Neonatal alloimmune thrombocytopenia and neutropenia associated
with maternal human leucocyte antigen antibodies and drug-induced
hemolytic anemia
Abstract:
Fetal and neonatal alloimmune
thrombocytopenia (FNAIT) is commonly associated with antibodies against
platelet antigens, and alloimmune neonatal neutropenia (ANN) is
frequently caused by anti-neutrophil antibodies.
Human leukocyte antigen (HLA)
antibodies are rarely reported to result in FNAIT or ANN, let alone the
combination of FNAIT and ANN. We report here a very unusual case of a
first twin pregnancy produced in vitro by donated oocytes where the
mother developed markedly elevated HLA antibodies in the absence of
anti-platelet or anti-neutrophil antibodies that provoked severe
thrombocytopenia and neutropenia in one of the twins. In addition,
drug-induced hemolytic anemia (DIHA) that required red blood cell
transfusion was detected in this twin. We hypothesize that the complete
HLA-incompatible twin pregnancy due to oocyte donation might have
contributed to the severity of the clinical manifestations.
Key words: fetal and neonatal alloimmune thrombocytopenia; alloimmune
neonatal neutropenia; HLA; drug-related hemolytic anemia; neonatal
Introduction
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is an alloimmune
disease caused by the incompatibility of fetal and maternal platelet
surface antigens during pregnancy. The mother produces immunoglobulin G
(IgG) through the placenta that acts on fetal or neonatal platelet
surface antigens, causing platelet destruction[1]. Numerous platelet
antigens and their corresponding antibodies are involved in FNAIT.
Severe FNAIT is mostly caused by platelet antigen (HPA) 1a. In neonates
with moderately severe to severe thrombocytopenia, petechiae, bruising,
and bleeding may be observed. The most serious complication is
intracranial hemorrhage[2], and approximately 80% of intracranial
hemorrhage (ICH) occurs in utero[3].
Alloimmune neonatal neutropenia (ANN) also uses a similar mechanism to
produce antibodies that act on the neutrophil surface antigens of the
fetus or neonatal paternally inherited human neutrophil antigens (HNAs),
resulting in neutropenia[4].
Human leukocyte antigen (HLA)-class I antigens are distributed on the
surface of platelets and neutrophils, and anti-HLA-class I antibodies
can act on platelets and neutrophils to cause FNAIT and ANN[5].
Although HLA antibodies have seldom been reported as an etiology for
NAIT and, more rarely, ANN, we report a case of neonatal alloimmune
thrombocytopenia and neutropenia caused by human leucocyte antigen-A2,
A24 and A68 antibodies without detectable antibodies to HNAs or HPAs.
The neonate also had anemia. Finally, we confirmed drug-induced
hemolytic anemia caused by anti-piperacillin sodium and tazobactam
sodium antibodies.
Case report
A male infant presented with diffuse bruising shortly after delivery.
The infant was delivered on September 4, 2020. He was G1P2 with a
gestational age of 37 weeks. He was delivered by a cesarean section from
a twin pregnancy. The birth weight was 2060 g, and the Apgar score was
10 points for 1 min, 5 min, and 10 min. The mother of the infant
received oocyte donation (OD) through in vitro fertilization-embryo
transfer (the two oocytes were from different donators) due to ovarian
failure. The mother’s blood type was B type and Rh positive, and the
father’s blood type was O type and Rh positive. During pregnancy, the
mother had regular check-ups in our hospital and other hospitals.
Ultrasound examination at 26 weeks of gestation revealed that the main
measurement values of the twins differed by 2-3 weeks, and the right
fetus had excessive amniotic fluid. At 37 weeks of gestation, due to
twin pregnancy and family members refusing attempted vaginal delivery,
cesarean section was performed under epidural anesthesia, and 2
live-born male infants were delivered. Both of them had clear amniotic
fluid, and the placenta and fetal membrane were delivered intact. The
birth weight of infant 1 was 3240 g, and no obvious abnormality was
found on physical examination.
The examination results were as follows: temperature 36.0℃, heart rate
123 beats/min, breathing rate 43 beats/min, blood pressure 54/26 mmHg (1
mmHg=0.133 kPa), and weight 2060 g. The infant presented with diffuse
bruising on the skin. The complete blood count revealed a white blood
cell (WBC) count of 3.29x109/L, absolute neutrophil
count of 1.38x109/L, hemoglobin of 164 g/L, and
platelet count of 32 x 109/L. The infant prothrombin
time was 19.20 sec, activated partial thromboplastin time was 85.2 sec,
thrombin time was 19.40 sec, and fibrinogen was 1.13 g/L. Immunoglobulin
G (IgG) for Toxoplasma , rubella virus, cytomegalic virus, herpes
simplex virus and other pathogens (TORCH) was negative. Blood gas
analysis and blood biochemical examination were generally normal.
Infant 2 was admitted to the neonatal intensive care unit (NICU). He was
treated with piperacillin sodium and tazobactam sodium for four days,
and the blood bacterial culture was negative. He received vitamin K1 and
sulphenamide to stop bleeding and cryoprecipitate transfusion twice to
supplement fibrinogen. A head ultrasound examination after birth showed
no intracranial hemorrhage. During the first month, the infant received
a total of 10 doses of IVIG (1 g/kg each). At first, he was transfused
with leukocyte-depleted platelets three times (10 ml/kg each), but the
platelet count did not rise significantly. He then received two
treatments with platelets that were irradiated and matched with the
infant’s mother. The platelet level increased to more than 120 x
109/L and finally to approximately 72-97
x109/L before discharge. Neutrophils decreased
continuously, and the lowest count was 0.41 x 109/L on
the 25th day after birth. Neutrophils can rise temporarily after
immunoglobulin, and no granulocyte colony stimulating factor was given
during NICU. After treatment with piperacillin sodium and tazobactam
sodium for three days, hemoglobin reached 68 g/L. The Coombs test was
positive, the infants were group O and RhD positive, and irregular
antibodies were negative. Hemolysis caused by acquired antibodies was
considered, and we confirmed drug-induced hemolytic anemia caused by
anti-piperacillin sodium and tazobactam sodium antibodies with
microcolumn gel tests and antihuman globulin tests (MGT-AGTs). Washed
red blood cells (WRBCs) were transfused, phototherapy was given, and
hemoglobin reached a level of 100 g/L on the 10th day after birth.
For detection of glycoprotein antigenic determinants, anti-HPA
antibodies and anti-HNA antibodies were negative in the mother and
children, but anti-HLA class I antibodies were positive. Anti-HLAA2,
HLA-A24 and HLA-A68 antibodies were detected in the sera of the mother
and children and showed strong positivity. To further prove that
anti-HLA class I antigen incompatibility is the cause of the anti-HLA
antibody, we further tested the HLA class I antigen of the children.
Table 1
HLA class I antibodies present in the mother and HLA A and B typing of
the infant.