HLA antibodies and neonatal alloimmune thrombocytopenia

A female baby with a severe thrombocytopenia at 18 x 10(9)/l was born to a 29-year-old (gestation 2/partum 2) mother. Scattered petechiae were present on her legs, arms, chest and face, but there was no bleeding, infection, fever or hepatosplenomegaly. A platelet antibody screening immunocapture test was positive, which was performed on the mother's serum 3, 12 and 38 days after delivery, but no platelet-specific antibodies were found by the monoclonal-antibody-specific immobilization of platelet antigen assay. The baby's platelets and lymphocytes and the father's platelets reacted strongly with the HLA antibodies present in the mother's serum. The neonate was treated with intravenous human immunoglobulin (Tegeline), 1 g/kg per day) 1, 2 and 3 days after delivery. The platelet count rose from 18 x 10(9)/l on day 0 to 37 x 10(9)/l on day 3 and to 227 x 10(9)/l on day 12. No platelet transfusion was needed. Several factors which developed hereafter lead us to think that this neonatal alloimmune thrombocytopenia is due to the transplacental passage of maternal HLA antibodies to the baby.     

The fetal and neonatal consequences of maternal alloimmune thrombocytopenia

Alloimmune thrombocytopenia is a relatively common and under-recognized entity. Prospective screening studies have suggested that at least 1 in every 1000 babies will be affected. While the severity of prospectively identified neonates is not as great as those 'routinely' identified as newborns, the incidence of intracranial haemorrhage in the fetus and neonate is the highest for any immune thrombocytopenia. Diagnosis is complex for the laboratory in view of the large number of platelet antigens and the importance of having sufficient numbers of typed controls. The importance of identifying the affected newborn extends to the likely need for antenatal management of the subsequent affected fetus. Studies to determine the optimal approach to this problem are ongoing. Ideally, prenatal screening of all pregnant women could be performed but this is not currently in practice.     

High-dose IgG treatment for neonatal alloimmune thrombocytopenia

Summary Twelve children with neonatal alloimmune thrombocytopenia (NAT) due to Zw^a incompatibility were treated with intravenous IgG (IVIG). Total doses ranged between 1 and 9 g. Ten out of 12 infants had a favorable response. It is concluded that IVIG can serve as an emergency treatment in NAT if material (or compatible) platelets are not available.This work was supported by the Deutsche Forschungsgemeinschaft (Mu 277/9–6)Presented at the International Workshop on ITP, August 26 and 27, 1988, Lucerne, Switzerland     

Advances in the management of alloimmune thrombocytopenia

There have been considerable advances in the clinical and laboratory diagnosis of alloimmune thrombocytopenia (AIT), and its postnatal and antenatal management. The antenatal management of AIT has been particularly problematic, because severe haemorrhage occurs as early as 16 weeks gestation and there is no non-invasive investigation that reliably predicts the severity of AIT in utero. The strategies for antenatal treatment have included the use of serial platelet transfusions that, while effective, are invasive and associated with significant morbidity and mortality. Maternal therapy involving the administration of intravenous immunoglobulin and/or steroids is also effective and associated with fewer risks to the fetus. Significant recent progress has involved refinement of maternal treatment, stratifying it according to the likely severity of AIT based on the history in previous pregnancies. However, the ideal antenatal treatment, which is effective without causing significant side-effects to the mother or fetus, has yet to be determined, and further clinical trials are needed.     

Predicting risk severity and response of fetal neonatal alloimmune thrombocytopenia

Fetal neonatal alloimmune thrombocytopenia (FNAIT) is a devastating bleeding disorder in the fetus or neonate caused by transplacental transport of maternal alloantibodies to paternal‐derived antigen on fetal platelets. In Caucasians, up to 80% of FNAIT cases result from maternal immunization to human platelet antigen (HPA)‐1a. New methods have developed facilitating detection of common and private antibodies against HPAs triggering FNAIT. Understanding the pathogenesis of FNAIT made it possible to develop a novel strategy to treat this disorder. To date, recombinant monoclonal antibodies directed against the β3 integrin and Fc receptors have been tested in a mouse model of FNAIT, and seem to be promising. Whether those novel treatments will eventually replace the conventional high dose immunoglobulin G in women with FNAIT is yet unknown.     

Prenatal diagnosis of neonatal alloimmune thrombocytopenia using allele-specific oligonucleotide probes

The prediction of neonatal alloimmune thrombocytopenia (NATP) in affected families has, in the past, been based on information about gene frequencies of the antigen systems involved, parental phenotyping, and fetal platelet counts. We explored the feasibility of allele-specific oligonucleotide probe typing for PIA antigens to determine the risk of second or subsequent fetuses in families where one infant had a diagnosis of anti-PIA1-mediated NATP. A total of eight families at risk for delivering an affected fetus were studied with both serologic and oligonucleotide typing. The correlation between serologic and oligonucleotide PIA types was 100%. Similarly, in an additional eight families not at risk for PIA1-mediated NATP, serologic and oligonucleotide typing maintained a perfect correlation. DNA isolated from fetal leukocytes as well as fetal amniocytes was successfully typed using this technology. Oligonucleotide-based typing of fetuses at risk for NATP whose fathers are heterozygous for the PIA antigens allows early recognition of affected fetuses so that prenatal therapy of mothers can be instituted if necessary. When fetuses are found to be unaffected, invasive, and/or expensive, prenatal interventions can be avoided.     

Fetal and neonatal alloimmune thrombocytopenia: progress and ongoing debates

Fetal and neonatal alloimmune thrombocytopenia (AIT) is a result of a parental incompatibility of platelet-specific antigens and the transplacental passage of maternal alloantibodies against the platelet antigen shared by the father and the fetus. It occurs in approximately 1 in 1000 live births and is the most common cause of severe thrombocytopenia in fetuses and term neonates. As screening programs are not routinely performed, most affected fetuses are identified after birth when neonatal thrombocytopenia is recognized. In severe cases, the affected fetus is identified as a result of suffering from an in utero intracranial hemorrhage. Once diagnosed, AIT must be treated antenatally as the disease can be more severe in subsequent pregnancies. While there have been many advances regarding the diagnosis and treatment of AIT, it is still difficult to predict the severity of disease and which therapy will be effective.     

Antigen-positive platelet transfusion in neonatal alloimmune thrombocytopenia (NAIT)

Neonatal alloimmune thrombocytopenia (NAIT) is a fetomaternal incompatibility most commonly induced by maternal anti-HPA-1a, IgG alloantibodies against a polymorphic epitope of the glycoprotein IIb/IIIa complex in approximately 97.5% of white patients. Current guidelines recommend transfusion of immunologically compatible platelets to prevent cerebral hemorrhage, the most severe complication in affected newborns. Such platelet concentrates, however, are often not readily available. In a retrospective analysis in German and Canadian centers, 27 newborns with NAIT were identified who received platelets from random donors. Unexpectedly, 24 of 27 newborns showed an increase above a threshold of 40 x 10(9) platelets per liter, with moderate (n = 8) or significant (n = 16) platelet count increments (more than 80 x 10(9)/L). We conclude that transfusion of platelet concentrates from random donors is an appropriate strategy in the management of unexpected, severe NAIT predominantly in first pregnancies, pending the availability of compatible platelets.     

Neonatal alloimmune thrombocytopenia

Neonatal alloimmune thrombocytopenia (NAIT) occurs when maternal alloantibodies to antigens present on fetal platelets cause their immune destruction resulting in thrombocytopenia in the newborn infant or fetus. Bleeding may be severe; intracranial haemorrhage and permanent neurological damage are the most serious complications. Despite the severity of the disease, there is often a delay in making the correct diagnosis and instigating appropriate treatment. Recent evidence that NAIT is more common than has previously been recognised, a better understanding of the molecular basis of platelet serology and advances in technology, which have made it possible to take blood samples from fetuses and transfuse them in utero, have all contributed to a growing interest in this condition. In addition, it is exciting to realise that an aggressive approach to the management of established cases and 'at risk' pregnancies can prevent serious neurological sequelae and dramatically improve the outcome for affected infants.