Anti-human platelet antigen (HPA)-1a antibodies: For better or for worse

Albeit a rare pregnancy complication, fetal and neonatal alloimmune thrombocytopenia (FNAIT) due to anti-human platelet antigen (HPA)-1a antibodies carries a significant risk of intracranial bleeding in the fetus and newborn. Reduced birth weight is another possible complication of FNAIT. Currently, there is no specific treatment to prevent or treat FNAIT, neither exist screening programs identifying women at risk of having a baby affected by FNAIT. Prophylactic and therapeutic strategies have been proposed, and the debate on screening programs is intensifying in several countries. The potential of polyclonal anti-HPA-1a IgG to prevent HPA-1a immunization is currently being tested in clinical trials. In this study we have developed a human monoclonal antibody (mAb) highly specific for HPA-1a, named 26.4. By in vitro experimentation, we have shown that this mAb can potentially be developed into a drug to specifically prevent maternal immunization to HPA-1a by potentiating the removal of fetal platelets from maternal circulation prior the immunization takes place. We have also demonstrated that this mAb outcompetes maternal anti-HPA-1a antibodies for binding to the antigen, and therefore mAb 26.4 can also be developed into a drug to treat FNAIT, by protecting fetal platelets from potentially harmful maternal anti-HPA-1a antibodies in cases when the immunization has already occurred. We have also shown that this mAb can be used as a diagnostic reagent to identify women at risk of HPA-1a immunization, as well as a standard for quantitation of anti-HPA-1a antibodies. Using an in vitro model, we have found that anti-HPA-1a antibodies affect trophoblast functions crucial for placental development. The latter finding sheds light on one of the possible causes of the reduced birth weight in FNAIT-affected babies

Anti-human platelet antigen (HPA)-1a antibodies may affect trophoblast functions crucial for placental development: A laboratory study using an in vitro model

Background: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a bleeding disorder caused by maternal antibodies against paternal human platelet antigens (HPAs) on fetal platelets. Antibodies against HPA-1a are accountable for the majority of FNAIT cases. We have previously shown that high levels of maternal anti-HPA-1a antibodies are associated with clinically significant reduced birth weight in newborn boys. Chronic inflammatory placental lesions are associated with increased risk of reduced birth weight and have previously been reported in connection with FNAIT pregnancies. The HPA-1a epitope is located on integrin β 3 that is associated with integrin α IIb (the fibrinogen receptor) on platelets and megakaryocytes. Integrin β 3 is also associated with integrin α V forming the α V β 3 integrin heterodimer, the vitronectin receptor, which is expressed on various cell types, including trophoblast cells. It is therefore thinkable that maternal anti-HPA-1a antibodies present during early pregnancy may affect placenta function through binding to the HPA-1a antigen epitope on invasive throphoblasts. The aim of the study was to examine whether interaction of a human anti-HPA-1a monoclonal antibody (mAb) with HPA-1a on trophoblast cells affect adhesion, migration and invasion of extravillous trophoblast cells. Methods: An in vitro model with human anti-HPA-1a mAb, clone 26.4, and the first trimester extravillous trophoblast cell line HTR8/SVneo was employed. The xCELLigence system was utilized to assess the possible effect of anti-HPA-1a mAb on adhesion and migration of HTR8/SVneo cells. Specially designed chambers precoated with Matrigel were used to assess the effect on the invasive capacity of cells. Results: We found that human anti-HPA-1a mAb 26.4 partia lly inhibits adhesion and migratory capacity of HTR8/SVneo cells. Conclusions: Our findings suggest that anti-HPA-1a antibodies may affect trophoblast functions crucial for normal placental development. Future studies including primary throphoblast cells and polyclonal anti-HPA-1a antibodies are needed to confirm these results

sj-docx-1-ndy-10.1177_27546330241242873 - Supplemental material for Healthcare resource utilisation and associated costs of adult attention deficit hyperactivity disorder in England

Supplemental material, sj-docx-1-ndy-10.1177_27546330241242873 for Healthcare resource utilisation and associated costs of adult attention deficit hyperactivity disorder in England by Marios Adamou, Sophia Abner, Peter Egger, Alessandra Venerus, Gianluca Lucrezi, Mariana Mota, Jeremy Charlton, Minesh Unadkat, Simon Meadowcroft and Christine Eksteen-Ramsden in Neurodiversity</p