Plasma proteome profiling of massive perivillous fibrin deposition (MPFD) in women with recurrent Miscarriages: Pathophysiological insights and biomarker discovery

Abstract

Introduction: Massive perivillous fibrin deposition (MPFD) leads to fetal growth restriction and intrauterine demise. As MPFD is typically diagnosed following an adverse event, there is a need for serum biomarkers for early detection.

Methods: We conducted a global proteomic profiling of maternal blood from women experiencing recurrent first-trimester miscarriages (≥3) diagnosed with fibrin-type MPFD with normal chromosomes (f-MPFD, n = 7). A miscarriage control group (MC, n = 18; recurrent miscarriages and normal placental chromosomes) and a normal control group (NC, n = 2; normal first-trimester pregnant women with ongoing pregnancies) were included. Global proteomic profiling of maternal plasma was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Differentially expressed proteins (DEPs) were identified and subjected to pathway enrichment analysis using Metascape, followed by functional network visualization. Candidate biomarkers were prioritized through partial least squares discriminant analysis (PLS-DA).

Results: A total of 833 proteins were identified, including 156 that were unique to f-MPFD. Proteomic analysis revealed significant upregulation of immune and coagulation pathways, including complement activation, neutrophil and platelet degranulation, and oxidative stress response. Concurrently, proteins involved in immune regulation, cell adhesion, and trophoblast-endocrine signaling (e.g., LNPEP, PAPPA, PSGs) were downregulated. Enrichment of both pro-inflammatory and regulatory components within the neutrophil degranulation pathway suggested a dysregulated inflammatory milieu. PLS-DA identified several discriminatory proteins (e.g., TGFB1, PKM, F5, EBI3) that may serve as candidate biomarkers for f-MPFD. Complement activation and downregulation of tolerance-related PSGs were consistent with a maternal alloimmune response.

Conclusion: f-MPFD was associated with protein aberrations related to systemic maternal immune dysregulation and procoagulant activation.

Keywords: Biomarker; Massive perivillous fibrin deposition; Placenta; Proteomics; Recurrent miscarriage.