Biomarker-based differentiation of pregnancy-associated thrombotic microangiopathies: A systematic review
Wiku Andonotopo, Muhammad Adrianes Bachnas, Mochammad Besari Adi Pramono, Julian Dewantiningrum, Efendi Lukas, I. Nyoman Hariyasa Sanjaya, Anak Agung Gede Putra Wiradnyana, Anak Agung Ngurah Jaya Kusuma, Khanisyah Erza Gumilar, Ernawati Darmawan, Dovy Djanas, Dudy Aldiansyah, Aloysius Suryawan, Ridwan Abdullah Putra, Theresia Monica Rahardjo, Rizna Tyrani Rumanti, Roland Frederik Lengkey, Julia Windi Gunadi, Hendra Subroto, Arief Setiawan, Aryani Aziz, Nuswil Bernolian, Donel Suhaimi, Agus Rusdhy Hamid, Laksmana Adi Krista Nugraha, Wibisana Andika Krista Dharma, Waskita Ekamaheswara Kasumba AndanaputraAbstract:
Pregnancy-associated thrombotic microangiopathies (TMAs), including hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome, preeclampsia, thrombotic thrombocytopenic purpura (TTP), and complement-mediated TMA/atypical hemolytic uremic syndrome (aHUS), remain among the most difficult conditions to distinguish during pregnancy and the postpartum period because they share overlapping clinical and laboratory manifestations despite fundamentally different pathogenic mechanisms and therapeutic strategies. This systematic review, conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, synthesized current evidence on the diagnostic utility of ADAMTS13, complement-related biomarkers, and angiogenic markers for differentiating these disorders. A comprehensive search of major biomedical databases identified 948 records. Following duplicate removal, title and abstract screening, full-text eligibility assessment, and application of predefined inclusion criteria, 35 studies were included in a qualitative synthesis. Quantitative meta-analysis was not undertaken because of substantial clinical and methodological heterogeneity across study designs, patient populations, biomarker assays, diagnostic definitions, and reported outcomes. Across the available evidence, severe ADAMTS13 deficiency consistently emerged as the most reliable laboratory indicator of TTP, whereas persistent postpartum hemolysis accompanied by acute kidney injury strongly supported consideration of complement-mediated TMA/aHUS. HELLP syndrome and preeclampsia demonstrated partial overlap with complement activation and disturbances of the von Willebrand factor–ADAMTS13 axis, reflecting shared endothelial injury rather than identical disease mechanisms. Angiogenic biomarkers, particularly the soluble fms-like tyrosine kinase-1/placental growth factor ratio, provided valuable adjunctive information for identifying placental disease but were most informative when interpreted alongside serial laboratory changes and the evolving clinical course. Overall, the evidence supports an integrated biomarker-based diagnostic framework that combines clinical assessment with ADAMTS13 testing, complement evaluation, angiogenic biomarkers, and postpartum laboratory trajectories to facilitate earlier disease-specific diagnosis and management while reducing preventable maternal and fetal morbidity.