Final Diagnosis:
The patient’s antibody panel was consistent with an anti-Jka antibody showing dosage
(stronger reactions with RBCs homozygous for the antigen of interest than heterozygous
RBCs). Interestingly, she was also positive for the Jka antigen raising the concern
of the presence of an autoantibody. DNA sequencing confirmed a partial Jka antigen
with the JK*01W.01, JK*01W.06 genotype and resulting Jk(a+w, b-) phenotype. The clinical history of sickle cell
disease with numerous prior transfusions, positive antibody panel for anti-Jka but
a lack of anti-Jka in her eluate, and the genotype results made us favor an anti-Jka alloantibody developed after exposure to red blood cells with the common Jka antigen. The patient
will need to receive Jka-negative blood in future transfusions while also being closely
monitored for formation of new antibodies particularly an anti-Jkb antibody given
she is Jkb- and nearly all Jka- RBC units will be Jkb+.
Discussion:
The Kidd (JK) blood group system consists of three commonly described antigens, Jka,
Jkb and Jk3, carried on an erythrocyte urea transporter glycoprotein (UT-B). The Kidd
protein (UT-B) is encoded by the JK gene, SLC14A1, on chromosome 18. This gene contains
the two major co-dominant alleles, JK*01 and JK*02 (Jka and Jkb respectively), which differ by a single amino acid (Asp280Asn) resulting
from a single nucleotide polymorphism (SNP) 838G>A. Four common phenotypes result
from the combination of these alleles: Jk(a+b-), Jk(a+b+), Jk(a-b+), and the rare
null phenotype Jk(a-b-).
Important nomenclature when discussing the alleles from different blood groups comes from the International Society of Blood Transfusion (ISBT) Working Party for Red Cell Immunogenetics and Blood Group Terminology which maintains a record of the current blood group systems with their respective alleles. In the ISBT naming system, W and N are incorporated when alleles are expected to produce weakened or null (negative) antigen expression. It is important to note that while this system only formally identifies alleles as weak, many weak alleles can produce an immunologically different antigen which is commonly referred to as a partial antigen. In cases of partial antigen expression, these individuals are at risk for becoming alloimmunized to the common antigen and producing a clinically significant alloantibody. Given that many weak alleles are uncommon or vastly unrecognized clinically, there is a lack of literature on most weak alleles and potential alloantibody production and clinical significance so it is generally best for patient safety to assume most weak alleles outside the RH system (which has a relatively robust body of literature) can potentially lead to expression of a partial antigen and apparent alloantibodies against these antigens may be capable of causing a hemolytic transfusion reaction.
In this case, the patient’s genotype was JK*01W.01, JK*01W.06. Both of these alleles carry the Jka-defining nucleotide 838G along with the 130G>A (Glu44Lys) mutation. JK*01W.06 also carries the 588A>G (Pro196Pro) mutation which may be referred to as silent given it does not result in an amino acid change, however different codons for the same amino acid can have different protein expression efficacy or alternative protein methylation so this may also contribute to the weakened Jka expression or production of a partial antigen.
Differentiating between an allo- and autoantibody is particularly important in this patient with a high likelihood of receiving transfusions in the future. Patients who have made an alloantibody are considered to be at significantly higher risk for additional alloimmunization (commonly referred to as an antibody responder phenotype). This is of particular interest in this case because the patient is also Jkb- and requiring the transfusion of Jka- RBCs due to this allo-anti-Jka will inherently expose her to Jkb+ RBCs during future transfusions. If she goes on to also produce allo-anti-Jkb would make it extremely difficult to transfuse her since she will then require null type, Jk(a-b-), blood which is extremely difficult to find due to the very low prevalence of this phenotype in the population.
Finally, it should be noted that the clinical significance of many alloantibodies produced by patients with uncommon weak alleles is not established due to their rarity or underrecognition. This is especially important to consider in a case such as this one where transfusion of implicated antigen negative blood will inherently expose the patient to another antigen they lack and which alloantibodies against are of known clinical significance. It is unclear if this allo-anti-Jka had caused a previous delayed hemolytic transfusion reaction since the patient was last transfused ~5 months ago and was discharged shortly after being transfused so no follow-up hemoglobin, DAT, or antibody screening was performed during the time period hemolysis would have been identifiable. However, a case of suspected hemolytic reaction in a patient with the same JK genotype and allo-anti-Jka has been recently reported. Our blood bank medical director has also personally encountered a previous case with the same JK genotype and allo-anti-Jka which was highly suspected to have caused a mild delayed hemolytic transfusion reaction. Therefore, we believe it is worthwhile to consider this antibody clinically significant and to transfuse her with Jka- RBCs although we discouraged any transfusion at this time because the patient was near her own baseline, her anemia was asymptomatic, and transfusion is not typically of benefit during a pain crisis. We also advocated for minimal transfusions in the future unless her anemia was severe and symptomatic and therefore only when transfusion is of clear benefit.
Kidd antibodies are notorious for being difficult to detect and are known to cause intravascular and extravascular hemolysis in transfusion reactions. This patient will need to be transfused Jka-negative blood and should be closely monitored for new antibody formation. This case highlights the importance of completing a full workup with incorporation of genotyping in the identification of partial antigens. Although partial and weak antigens are commonly talked about with the RhD system (e.g., partial and weak D), it is important to remember that these can be present across all blood group systems.
References
Wester, E.S., Storry, J.R. and Olsson, M.L. (2011), Characterization of Jk(a+weak):
a new blood group phenotype associated with an altered JK*01 allele. Transfusion,
51: 380-392. https://doi.org/10.1111/j.1537-2995.2010.02795.x
Soleimani, R., et al., (2023), SLC14A1 gene sequencing shows the JK*01W.06 allele
in a JK1 patient with an anti-JK1. Hematology, transfusion and cell therapy, S2531-1379(23)02591-9.
https://doi:10.1016/j.htct.2023.10.004
ISBT 009 JK Alleles v8.2 31-DEC-2023. International Society of Blood Transfusion (ISBT). Available at: https://www.isbtweb.org/resource/009jk.html.
Board-type questions
1. Which combination of antigen typing and antibody screening results would be most
consistent with an alloimmunized patient with a partial Jka antigen and no recent
transfusions?
A. Jka positive with anti-Jka antibodies, DAT-
B. Jka positive with anti-Jka antibodies, DAT+
C. Jka positive with anti-Jkb antibodies, DAT+
D. Jka negative with anti-Jka antibodies, DAT-
2. What is the best approach to transfusing a patient with an antibody of unknown/unclear
clinical significance?
A. Transfuse a small amount of RBCs (~50mls) and evaluate for hemolysis (biological
crossmatch)
B. Transfuse antigen positive units if crossmatch compatible
C. Transfuse antigen negative units only
D. Send for a monocyte monolayer assay (MMA) test
E. Transfuse antigen positive units despite crossmatch incompatibility