Haematopoietic Microenvironment Remodelling in Pregnancy-Associated Aplastic Anaemia: An Original Single-Cell Multiomics Investigation at Nigerian Teaching Hospitals

This dissertation conducts a comprehensive single-cell multiomics investigation of haematopoietic microenvironment remodelling in pregnancy-associated aplastic anaemia (PAAA), an understudied and potentially fatal complication of pregnancy in Nigeria, developing an original mechanistic framework that distinguishes PAAA from classical acquired aplastic anaemia. PAAA is disproportionately reported in sub-Saharan Africa, yet its pathophysiology remains obscure, contributing to delayed diagnosis and inappropriate treatment. Using a prospective multi-centre design at the University of Nigeria Teaching Hospital, Federal Teaching Hospital Abakaliki, and University College Hospital Ibadan, bone marrow aspirates and paired peripheral blood were collected from 40 PAAA cases, 40 classical AA controls matched by severity, and 20 healthy pregnant controls. Integrated single-cell RNA sequencing and chromatin accessibility (CITE-seq with ATAC) were performed. Plasma cytokine profiling and T cell receptor repertoire sequencing supplemented cellular analysis. Single-cell analysis identified a PAAA-specific regulatory T cell dysfunction signature absent in classical AA, characterised by reduced FOXP3 expression and impaired suppressive capacity against autoreactive effector T cells. Stromal niche cells in PAAA showed a unique interferon-stimulated gene signature linked to placental antigen cross-presentation. An original PAAA Pathogenesis Model proposing foetal antigen-driven immune dysregulation as the initiating event is developed and supported by the multiomics data. The model predicts immunosuppressive therapy response with 84 percent accuracy. Keywords: pregnancy-associated aplastic anaemia, single-cell multiomics, haematopoietic microenvironment, pathogenesis, Nigeria.