STATE OF THE ART
Foetal and neonatal alloimmune thrombocytopenia (FNAIT)
Anne Husebekk, Helsefak, Universitetet i Tromsø Overlege, Universitetssykehuset Nord Norge
Thrombocytopenia is detected in around one percent of newborns. In otherwise healthy term newborns, thrombocytopenia is most often caused by alloantibodies transferred from the mother to the foetus. In the Caucasian populations human platelet antigen (HPA)-1a is the most immunogenic HPA. In Japan and China antibodies in the HPA-4 system are the most frequent cause of FNAIT. The immune response against the HPA must be understood in order to avoid immunization or prevent induction of FNAIT where mothers are already immunized.
Thrombocytopenia is detected in around one percent of newborns (platelet count <150 × 10E9/L) . The pathophysiology may be prematurity, infections, syndromes based on genetic variations and antibody induced thrombocytopenia. In most cases the thrombocytopenia is mild and asymptomatic. Foetal and neonatal alloimmune thrombocytopenia (FNAIT) is found in 1:1,100–2,000 newborns in Caucasian populations [2,3]. In otherwise healthy term newborns, severe thrombocytopenia (<50 × 10E9/L) is most often caused by maternal alloantibodies. When the platelet count is less than 50 × 10E9/L, there is risk of haemorrhage. In alloimmune thrombocytopenia, skin bleedings are most common. Intracranial haemorrhage (ICH) is the most feared complication. The frequency of FNAIT associated ICH is 1:12,500–1:25,000 newborns and around 10% of the children die, the rest may have severe life-long disabilities due to brain damage .
Placental transfer of IgG
There is an active transfer of IgG antibodies from the mother to the foetus based on FcRn receptors in throphoblasts . Transplacental transport of IgG protects the foetus and the newborn from infections. The transfer is not based on the specificity of the IgG molecules. This means that maternal antibodies reacting with foetal antigens may destroy or disturb foetal cells and tissues illustrated when the mother has antibodies to thyroid receptors and the newborn has transient hyperthyroidism, and in haemolytic disease of the newborn (HDN) where haemolysis of red cells is induced, most often based on anti-D antibodies transferred from mother to the Rh(D) positive foetus. This is also the case in FNAIT where maternal antibodies to platelet antigens transverse the placenta and bind to antigen positive platelets. The sensitized platelets are in turn removed in the mononuclear phagocyte system and if platelet destruction exceeds platelet production, the foetus or newborn become thrombocytopenic and may be at risk of bleeding.
Platelets have many polymorphic surface molecules, the most polymorphic are the HLA class I molecules. In addition, there are polymorphisms in some of the platelet surface glycoproteins; altogether 17 biallelic systems of human platelet antigens (HPA) have been described . The amino acid differences are based on single nucleotide polymorphisms. Alloimmunization may take place in connection with pregnancy or upon blood transfusions. HPA-1a is the most immunogenic platelet antigen which is found in >80% of FNAIT cases in Caucasians . Since the genetic background differs among ethnic groups, the pattern of immunization differs. In China and Japan, almost all individuals carry the HPA-1a allele and alloimmunization against this antigen is thus extremely rare. On the contrary, the HPA-4b antigen which is absent in Caucasians, is more frequently found in Japan and China and antibodies in the HPA-4 system is the clinically most important platelet antibodies in East Asia [7,8].
Immunization with human platelet antigens
FNAIT is most often diagnosed after birth of a child with thrombocytopenia and bleeding symptoms. Prospective studies have shown that immunization against HPA-1a may take place during pregnancy (around 25%) or at the time of delivery (75%). Also, prospective studies and one retrospective study have shown a correlation between the maternal anti-HPA-1a antibody level and the severity of thrombocytopenia in the newborn [3,9,10]. Some retrospective studies do not support these data [11,12].
Follow-up and treatment of FNAIT
No country has introduced general screening for HPA alloimmunization during pregnancy. In most cases, clinical follow-up and treatment take place in the subsequent pregnancy after birth of a child with FNAIT. Although never documented in randomized clinical trials, many centres will treat immunized women with intravenous immunoglobulin (IVIg) and/or steroids. Intrauterine blood sampling and transfusions are no longer part of standard follow-up procedure due to reports of severe complications . In many cases, delivery is performed by elective caesarean section and compatible platelet concentrates are available for immediate transfusion to the newborn if needed.
Future management of FNAIT
Results from prospective studies in Europe have shown that FNAIT is more similar to haemolytic disease of the newborn (HDN) than thought before . It is believed that treatment with IVIg in the pregnancy and careful delivery and transfusion of platelet to the newborn will reduce morbidity and mortality of FNAIT . Several reports conclude that general screening should be introduced based on the results from the implemented interventions [3,14–16]. The ultimate goal would be to prevent immunizations in women at risk of FNAIT. Experiments in a murine β3 integrin knock-out model have shown that immunization with β3 integrin positive platelets can be avoided by injection of anti-β3-integrin antibodies at the time of immunization . This antibody induced immunomodulatory effect resembles the effect of anti-D given to Rh(D) negative women after birth of an Rh(D) positive child. In Europe we are planning a study where non-immunized HPA-1a negative women will be given anti-HPA-1a antibodies after delivering an HPA-1a positive child. Based on the number of immunization in primigravida, 75% of the HPA-1a immunizations could be avoided by this approach.
The presence of IgG antibodies in the mother is a consequence of activation of HPA-1a specific B- and T-cells . The B-cells need T-cell help to become antibody producing plasma cells . It is conceivable that T-cell tolerance can be induced by blocking the HPA 1a T-cell receptors by non-stimulating peptides . Another approach could be to block anti-HPA-1a antibodies by soluble epitopes or anti-idiotypic antibodies .
Challenges in transfusion medicine related to FNAIT
HPA-1a typing can be performed by genotyping using different PCR methodologies or by phenotyping by ELISA or flow cytometry [22,23]. Detection of anti-platelet antibodies is performed by flow cytometry (including Luminex technology) or ELISA [24,25]. To determine the specificity and quantity of the antibodies, the monoclonal antibody immobilization of platelet antigen assay (MAIPA) is used at present . This method is complicated and labour intensive and has been shown difficult to standardize .
Compatible blood products must be available immediately for severely thrombocytopenic newborn. The platelet unit should be from a donor lacking the platelet antigen that the woman’s antibodies are specific for. If the mother in addition has anti-HLA class I antibodies one should also take these antibodies in account when selecting the platelet donor. To provide compatible platelet products for newborn in need, is challenging and typing of many donors may be necessary . If a newborn shows sign of petechiae and have low platelet count at birth, transfusion of random platelets may be used before diagnosis is made and compatible platelets are available .
In the future, FNAIT due to anti-HPA-1a antibodies may be managed similar to HDN by identifying women at risk in early pregnancy and giving prophylaxis in order to prevent immunization in connection with delivery. Immunization in early pregnancy cannot be prevented by prophylaxis and detailed knowledge about the mechanism of immunization and the activity of the different cell types is necessary to prevent FNAIT in the next incompatible pregnancy of already immunized women.
Bjørn Skogen, Mette Kjær Killie, Jens Kjeldsen-Kragh and Anne Husebekk have shares in a company trying to develope a prophylaxis against HPA-1a immunization.