Neonatal Alloimmune Thrombocytopenia (NAIT)
CLINICAL SUMMARY: A female infant at 28 weeks gestational age was delivered by Caesarian section to a 32-year-old G5P2022 woman. The infant was the product of a monochorionic twin gestation. At delivery the infant was without respirations, limp and cyanotic. No heart sounds were auscultated. Initial lab data revealed:
Despite resuscitative efforts, the infant died one hour after delivery.
Twin B also presented with respiratory distress at birth. Initial laboratory workup revealed:
Twin B recovered and was discharged to home three weeks after birth.
AUTOPSY FINDINGS: At autopsy, the infant weighed 1450 grams (expected weight of 1100 grams). The crown-heel length was 39 cm (expected crown-heel length 39 cm). Large peritoneal, pleural, and intracranial hemorrhages were present. Petechiae were observed on the serosal surfaces throughout the body. Pathology seen in slides AU-02 (A-E) was present in most organs. The placenta was a diamniotic, monochorionic twin placenta consistent with 28 weeks gestational age. Twenty milliliters of blood was adherent to the maternal surface.
Questions and Discussion: (correct response is underlined)
The clinical workup of thrombocytopenia in this case included alloimmune thrombocytopenia. The mother’s platelet count was within normal limits. Analysis of the mother’s serum revealed antibodies to the platelet antigen, HPA-5b (BRa). Genetic testing revealed that the mother was homozygous for the antigen, HPA-5a (Brb) and that the father was heterozygous (HPA-5b/HPA-5a) for the HPA-5 system. HPAs represent glycoprotein polymorphisms on the platelet surface. They constitute a diallelic antigen system with the alleles designated as “a” and “b.” The HPA-5 system is localized to the integrin α2 subunit of human platelets.
Thrombocytopenia, defined as a platelet count of less than 150,000/mm3, is seen in up to 4% of newborns. Most cases spontaneously resolve. Severe thrombocytopenia, defined by a platelet count less than 50,000/mm3, is an uncommon event. In a study of 15,932 newborns by Burrows and Kelton, severe thrombocytopenia determined from cord blood samples was present in 19 infants.1 Six had platelet counts less than 20,000/mm3. All six cases were due to Neonatal Alloimmune Thrombocytopenia (NAIT). NAIT should not be confused with maternal thrombocytopenia. In the series by Burrows and Kelton, common etiologies for maternal thrombocytopenia consisted of idiopathic thrombocytopenia of pregnancy, hypertensive disease of pregnancy, and immune thrombocytopenias (idiopathic thrombocytopenia purpura and systemic lupus erythematosus).1
NAIT should be considered as a potential diagnosis in any neonate with severe thrombocytopenia. NAIT has been reported to account for up to 27% of severe cases of thrombocytopenia.2 Intracranial hemorrhage is observed in 10-20% of NAIT cases.1,2 Diffuse parenchymal hemorrhage and petechiae are other morphologic features. Fifty percent of the NAIT cases with intracranial hemorrhage occur prenatally.
Prematurity is also associated with thrombocytopenia. The hemorrhage in prematurity is usually periventricular due to the sensitivity of the germinal matrix to hypoxia. In Grade IV intraventricular hemorrhage, extension of blood from the ventricle into the surrounding parenchyma is a finding. Petechiae are not usually present at birth and the platelet count at delivery is not less than 20,000/mm3. Platelet counts less than 20,000/mm3 have been observed in the ICU setting in premature infants, but are not usually present at birth.
Traumatic delivery is associated with intracranial hemorrhage. However, the diffuse parenchymal hemorrhage and low platelet count seen in this case are not features associated with traumatic delivery.
Twin-twin transfusion syndrome was also in the clinical differential diagnosis for this case. Twin-twin transfusion syndrome is associated with antenatal hemorrhage. In a recent study, the incidence of twin-twin transfusion syndrome in monochorionic placentas was 6.2%.3 Twin-twin transfusion syndrome is associated with monochorionic placentas where deep artery-vein anastomoses exist. In the chronic form, there is transfer of blood between the two twins. The donor twin is growth retarded, hypovolemic and anemic in contrast to the recipient twin which is larger than the gestational age, plethoric and hypervolemic.4 A 5 gm/dL difference in hemoglobin concentration and a 20% difference in body weight have been used as diagnostic features.3 Decreased platelet counts have been reported in twin-twin transfusion syndrome. Alloantibodies to human platelet antigens are not a feature of twin-twin transfusion syndrome.
NAIT is a syndrome characterized by thrombocytopenia due to the passive transfer of maternal IgG antibodies that are directed against fetal platelet antigens inherited from the father and absent in the mother. The incidence of NAIT is 1 out of 1,000-2,000 live births. Maternal exposure to fetal platelet antigens absent on maternal platelets may lead to IgG antibody production. The IgG antiplatelet antibodies, if formed, cross the placenta and destroy fetal platelets.2 This mechanism is distinct from idiopathic thrombocytopenia purpura where autoantibodies to platelet antigens destroy maternal platelets, cross the placenta and destroy fetal platelets. Amegakaryocytic thrombocytopenia, in contrast, is a genetic disease that is not associated with antiplatelet antibodies.
The severity of NAIT varies from mild thrombocytopenia without significant bleeding to severe thrombocytopenia leading to diffuse parenchymal hemorrhage and intracranial hemorrhage. Serologic studies have identified 24 distinct platelet specific alloantigens. The terminology is confusing based on the order they were discovered. However, they have been standardized into one of the HPA subtypes as discussed by several authors.5
Human platelet antigens (HPA) represent polymorphisms involving glycoproteins IIb/IIIa, Ib/IX, and Ia/IIa on the surface of platelets.2 Most involve a single amino acid substitution in the glycoprotein. For example, HPA-1 is characterized by the Leu33/Pro33 polymorphism.5 HPA-1a contains a leucine at position 33 of GP IIIA (β3 integrin), whereas, HPA-1b contains a proline molecule at this position. Anti-HPA-1a antibodies have been demonstrated to inhibit clot retraction and platelet aggregation by interfering with the binding of fibrinogen.5 In a recent series of 1162 cases of NAIT, 79% of alloantibodies were directed against the HPA-1a antigen, 9% against the HPA-5b antigen, 4% against the HPA-1b antigen and 2% against the HPA-3b antigen.2 Alloantibodies directed against the other HPAs accounted for less than 1% of the cases. In the HPA-5 system, HPA-5a contains a glutamine at position 505 of the α2 integrin subunit, whereas, HPA-5b contains a lysine molecule at this position.5 Antibodies to HPA-1a and HPA-5b, as in this case, represent the two most common antigen systems involved in NAIT.
See discussion after question 1.
In this case, the preliminary autopsy findings of diffuse petechiae consistent with thrombocytopenia and parenchymal hemorrhages were transmitted to the treating physicians who attended the autopsy. These findings were instrumental in refining the clinical differential diagnosis, in management of the other twin and in directing laboratory testing for antiplatelet antibodies. This case illustrates the value of the pediatric autopsy in not only confirming or rendering a diagnosis but also providing information that is of value for patient management.6
Key Teaching Points: