Neonatal alloimmune thrombocytopenia
Synonyms
4
Overview
Neonatal alloimmune thrombocytopenia (NAITP, NAIT, NATP or NAT) is a disease that affects babies in which the platelet count is decreased. Platelet antigens are inherited from both mother and father. NAIT is caused by antibodies specific for platelet antigens inherited from the father but which are absent in the mother. Fetomaternal transfusions (or fetomaternal hemorrhage) results in the recognition of these antigens by the mother's immune system as non-self, with the subsequent generation of allo-reactive antibodies which cross the placenta. NAIT, hence, is caused by transplacental passage of maternal platelet-specific alloantibody and rarely human leukocyte antigen (HLA) allo-antibodies (which are expressed by platelets) to fetuses whose platelets express the corresponding antigens. NAIT occurs in somewhere between 1/800 and 1/5000 live births. More recent studies of NAIT seem to indicate that it occurs in around 1/600 live births in the Caucasian population.
Symptoms
Frequently, the thrombocytopenia is mild and the affected neonates remain largely asymptomatic. In these cases, therapeutic interventions are not indicated. In case of severe thrombocytopenia, the neonates may exhibit hemorrhagic complication at or a few hours after delivery. The most serious complication is intracranial hemorrhage, leading to death in approximately 10% or neurologic sequelae in 20% of cases.
Causes
About 80% of cases of NAIT are caused by antibodies against platelet antigen HPA-1a, 15% by anti-HPA-5b, and 5% by other antibodies (e.g. HPA-1b, HPA-15, HPA-3 and HPA-9b). HPA-1a is present in 98% of the population of the United States, suggesting that approximately 2% of women who are HPA-1a negative may be at risk for NAIT during pregnancy. Of course, the antigen expression of the father must also be taken into account—in most cases the father is HPA-1a/1a or 1a/1b and the mother is HPA-1b/1b with anti-HPA-1a antibodies. In Asians, HPA-4 antigens are the most frequently implicated.
Studies have shown a relationship between maternal HLA type DRw52a (DRB3* 0101) and the development of anti-HPA-1a.
The offending antibodies are IgG subtype and therefore capable of crossing the placenta and entering the fetal circulation.
Unlike hemolytic disease of the fetus and newborn, NAIT occurs during the first pregnancy in up to 50% of cases, and the affected fetuses may develop severe thrombocytopenia (<50,000 μL−1) very early during pregnancy (as early as 20 weeks gestation, consistent with the development of platelet antigens, and the majority of the time in utero). Usually, the thrombocytopenia increases as gestation progresses. During the first pregnancy, NAIT is often not detected until birth when the newborn presents with classic symptoms of thrombocytopenia including petechiae, bruising or intracranial hemorrhage.
In utero intracranial hemorrhage occurs in about 10% to 30% of affected cases (and NAIT is thought to be the underlying cause in the majority of cases of intracranial hemorrhage due to thrommbocytopenia- greater than all other causes of thrombocytopenia combined). The risk of hemorrhage is inversely related to the platelet count with the greatest risk when the platelet count is below 100,000 μL−1.
The recurrence of NAIT has been estimated to be more than 80% in subsequent pregnancies with incompatible fetuses (i.e. subsequent pregnancies which also carry the target platelet antigen). Subsequent cases of NAIT may be equivalent or more severe.
The fetal response to NAIT is variable and may include compensatory extramedullary hematopoiesis. Rarely, fetal hydrops may develop. Fetal anemia (in presence of red cell incompatibility) may also occur.
Diagnosis
Maternal and paternal platelet antigen phenotyping and screening of the maternal serum for anti-platelet antibodies can be performed.
Additionally, platelet antigen genotyping can be performed on the maternal and paternal blood to determine the exact nature of the incompatibility.
Neonatal platelet counts on laboratory testing are typically under 20,000 μL−1. Higher counts may suggest a different diagnosis, such as maternal immune thrombocytopenic purpura.
Treatment
During pregnancy
Cordocentesis can be performed in utero to determine the platelet count of the fetus. This procedure is only performed if a prior pregnancy was affected by NAIT. Intrauterine transfusions can be performed during cordocentesis for primary prevention of intracerebral hemorrhage. Any administered cellular blood products must be irradiated to reduce the risk of graft-versus-host disease in the fetus. Additionally, all administered blood products should be CMV reduced-risk (CMV seronegative and leukoreduced are considered essentially equivalent for the purposes of CMV risk reduction).
If intrauterine platelet transfusions are performed, they are generally repeated weekly (platelet lifespan after transfusion is approximately 8 to 10 days). Platelets administered to the fetus must be negative for the culprit antigen (often HPA-1a, as stated above). Many blood suppliers (such as American Red Cross and United Blood Services) have identified HPA-1a negative donors. An alternative donor is the mother who is, of course, negative for the culprit antigen. However, she must meet general criteria for donation and platelets received from the mother must be washed to remove the offending alloantibody and irradiated to reduce the risk of graft-versus-host disease. If platlet transfusions are needed urgently, incompatible platelets may be used, with the understanding that they may be less effective and that the administration of any blood product carries risk.
The use of Intravenous immunoglobulin (IVIG) during pregnancy and immediately after birth has been shown to help reduce or alleviate the effects of NAIT in infants and reduce the severity of thrombocytopenia. The most common treatment is weekly IVIG infusions at a dosage of 1 g/kg beginning at 16 to 28 weeks of pregnancy, depending on the severity of the disease in the previous affected child, and continuing until the birth of the child. In some cases this dosage is increased to 2 g/kg and/or combined with a course of prednisone depending on the exact circumstances of the case. Although this treatment has not been shown to be effective in all cases it has been shown to reduce the severity of thrombocytopenia in some. Also, it is suspected that (though not understood why) IVIG provides some added protection from intercranial haemorrhage (ICH) to the fetus. Even with IVIG treatment, the fetal platelet count may need to be monitored and platelet transfusions may still be required.
The goal of both IVIG and platelet transfusion is to avoid hemorrhage. Ultrasound monitoring to detect hemorrhage is not recommended as detection of intracranial hemorrhage generally indicates permanent brain damage (there is no intervention that can be performed to reverse the damage once it has occurred).
Before delivery, the fetal platelet count should be determined. A count of >50,000 μL−1 is recommended for vaginal delivery and the count should be kept above 20,000 μL−1 after birth.
After birth
The most rapidly effective treatment in infants with severe hemorrhage and/or severe thrombocytopenia (<30,000 μL−1) is the transfusion of compatible platelets (i.e. platelets from a donor who, like the mother, lacks the causative antigen). Additionally, if the thrombocytopenia in the infant at birth is not severe enough to warrant a transfusion of platelets (>30,000 μL−1) an infusion of IVIG (1 g/kg/day for two days) in the infant has been shown to rapidly increase platelet count and reduce the risk of related injury.
After a first affected pregnancy, if a mother has plans for a subsequent pregnancy, then the mother and father should be typed for platelet antigens and the mother screened for alloantibodies. Testing is available through reference laboratories (such as ARUP). DNA testing of the father can be used to determine zygosiity of the involved antigen and therefore risk to future pregnancies (if homozygous for the antigen, all subsequent pregnancies will be affected, if heterozygous, there is an approximate 50% risk to each subsequent pregnancy). During subsequent pregnancies, the genotype of the fetus can also be determined using amniotic fluid analysis or maternal blood as early as 18 weeks gestation to definitively determine the risk to the fetus.