Neonatal Jk^a hemolytic disease combined with alloimmune thrombocytopenia with extreme anemia: a case report with literature review

Abstract

Background

Only isolated occurrences of neonatal Jk^a hemolytic disease have been identified, and no cases of Jk^a hemolytic disease combining fetal and neonatal alloimmune thrombocytopenia (FNAIT) have been reported. The majority of medical professionals lack sufficient knowledge regarding Jk^a hemolytic disease, which could result in missed diagnoses and early misdiagnoses.

Case presentation

In this study, a case of a male newborn with extreme anemia and thrombocytopenia is reported. The newborn and his mother were identified as blood groups O RhD + and Jk(a + b+), and O RhD + and Jk(a-b+). Anti-Jk^a was identified in the plasma of both the mother and newborn. Thrombocytopenia and upper gastrointestinal bleeding were observed in the newborn, and both mother and newborn tested positive for platelet antibodies. The extreme anemia and thrombocytopenia were successfully treated with red cell transfusions and immunoglobulin.

Conclusion

Co-existence of neonatal Jk^a hemolytic disease and FNAIT is very rare in newborns with significant clinical manifestations. Early diagnosis and timely treatment are crucial for improving patient outcomes.

Background

The Kidd blood group antigen, also known as the Jk antigens, is encoded by the Jk gene (SLC14A1). The currently identified polymorphic antigens Jk^a and Jk^b and the high-frequency antigen Jk3 comprise the four phenotypes: Jk(a + b-), Jk(a-b+), Jk(a + b+), and Jk(a-b-) [1]. Although the mechanism and clinical manifestations are similar to those of ABO hemolytic disease, neonatal Jk^a hemolytic disease is extremely rare [2, 3], and only sporadic cases have been reported, while cases combined with fetal and neonatal alloimmune thrombocytopenia (FNAIT) have not been documented. Most clinicians are not adequately informed about Jk^a hemolytic disease, which may potentially lead to early misdiagnosis and missed diagnosis. In this study, a male newborn with neonatal Jk^a hemolytic disease combined distinctively with FNAIT was retrospectively analyzed. The clinical features of Jk^a hemolytic disease in neonates were also summarized based on the literature.

Case presentation

The mother was G2P1 and had an irregular fetal heart rate and decreased fetal movement on day 3 before delivery. She showed recovery after treatment with oxygen. She gave birth by emergency cesarean section in our hospital due to significantly reduced fetal movement and an unresponsive non-stress test. The mother, who is healthy without a history of thrombocytopenia or bleeding tendency, had a negative test for irregular antibodies and a normal platelet (PLT) count during the first pregnancy three years ago and gave birth to a healthy, full-term infant without a history of thrombocytopenia, anemia, or hemolysis. During this pregnancy, the mother did not undergo screening for irregular antibodies and showed a normal count of PLT with 277 × 10⁹/L (100–300 × 10⁹/L) two weeks before delivery. The platelet count on the day of delivery was 244 × 10⁹/L, and the irregular antibodies test was positive.

The newborn boy was born at 39 weeks of gestational age with a birth weight of 3.36 kg. At birth, the newborn presented with pale skin, absent respiration, and no muscle tone. Following initial resuscitation and positive pressure ventilation, the newborn’s condition improved, as evidenced by an Apgar score of 2-5-5 at 1, 5, and 10 min. The newborn had pale skin without edema and a blood pressure of 65/40 mmHg when admitted to the neonatal intensive care unit. Auscultation revealed no cardiac or pulmonary abnormalities. The liver was palpated 1.5 centimeters below the right costal margin, and the spleen was not palpable. The newborn was mechanically ventilated with a blood gas pH of 7.294 (7.35–7.45), a base excess of -16.9 mmol/L (± 3 mmol/L), hemoglobin (HGB) of 30.8 g/L(150–220 g/L), a hematocrit of 10.1% (45-65%), and a lactic acid level of 19.6 mmol/L (< 2 mmol/L). Severe anemia, asphyxia, and metabolic acidosis were diagnosed first. As the blood pressure quickly dropped to 39/22 mmHg, 10 ml/kg of saline and an emergency transfusion of 18 ml/kg of homologous red blood cells were given. His pallor improved, and emergency chest and abdominal radiography and multi-organ ultrasound were normal. The first complete blood count showed HGB of 92 g/L with a reticulocyte count of 3.5% (3-6%) and PLT count of 13 × 10⁹/L. The first set of bilirubin and lactate dehydrogenase was 57.5 umol/L and 4938 U/L (150–407 U/L), respectively. Coagulation functions were normal with prothrombin time 14 S (11–14.5 S), activated partial thromboplastin time 37.9 S (28–42 S), and fibrinogen 1.93 g/L (2–4 g/L). On day 2, the peripheral blood film exhibited echinocyte (3+), and the local central blood bank reported that the blood groups of the mother and newborn were O RhD+, Jk(a-b+), and O RhD+, Jk(a + b+), respectively. The direct anti-human globulin (DAT) measured with microcolumn gel was positive (2+) for anti-IgG and C3d in the sample of the newborn, and anti-Jk^a was identified in the samples of the mother and newborn by elution assay. The diagnosis of Jk^a hemolytic disease was confirmed. The newborn’s complexion remained pale with hypotension, and HGB was 89 g/L. A second transfusion of 18 mL/kg of donor Jk(a-b+) red blood cells was administered with albumin and dopamine (10 ug/kg/min) to maintain blood pressure. The patient’s pale skin returned to normal color, HGB improved to 114 g/L, and lactate dehydrogenase decreased to 2095 U/L, and respiratory support was downgraded to non-invasive ventilation, which was discontinued after three days, with a total time on oxygen of 84 h. After a third red blood cell infusion on day 3, HGB increased to 154 g/L and remained stable (Fig. 1). To rule out the possibility that anti-CD36 antibodies might cause anemia and thrombocytopenia, we tested the levels of CD36 and found that expression of CD36 antigen by peripheral blood monocytes was positive in both the mother and newborn by flow cytometry (Fig. 2). Normal G6PD activity and maternal hemoglobin electrophoresis also excluded G6PD deficiency and fetal-maternal transfusion.

Fig. 1

Trends in hemoglobin, bilirubinometer(A), and platelets(B) during hospitalization and follow-up. DAT, direct antiglobulin test; HGB, hemoglobin; IVIG, intravenous immunoglobulin; PLT, platelet; PT, phototherapy; TCB, transcutaneous bilirubinometer; TF, transfusion; TSB, total serum bilirubin.

The newborn had a bilirubin with a peak value of 221 umol/L on day 4 and received phototherapy twice. A PLT count of 13 × 10⁹/L was observed after the first transfusion, which increased to 96 × 10⁹/L after the second red cell transfusion and intravenous immunoglobulin (IVIG) administration with a dose of 0.75 g/kg. On day 2, the PLT count was 73 × 10⁹/L, and upper gastrointestinal bleeding occurred, which improved with gastric lavage and topical thrombin treatment (Fig. 1). Subsequently, the platelet antibodies of the mother and the newborn were identified as being positive in the local central blood bank, detected by the monoclonal antibody solid-phase platelet antibody test (Changchun Brother Biotech Co., Changchun, China) for both platelet-associated antibody and platelet-specific antibody. On day 7, the infant’s cranial MRI and hearing screening revealed no abnormalities, and the repeated DAT test remained positive. The Kidd blood group of his father and sister was identified as Jk (a + b-) and Jk (a + b+). The newborn was discharged on day 8 after birth, and the DAT decreased to weakly positive after one week. Repeated HGB and PLT tests, as well as physical growth and neurodevelopmental follow-up, demonstrated normal values (Fig. 1).

Fig. 2

Positive expression of CD36 antigen by peripheral blood monocytes in mother (A) and the term newborn (B)

Literature review

A systematic search for literature published between the establishment of the database and May 31, 2024, was performed in the PubMed, Web of Science, and Embase databases and the Chinese databases China National Knowledge Infrastructure, Wan Fang, and China Science and Technology Journal databases, using the keywords ‘infant’ or ‘newborn’ or ‘neonate’ and ‘Jk^a’ and ‘thrombocytopenia.’ Articles lacking detailed information and review articles were excluded. A total of 14 articles were identified, detailing a total of 14 cases of neonatal Jk^a hemolytic disease [4,5,6,7,8,9,10,11,12,13,14,15,16,17]. No more cases of Jk^a hemolytic disease in combination with FNAIT were found. Gestational age was reported in 12 cases, all of which were either term or late preterm. All 15 cases were positive for DAT and anti-Jk^a antibodies (100%), of which 7 (46.7%) demonstrated coexistence with other blood group antibodies (Table 1). All cases reported initial or maximum bilirubin values ranging from 69.8 to 441.2 umol/L, and 13 cases exhibited anemia with reported HGB values between 30 g/L and 144 g/L. This included three cases of severe anemia (30.8–75 g/L). Of the cases that reported receiving therapeutic interventions, 10 received phototherapy (10/11). Five cases each received blood transfusions, IVIG infusions, and exchange transfusions (5/11, 5/12, and 5/13, respectively). The outcome was favorable in 13 cases (86.7%), while one case of kernicterus (6.7%) and one case of death occurred (6.7%).

Table 1 Clinical characteristics of 15 cases of neonatal Jk^a hemolytic disease

Discussion and conclusion

Hemolytic disease of the fetus and newborn (HDFN) is an alloimmune hemolytic disease caused by maternal-fetal blood group incompatibility. ABO incompatibility is the most common form of HDFN, followed by the Rh incompatibility [2]. The pathogenesis and manifestations of Kidd hemolytic disease are analogous to those of ABO or Rh hemolytic diseases [1]. Therefore, in neonates presenting with jaundice and anemia and without ABO/Rh blood group incompatibility between mother and baby, the possibility of a rare blood group incompatibility should be considered. The severity of hemolysis correlates with the strength of the antibody, the type of immunoglobulin, and, if combined, other antibodies. The clinical presentation exhibits varying degrees of jaundice and anemia. Velasco Rodriguez et al. [18] observed that 76.9% of the 13 cases of HDFN secondary to anti-Jk^b received phototherapy alone or no treatment, and only one case required a blood transfusion. All cases in this paper displayed anemia, including three cases of severe and extreme anemia, which is higher than previously reported in the literature [19, 20]. The fetal heart rate and movement abnormalities observed prenatally may be attributed to responses to fetal ischemia resulting from intrauterine hemolysis. However, the blood group identification and ultrasound detection of the middle cerebral artery blood flow were unfortunately not performed. In some cases, the presence of antibodies from multiple blood groups may exacerbate the symptoms of hemolysis [21]. Seven of the fifteen cases in this study had mixed antibodies, resulting in a more severe hemolytic reaction with an earlier onset of jaundice. Five of these cases required blood exchange therapy, and even one child died.

Kidd hemolytic disease rarely occurs during the first pregnancy. However, in the second pregnancy, immune memory leads to the rapid production of antibodies that destroy fetal erythrocytes, resulting in hemolysis [22]. Of the 15 cases analyzed in the study, only two developed in the first pregnancy, which could be related to maternal blood transfusion or certain viral or bacterial infections, leading to antigenic mimicry [6, 14]. It is noteworthy that in the 15 cases of Jk^a hemolysis, no cases of ABO incompatibility were observed. In cases of maternal ABO incompatibility, fetal erythrocytes entering the mother are destroyed by agglutination with anti-A or anti-B antibodies. This prevents other incompatible antigens from stimulating the mother, thereby protecting the fetus from hemolysis [23]. In addition, this case features a rare combination of FNAIT, a condition that has only been reported in recent literature [24]. It remains unclear whether there is a mutual influence between Jk^a hemolytic disease and FNAIT. A study has demonstrated that platelet anti-CD36 antibodies cause fetal severe anemia by inhibiting erythroid progenitor cell differentiation and promoting progenitor cell apoptosis, in addition to reducing PLT [25]. However, in this case, the peripheral blood monocytes of both mother and child expressed the CD36 antigen, ruling out this possibility.

In addition to HDFN, Jk^a incompatibility may result in acute or delayed hemolytic transfusion reactions. It is therefore essential to provide Jk antigen phenotype matched units in cases where Jk alloantibodies have been identified [20, 26]. If the hemolysis is not life-threatening, it is vital to use blood group-compatible red cells (the Jk^a antigen is identical to the mother, while other blood groups are identical to the newborn and be negative for antigens that correspond to any antibodies that the mother may have). In this case, the baby suffered hypovolemic shock after birth and required an emergency transfusion, which was carried out using the polybrene method for rapid cross-matching of blood while investigations for HDFN were not done and Kidd blood group antigen specificities were not known.

HGB levels showed a transient increase and then decreased. Validation with the microcolumn agglutination method on the second day revealed a discrepancy in the matching results. The diagnosis of HDFN secondary to Jk^a antibodies was subsequently confirmed, and the neonate was given two consecutive transfusions of Jk (a-b+) washed red cells and did not become anemic again despite a positive DAT.

Given the potential of Jk^a hemolytic disease to cause significant complications, it is imperative to prioritize prevention and prenatal diagnosis. Screening for blood group antigens and irregular antibodies is recommended during pregnancy, particularly in women with multiple pregnancies or a history of blood transfusion [20, 23]. In the case of an irregular positive antibody result, it is important to identify the specific antibodies involved and to develop a follow-up plan and treatment strategy based on the antibody titer and the status of the fetus. Intrauterine red blood cell transfusion or early delivery may be required [27].

In general, HDFN secondary to antibodies against non-ABO/Rh antigens should be considered in cases of hemolytic anemia in a newborn in the absence of ABO or Rh incompatibility. Prompt maternal and neonatal DAT testing and antibody identification are essential for diagnosis, followed by aggressive treatment to minimize the risk of adverse outcomes.