Anti‐Fy3 in sickle cell disease: a difficult transfusion problem (2008)

A 49-year-old woman with sickle cell disease was admitted with fever, shortness of breath and abdominal pain. She had had multiple previous admissions with crises and received numerous blood transfusions over many years resulting in the formation of multiple allo-antibodies (anti-K, anti-S, anti-M, anti-Fya, anti-Lea, anti-Leb, anti-Lua and a Knopps-related antibody). Her blood group was O RhD− (r′r). Previous complications included a life-threatening episode of hyperhaemolysis several years ago following transfusion of M+ units and an exchange transfusion, a month earlier, as treatment for acute chest syndrome. For this she received six units of Orr K-M-S-Fya-X-matched compatible blood. Blood tests confirmed a haemoglobin level of 57 g/l, a raised C-reactive protein and acute renal failure. Initial management with fluids, oxygen, analgesia and broad spectrum antibiotics was instigated and blood was requested from the National Blood Service (NBS). Escherichia coli septicaemia was confirmed on blood cultures. The NBS contacted us later that evening to inform us that she had developed anti-Fy3 and that a search of the country had identified only four compatible RhD− units, two of which were in the frozen blood bank in Liverpool. None of these could be rapidly obtained and so overnight she was managed without transfusion. With fluid resuscitation, the following morning her renal function had improved but the dilutional effects had lowered her haemoglobin to 36 g/l and she was increasingly short of breath. All four compatible units were given that day. Over the next few days she gradually improved and was discharged within a week. Nine days later she was admitted again with a further abdominal crisis. A nationwide search identified no further available compatible RhD− units in the UK. Fortunately, she recovered without the need for transfusion. Anti-Fy3 is a clinically significant antibody which reacts equally strongly with Fya+ and Fyb+ red cells and has been associated with haemolytic transfusion reactions (Jensen et al, 1988; Olteanu et al, 2005). It arises in individuals with the Fy(a-b-) phenotype which is very rare in most ethnic populations (<1%) but common in Black Africans (up to 75%). This variability can be explained by the fact that this null phenotype confers protection against infection by Plasmodium vivax which uses Duffy protein as a binding site during invasion of erythrocytes (Barnwell et al, 1989). As the sickle variant of HBB confers protection against falciparum malaria these two mutations may co-exist in the Black African population, as was the case with our patient. Current guidelines (Chapman et al, 2004) recommend that phenotype matching in patients likely to require multiple transfusions is extended to include Rh and Kell antigens only (in our patient the anti-K was formed years before this was standard practice). Consequently, the risk of a patient with the Fy(a-b-) phenotype being exposed to Duffy antigen through transfusion is very high with the attendant risk of sensitization. The formation of anti-Fya is commonly seen in these patients but antibodies directed against the Fyb antigen (including anti-Fyb and anti-Fy3) are much rarer (Rosse et al, 1990). As was the case in our patient they tend to form after multiple transfusion episodes in those already sensitized with anti-Fya. We now know that this is because most Africans with Fy(a-b-) red cells have a structurally normal Fyb allele with a mutation in the GATA-1 site to which the erythroid transcription factor binds (Tournamille et al, 1995). Consequently, there is a failure to transcribe Duffy protein onto the erythrocyte membrane resulting in the null red cell phenotype. However, Duffy protein is also present on other tissue cells, such as lung, spleen and colon (Chaudhuri et al, 1995) and this is normally expressed, preventing the formation of antibody against Fyb. In this case several factors make the finding of compatible units difficult. First, the presence of anti-Fy3 restricts compatibility to those of Black African ethnicity in a country where this population is poorly represented in the donor pool. Second, this patient has other allo-antibodies, which have to be considered (anti-K, anti-S and anti-M are all clinically significant). Finally and very importantly, she is also RhD−ve, when 95% of Black Africans are RhD+. Previous attempts to reduce transfusion requirements using hydroxycarbamide had failed. Had she required transfusion during her second admission difficult decisions would have had to have been made. Otherwise compatible D+ units were available but the inevitable formation of anti-D would mean this could only be used once in a life-threatening situation. Similarly, otherwise compatible M+ units were available but given the history of hyperhaemolysis, use of these would carry significant risk. A final option was to look outside UK for compatible units. On her second admission, the NBS contacted the US blood donor service, which has a much larger pool of Black African donors and found that there were over 150 potentially compatible RhD−ve, Fy(a-b-) individuals on record. Amsterdam also has a large frozen blood bank which could be approached. The problem is that the time and logistics required to obtain such units mean that they could not be used urgently. The case highlights some of the difficult serological problems encountered in heavily transfused patients with sickle cell disease. One suggestion to improve practice in these difficult patients would be to regularly perform antibody screens when stable in between crises. This would potentially facilitate detection of new alloantibodies outside of a crisis situation, allowing time to co-ordinate searching for and acquiring compatible units. Whether this is practically possible in busy departments is, however, debatable.