The Kpa antigen is part of the Kell blood group system (ISBT 006). This system comprises 38 antigens carried by a 732-amino acid transmembrane glycoprotein known as CD238. The nomenclature derives from ‘Kelleher’, the first producer of an anti-K antibody, and ‘p’ for ‘Penney,’ the name of the first patient identified as an Anti-Kpa producer [3]. This antigen, first discovered in 1957, has gained notoriety due to its rarity and its involvement in transfusion reactions and hemolytic disease of the fetus and newborn (HDFN) [3].

The Kpa antigen, referred to by the International Society of Blood Transfusion (ISBT) as KEL3, is an allelic variant of the protein encoded by the KEL gene, located on chromosome 7q32-q36 [3]. This gene gives rise to the Kell glycoprotein, a metalloenzyme expressed in the erythrocyte membrane that performs several functions such as regulation of cell growth and interaction with other membrane proteins [3].

The variation in Kpa is due to a polymorphism in the KEL gene, which generates an amino acid difference in the resulting protein [3]. This makes Kpa a low frequency antigen in most populations, with an estimated prevalence of <2 % in Caucasians and virtually absent in other ethnic groups. Conversely, its antithetical partner, the Kpb antigen (KEL4), is a high-frequency antigen, appearing in >99 % of individuals [3].

Table 1 illustrates the phenotypes of the Kell system, frequency in European and African populations and the reported clinical significance:

Information on the frequencies of KEL:3,4 phenotypes in patients with hemoglobinopathies and blood donors in South America is scarce due to the rarity of these specific variants in the general population and the limited specific genetic research in this region [3,4]. Thus, genetic studies focused on local populations, especially in polytransfused patients and blood donors, is necessary [3,4].

The low frequency of the Kpa antigen reduces the likelihood of sensitization in the general population [4]. However, when it does occur, the formation of anti-Kpa antibodies can have serious clinical implications [4]. Sensitization to Kpa occurs primarily through blood transfusions or, less frequently, during pregnancy when a Kpa-negative mother is exposed to Kpa-positive fetal red blood cells [4].

The production of anti-Kpa is less common than that of other Kell system antibodies, such as anti-K. The latter is known to suppress erythropoiesis by an immunologic mechanism that affects both the production of erythroid progenitors in the bone marrow and the survival of mature erythrocytes in the circulation [4]. Anti-K can bind to erythroid progenitor cells expressing the Kell antigen in the bone marrow and trigger mechanisms such as macrophage-mediated phagocytosis or functional interference where antibodies block signals essential for the proliferation and maturation of these cells, directly affecting erythropoiesis [4].

Alloimmunization against the Kpa antigen is extremely rare, even in polytransfused patients, such as those with hemoglobinopathies [5]. Anti-Kpa can mediate hemolytic reactions in patients receiving incompatible blood by causing extravascular hemolysis through opsonization of erythrocytes leading to destruction in the reticuloendothelial system primarily in the spleen and liver [5]. Fortunately, due to the low prevalence of Kpa, the risk of developing such antibodies and having a transfusion reaction is relatively low compared to other blood systems [5].

Anti-Kpa can be difficult to detect in routine pre-transfusion testing, which could lead to failure to identify the antibody prior to transfusion [5]. In addition to immune destruction of red blood cells, anti-Kpa can possibly cause suppression of fetal erythropoiesis with consequent severe anemia as reported by Tuson et al. where the first case of probable erythropoiesis suppression attributable to anti-Kpa is described in a twin pregnancy where only one of the twins was affected [6].

Anti-Kpa is an immunoglobulin G (IgG), predominantly of the IgG1 subtype. While naturally occurring antibodies are extremely rare, they have been reported in a 12-month-old infant with recurrent infections as a cross-reaction to bacterial capsule antigens [7].

Alloimmunization against the Kpa antigen is extremely rare; the medical literature documents very few cases of perinatal anemia or miscarriages associated with anti-Kpa antibodies [3–5]. Most studies and reports focus on antibodies against other Kell system antigens, such as K1 (KEL1), due to their higher prevalence [3–5].

The 2013 report by Rossi et al. documents a case of HDFN caused by the anti-Kpa antibody [8]. In this case, a pregnant woman developed anti-Kpa antibodies resulting in severe fetal anemia. The diagnosis was confirmed by serologic testing and prenatal imaging studies that revealed signs of hydrops fetalis, a severe complication in HDFN. This antibody was initially identified as part of an investigation for parvovirus B19-induced fetal anemia. Clinical management included multiple intrauterine transfusions to correct the fetal anemia, which allowed the pregnancy to be prolonged to a point where delivery was viable. The newborn, although affected by anemia, was stabilized after birth, but required additional monitoring and treatment. This case underscores the importance of early detection and proper management of alloimmunization by antibodies such as anti-Kpa, because of the possibility of serious consequences if not treated early [9]. However, the paucity of specific reports makes it difficult to accurately assess the frequency and severity [9].

Extended erythrocyte phenotyping facilitates the identification of anti-Kpa in patients requiring transfusion. This is particularly critical for polytransfused patients and women of childbearing age, as alloimmunization within the Kell system can significantly impact future pregnancies [10]. In the laboratory, identification of an anti-Kpa antibody is carried out through serological testing, using techniques such as the indirect antiglobulin test (IAT) [10]. In cases where serological analysis is inconclusive, genetic testing may be useful to detect polymorphisms in the KEL gene [10].

In transfusion situations, it is suggested to administer Kpa-negative red blood cell units to alloimmunized patients, although some studies suggest that serologically compatible units may also be adequate, given the low relative risk of severe hemolysis [11]. However, in scenarios such as hemolytic disease of the newborn, anti-Kpa may generate fetal anemia, although to a lesser degree than other Kell system incompatibilities [11].

For patients requiring transfusions, the general recommendation is to use blood units that are compatible by crossmatching at 37  °C in the antiglobulin phase without the need to routinely select Kpa-negative units due to the low prevalence of the antigen in the population [12]. However, in situations where anti-Kpa has been identified, for example in HDFN and sickle cell disease, it is essential to ensure strict compatibility to prevent severe complications [12].