Bleeding or no bleeding? Anti‐endothelial alphaVbeta3 antibodies as a major cause of intracranial haemorrhage in fetal–neonatal alloimmune thrombocytopenia

Abstract

Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a severe bleeding disorder which can result in intracranial haemorrhage (ICH), leading to death or neurological sequelae. In Caucasians, maternal anti‐HPA‐1a antibodies (abs) are responsible for the majority of FNAIT cases. However, the correlation between fetal platelet counts and risk of bleeding is loose. ICH was also observed in FNAIT cases with platelet counts within reference ranges. These observations question the exclusive role of thrombocytopenia in ICH. Recently, we observed stronger binding of anti‐HPA‐1a antibodies from mothers with ICH‐positive (+ICH) FNAIT to endothelial cell‐derived αvβ3 when compared to anti‐HPA‐1a from ‐ICH. Differential absorption experiments demonstrated that anti‐HPA‐1a is not a single antibody entity. Sera from immunized women may contain three different subspecificities: anti‐β3, anti‐αIIbβ3 and anti‐αvβ3. Anti‐β3 appears to be the dominant subtype of anti‐HPA‐1a. However, anti‐αvβ3 was only found in +ICH sera, and only the anti‐αvβ3, but not anti‐β3 subtype, induced apoptosis and disturbed tube formation of endothelial cells in vitro. Therefore, we believe that this anti‐HPA‐1a subtype plays a significant role in the development of ICH. Together with other subtypes, anti‐αvβ3 may trigger bleeding in a threshold model of FNAIT/ICH, where bleeding occurs if yet undefined levels of anti‐endothelial (loss of integrity) and/or antiplatelet (low platelet count) activities are achieved. Thus, defining anti‐HPA‐1a subtypes may have significant potential in the prediction of ICH. With upcoming nation‐wide screening programmes, detection of anti‐HPA‐1a subtypes could prove helpful to allocate treatment to appropriate (at‐risk) cases, especially in countries with restricted resources.