Antiendothelial αvβ3 Antibodies Are a Major Cause of Intracranial Bleeding in Fetal/Neonatal Alloimmune Thrombocytopenia. Arterioscler Thromb Vasc Biol 2016 Aug;36(8):1517-24
Date
06/11/2016Pubmed ID
27283740Pubmed Central ID
PMC5140275DOI
10.1161/ATVBAHA.116.307281Scopus ID
2-s2.0-84973532000 (requires institutional sign-in at Scopus site) 77 CitationsAbstract
OBJECTIVE: Fetal/neonatal alloimmune thrombocytopenia is a severe bleeding disorder, which can result in intracranial hemorrhage (ICH), leading to death or neurological sequelae. In whites, maternal anti-human platelet antigen-1a (HPA-1a) antibodies are responsible for the majority of cases. No predictive factors for ICH are available to guide prophylactic treatment during pregnancy. In this study, we investigated antibodies from mothers with ICH-positive fetal/neonatal alloimmune thrombocytopenia and with ICH-negative fetal/neonatal alloimmune thrombocytopenia to identify serological and functional differences between the groups.
APPROACH AND RESULTS: In an antigen capture assay, we observed a stronger binding of +ICH antibodies to endothelial cell (EC)-derived αvβ3. By absorption experiments, we subsequently identified anti-HPA-1a antibodies of anti-αvβ3 specificity in the +ICH but not in the -ICH cohort. Only the anti-αvβ3 subtype, but not the anti-β3 subtype, induced EC apoptosis of HPA-1a-positive ECs by caspase-3/7 activation, and mediated by reactive oxygen species. In addition, only the anti-αvβ3 subtype, but not the anti-β3 subtype, interfered with EC adhesion to vitronectin and with EC tube formation.
CONCLUSIONS: We conclude that the composition of the anti-HPA-1a antibody subtype(s) of the mother may determine whether ICH occurs. Analysis of anti-HPA-1a antibodies of the anti-αvβ3 subtype in maternal serum has potential in the diagnostic prediction of ICH development and may allow for modification of prophylactic treatment in fetal/neonatal alloimmune thrombocytopenia.
Author List
Santoso S, Wihadmadyatami H, Bakchoul T, Werth S, Al-Fakhri N, Bein G, Kiefel V, Zhu J, Newman PJ, Bayat B, Sachs UJAuthors
Peter J. Newman PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinJieqing Zhu PhD Assistant Professor, Associate Investigator in the Biochemistry department at BloodCenter of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAntibody Specificity
Antigens, Human Platelet
Apoptosis
Autoantibodies
CHO Cells
Case-Control Studies
Caspase 3
Caspase 7
Cell Adhesion
Cricetulus
Endothelial Cells
Female
Gestational Age
Human Umbilical Vein Endothelial Cells
Humans
Infant, Newborn
Integrin alphaVbeta3
Integrin beta3
Intracranial Hemorrhages
Male
Maternal-Fetal Exchange
Neovascularization, Physiologic
Pregnancy
Reactive Oxygen Species
Thrombocytopenia, Neonatal Alloimmune
Transfection
