Massive fetal hemorrhage and fetomaternal alloimmune thrombocytopenia from human platelet antigen 5b incompatibility: an unusual association

Abstract

We describe a case of fetomaternal alloimmune thrombocytopenia (AIT) to human platelet antigen (HPA) 5b presenting with severe fetal renal hemorrhage followed 1 week later by diffuse subdural hemorrhage. A 35-year-old Caucasian primigravida was referred to our center at 22 weeks of gestation for suspected severe bilateral hydronephrosis. The woman had unremarkable surgical and medical histories, had not received any blood transfusion nor was receiving any anticoagulant therapy. The targeted ultrasound examination revealed two normal fetal kidneys and no sign of hydronephrosis. However, both kidneys were surrounded by large hypoechoic cyst-like structures with some freely floating specks, indicative of uncoagulated hematomas (Figure 1). There was concurrent significant ascites, possibly of hematic origin. No other congenital or acquired anomaly was detected. The patient was counseled about the unusual nature of the fetus' abdominal problem and agreed to undergo the panel of blood tests that are advisable in cases of fetal hemorrhage. These included serology for parvovirus B19 and cytomegalovirus, and tests to disclose possible AIT. At a follow-up ultrasound examination 5 days after the initial one, in addition to an increase in ascites, the presence of a diffuse subdural, probably hematic, effusion was noted (Figure 2) which was confirmed on magnetic resonance imaging. Ultrasound image showing bilateral perirenal hemorrhage (LKH, left kidney hemorrhage). Note how the hemorrhage has dislodged the left kidney from its usual position. A, ascites; arrows, right kidney; arrowheads, left kidney). Ultrasound images in different planes showing the subdural hemorrhage (arrowheads and arrows) at different levels: (a) axial view; (b) parasagittal view of the insula/sylvian fossa; (c) midsagittal view; and (d) coronal view of the frontal subdural spaces. At all the sites, visible speckles of blood (arrows and arrowheads) were seen freely moving in the subdural spaces. C, cerebellum; CC, corpus callosum. All serological tests for prenatal infections proved negative, whereas the assessment of platelet antigens showed parental incompatibility for HPA-5b. Maternal anti-HPA-5b antibodies were detected with a high titer (> 1 : 128), whereas no antibodies against any other platelet glycoproteins were found. Cross-matching maternal and paternal blood was positive. A definitive diagnosis of fetomaternal HPA-5b alloimmunization was established. The peak systolic velocity of the middle cerebral artery was on the 95th centile for gestational age, which could be consistent with the presence of mild post-hemorrhagic anemia1. A cordocentesis to ascertain fetal platelet and red blood cell counts was proposed, but the patient declined and opted for termination of pregnancy. This was performed by prostaglandin administration via vaginal suppositories at another institution closer to the patient's residence. The necropsy report confirmed the presence of bilateral perirenal and diffuse subdural hemorrhage. The ascites was blood tinged. No other anomalies were found. AIT results from maternal immunization against fetal platelet antigens of paternal origin. Maternal exposure to these antigens during pregnancy can lead to production of various classes of immunoglobulins: the IgG antibodies are small enough to cross the placental barrier and enter the fetal circulation, causing severe thrombocytopenia. Unlike hemolytic disease of the newborn, AIT can also occur in the first pregnancy if there is parental incompatibility. According to the time of onset, the disease can be referred to as fetomaternal or neonatal AIT. The former often leads to severe hemorrhage and even intrauterine death during the second trimester, whereas the latter represents the most common cause of severe thrombocytopenia in neonates2. To date, five biallelic HPA alloantigen systems have been found to be more frequently associated with severe AIT; they are inherited autosomally and in each codominant antigen pair the more common antigen is designated ‘a’ and the rarer antigen is designated ‘b’. HPA-5 is the biallelic system expressed on the platelet glycoprotein (GP) Ia/Iia. The HPA-5a/b polymorphism is based on a single base variation at position 505 on the GP Ia gene3. Among the various platelet antigens involved in AIT, immunization against HPA-1a (P1A1) is by far the most common cause of severe fetal and neonatal thrombocytopenia among individuals of Caucasian origin, accounting for 80–85% of cases4-6. Anti HPA-5b (Br) accounts for 10–15% of AIT cases3, 4-6, and the remaining 5% are due to multiple antigen alloimmunization. In the neonate, HPA-5b alloimmunization has significantly less severe manifestations than HPA-1a alloimmunization, with a reported incidence of intracranial hemorrhage of 0–8% and 14–30% respectively5-7. In pregnancy, the diagnosis of AIT usually follows the detection of massive fetal hemorrhage leading to severe anemia or death, and is due to HPA-1a in the overwhelming majority of cases2, 6; to the best of our knowledge, severe hemorrhage due to HPA-5b alloimmunization has not previously been reported in the fetus. Another peculiarity of this report regards the sites of the fetal hemorrhage, namely the kidneys and subdural spaces. In particular, the latter site of hemorrhage is uncommon for AIT, the most common site of cerebral hemorrhage being intraparenchymal6. We do not know why the hemorrhage was subdural in this case; it may be speculated that this rare location may be related somehow to the type of antigen involved in the immunization, although reports addressing the types of lesion related to HPA-5b AIT in the neonate confirm the preferential intraparenchymal location6. We acknowledge that a limitation of this report is that we do not have direct evidence of the presence of thrombocytopenia as the couple declined cordocentesis. However, the high anti-HPA-5b titer (> 1 : 128) and the concurrent presence of massive fetal hemorrhage in two places make the causal relationship very likely. In fact, at least in some reports, raised anti-HPA-5b titers (> 1 : 32 or ≥ 1 : 64) have been associated with a higher risk of neonatal thrombocytopenia8 and, furthermore, in the case of anti-HPA-1a AIT, the maternal antibody titer has been shown to be predictive of fetal thrombocytopenia9. A thorny issue is the therapy of choice for AIT. At least when directed against HPA-1a, this condition progressively worsens if untreated and leads, with increasing frequency, to severe fetal hemorrhage; spontaneous regression has never been reported. Therefore, once diagnosed, AIT should be treated. However, the various therapies proposed so far (weekly high-dose intravenous immunoglobulins alone or with steroids, fetal platelet transfusions with antigen-negative platelets) have yielded controversial results2, acknowledged by a recent report in the Cochrane Library10. Likewise, the suggested employment of Cesarean section as a means of preventing perinatal intracranial hemorrhage has yet to be supported by conclusive data10. In conclusion, we have described the prenatal diagnosis of massive fetal multiorgan hemorrhage due to fetomaternal AIT against the HPA-5b antigen, which has not previously been related to such severe lesions in the fetus. D. Paladini*, G. M. Maruotti*, G. Sglavo*, G. Fratellanza , M. Quarantelli , P. Martinelli*, * Fetal Cardiology Unit, Department of Obstetrics and Gynecology, University Federico II of Naples, Via Petrarca 72, Naples 80122, Italy, Department of Immunohematology, University Federico II of Naples, Via Petrarca 72, Naples 80122, Italy, Biostructure and Bioimaging Institute, National Research Council, Naples, Italy