [1]. Donors lacking different antigen-negative combinations are referred to as ‘antigen negative’ and can be found in about 1 : 200.

Question 2 Question 5 As regard to obtain a rare blood unit from the international frozen blood programme, we have no experience insofar over

In Israel, there is a national registry [2,3,4,5] of 872 rare blood donors and also a larger group of 6437 ‘antigen negative’ donors.

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In most cases that are referred to our laboratory, we can supply rare blood or antigen-negative units, including rare phenotypes, such as p, K:–22, Ge:–2, Yt(a–), Kp(b–), Fy(a–b–) and k. We are short of Oh, Ko, Jr(a–), U–, Vel– and Lan– blood units. Most of our Ge:–2 donors are not donating blood despite numerous efforts.

Question 5 According to our guidelines, rare blood units can be used for transfusion at the discretion of the treating physician, even if not all the required tests were performed and additional blood is not available for further testing.

References Question 3 When in need for rare blood or multiple ‘antigen negative’ transfusions, which cannot be found in Israel, we search the WHO International Panel of Rare Donors [6]. Through the WHO International panel, we contact the National Panels that might have compatible rare blood units and/or donors. In the past 5 years, we appealed to the WHO International Panel of Rare Donors four times as described below. 1. We approached Umea (Sweden) and the American Rare Donor Program (ARDP) in 2004 for blood units of the rare p phenotype for a woman with acute myelocytic leukaemia. We supplied 9 units from our donors and frozen inventory. Six p units received from Umea and the ARDP were frozen in our inventory between the years 1977–1991 and were thawed. Another two fresh RBC units were received from Umea, Sweden. Additional units were allocated by the ARDP, but the patient died due to multiple organ failure prior to shipment of the blood units. 2. In 2005, 8 A Rh+, e–, Fy(a–), Jk(a–) blood units were obtained from the National Blood Service (NBS) in the UK for a patient with alloantibodies who underwent liver transplantation and needed 30 RBC units. 3. In 2006, three O+, k–, c–, E–, Jk(b–) blood units were shipped from the NBS, UK for a patient with ischemic heart disease and alloantibodies. The patient was bleeding and we supplied 13 units. 4. Two Jr(a–) units were obtained in 2008 from the ARDP for a pregnant woman with anti-Jra. These units were not transfused and are stored in our frozen inventory.

Question 4 In every case that we approached the International Blood Group Reference Laboratory (IBGRL) and the national panels in the UK, USA, Sweden, Japan or Belgium, our experience was of a wonderful cooperation and willingness to assist. The major limitation of importing a blood unit is that from starting the search at least 72 h elapse before blood can be transfused to the patient. Therefore, this is not the optimal solution when there is an immediate need for blood units. Shipment of frozen units is usually more cumbersome. Another problem arises when the method of freezing the RBC units in the requesting and shipping blood centres are different, therefore units can only be thawed in the shipping centre and can be delivered only to nearby countries in order not to exceed the expiry time of 24 h. Using the Hemonetics ACP215 system and the 14-day expiry date post-thawing, this obstacle should be overcome.

1 Flickinger C, Petrone T, Church A: Review: American Rare Donor Program. Immunohematology 2004; 20:239–243 2 Levene C, Asher O, Shinar E, Yahalom V: Rare blood donors: a personal approach. Immunohematology 2006; 22:64–68 3 Yahalom V, Rahimi-Levene N, Yosephi L, Shinar E, Levene C: The Gerbich negative phenotype in Israel. Transfus Clin Biol 2001; 8(Suppl. 1):395 4 Levene C, Shinar E, Yahalom V: Rare blood group [Tj(a–)] in Israel 1975–99. Vox Sang 2000; 78(Suppl. 1):10 5 Levene C, Bar-Shany S, Many N, Moulds JJ, Cohen T: The Yt blood groups in Israeli Jews, Arabs, and Druse. Transfusion 1987; 27:471–474 6 Woodfield G, Poole J, Nance ST, Daniels G: A review of the ISBT rare blood donor program. Immunohematology 2004; 20:244–248 V. Yahalom, O. Asher & C. Levene National Blood Group Reference Laboratory Magen David Adom – National Blood Services Ramat Gan 52621 Israel E-mail: [email protected]; [email protected]; [email protected]

M. A. Villa, N. Revelli, N. Greppi & M. Marconi

Question 1 A blood donor may be defined rare if he or she is negative for a high-frequency antigen, negative for a combination of common antigens or IgA deficient [1]. In the Rare Blood Components Bank for the Region of Lombardy, blood donors of any ABO blood group are classified ‘rare for high-frequency antigens’ either when they are negative for an antigen found in over 99·9% of random subjects or when they have a rare Rh phenotype, as reported in Table 1. In order to be classified as ‘rare for combination of common antigens’, a blood donor must be group O or group A and must meet one of the criteria reported in Table 2.

Question 2 In January 2005, the Rare Blood Components Bank – Reference Centre for the Region of Lombardy started its activity in our facility with regional government funds: its chief institutional aims are to identify rare donors in the region with a view to establishing a regional register, and to set up and manage a regional bank of fresh and frozen rare blood units. To this day, it is the only such programme in our country, which lacks a nationwide rare donor panel and bank of frozen RBC units. From January 2005 to December 2007, we typed 37 382 blood donors, identifying 5542 rare donors (of which

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Table 1 Definition of donor ‘rare for high-frequency antigens’ ABO group All ABO groups

Phenotype Oh CCDEE, CCdEE, CCdee, ccdEE, partial or total deletion of Rh antigen LW(a–b+), LW(a–b–) k–, Kp(b–), Js(b–), Ko Lu(b–) Fy(a–b–) Jk(a–b–) S–s–U–, S–s–U+, U var Co(a–) Do(b–) AnWjVelVel var I– Di(b–) pp Er(a–) Sc– At(a–) Cr(a–) Yt(a–) Pk Ok(a–) Ge– Jr(a–) Lan– Gy(a–) P JMH– In(b–) Tc(a–) Hy(–)

Table 2 Definition of donor ‘rare for combination of common antigens’ ABO

KEL

RH

MNS

JK

FY

0 A

K–k+

CCDee – ccdee ccDee – ccDEE

S+s– or S–s+

Jk(a+b–) or Jk(a–b+)

Fy(a–b+) or Fy(a+b–)

descent are the most difficult to find [1]: this is because the changes in the ethnic composition of our territory ensuing from recent immigration have not been accompanied by similar changes among the blood donor population, where non-Caucasian donors are still underrepresented.

Question 4 Given the large number of donors typed by our bank, we have not encountered major problems in finding compatible RBCs for alloimmunized patients: this is also because the cases involved a mixture of antibodies to common antigens in 36% of cases, and only 11% of patients had antibodies against highfrequency antigens (two anti-PP1PK, three anti-Vel, two anti-JMH, one anti-Ku, one anti-Kpb, one anti-Ge2, one anti-P, two anti-Yta, one anti-Lub, one anti-H, one anti-Lan, one anti-AnWj, one anti-Lu(a–b–) and 1 anti-Jra). Due to the changes in the ethnic make-up of the population mentioned above, in the last few years our hospital has had to face an increasing demand of RBCs for patients of African descent with phenotypes that are extremely rare in the prevalent Caucasian population: this problem is made more challenging by the fact that nonCaucasians have a lower donor rate, and that a considerable number of these patients have inherited haematological diseases (e.g. SCD, thalassaemia) requiring frequent RBC transfusions, and are thus at much higher risk of alloimmunization.

Question 5 5250 are rare for a combination of common antigens, 266 are negative for high-frequency antigens and 26 have a rare Rh phenotype). In the same period, we collected 3795 rare blood units, of which 80 were frozen. A total of 168 requests of investigations were referred to our Immunohematology Reference Laboratory: of these cases, 86 (51%) required the selection of compatible RBCs on our part, and only one of these requests was unfilled (1·2%). Our panel and bank currently lack the following relevant phenotypes: Sc:–1, LW(a–b+), LW(a–b–), K0, Jk(a–b–), Uvar, Di(b–), I–, the relevant phenotypes of the Dombrock system and those belonging to the 901 Series (except Vel– e Lan–).

Question 3 In case no compatible donors or RBCs are available in our Rare Blood Components Bank, we generally resort to the ARDP, of which we are members. We also appeal to other frozen RBC banks in Europe. In the past 5 years, we appealed twice to panels of rare donors outside Italy, once to ARDP and once to Red Cross Finland: this was for the transfusion management of one child affected by thalassaemia intermedia with anti-Jka autoantibodies and anti-Sc1 and anti-K alloantibodies and of one newborn to a woman with anti-P alloantibodies, respectively. In both cases, we managed to obtain compatible donors. Phenotypes typically found in individuals of African

According to Italian law, frozen RBCs may be kept for up to 10 years, and they must comply with all laws and regulations in force at the time they are used. Since this may require the performance of additional testing upon deglycerolization of the RBC unit, in our institution a serum sample of 1–2 ml is always frozen along with the unit [2]. In case a sample is not available, the unit is not suitable for transfusion and must be discarded. In extreme cases of urgency, the choice of transfusing a rare donor unit lacking a required test is left to the clinician.

References 1 Flickinger C, Petrone T, Church A: Review: American Rare Donor Program. Immunohematology 2004; 20: 239–243 2 Anstee D, Levene C, Mallory D, Overbeeke M, Poole J, Reid M, Smart E, Tani Y, Wendel S, Woodfield G: Rare Blood. An ISBT Working Party Report on Rare Blood Donors. Vox Sang 1999; 77:58–62 M. A. Villa, N. Revelli, N. Greppi & M. Marconi Centro Trasfusionale e di Immunoematologia Fondazione IRCCS Ospedale Maggiore Policlinico Mangiagalli e Regina Elena via Francesco Sforza, 35 20122 Milan Italy E-mail: [email protected]; [email protected]; [email protected]; [email protected]

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Question 3

Y. Tani

Question 1 A rare donor is defined as one that the frequency of whose blood phenotype is one in 100~1000 or less in Japan. Rare blood phenotypes are classified in two categories according to their frequencies (Table 1).

Question 5

Group I (35) para-Bombay En(a–) Nsat/Nsat Rhmod –D– Kp(a+b–) Kp(a–b–) Jk(a–b–) Lan JMH– Er(a–)

p MiV/MiV cD– Kmod IFC– Ok(a–)

Pk S–/s–/U– LW(a–b–) K14– UMC– Dr(a–)

Jr(a–)

Do(a+b–)

I– Ge:–2,–3 Lu(a–b–) k McLeod Er(a–)

Group II (5) S–

Fy(a–b+) Di(a+b–)

Question 2 We have a national panel of rare donors and keep frozen units in each blood centre. Osaka blood centre manages the data of registered rare donors and frozen units in all over Japan. We find almost 100% of compatible RBCs. En(a–), MkMk, U– and Gy(a-) phenotypes are lacking in our blood centres. Table 2 Screening for rare blood by monoclonal antibodies (1987–2006)* Monoclonal antibody

Number of tested

Rare blood

Number of detectded

Frequency

anti-U+N

2 062 873

U–

3

0.00015%

anti-Ena

1 369 681

En(a–)

2

0.00002%

MkMk

1

0.00001%

183

0.00082%

10

0.00005%

Lu(a–b–)

607

0.00902%

Ko

286

0.00176%

McLeod or Kmod

83

0.00112%

Fy(a–b–)

0

anti-Hro

2 285 766

–D– Rhnull

anti-CD44

6 730 998

anti-K2, anti-K5, anti-K14

16 290 609

anti-Fy3

795 239

0% .

anti-Ge

6 648 374

Ge–

17

0 00027%

anti-IFC

237 459

IFC–

0

0%

i

0

anti-I

1 086 228 a

anti-Jr

anti-Lan

Question 4 No particular problems so far.

Table 1 Rare blood in Japan

Bombay Mk/Mk Rhnull Ko Fy(a–b–) Gy(a–)

We appeal to the WHO International Panel of Rare Donors. We appealed none in the past 5 yeas but once (for Ge–) 9 years ago. Donors of En(a–) and MkMk phenotypes were the most difficult to find (Table 2).

10 708 646 713 523

*Including repeat donors.

Jr(a–) Lan–

0% .

4454

0 04159%

14

0.00196%

We replace them by new frozen units on which all tests required at present were performed. Yoshihiko Tani Japanese Red Cross Osaka Blood Center 2-4-43, Morinomiya Joto-ku Osaka, 536-8505 Japan E-mail: [email protected]

C. C. Folman, M. de Haas, M. M. W. Koopman & E. Beckers

Question 1 The definition of a rare donor we use is a donor with a phenotype that is present in less than 1% of the population.

Question 2 In the Netherlands, we have the Sanquin Bank of Frozen Blood (SBFB), previously named the Blood Bank of the Council of Europe, which we actively try to update with relevant ‘rare donors’ in several ways. • If the National Reference Laboratory of Erythrocyte Serology from Sanquin identifies a patient with a rare phenotype, the physician is asked to approach family members to provide a blood sample for typing and, eventually, when relevant, to become a donor for the SBFB. In some cases, the patient him or herself can also be asked to become a donor. • Sanquin has a national typing programme of donors, which provides for each donor an ABO, rhesus phenotype and Kk typing with k typing if K positive. In addition, about 30% of the donors is typed for Fy, Jk, MNSs and a few percent of the donors are typed for Kp(a), C(w), Co(b), Wr(a), Lu(a), Le(a), Le(b) and P1. • A programme is conducted aiming to type large cohorts of donors for high-frequency antigens, such as Vel and Lu(b); however, this programme is hampered by the lack of availability of suitable typing reagents. • To type for Do(a) and Js(a), medium-throughput genotyping assays have been designed and applied to provide compatible blood for some cases. Sanquin is carefully watching the developments within the field of high-throughput blood group antigen genotyping.

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• Some rare erythrocyte units are presented to our SBFB by the Blood Bank in Umea, Sweden, and the Blood Bank Bern in Switserland. This applies when their own stock is up to date and a donor with a rare phenotype has come in. In approximately 95% of the cases, we can find compatible units in our own (frozen) stock of the SBFB. In the past few years, we have had a few examples of requests for rare units that we could not supply from our own bank; for instance, units negative for U and RhD; Fy3-negative units in combination with other specific typings; Lu(a–b–) D-negative units from the In(Lu) genotype; units negative for At(a); Cr(a)-negative units.

D. S. Gounder, P. Flanagan & L. Wall

Question 1 We do not have any specific definition of a rare donor. However, a rare donor could be defined as someone whose blood is rarely needed for transfusion and could also be defined as a donor whose blood may be required reasonably frequently and this alludes to transfusion needs of patients who have formed multiple alloantibodies [1].

Question 2

If we do not have compatible donors available, either as fresh units or as donors on-call, to be identified by the blood bank information system (eProgesa) of our national sanquin blood bank, we approach several European and/or USA centres with a request. In the past 5 years, we have appealed approximately 10 times to other institutions and obtained units in all cases, however not always a sufficient number of units. Most difficult to find were units negative for U and RhD.

We have a national panel of rare donors that is confined to a handful of active donors. We also have an inventory of donors whose extended phenotype may be needed for patients with multiple alloantibodies. We also have a national bank of frozen RBC units. For some of the units in storage, there are no active donors in our donor panel. These units were mainly donated many years back. In a majority of cases, we are able to find compatible blood for our patients. Relevant phenotypes that are presently absent from our frozen bank and that we consider appropriate for storage include the p phenotype, Ge2- and Ge3-negative phenotype and Js(b–) and U– phenotypes.

Question 4

Question 3

The search for compatible units for a patient with RBCs antibodies against high-frequency antibodies is a timeconsuming exercise, demanding a high level of interaction with various disciplines and logistic skills.

We would appeal to the WHO International Panel of Rare Donors to identify the location of the rare units. For ongoing provision of the rare units, which has happened in a recent case, we would maintain direct communication with the relevant transfusion service. Over the past 5 years, we have appealed about five times for –D– and Ko units.

Question 3

Question 5 When there is a request of thawing units that are incompletely tested, we will inform the physician who ordered the blood product and ask for written consent whether he or she agrees to transfuse the thawed erythrocyte concentrate to the patient. C. C. Folman, M. de Haas Sanquin Division Diagnostic Services Department of Immunohaematology Diagnostics Amsterdam The Netherlands E-mail: [email protected]; [email protected] M. M. W. Koopman Sanquin Division Blood Bank North West Region Clinical Consulting Services Amsterdam The Netherlands E-mail: [email protected] E. Beckers Sanquin Division Blood Bank South West Region Clinical Consulting Services Rotterdam The Netherlands E-mail: [email protected]

Question 4 Recently, we had difficulty in finding group O Ko RBCs for a child with the Mcleod phenotype. We needed to institute a management plan for the use of K– blood. Since then the patient has had successful bone marrow transplantation.

Question 5 We do have units in storage that have not had accreditation done as required at present, but we have never had to be asked for their use. However, we would consider their issue based on a risk–benefit analysis.

Reference 1 Anstee D, Levene C, Mallory D, Overbeeke M, Poole J, Reid M, Smart E, Tani Y, Wendel S, Woodfield G: Rare Blood. An ISBT Working Party Report on Rare Blood Donor. Vox Sang 1999; 77:58–72 D. S. Gounder, P. Flanagan & L. Wall New Zealand Blood Service 71 Great South Road Private Bag 92 071 Epsom Auckland New Zealand E-mail: [email protected]

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E. Aranburu Urtasun

Question 1 A rare donor or a rare RBC phenotype is defined as one that occurs with a frequency of 1 : 1000 or less in a random population. Rare phenotypes are further divided into two categories: highfrequency antigen negative and multiple antigen negative’. Multiple antigen negatives are rare blood donors, because they lack a combination of relatively common antigens [1,2].

Question 2 In 1996 at the VIIth Congress of the SETS (Spanish Society of Blood Transfusion) in Santiago de Compostela, a Foro was organized about ‘The creation of a national bank of rare phenotype donors’. The actual situation outlined by the results of a questionnaire sent to all blood services/centres with more than 10 000 units/year were analysed by professionals who came from all over the country. There was a total consensus. The conclusions were published in the official journal of the Spanish Association of Haematology and Haemotherapy and also sent to the Committee of Directors of Blood Transfusion Centres [3]. In 1998, the committee approved the idea and decided to divide the country into two areas for the sake of efficiency. The north area includes the Transfusion Centres of the Communities of Galicia, Cataluña, Euskadi, Asturias, Aragon, La Rioja, Baleares, Santander and Navarra, coordinated by the Blood Bank of Navarra. The south area includes the Transfusion Centres of the Communities of Castilla-La Mancha, Valencia, Murcia, Extremadura, Andalucia and Madrid, coordinated by the Blood Centre of Madrid. From 1998 to 2003, the activities of the north area were registered and published annually in the Journal of the Spanish Association of Blood Transfusion [4]. In 2003, this activity was discontinued. In 2004, a project to the SETS was presented in order to support and promote the idea of ‘a national organization of rare blood donors’ in contact with the European Sanquin programme [5,6]. As far as I know, all the needs of rare phenotypes patients were covered during this period of time (1998–2003). During this time, the phenotypes that were more difficult to find and that we did not have in stock in the country were: Yta–, Coa–, Jsb–, Lan–, Ge–, I–, Jra– and Br–.

Question 3 Since 2003, there has not been a coordinated registry of rare donors and/or units. Each blood service/centre has had to deal with the problem of looking for compatible donor/units. Sometimes turning to others centres within the country and in some occasions to the European programme. The European directive 2002/98/CE was overtaken by Spanish legislation the 16th of September of 2005. The article

no. 34 defines the functions of the blood centre. In point f, it says that ‘[...] to be the reference to those cases of low prevalence into the population that can need low frequency blood components or reactive.’ This article stresses the necessity of rare blood donors.

Question 4 In 2005, an autologous frozen donation was used, obviously, with the permission of the patient, for a case where the mother and the newborn were affected. The mother was immunized by the Jra antigen of the newborn. This single unit was prepared for the caesarean section. There was enough time to turn to the Sanquin programme where there were 14 available units before proceeding with the operation. To have 2 units from the Sanquin Bank of Frozen Blood would have been better.

Question 5 I have no knowledge of any case in which a unit on which not all the tests required had been performed, had been transfused. I think that units in these circumstances would have been rejected.

References 1 Mourant AE: The establishment of the international panel of blood donors of rare types. Vox Sang 1965; 10:129–132 2 Mallory D, Malamut D, Sandler SG: A decade of rare donor services in the United States. Report of the American Red Cross Rare Donor Registry (1981–1990). Vox Sang 1992; 63:186–191 3 Aranburu Urtasun E: Red Nacional de Hematíes Fenotipados: Informe sobre la Situación Actual. Banco de Sangre de Navarra. Sangre 1997; 42:247–250 4 Aranburu Urtasun E: Red de hematíes fenotipados. Banco de Sangre de Navarra SETS 2002; 43:23–25 5 Aranburu Urtasun E: Depósitos de hematíes con Fenotipos raros: Propuesta de Trabajo para su Organización a nivel estatal. Banco de Sangre de Navarra Año 2005 6 http://www.sanquin.nl E. Aranburu Urtasun Laboratorio de HLA y Biología Molecular Centro de Transfusión Sanguínea de Navarra c/ Irunlarrea 3 31008 Pamplona Navarra-Spain E-mail: [email protected]

H. Hustinx & C. Niederhauser

Question 1 Rare donors in Switzerland are characterized by the absence of a high-frequency antigen, such as k, Kpb, Lub, Coa, Vel, Yta, P and LAN. In addition, other rare phenotypes, for instance, Ko, Lu(a–b–), Jk(a–b–), Rh null or Fy(a–b–), are included. Furthermore, some blood group combinations, such as e– and s– negative that are also Fya– and/or Jka–negative, are registered (frequency partially 1 : 4000).

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Question 2 After the decision, taken in 1990, not to build up a national blood bank of frozen RBCs, the Blood Transfusion Service Berne began to collect rare donors. Three years ago, the rare donor file from the Blood Transfusion Service Berne was extended to a national donor file. This file is updated three times per year and is accessed through a password-protected web site. The file is organized by the national reference laboratory for blood group, which is located at the Blood Transfusion Service in Berne. The rare donor file includes donors from all 13 regional Blood Transfusion Service in Switzerland. Requests for a rare RBC unit can be placed 24 h a day, 7 days a week. In most cases, when a special RBC unit was requested, it was available from a donor in the Swiss file. For many years, there has been a narrow collaboration with the German rare donor programme organization. An effort has been made in the last couple of years to integrate also German and Austrian rare donors in the Swiss rare donor file. Occasionally, foreign blood banks request blood concentrates of a rare phenotype. In the past, special RBCs were sent to Germany, USA, Greece and the Netherlands. In addition, a close cooperation exists with the Sanquin Blood Bank of Frozen Blood in Amsterdam and several RBCs have been deposited at this site, in particular several Kpb-negative, Vel-negative, Pk, Jk(a–b–), and –D–/–D– units. An important point to consider is whether the rare RBC units are really necessary when a request for them is made. A dialogue with the responsible doctor must determine if the patient really needs a unit with the specific phenotype or if perhaps an autologous donation could be considered. The blood bank must in addition discuss with the responsible doctor whether a patient that would normally be transfused with allogeneic blood (e.g. pregnant women) can perhaps be treated with an autologous donation. This was done in the cases with very rare antibodies, such as anti-Ata or anti-U are present.

Question 3 If no compatible donor is available in the Swiss Rare Donor File, we would appeal to one of the following sources of rare blood: the WHO panel of rare donors in Bristol, INTS, Paris, or the Sanquin Bank of Frozen Blood, Amsterdam. Within the last 10 years, we have imported in one case, three R1R1, Kpb- and Fyb-negative units from Japan and one from National Blood Service, London, in another case two Kpb– units from Sanquin Bank of Frozen Blood, Amsterdam, in a further case 2 Ko units from National Blood Service, London (i.e. for a patient with anti-K11) and in the last case, 2 Lan-negative units from the American Red Cross (Rare Donor file) and Germany.

Question 4 The major problem encountered is not the search for the corresponding RBCs, but the logistic problem in transporting the blood product. It is important here to differentiate between

problems that arise if an RBC is from the national rare donor file and has to be shipped within Switzerland or when the rare RBCs must be either imported or exported. Within Switzerland, rarely logistic problems arise but a major hurdle occurs when the blood has to be transported across country borders. Because it occurs infrequently, it is in most cases urgent, happens also at weekends and can involve several different Swiss border sites that are seldom straight forward. In addition, the time required for the transport from abroad must also taken into account as the expiry time of thawed RBCs is unfortunately still very short. It would be desirable if a European or international body could set up a standardized and perhaps simplified import/ export procedure for the international transport of urgent labile blood products.

Question 5 An import licence issued by the Swiss health authority (Swissmedic) is compulsory to import or export blood products into Switzerland. The handling procedure for previously frozen RBCs has not been dealt within the Swiss regulations. Thus, at present there are no restrictions for the importation of frozen RBCs in force and therefore the responsible doctor has the final decision whether to transfuse the patient with a foreign product, even if not all the Swiss mandatory infectious disease parameters have been performed. All the points mentioned above must be discussed with the responsible doctor prior to order the frozen RBCs from abroad. H. Hustinx, C. Niederhauser Blood Transfusion Service SRC Berne Murtenstrasse 133 3008 Berne Switzerland E-mail: [email protected]; [email protected]

E. Massey, A. Gray, M. Needs, G. Daniels & T. Callaghan

Question 1 A rare donor is one who has a RBC phenotype found in less than 1% of the donor population. Question 2 We have a national panel of rare donors covering a wide range of phenotypes. We store approximately 500 frozen donations in the National Frozen Blood Bank (NFBB) all of which have been fully typed for the major blood group systems. Forty phenotypes are included in NFBB inventory, including as many listed in the international donor panel of the ISBT as possible [1]. We try to have at least 10 group O units of each rare Rh type. We also attempt to maintain stocks of at least 10 O RhD-positive and 10 O RhD-negative units

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for each of the other rare types listed in our inventory. The stored O RhD-positive donations are extended to include at least 10 R1R1 and 10 R2R2, if the demand for RBCs of a specific phenotype has been historically high, for example, Vel–, Fy(a–b–) and S–s–U–. Many stored donations for the latter two phenotypes will be Ro. Group A or B units are frozen, if they are of a particularly rare type. If we do not have a current donor, or if there is only one donor of a specified phenotype, we may consider extending the shelf life of stored donations, otherwise we store frozen RBCs for 10 years. The number of donations of each type will vary depending on demand and the rapidity of restocking. We try to predetermine, as far as possible, a priority order for antigen negativity if a patient has multiple alloantibodies. If no cells are available that lack all antigens against which the recipient has alloantibodies, we will start with the cells that are incompatible with the smallest number of antibody specificities and specifically choose the least clinically significant antigens. The decision regarding the clinical significance of antibodies will be largely based on published reviews, case reports and case series, but the individual recipient’s transfusion history will of course be considered [2,3]. Gradually, greater numbers of incompatible antigens of increasing significance will be accepted depending on the urgency of transfusion and the availability of compatible RBCs. Of the types listed in the NFBB inventory, we currently completely lack Sc:–1, P1k and Ge:–2,–3. We also lack group O examples of –D– and •D•. We have had problems with meeting demand for McLeod phenotype and U-negative units. Question 3 Using the strategy outlined in response to Question 2, we have only needed to import RBCs from abroad on one occasion in the last 5 years as far as we are aware (Rhnull). We have asked colleagues in other countries about the availability of cells of specific phenotypes on other occasions, but have not needed to request that they are issued to us. Our first ports of call would be the European Bank of Frozen Red Cells or the WHO International Panel of Rare Donors. Question 4 We will permit directed or autologous donation if the benefits outweigh the risks and the identified donor is fit to donate. Bombay phenotype and Rhnull donations are particularly difficult to obtain. Unpredictable peaks in demand for components of a specific phenotype may disproportionately deplete stocks of other phenotypes. Historically, we had limited supplies of reagents for Dombrock system serology, but this is being addressed by molecular typing. Molecular typing will also be introduced for screening for donors of other rare phenotypes, particularly where serological reagents are in short supply.

Question 5 Any component that does not reach full current specification would only be released if a consultant in blood transfusion medicine working for the NHS Blood and Transplant completed a concessionary issue form in agreement with the physician treating the intended recipient. Some units in the NFBB may have been stored prior to the introduction of human T-cell lymphotrophic virus I and II testing in the UK. We do not store units that are positive for mandatory markers of infection.

References 1 Woodfield DG, Anstee DJ, Flegel WA, Joshi SR, Le Pennec P, Levene C, Lin M, Nance S, Novaretti M, Overbeeke M, Poole J, Reid M, Smart E, Wendel S,Yaholm V, Tani Y, Zhu Z: Rare Blood: An Updated Report from the International Society of Blood Transfusion Working Party on Rare Blood Donors; available at http://www.isbt-web.org/files/documentation/updated_report_ rare_blood_donors.pdf http://www.isbt-web.org/members_only/ files/society/working_rbd_updated_report.pdf 2 Daniels G, Poole J, de Silva M, Callaghan T, MacLennan S, Smith N: The clinical significance of blood group antibodies. Transfus Med 2002; 12:287–295 3 Win N: The Clinical Significance of Blood Group Alloantibodies and the Supply of Blood for Transfusion. Updated 2007; available at http://www.blood.co.uk/hospitals/library/doc/ SPN_DDR_RC_020_03_Alloantibodies.doc E. Massey G. Daniels International Blood Group Reference Laboratory NHS Blood and Transplant North Bristol Park Northway Filton Bristol BS34 7QH UK E-mail: [email protected]; [email protected] A. Gray M. Needs Red Cell Immunohaematology NHS Blood and Transplant 75 Cranmer Terrace Tooting London SW17 0RB UK E-mail: [email protected]; [email protected] T. Callaghan Consultant Haematologist National Frozen Blood Bank NHS Blood and Transplant 14 Estuary Banks Speke Liverpool L24 8RB UK E-mail: [email protected]

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C. Flickinger, S. J. Nance & G. M. Meny

Question 1 The American Rare Donor Program, a cooperative programme of the AABB and the American Red Cross, defines a rare donor as a donor who meets one of the following criteria [1]: a. high-prevalence antigen negative; that is, occurs in less than one in 1000 donors; b. multiple common antigen negative; that is, the donor must be group O or group A and meet one of the following sets of criteria: Set 1

Set 2

R1, R2, R0, or rr AND K:–1 AND Fy(a–) or Fy(b–) AND Jk(a–) or Jk(b–) AND S– or s–

R1, R2, or rr AND K:–1 AND Fy(a–b–)

OR

c. IgA deficient, that is, IgA of a level < 0·05 mg/dl, tested on samples from two separate draw dates.

Question 2 The ARDP has a database of approximately 38 000 active rare donors. Information on rare donors is entered into the database from its 81 member immunohaematology reference laboratories. Units collected from the rare donors are stored at the member facility that identified the donor and can be shipped to other member facilities when a request is made [2]. The ARDP is able to fill approximately 95% of its requests for rare blood components from its active rare donors or from international imports. Phenotypes for which the ARDP has received requests but for which there are no registered donors include: En(a–), In(b–), K0 and McLeod. The ARDP also had no registered donors to fill an unusual request for units that were both K:–2 and Vel–. Other phenotypes that present a challenge to the ARDP include those that are multiple common antigennegative and-negative for a high-prevalence antigen.

Question 3 When rare donors and/or rare units are not available in the USA and the transfusion need persists, the ARDP contacts the WHO International Panel of Rare Donors, the European Bank of Frozen Red Cells and/or other national panels/banks for assistance. In the last 5 years, 18 requests were made to these resources for rare units; 17 (94%) of them were filled. The one unfilled request was for O positive, K0, E–, Fy(a–), Jk(a–) and S–. There were no registered donors of this phenotype in the USA or in the countries contacted.

Question 4 Approximately 5% of the requests to the ARDP for rare blood components are unfilled. From January 2005 to January 2008, unfilled requests included the following phenotypes:

At(a–) En(a–) Hy– K0

Cr(a–) Ge:–2 In(b–) Lan–

Di(b–) Ge:–2,3 Jk:–3 Lu(a–b–)

E–,hrS– Gy– K:–2, Vel– Wes(b–)

Unfilled requests resulted from factors such as no registered donors of the requested phenotype, inability to contact the donor, ineligibility or deferral of the donor, several requests or numerous units requested of the same phenotype depleting the inventory, or additional alloantibodies adding to the complexity of the request as in the K0 request noted earlier. In addition, challenges to the ARDP include decreasing reagent availability especially for antigens of low prevalence, such as Jsa and V, breakage of frozen RBC units during shipping, member facilities transitioning to ISBT and challenges in shipping ISBT-labelled components to non-ISBT members because of computer incompatibilities, and the inability of the serologic phenotype to predict compatibility when variant antigens are present; such cases require molecular selection of the donors [3]. No problems were encountered in finding compatible RBCs internationally except for the K0 request noted earlier.

Question 5 In the USA, RBCs frozen prior to current mandated testing cannot be released for transfusion unless a sample from the donor is tested and found to be negative or the units are approved for use through a Materials Review Board process. Units from other countries are considered untested by US regulatory agencies and can only be imported if a mechanism exists in the receiving facility that ensures their transfusion only to the patient for whom they were imported. Imported units not transfused are discarded. C. Flickinger, G. M. Meny American Rare Donor Program American Red Cross Biomedical Services 700 Spring Garden Street Philadelphia PA 19123 USA E-mail: [email protected]; [email protected] S. J. Nance Senior Director, Immunohematology Reference Laboratory Biomedical Services Operations Director, American Rare Donor Program Adjunct Assistant Professor Department of Pathology and Laboratory Medicine University of Pennsylvania American Red Cross Biomedical Services 700 Spring Garden Street Philadelphia

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PA 19123 USA E-mail: [email protected]

References 1 Flickinger C, Petrone T, Church A: Review: American Rare Donor Program. Immunohematology 2004; 20:239–243

2 Flickinger C: In search of red blood cells for alloimmunized patients with sickle cell disease. Immunohematology 2006; 22:136–142 3 Vege S, Westhoff CM: Molecular characterization of GYPB and RH of donors in the American Rare Donor Program. Immunohematology 2006; 22:143–147

© 2008 The Author(s) Journal compilation © 2008 Blackwell Publishing Ltd., Vox Sanguinis (2008) 95, 236–253