Phenotype matching for sickle cell patients: A review and recommendations for transfusion practice

Authors: Robert Skeate, MD, MSc and Mindy Goldman, MD, FRCPC
Online publication date: July 2014

Key points

  • Alloimmunisation is common in sickle cell disease patients, and may complicate transfusion therapy.
  • Patient phenotyping and prophylactic matching to reduce alloimmunisation is recommended.
  • Transfusion requirements and the presence or absence of red cell antibodies influence recommendations on the extent of phenotyping and the utility of genotyping for sickle cell disease patients.

Transfusion therapy in sickle cell disease patients

Red cell transfusion is a mainstay of therapy for sickle cell disease patients. Indications for transfusion include acute aplastic crisis, acute splenic or hepatic sequestration, symptomatic anemia, stroke treatment and prevention, acute chest syndrome treatment and prevention, and in preparation for major surgery.1, 2 While much of the evidence supporting the effectiveness of these transfusions is of relatively low quality, randomized controlled trials have demonstrated that prophylactic red cell transfusions significantly decrease the frequency of stroke events in at-risk pediatric patients with sickle cell disease.3, 4

Red cell transfusion therapy can be delivered via simple transfusion or as an exchange transfusion. Exchange transfusions are typically employed when patients are experiencing acute, serious complications such as acute stroke or acute chest syndrome, but are also used in prophylaxis treatment regimens in high-risk patients. The advantages of red cell exchange include no or small net iron gain, rapid and effective reduction of HbS levels to target levels (~30%), and ability to set final hematocrit at a level that optimizes blood viscosity.5, 6 The disadvantages are increased red cell use and donor exposures, increased expense, and the need for special equipment and expertise.7 The increased donor exposures do not appear to increase the risk of alloimmunization, however.8 From the blood centre perspective, the need for multiple antigen-negative units on the same day to perform the exchange can be a significant challenge.

Alloimmunization rates in sickle cell disease patients

Sickle cell patients commonly become alloimmunized to red cell antigens.9 Garratty found a range of 8 – 35% with a median of 25% in 12 articles reviewed.10 These alloimmunization events interfere with patient care by leading to delays in transfusion, and can lead to clinically important complications such as delayed hemolytic transfusion reactions.11 Dr. Garratty points out that these reactions in sickle cell patients can be severe and may be associated with other sickle cell disease complications such as pain crisis.10 Sickle cell patients can rarely develop hyperhemolysis syndrome after transfusion (rapid hemolysis of transfused and recipient red cells with worsening hemolysis with additional transfusions), but this complication is inconsistently associated with the presence of red cell antibodies so the relationship between it and alloimmunization requires further elucidation.12

The most common antigens against which sickle cell patients make alloantibodies are Rh (C, E) and Kell, but other antigens are also represented.13 Table 1 from a classic paper on this topic by Dr. Vichinsky and colleagues in the New England Journal of Medicine in 1990 shows the frequency of antibodies of various specificities identified in the 32 alloimmunized sickle cell patients studied, 17 of whom had multiple antibodies.14

Table 1: Distribution of the 68 Red-Cell Alloantibodies in 107 Patients receiving transfusion for sickle cell anemia
Antibody No. (%)
K 18 (26)
E 16 (24)
C 11 (16)
Jkb 7 (10)
Fya 4 (6)
M 3 (4)
Lea 3 (4)
S 2 (3)
Fyb 2 (3)
e 1 (2)
Jka 1 (2)

A likely major contributing factor to the high rates of alloimmunization is that the racial mix of the donor base (predominantly Caucasian) does not match that of the sickle cell patient population (non-Caucasian, typically of African descent) leading to frequent antigen mismatch between donor and recipient.14 For example, Castro and colleagues did an analysis of how many sensitization events could have been prevented in a group of 137 alloimmunized sickle cell patients had various strategies of prophylactic phenotype matching been in place. Part of this analysis was to calculate the predicted frequency of the phenotypes needed to match the patients for both “White” and “African-American” blood donors (see Table 2, right hand columns).15 The “White donors” and “African-American donors” columns show how different the frequencies for the relevant phenotypes are for the two racial populations, and show how supporting sickle cell patients with a Caucasian donor pool could increase the risk of alloimmunization.

Table 2: Projections for preventing alloimmunization in patients with SCD who received transfusions, according to different phenotype-matching protocols
Phenotypematching protocol n (%)* Patients with SCD whose alloantibodies would have been prevented, if a matching protocol had been used, n (%)† Phenotype Donor requirements for phenotype matching Phenotype frequency ‡ in
White donors (%) AfricanAmerican donors (%)
ABO and D, only None (current study) 249 (70.9) ABO and D, only N/A N/A
Protocol 1: D, C, c. E. e 51 (37.2) 289 (82.3)

D+C-c+E-e+(R0)§ or

3.2

42.3

D-C-c+E-e+(rr)§ 15.0 N/A
Protocol 2: D, C, c, E, e, K 73 (53.3) 307 (87.5) D-C-c+E-e+, K- 13.6 41.2
Protocol 3: D, C, c, E, e, K, S 76 (55.5) 310 (88.3) D-C-c+E-e+, K-, S- 6.1 28.4
Protocol 4: D, C, c, E, e, K, S, Fy2 86 (62.8) 320 (91.2) D-C-c+E-e+, K-, S-, Fy(a-) 2.1 14.6

* Percentage of 137 patients with SCD who received transfusions who formed alloantibodies.

‡ Phenotype frequencies were calculated from tables in the Technical Manual and from D – frequency in unselected plateletpheresis donors.

† The number of all patients who received transfusions (351) is used as the denominator.

§ Most transfusion services select D-(rr) RBC units for D+ recipients who require C-E- RBCs.

249 of the 351 sickle cell patients (70.9%) represented in Table 2 had not developed alloantibodies (i.e. ~30% alloimmunization rate) with standard US transfusion practice at that time (ABO and D matching). Similar to the Vichinsky paper, most of the antibodies were directed against RHCE and Kell antigens. While a theoretical exercise, the analysis on the left half of Table 2 does show that as more aggressive prophylactic phenotype matching strategies are implemented, the predicted frequency with which the patients would have developed red cell antibodies goes down significantly (to 6.6% with protocol 5). However, the incremental benefit of adding additional antigens decreases as the strategies become more aggressive (2.2% improvement between protocols 4 and 5).

Antigen matching to reduce alloimmunization

Tahhan et al., performed a retrospective chart review comparing alloimmunization rates of 40 patients who received antigen matched (C, E, Kell, S, Fya, Fyb) blood vs. 46 patient who received some matched and some non-matched transfusions.16 There were no alloimmunization events in the matched group while the mixed group had an alloimmunization rate of 16%.

Ameen and colleagues did a retrospective review of transfused Kuwaiti patients comparing rates of alloimmunization in a group that did not receive extended matched red cells (Group 1, 110 patients) with a group that received C, c, E, e, and Kell matched red cells (Group 2,123 patients).17 Group 1 had an alloimmunization rate of 65% and Group 2 had an alloimmunization rate of 23.6%. These high rates were observed despite the racially homogeneous nature of the population. The authors conclude that antigen matching is important for sickle cell patients.

Dr. Vichinsky and colleagues formally investigated the hypothesis that prophylactic antigen matching would decrease the frequency of alloimmunization in sickle cell patients with a planned secondary analysis as part of the STOP trial.18 The 63 patients randomized to the transfusion arm received 1830 RBC transfusions over the course of an average of 21 months. The red cell units were matched for (ABO and D) C, E, and Kell. Only 29 of the units transfused were not matched for these antigens (11 of 63 (16%) patients were exposed). Sixteen percent of the patients developed new antibodies (5% warm autoantibodies, 3% clinically insignificant antibodies, and 8% new alloantibodies). Despite the attempts to provide C, E, and Kell matched blood, 4 of the 5 patients who developed new alloantibodies had anti-E or anti-Kell. Only 1 patient developed clinically significant non-E or Kell antibodies (new anti-Fy(a) and S). The documented rate of new antibody formation in this study was 0.5% per unit of exposure (compared to a 3% rate for patients receiving non-matched red cells calculated from the previously published literature). The rate of hemolytic transfusion reactions “dropped to 10 percent of the established rate of 0.11%”. They concluded that it was feasible and useful to prophylactically match for C, E, and Kell in sickle cell patients.

A group of investigators performed a two-year follow-up investigation of the participants in the STOP trial.19 All of the participants were offered transfusion therapy on an ongoing basis following the close of the trial (78 patients). They were transfused with antigen-matched blood as per the STOP trial described above. Alloimmunization rates remained low (0.5% rate of new antibody formation per unit of exposure) during the two-year post-trial analysis.

Lasalle-Williams and colleagues reported on 14 years of experience with antigen matching at their institution.20 They transfused antigen-matched red cells to 99 sickle cell patients between 1993 and 2006 (6946 units matched for Rh (C, c, D, E, e); Kell (K, k); Duffy (Fya, Fyb); Kidd (Jka, Jkb); Lewis (Lea, Leb); and MNS (M, N, S, s) with mismatches for Lewis and MNS antigens preferred when complete matches were not available). They reported an alloimmunization rate of 7%. In their paper they present a table summarizing much of the reported literature on the effect of antigen matching for sickle cell patients. Overall, mismatched blood appears to result in a 1/3 rate of alloimmunization, and matched ~10% rate (see Table 3).

Table 3: Studies evaluating alloimmunization and matching for RBC antigens
Matching ABO, D only
Reference # of patients/transfusions % alloimmunized/# of alloantibodies per 100 units transfused

Ambruso et al.

85/1,941
 

34%/3.4

 

Rosse et al. 1,044/----* 18-31% (27% in study group)/-----
Vichinsky et al. 107/---- 30%/-----
Aygun et al.

140/3,239

(pediatric and adult patients)

37%/2.8
Castro et al. 351/8,939 29%-35%/3.8
Sakhalkar et al 387/14,263 31%/1.7
Matching extending beyond ABO, D, including C, E, K
  # of patients/transfusions % alloimmunized/rate, alloantibodies per 100 units transfused
Vichinsky et al.

Extended matching for C, E, K

61/1,830

8-11%/0.5
Sakhalkar et al.

Extended matching for C, E, K

113/2,345

5%/0.26
Matching extending beyond ABO, D, in addition to C, E, K
  # of patients/transfusions % alloimmunized/rate, alloantibodies per 100 units transfused
Tahhan et al.

Extended matching to K, C, E, S,

Fya , Fyb

40/-----

0/------

* Bar notes data not provided or available

US clinical practice around antigen matching

Clinical practice around antigen matching has varied. Osby and Schulman reported an analysis of a 2003 College of American Pathologists proficiency testing survey that queried participants regarding their current strategy for antigen matching for sickle cell patients.21 1182 labs responded, and the majority (743) reported that they did not routinely perform phenotyping for sickle cell patients. 439 did phenotype sickle cell patients, 330 of which did so as part of an effort to provide phenotype matched blood prophylactically. Of those that prophylactically matched, 85% (280) matched for C, E, and Kell. However, when Afenyi-Annan and Brecher surveyed 50 academic centers in 2004, 27 (73%) reported prophylactic matching.22 24 of the 27 (89%) matched for C, E, and Kell. The overall summary of these investigations is that the minority of hospitals do not provide prophylactic antigen matching for sickle cell patients, but that the majority of academic centers, where sickle cell patients commonly receive treatment, do prophylactically match. These results may not reflect current practice, since the most recent surveys date from 2004. Most of the hospitals surveyed were in the US, but some Canadian hospitals did participate in both surveys.

The November 2012 issue of the journal Immunohematology is dedicated to a series of reports of the transfusion practices of different hospital systems in the US that focus on care for sickle cell patients. The programs have a variety of approaches. Some prophylactically match for a subset of antigens (RHCE and Kell) until a patient develops an antibody, then use more extensive matching once a patient is sensitized (Kidd, Duffy, MNS).23, 24, 25 Some that match for the RHCE and Kell antigens will match for C, c, E, e, and Kell,23, 24 while others will only match for C, E, and Kell. 25, 26, 27 Some programs prophylactically match for RHCE and Kell then add additional antigen requirements as needed when patients develop antibodies without progressing to extended antigen matching.26, 27

A few of the programs do not match until after the patient has declared him / herself to be an antibody producer by becoming sensitized.28, 29 At Children’s National Medical Center in Washington, DC, sickle cell patients who develop one antibody receive Rh (C, c, E, e) and Kell matched blood, and those that make two receive blood matched additionally for Duffy, Kidd, and S.28 At Johns Hopkins in Baltimore, extended phenotype matching (all Rh, Kell, Kidd, Duffy, and MNS antigens) is performed after a sickle patient develops his/her first antibody.29 The authors of the report from one of these groups conclude their article “…the transfusion physicians at our institution remain unconvinced that phenotype matching RBCs for all patients with SCD, before they have shown the ability to make alloantibodies, is either cost-effective or medically prudent.” 29 There is support in the scientific literature for the idea of a subgroup of recipients who are at the greatest risk of antibody formation.30 

These programs all report important drops in alloimmunization rates with their strategies, but also report struggling to obtain all the needed rare blood, and ongoing instances of mismatched blood exposure and new sensitizations. Patients also become sensitized when they are seen at facilities that do not participate in their antigen matching programs.

Canadian clinical practice around antigen matching

To get a contemporary sense of practice in Canada, we performed an informal survey of selected transfusion medicine experts in Canada who practice at hospitals that commonly provide care to sickle cell patients. In Toronto, Hospital for Sick Kids and the University Health Network Hospitals phenotype (and genotype when possible) their sickle cell patients for C, c, E, e, K, k, Fya, Fyb, Jka, Jkb, S, s. If a patient is not allostimulated, they prophylactically antigen match for C, c, E, e, K, k. Patients with red cell antibodies receive units matched for C, c, E, e, K, k, Fya, Fyb, Jka, Jkb, S, s (and negative for the antigens against which antibodies are directed). The experts in Edmonton phenotype for C, c, E, e, K, k, Fya, Fyb, Jka, Jkb, S, s, M, N, Lua, Lub. Like the group in Toronto, they provide C, c, E, e, K, k matched units for non-alloimmunized patients and extended matching for patients with antibodies (in their case, however, there would be additional antigens to match for given the more extensive typing up front). The interviewed expert in Montreal provides C, E, K matched units to unstimulated patients, provides units that are negative for the relevant antigen for patients that develop one antibody, and gives full phenotype matched units for those patients who develop a second clinically significant antibody.

These protocols are quite similar and suggest a very high degree of agreement among Canadian experts as to what the best approach is for transfusion of sickle cell patients.

An important caveat to be aware of with regards to the phenotype profile of sickle cell patients is the fact that the vast majority of those who are Fy(b-)actually only lack Fy(b) on their red cells (i.e. they still have the antigen on other tissues).31 This results from a mutation that impairs promoter activity by disrupting a binding site for the GATA1 erythroid transcription factor. As a result they are not at risk of forming anti-Fy(b). In practice, this allows transfusing physicians to choose Fy(b+) units for their Fy(b-) sickle cell patients (especially if a genotype has been performed that shows the presence of the GATA mutation), which greatly enhances the availability of matching red cell units for these patients.32 Canadian transfusion physicians incorporate this fact into their protocols for transfusing sickle cell patients.33

Meeting the need for phenotyped units at Canadian Blood Services

Unfortunately there are a lot of important facts that are not known regarding transfusing sickle cell patients in Canada. While many Canadians are of Caribbean or West African origin, the actual prevalence of the disease in Canada is not known.34 In 2013, 760 red cell exchange procedures were reported to the Canadian Apheresis Group. Due to limitations in the current computer system, we do not know the number and fill rate of phenotype requests for sickle cell patients.

The experiences of our Canadian Blood Services staff and of our transfusing physicians match those reported by specialty sickle cell treatment centers in the US, all of which struggle to meet increasing demand for matched units for their patients.23-29 

Canadian initiatives to meet the need for phenotyped units

The Donor Testing-based national phenotyping program has the potential to make a huge impact on Canadian Blood Services’s ability to support our sickle cell patients. The goal of the program is to phenotype 35% of our donor base for C, c, E, e, Kell, Fy(a), Fy(b), Jk(a), Jk(b), S, and s. Mainly group O and A donors are phenotyped. When typing is performed on two separate donations, the phenotype will then print on the product label. With 35% of the donor based tested the requests for multiple antigen negative units should be more easily met and hopefully our support for sickle cell patients will improve.

Additionally, in order to limit the impact of phenotype requests on availability of RhD negative red cells, Canadian Blood Services is contacting lapsed R0R0 or R0r (D+, C-, E-, more common in Blacks) donors to enhance the supply of C-, E- units that are frequently needed for sickle cell disease patients while limiting the need to use rr (D-, C-, E-, more common in Caucasians) red cells to meet these requests. Canadian Blood Services is also trying to enhance recruitment and targeted phenotyping of donors in various ethnic and racial minority groups to better match the needs of the diverse Canadian population. Targeted genotyping of donors with phenotypes of particular interest (such as S-s-) to meet demand for rare units (such as U-) that arise in the sickle cell patient population is also underway.

Recommendations regarding the provision of phenotyped blood

Since it is challenging to meet the increasing transfusion needs of sickle cell disease patients in Canada on a daily basis, general guidelines can assist in optimal management and prioritization of orders, particularly if units are not available to meet all requests. These are meant to assist in allocation of a shared scarce resource to ensure optimal patient benefit, and not as a replacement for individual medical judgment or institutional policies. Complex patients, such as those with an autoantibody in addition to alloantibodies, and specific clinical situations, such as pregnancy, may involve additional considerations. Recommendations may change as new clinical data become available and new technologies, such as donor and recipient genotyping, evolve.

Patients who have not developed any antibodies:

  1. Perform the patient’s phenotype.
  2. Transfuse red cells that are prophylactically matched for C, c, E, e, and Kell.

Patients who have developed an antibody or multiple antibodies:

  1. Perform the patient’s phenotype.
  2. Consider genotyping the patient, particularly if they require frequent transfusion and/or have multiple antibodies. Genotyping may demonstrate the presence of rare alleles, or absence of high incidence antigens, particularly in the Rh system, and may help in the interpretation of complex serologic results. Patients who are Fy(b-) may also benefit from genotyping, since individuals who have the GATA box mutation express Fy(b) on non-erthyroid tissue and are therefore extremely unlikely to produce anti-Fy(b). Removing the need to provide Fy(b-) units to such patients greatly expands the pool of potentially matched units for other antigen systems.
  3. Transfuse red cells that are matched for all clinically significant antigens against which antibodies are directed. These patients have demonstrated that they are immunologic responders, and therefore are more likely to develop antibodies against other antigens. Therefore, if possible, prophylactic matching should include Fy(a), Jk(a), Jk(b), S, and s, in addition to C, c, E, e, and Kell.

Rationale and supporting information

  1. The rationale and supporting information for these recommendations is detailed in this manuscript. In summary, these recommendations:
  2. Provide good protection for sickle cell patients against alloimmunization and associated complications
  3. Incorporate the likely fact of a category of patient that is a “responder” that is more likely to make antibodies by enhancing antigen matching once a patient makes an antibody
  4. Are consistent with / somewhat more aggressive than protocols that are in place for centers that see many sickle patients in the US
  5. Are consistent with / somewhat more aggressive than most of the clinical protocols at the interviewed Canadian centers that see many of the sickle cell patients
  6. Are supported by current Canadian Blood Services infrastructure and procedures for phenotyping through Canadian Blood Services Donor Testing Laboratories
  7. Will likely be even better supported by Canadian Blood Services as the ethnic diversity and the proportion of donors of known phenotype increase
  8. Are less likely to require accessing frozen rare red cell inventory or recruitment of rare donors than more aggressive matching protocols

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