Fetal and Neonatal Alloimmune Thrombocytopenia
Luis D. PachecoRichard L. BerkowitzKenneth J. MoiseJames B. BusselJanice G. McFarlandGeorge R. Saade
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In Brief Fetal and neonatal alloimmune thrombocytopenia constitutes the most common cause of severe thrombocytopenia in fetuses and neonates and of intracranial hemorrhage among term newborns. The cornerstone of therapy involves the use of steroids and intravenous immunoglobulins. Despite the risk of potentially devastating consequences to the fetus, fetal blood sampling has typically been used to document response to therapy. We propose a therapeutic algorithm based on risk stratification with individualized treatment optimization without the use of fetal blood sampling. Management of fetal and neonatal alloimmune thrombocytopenia requires a priori risk stratification, and treatment should be tailored accordingly.Keywords:
Neonatal alloimmune thrombocytopenia
Risk Stratification
Isoantibodies
Purpose of review The purpose of the review is to show the similarities between haemolytic disease of the foetus and newborn (HDFN) and foetal and neonatal alloimmune thrombocytopenia (FNAIT) and to describe the background and challenges related to the current endeavours of developing a prophylaxis against FNAIT. The rationale for this prophylaxis is similar to the prophylaxis which has been used with great success for the last 40 years against RhD-associated HDFN. The idea is to prevent human platelet antigen (HPA)-1a-associated FNAIT by administering anti-HPA-1a immunoglobulin G (IgG) to nonimmunized HPA-1a-negative women after delivery of an HPA-1a-positive child. Recent findings Results from a Norwegian screening and intervention study on FNAIT have indicated that about 75% of women with antibodies against HPA-1a are immunized in relation to delivery. This observation leads to the possibility of preventing HPA-1a-associated FNAIT in the same way as today's prevention of HDFN. Results from a proof-of-concept study in a murine FNAIT model have shown that the production of alloantibodies against platelets can be suppressed by administrating antiplatelet antibodies after the antigenic challenge. Even more interesting, the prophylactic antiplatelet antibodies could also significantly reduce the clinical consequences of FNAIT in this FNAIT model. Summary These novel observations have paved the way for clinical studies. Production and testing of anti-HPA-1a IgG for clinical use will be carried out by a European Union-funded consortium. If the results from the clinical trial are favourable, there is a chance that a medicinal product for the prevention of FNAIT will be available within this decade.
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BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a severe bleeding disorder caused by maternal antibody–mediated destruction of fetal or neonatal platelets (PLTs). Results from our recent large screening study suggest that the pathophysiology of FNAIT is more similar to hemolytic disease of the fetus and newborn (HDFN) than previously thought. Immunization against HPA‐1a might therefore be preventable by a prophylactic regimen of inducing antibody‐mediated immune suppression (AMIS), which has been documented to be a useful prophylaxis against HDFN. This preclinical proof‐of‐concept study investigated whether passive administration of anti‐β3 integrin could induce AMIS and thereby prevent clinical complications of FNAIT. STUDY DESIGN AND METHODS: A murine model of FNAIT using β3 integrin (GPIIIa)‐deficient (β3−/−) mice was employed for this study. AMIS in β3−/− mice was induced by intravenous administration of human anti‐HPA‐1a immunoglobulin G or murine anti‐β3 antisera given as prophylaxis after transfusion of HPA‐1a–positive human PLTs or murine wild‐type PLTs, respectively. RESULTS: AMIS against both human and murine PLT antigens was induced using this prophylactic approach, reducing the amount of maternal PLT antibodies by up to 90%. Neonatal PLT counts were significantly increased and pregnancy outcome was improved in a dose‐dependent manner. The incidence of intracranial hemorrhage, miscarriage, and dead‐born pups in mice receiving high‐dose prophylaxis was reduced to that of normal controls. We also observed that the severity of thrombocytopenia inversely correlated with birth weight. CONCLUSION: This work conceptually proves that prophylactic administration of PLT antibodies induces AMIS and prevents poor pregnancy outcome in FNAIT.
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A technique is described which permits the detection of platelet-specific, noncomplement-fixing ("blocking') PlA1 antibodies in serologically negative sera of mothers from children suffering from neonatal alloimmune thrombocytopenia. The technique consists of (1) antibody enrichment in eluates prepared from maternal serum and PlA1-positive platelets, and (2) quantitation of antibodies in eluates by the platelet radioactive anti-IgG test. With this assay, PlA1 antibodies were demonstrated in 6 out of 7 maternal sera, and anti-A antibodies in one. It proved valuable also for longitudinal studies for periods up to 30 months after delivery.
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It has been suggested that type I cluster of differentiation 36 ( CD 36)‐deficient individuals are at risk of developing anti‐ CD 36 isoantibodies (also known as anti‐Nak a ) after receiving platelet transfusions or during pregnancy. These antibodies are responsible for several immune thrombocytopenic disorders including fetal/neonatal alloimmune thrombocytopenia ( FNAIT ), post‐transfusion purpura and platelet‐transfusion refractoriness ( PTR ). In Asian populations, anti‐ CD 36 isoantibodies are more frequently found in PTR and FNAIT patients compared to alloantibodies against human platelet antigens. In this short review, we illustrate the relevance of CD 36 by providing information on the frequency and molecular basis of CD 36 deficiency, laboratory diagnostic tests of CD 36 antigens/antibodies and treatment of immune‐mediated thrombocytopenia caused by anti‐ CD 36 antibodies.
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Abstract A technique is described which permits the detection of platelet‐specific, noncomplement‐fixing (‘blocking’) Pl A1 antibodies in serologically negative sera of mothers from children suffering from neonatal alloimmune thrombocytopenia. The technique consists of (1) antibody enrichment in eluates prepared from maternal serum and Pl A1 ‐positive platelets, and (2) quantitation of antibodies in eluates by the platelet radioactive anti‐IgG test. With this assay, Pl A1 antibodies were demonstrated in 6 out of 7 maternal sera, and anti‐A antibodies in one. It proved valuable also for longitudinal studies for periods up to 30 months after delivery.
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Neonatal alloimmune thrombocytopenia
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A technique is described which permits the detection of platelet-specific, noncomplement-fixing (‘blocking’) P1^AI antibodies in serologically negative sera of mothers from children suffering from neonatal alloimmune thrombocytopenia. The technique consists of (1) antibody enrichment in eluates prepared from maternal serum and P1^A1-positive platelets, and (2) quantitation of antibodies in eluates by the platelet radioactive anti-IgG test. With this assay, P1^A1 antibodies were demonstrated in 6 out of 7 maternal sera, and anti-A antibodies in one. It proved valuable also for longitudinal studies for periods up to 30 months after delivery.
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Thrombocytopenia has been shown to be present in about 1% of unselected newborns. Alloantibodies to platelets induce the most severe thrombocytopenia.Samples from 195 mothers who had just given birth to thrombocytopenic children, were analysed by platelet antigen genotyping and detection of platelet specific antibodies.75 mothers were typed human platelet antigen (HPA) 1bb, and in 65 mother, anti-HPA 1a antibodies could be detected. Anti-HPA 5b antibodies were detected in three samples and anti-HLA antibodies in 73 samples.Alloantibodies were shown to be an important cause of thrombocytopenia in the new-born children and anti-HPA 1a antibodies were, as expected, the most common platelet-specific antibody involved. Anti-HLA class 1 antibodies were detected as the only antibody in 51 cases of thrombocytopenia. Though it is not yet formally shown, this may indicate that anti-HLA class 1 antibodies may cause thrombocytopenia in the fetus and new-born. Based on the assumption that neonatal alloimmune thrombocytopenia is present in 1:1,000 new-born, 25% of the neonatal alloimmune thrombocytopenia cases in Norway are verified by laboratory analysis. Alloantibodies to thrombocytes are of clinical importance in future pregnancies and transfusions. The cost and benefit of a national screening program for anti-HPA 1a antibodies in all pregnant women should be carefully considered.
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