Categories
Nevin Manimala Statistics

Age-restricted functional and developmental differences of neonatal platelets

J Thromb Haemost. 2022 Aug 12. doi: 10.1111/jth.15847. Online ahead of print.

ABSTRACT

BACKGROUND: Developmental ontogeny of neonatal thrombopoiesis retains characteristics that are distinct from adult although molecular mechanisms remain unestablished METHODS: We applied multiparameter quantitative platelet responses with integrated ribosome profiling/transcriptomic studies to better define gene/pathway perturbations regulating the neonatal-to-adult transition. A bioinformatics pipeline was developed to identify stable, neonatal-restricted platelet biomarkers for clinical application RESULTS: Cord blood (CB) platelets retained the capacity for linear agonist-receptor coupling linked to phosphatidylserine exposure (PS) and α-granule release, although a restricted block in cross-agonist activation pathways was evident. Functional immaturity of synergistic signaling pathways was due to younger ontogenetic age and singular underdevelopment of the protein secretory gene network, with reciprocal expansion of developmental pathways (E2F, G2M checkpoint, c-Myc) important for megakaryocytopoiesis. Genetic perturbations regulating vesicle transport and fusion (TOM1L1, VAMP3, SNAP23, and DNM1L) and PS exposure and procoagulant activity (CLCN3) were the most significant, providing a molecular explanation for globally-attenuated responses. Integrated transcriptomic and ribosomal footprints identified highly-abundant (ribosome-protected) DEFA3 (encoding human defensin neutrophil peptide 3) and HBG1 as stable biomarkers of neonatal thrombopoiesis. Studies comparing CB- or adult-derived megakaryocytopoiesis confirmed inducible and abundant DEFA3 antigenic expression in CB megakaryocytes, ~3.5-fold greater than in leukocytes (the most abundant source in humans). An initial feasibility cohort of at-risk pregnancies manifest by maternal/fetal hemorrhage (chimerism) were applied for detection and validation of platelet HBG1 and DEFA3 as neonatal thrombopoiesis markers, most consistent for HBG1 which displayed gestational age-dependent expression.

CONCLUSIONS: These studies establish an ontogenetically-divergent stage of neonatal thrombopoiesis, and provide initial feasibility studies to track disordered fetal-to-adult megakaryocytopoiesis in vivo.

PMID:35962592 | DOI:10.1111/jth.15847

By Nevin Manimala

Portfolio Website for Nevin Manimala