Perinatal/Neonatal Case Presentation

Massive intracranial hemorrhage caused by neonatal alloimmune thrombocytopenia associated with anti-group A antibody

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Neonatal alloimmune thrombocytopenia (NAIT) is a rare but clinically important etiology of intracranial hemorrhage. There have been no reported cases of intracranial hemorrhage caused by anti-group A or anti-group B antibodies. A Japanese boy weighing 1550 g was born at 37 weeks. He suffered from refractory thrombocytopenia and developed severe intracranial hemorrhage on his second day. Despite repeated platelet, red-cell and fresh-frozen-plasma transfusions, he died at day 10 of life. Serological studies and genotyping of the patient and his parents were performed. There were no incompatible genotypes of platelet antigens between the patient and the mother. Serological studies revealed that the mother had extremely high-titer anti-group A immunoglobulin G2 (4096-fold) that reacted strongly with the father's platelets. The reaction against the father's platelets disappeared when her serum was adsorbed with group A red blood cells. Maternal anti-group A antibody was associated with NAIT and severe bilateral intracranial hemorrhage.


Neonatal alloimmune thrombocytopenia (NAIT) is a rare but clinically important etiology of neonatal thombocytopenia caused by maternal immunoglobulin (Ig) G alloantibodies directed against fetal platelet antigens. In a Japanese population study, platelet antibodies were detected in 0.91% of maternal samples and thrombocytopenia was observed in 18 of 24 630 (0.07%) neonatal samples.1 The most serious complication of NAIT is intracranial hemorrhage (ICH), which occurs in approximately 10–20% of affected newborns.2 It is well documented that antibodies to human platelet antigen (HPA) -1a and HPA-4 are the most important cause of NAIT in Caucasians and Asians, respectively. NAIT may rarely be caused by other antigens, and Curtis et al.3 reported blood group B antibodies as a causative antigen, but little is known about the pathogenesis of NAIT by ABO antigens. We report a case of severe intracranial hemorrhage associated with NAIT from an anti-group A isoantibody.


A Japanese boy was delivered at 37 weeks of gestation to a 36-year-old gravida2 para1 by emergency cesarian section because of non-reassuring fetal status. He did not have any relatives who were known to have suffered NAIT previously. The outcome of her first pregnancy had been spontaneous abortion. Our patient's measurements at birth were: weight 1550 g (third percentile), length 44 cm (<tenth percentile) and head circumference 30 cm (tenth percentile), suggesting that he was small for gestational age. His Apgar score at 1 min was 5. Hepatomegaly, splenomegaly and gastric hemorrhage were noted at birth, and he was transferred to a secondary-referral neonatal intensive care unit (NICU) on day 0 of life. Blood types of his family were as follows: father - group A, D(+), mother - group O, D(+), the patient - group A, D(+). His mother's platelet counts during pregnancy were normal.

On admission, his hemoglobin was 13.6 g dl−1, platelet count was 2.1 × 104 μl−1 and gastrointestinal bleeding continued. He was pale with generalized petechiae, but head ultrasound was normal. He was transfused with fresh-frozen plasma and platelets. Toxoplasma, rubella, cytomegalovirus and herpes simplex virus serologies were negative. On his first day, his hemoglobin dropped to 6.4 g dl−1 without ICH and he was transfused with group-A packed red cells. On his second day of life, though his platelet count had increased to 12.4 × 104 μl−1, his hemoglobin dropped to 5.4 g dl−1 and his systolic blood pressure deteriorated despite transfusion. Ultrasound revealed new ICH, and head computed tomography showed a severe subdural hematoma with parenchymal hemorrhage causing midline shift of the brain stem. Then he was transferred to our tertiary-referral NICU. He was in compensated hemorrhagic shock with continued pallor and generalized petechiae, a hemoglobin count of 6.7 g dl−1 and a platelet count of 4.5 × 104 μl−1. His total serum bilirubin was 7.0 mg dl−1, and during his stay in our NICU, he never showed icterus. On his nineth day of life, he again developed anemia and thrombocytopenia, which was refractory despite continuous transfusion. His head computed tomography revealed new parenchymal hemorrhage (Figure 1), and he died at tenth day of life.

Figure 1

Axial and coronal sections of head computed tomography (CT) of the patient at nineth day of life. The CT showed old subdural and parenchymal hemorrhage around the left temporal lobe and new multiple parenchymal hemorrhages from the frontal to the parietal lobe.

Informed consent for postmortem computed tomography, autopsy and presentation was obtained from the parents. Autopsy showed encephalomalacia, hepatomegaly and splenomegaly. Microscopic examination revealed liver cell necrosis and cholestasis, but there was no hemophagocytosis.


Platelet-reactive antibodies of the patient and mother were characterized by measuring specificity and titer using mixed passive hemagglutination (MPHA)4 and were detected with the anti-PLT-MPHA-Screen kit (Beckman Coulter, Tokyo, Japan). Crossmatching between maternal serum and paternal platelets was performed using the Magnetic-MPHA method.5

The IgG subclass isotype was determined by flow cytometry (Cytomics FC500, Beckman Coulter, Brea, CA, USA) with commercial murine anti-human monoclonal IgG1, IgG2, IgG3 and IgG4 antibodies (The Binding Site Group Limited, Birmingham, England).

Their HPA and human leukocyte antigen (HLA) were genotyped by WAKFlow HPA typing kit Ver.5 (Wakunaga Pharmaceutical, Hiroshima, Japan) and Genosearch-HLA/A, /B, /C kit, Ver.2 (Medical and Biological Laboratories, Nagoya, Japan), respectively.


The anti-platelet-MPHA-Screen revealed that the patient and his mother had no anti-HPA or anti-HLA antibodies. The parents and the case had no HPA or HLA genotype incompatibility (Table 1). However, the mother's serum sample contained an extremely high level of anti-group A antibody (4096-fold) that reacted strongly with the father's platelets. The reaction completely disappeared when the mother's serum was absorbed with standard group A red blood cells but not group O red blood cells. Flow cytometry analysis showed that maternal serum contained a high level of IgG2 antibody, with a sample to negative control ratio of 8.3.

Table 1 Serological studies and genotyping of the patient and his parents


ICH is the most lethal complication in NAIT-affected newborns. A case series reported that the incidence of ICH in babies with NAIT is about 14%.6 Wilke et al.7 reported a premature newborn that suffered from anti-HPA-1a antibody-derived NAIT and showed massive ICH. Their case underwent operation on the third day of life for a massive left parenchymal lesion. Our case also had a subdural and parenchymal hemorrhage and a midline shift of his brain stem already at admission to our NICU. After discussion with the pediatric neurosurgeon and the patient's parents, we concluded that his massive ICH with midline shift of the brain stem was inoperable.

Intrauterine fetal demise and intrauterine growth restriction are other well-known complications of NAIT.8 The most frequent antigen causing NAIT is different among ethnic groups; the HPA-4 system is the most frequent cause of NAIT in Asians. There are a few reports of NAIT caused by ABO antigens.3 Curtis et al.3 reported that high-titer blood group antibodies acquired from the mother can cause thrombocytopenia in high-expresser infants. They also reported that there is a population with platelet expression of group A antigen that is about 10 to 20 000 times higher than the general population.9 Ogasawara et al.10 showed that platelets from a high expresser of blood group B were rapidly destroyed upon being transfused to a group O patient, supporting the importance of high-expressor status.

In our case, the direct cross match showed that maternal anti-group A IgG reacted with paternal group A antigen presented on paternal platelets. Although we could not examine the patient's own antigen-presenting levels on platelets because of his death, examination of his parents strongly suggested that high-titer anti-group A antibody from his mother destroyed his platelets, which expressed the group A antigen inherited from his father. Although we could not genotype for rare antigens or screen for rare antibodies, due to lack of sample availability, our data shows that the chance that this case of NAIT was caused by such rare phenotypes is very small.

Secondary intracranial hemorrhage might have occurred in this case because random-donor-transfused platelets might have been destroyed by the anti-group A antibody in the patient's circulation. Although washed, irradiated maternal platelets or antigen-negative donor platelets are recommended in NAIT, random-donor platelets are recommended for patients, such as ours who bleed suddenly before any evidence of alloimmunization.11

The patient's parents were counseled that NAIT could recur in a subsequent pregnancy. As NAIT tends to be more severe in subsequent pregnancies, antenatal management is critical. Although the optimal strategy for prevention and treatment of NAIT is controversial,12 maternal intravenous immunoglobulin and oral glucocorticoid therapy should be considered.


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We thank Drs Norihisa Koyama, Sumio Fukuda, Keiko Mouri and Patricia Bachiller for their helpful advice.

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Correspondence to T Sugiura.

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Kato, S., Sugiura, T., Ueda, H. et al. Massive intracranial hemorrhage caused by neonatal alloimmune thrombocytopenia associated with anti-group A antibody. J Perinatol 33, 79–82 (2013) doi:10.1038/jp.2011.204

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  • intracranial hemorrhage
  • neonatal alloimmune thrombocytopenia
  • intrauterine growth restriction
  • anti-group A antibody
  • immunoglobulin G2

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