Inhibition of β3 integrin activation in anti-human platelet antigen (HPA) 1a-mediated fetal and neonatal alloimmune thrombocytopenia (FNAIT) is associated with disease severity, according to findings recently published in Blood.
Maternal alloimmunization against HPA-1a is the most common cause of FNAIT. Disease presentation can vary widely within this patient population, from asymptomatic to life-threatening. However, no standard prenatal test currently exists to predict high-risk cases.
HPA-1a is located on the β3 protein subunit, which forms part of the cellular receptors αvβ3 and αIIbβ3. While αIIbβ3 is primarily located on platelets, αvβ3 is located in blood vessels. The researchers found that anti-HPA-1a antibodies prevent αvβ3 and αIIbβ3 from binding with fibrinogen, vitronectin and fibronectin. These interactions are necessary for blood clotting and tissue repair.
Even though HPA-1a is not located close to the receptors’ binding sites, the anti-HPA-1a antibody still interferes with binding. The study demonstrated that the inhibitory effect of the antibody is directly mediated by its antigen-binding region and is independent of the bulky antibody tail.
Read more about FNAIT causes and risk factors
Next, the authors investigated implications for disease severity using blood samples from 14 cases of severe FNAIT, 35 mild cases, 9 individuals with non-HPA-1a-mediated thrombocytopenia and 8 healthy controls. Disease severity was positively correlated with stronger inhibition of αvβ3 and αIIbβ3.
“These results aid development of a prenatal diagnostic test to identify pregnancies at high risk of developing FNAIT and associated severe complications,” the authors wrote.
For example, fibrinogen binding may be used in future diagnostic tests to improve risk stratification. Moreover, studying these interactions further could support the development of preventive treatments.
Beyond FNAIT, better understanding how anti-HPA-1a antibodies interact with β3 integrins could help to develop drugs that better block these receptors. This is of particular interest because existing β3 integrin inhibitors cause side effects or do not work as intended.
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