Would it be possible to prevent HPA‐1a alloimmunization to reduce the incidence of fetal and neonatal alloimmune thrombocytopenia?

F etal and neonatal alloimmune thrombocytopenia (FNAIT) has been considered the platelet (PLT) equivalent of hemolytic disease of the fetus and newborn (HDFN). These conditions are caused by destruction of fetal PLTs or red blood cells (RBCs), respectively, by maternal alloantibodies that have crossed the placenta. Knowledge and awareness of FNAIT and treatments for this disease have lagged behind those for HDFN because of the relatively low incidence of FNAIT (86 per 100,000 live births in a recent review of data) compared to HDFN (approx. 1%, before it became preventable) and early discovery of the cellular pathogenesis of HDFN that led to introduction of Rh immune globulin prophylaxis (RhIG) in 1968. This therapy has been incredibly successful at preventing HDFN, which raises the question of whether it would be possible to do the same for FNAIT? The following discussion is restricted to the antibodies responsible for the great majority of cases of HDFN and FNAIT among Caucasian populations, anti-D and anti-human PLT antigen (HPA)-1a, respectively. Both diseases can result in death or lifelong disability. With HDFN, severe neurologic complications are due to the destruction of brain stem basal ganglia by bilirubin toxicity occurring with severe jaundice in neonates (kernicterus). More variable neurologic impairment such as blindness and cerebral palsy is caused by intracranial hemorrhage (ICH) in FNAIT. In countries with stringent anti-D prophylaxis programs, the incidence of these encephalopathies is now similar with HDFN and FNAIT, approximately 2 per 100,000 births. Underreporting occurs with both diseases. Despite some similarities, there are contrasting features of the clinical presentation, antibody response, and current therapies of these two alloimmune cytopenias, listed in Table 1. Several curious differences between the generation of maternal anti-HPA-1a and anti-D responses are as yet unexplained. First, in several studies, FNAIT often occurs in primigravidae, while this is rare for HDFN. This observation suggests immunizing factor(s) are present during HPA-1a–incompatible pregnancies, in addition to HPA-1a–positive fetal PLTs. Second, unusually for an alloantibody response, HPA-1a immunization and FNAIT are highly restricted to women with HLA Class II DRB3*0101 (91%) or DQB1*0201 (94%). (Approximately one third of the population have these alleles, which are also associated with some autoimmune diseases.) Third, anti-HPA-1a concentrations in alloimmunized women persist after pregnancy, whereas anti-D gradually declines within months or years of immunizing events. Fourth, although anti-HPA-1a is responsible for approximately 80% of cases of FNAIT, it is rarely stimulated by transfusion. In contrast, anti-D is the most frequent antibody produced after mismatched (but ABO-compatible) transfusion and pregnancy. Finally, while IVIG administration to pregnant women can prevent ICH in FNAIT, it has little or no effect in ameliorating HDFN. FNAIT is usually diagnosed after the birth of an affected baby, by the presence of widespread petechiae or purpura but occasionally after ICH or a perinatal death. Subsequent pregnancies are managed predominantly by IVIG infusion to the mother. The dose and duration of IVIG are dependent on the likely severity of fetal thrombocytopenia, assessed by previous history. Administration of steroids and/or intrauterine transfusion (IUT) of HPA1a–negative PLTs (after fetal blood sampling to determine PLT count) is performed only in a few selected cases. The management options have changed little in 20 years but the choice has greatly shifted toward the increased use of IVIG that has largely replaced fetal interventions except for the most severe cases. There is as yet no primary prevention for FNAIT. To introduce antenatal screening programs to detect either HPA-1a–alloimmunized women (0.1%-0.2%) or at-risk women (HPA-1a negative [ 2%], perhaps also being DRB3*0101 positive, i.e., approx. 0.7% of all pregnancies), treatment must be available. The current therapy given to women with antibodies would be IVIG. IVIG is expensive. Currently it is only used for HPAalloimmunized women identified as a result of affected pregnancies. The cost per pregnancy treated (approx. $100,000-$400,000) depends on the dose (1 or 2 g/kg/ week), weeks of treatment (10-25 weeks), and manufacturer of IVIG. If a screening program were adopted and a cheap low dose were to be given to all alloimmunized women (2 per 1000) this therapy would cost $800 million in the United States (£100 million in the United Kingdom). TRANSFUSION 2012;52:1393-1397.