Antibodies in fetal and neonatal alloimmune thrombocytopenia (FNAIT) do not selectively attach to blood vessel cells, but instead show stronger reactivity toward platelet proteins, according to a study published recently in Blood.
This challenges earlier research that suggested antibodies binding only to endothelial cells explained severe brain bleeding in affected newborns.
Investigators found that antibodies consistently attached more tightly to αIIbβ3, a platelet-specific integrin, than to αvβ3, which is present on both platelets and endothelial cells. While binding differences decreased when integrins were in their activated form, exclusive recognition of αvβ3 was not observed. These results suggest that the structure and shape of integrins play a crucial role in how antibodies behave.
“[O]ur data demonstrate that anti-HPA-1a antibodies preferably bind to the inactive integrin conformation which contributes to their preference for αIIbβ3 over αvβ3,” stated this study’s authors. They continued, “These findings emphasize the need to reconsider the suggested relationship between endothelial cell-specific antibody properties and disease outcome in FNAIT.”
This study included maternal sera from 29 severe and 65 mild cases of FNAIT. Severe disease was defined by intracranial hemorrhage or internal organ bleeding, events that led to 13 perinatal deaths. Mild disease was characterized by low platelet counts and limited bleeding. Platelet counts were significantly lower in severe compared with mild cases. Importantly, the presence of additional anti–HLA class I antibodies did not alter platelet levels.
Read more about causes and risk factors for FNAIT
To test antibody specificity, researchers engineered human cell lines that expressed either αIIbβ3 or αvβ3 with HPA-1a or HPA-1b epitopes. Antibodies bound both integrins but always favored αIIbβ3. When αIIbβ3 was removed, reactivity disappeared, and no hidden αvβ3-exclusive antibodies were detected. Additional experiments with platelets and endothelial cells confirmed this absence.
Further testing showed that antibodies preferred αIIbβ3 across both mild and severe disease groups, although the strength of binding varied among patients. Even though binding studies demonstrated stronger reactivity to αIIbβ3, antibody-dependent killing of cells was similar whether they displayed αIIbβ3 or αvβ3. Structural modeling revealed that antibody recognition depended on whether integrins were bent and inactive or extended and active, with the inactive form exposing key sites more fully.
These results suggest that severity of disease in FNAIT is more closely tied to platelet destruction and antibody levels than to endothelial-specific antibody binding. For patients and families, this means that the risk of serious bleeding, such as brain hemorrhage, may not come from antibodies targeting blood vessel cells as once thought. Instead, further studies are needed to clarify which antibody and platelet interactions best predict severe outcomes and to guide future care.
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