Platelet alloimmunization is commonly seen in patients with hemato-oncological disorders requiring frequent red blood cell and platelet transfusions1 and may be associated with refractoriness to platelet transfusions (RPT). There may also be an association between platelet transfusion failure and patient survival, which increases the clinical importance of RPT.2

RPT is defined as inappropriately low platelet count increments following exposure to antigens after two or more (usually consecutive) transfusions and must be determined by objective data which determine platelet transfusion outcomes.3 This condition may be caused by immune and non-immune factors. More than 80% of RPT cases are related to non-immune causes. Thus, immune causes occur in less than 20% of the cases involving alloimmunization against human leukocyte antigens (HLA) and, to a lesser extent human platelet antigens (HPA), following exposure after transfusion, pregnancy, or transplantation. Among the immune causes, HLA antibodies are responsible for approximately 80–90% of RPT cases and HPA antibodies for approximately 10–20% of cases, associated or not with HLA antibodies.4

Providing an adequate post-transfusion platelet count increment to refractory patients is not an easy task; transfusion of HLA-matched platelets is one possibility.5 However, it is very difficult to find multiple HLA-compatible related donors for one individual.

The HLA system is highly polymorphic6 and the probability of finding identical matches may be around 10% of donations.7,8 When a full match cannot be found, different strategies are used to select partially HLA-matched donors. HLA class I specificities can be grouped into cross-reactive groups (CREG), mismatches with antigenic similarity that result in less allorecognition or immune activation.9 The grading system described by Duquesnoy et al. in the 1970s10 (Table 1) is defined according to the presence of HLA CREGs and is still widely used by transfusion services. Although in some cases, the selection of mismatched donors based on HLA CREGs may fail to produce adequate increments,11 this strategy can increase the number of potential donors in the same donor base.8

Pool size calculations can be an essential component for the rational planning of platelet support programs.12 It is estimated that to provide at least five completely compatible donors for more than 80% of patients, 500, 1000, and 1500 donors would be needed for the Japanese, European Caucasoid and North American Caucasoid populations, respectively.13 However, for a highly mixed population such as in Brazil, which is comprised of European, African and Amerindian roots,14 the pool size required to provide these patients with adequate platelet support is unknown.

The unrelated donor pool size that might be necessary if a center wants to provide patients with unrelated HLA-compatible platelets was estimated using a random sample from the Brazilian population. A mathematical model was created for compatibility analysis and its application was illustrated in a population of 154 cancer patients. The findings of this study may help to establish the transfusion of unrelated HLA-compatible platelets, which currently is not a routine procedure in many Brazilian centers.

The present projection model shows that pools of 31,940, 1710 and 321 donors would be necessary to match 80% of the patients with at least five CC, PC or LC donors, respectively. This calculation, based on a different mathematical model, has already been performed for the Japanese, European Caucasoid and North American Caucasoid populations in which 500, 1000, and 1500 donor candidates would be needed to find at least five LC donors for more than 80% of each of these populations. On the other hand, to find at least five CC, 5000, 18,000 and 25,000 preselected donor candidates would be necessary for these populations, respectively.13 In another study, the authors concluded that 1500 platelet donors would be required to supply 75% of the patients with eight LC donors in the North American Caucasoid population. This calculation would meet the transfusion needs of community donor platelet apheresis programs in a reference center (Seattle) of the United States.19

Brazil's ethnic and genetic heterogeneity, which is related to the allelic variants present in the first populations that inhabited the country,20 combined with the existence of many HLA polymorphisms, has most likely made it more difficult to find at least one CC, even when a database of 65,500 individuals is used. However, this heterogeneity seems to have acted as a facilitator when cross-reactive antigens are accepted, as in the grading system of Duquesnoy.

BX or B2X mismatched products have already been reported as an acceptable match for platelet transfusions when the recipients’ lymphocytotoxic antibodies have low reactivity,21 even though this type of blood product can increase the chances of alloimmunization and make future transfusions difficult. This study shows that, for this level of compatibility, the pool may be feasible and should have 321–1710 donors. However, to provide five matching CC donors, a larger number of donors would be needed (31,940). These data support the strategy of including any single cross-reactive antigen while selecting donors, particularly if the patient to be transfused presents low titers of antibodies and consequently a low probability of alloimmunization.

Successful transfusion of patients with platelet refractory thrombocytopenia is extremely important. However, many potential donors are needed to sustain HLA-matched platelet transfusion programs because of the considerable variety of HLA types and the constant needs of these patients. The question of the required donor pool size should also consider feasibility and costs.12 The latter is one of the reasons why there are no well-established unrelated HLA-matched platelet transfusion programs in most Brazilian services. Pool size calculations may provide essential data for rational planning of platelet transfusion support programs and guide institutions that aim to build a platelet donor registry.

The use of HLA-matched platelets is not the only approach used to manage alloimmune RPT. Crossmatching and support with antigen negative platelet units allow rapid selection of donors, mainly in patients with uncommon HLA types for whom it might be virtually impossible to find HLA-compatible donors.22–24 Recently, the use of the HLAMatchmaker algorithm has been reported as an emerging concept for the management of refractory patients.25,26 The combination of matching compatible antigens and the application of mismatch acceptability determined by serum screening for HLA antibodies has offered an effective approach to an HLA-based platelet transfusion support policy for refractory patients.27,28 The lack of antibody specificity is a major limitation in this study as it does not account for the relative frequencies of certain antibodies in the population.

Although the frequency of immune refractoriness has declined during the past decade due to the application of universal leukoreduction of platelet preparations,2,29 RPT is a complex process and poses a great challenge in the treatment of thrombocytopenic patients. However, universal blood leukoreduction is not frequent in the transfusion practices of Brazil and thus RPT is still a difficult nationwide problem. Knowing how large the donor pool has to be, may help and stimulate different centers in Brazil to build unrelated platelet donor panels.

In conclusion, according to the projection model, 31,940 and 321 donors would be necessary to provide at least five CC or LC donors, respectively to 80% of the patients in the Brazilian population. Furthermore, 23,393 and 2500 donors would be enough to match 100% of the patients with five PC and LC donors, respectively. On the other hand, the CC pool size to match 100% of patients is not possible to calculate possibly because of the great racial miscegenation of Brazilians.

The authors declare no conflicts of interest.