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S.R. Boyd, L. Sarrazin, P. Chen, S. Briggs, H. Yang, H. Ni; Abnormal Retinal Vascular Development in a Mouse Model of Fetal & Neonatal Alloimmune Thrombocytopenia (FNAITP) – Beta3 Integrins and a Potential Role for the Ophthalmologist in Neonatal Screening . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5322.
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FNAITP is an immune disorder in which maternal antibodies cross the placenta and bind to platelet surface antigens such as ß3 integrin (αIIbß3) inherited by the fetus from the father. The ensuing platelet lysis carries a major risk of bleeding and intracranial haemorrhage. FNAITP is estimated to affect 1/1,000 liveborn neonates to varying degrees.
Because ß3 integrin is also found on endothelial cells, and the retinal vasculature is known to express αvß3 integrins, we asked whether a severe form of FNAITP might also include direct vascular damage or inhibition of angiogenesis, and whether this could be detected by evaluation of the developing retina in a murine model.
Female ß3–/– mice were twice immunized with ß3+ platelets and mated with wildtype males. Rates of miscarriage and neonatal haemorrhage were evaluated, along with maternal and neonatal titres of anti–ß3 antibodies. In a second series, mothers with a history of FNAITP received intravenous IgG (IVIG) once weekly during subsequent pregnancies to determine whether this treatment could reduce antibody–mediated thrombolysis or vascular damage. Quantification of vessel inhibition was performed by wholemount immunohistochemical analysis of PND2 retina, stained with Lectin SB4 and collagnen IV, using a pre–built radial grid overlay to measure vessel growth from the optic nerve head. Up to eight measurements were obtained per eye.
Sensitized pregnant females with demonstrable anti–ß3 antibodies had high rates of miscarriage, and gave birth to stillborn or small pups, often with notable haemmorhage. Preliminary data suggest that new vessel growth in the retina was reduced in pups born to b3–/– mothers, and that IVIG was able to cross the placenta and lessen the inhibition of new vessel growth. This study also demonstrates the utility of evaluating retinal vascular growth as a marker of disease.
We have demonstrated that anti–ß3 integrin antibodies in female pregnant mice can 1) cross the placenta causing thrombocytopenia and severe bleeding in fetuses; 2) block retinal vascular development; 3) cause miscarriage and stunted fetal growth; and, 4) that IVIG is able to lessen vascular injury. Based on these data we suggest that ophthalmic screening of retinal vascular development should be considered for newborns with unexplained haemorrhage or a suspicion of FNAITP.
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