Pregnancy-related Thrombotic Microangiopathy has a spectrum of underlying causes

Abstract

Objectives: Pregnancy-associated Thrombotic Microangiopathy (pTMA) encompasses disorders leading to significant maternal morbidity and mortality and risks to the newborn. The complement system plays a key role in TMA pathogenesis, with pregnancy triggering susceptibility in women. Due to its rarity, timely diagnosis and management of pTMA remain challenging. This study aimed at identifying potential triggers and mechanisms in pregnant women with severe TMA, from an obstetric perspective.

Study design: Clinical and molecular data from 11 women with pregnancy-related TMA complications (2012-2022) were analyzed. Blood samples during acute TMA stages were tested for anti-factor H (FH) and anti-ADAMTS13 antibodies using ELISA and Western blotting. Next-generation sequencing and MLPA assays evaluated genetic variants in TMA-related genes.

Results: Clinical records showed similar presentations despite diverse diagnoses, including preeclampsia, HELLP syndrome, AFLP, atypical HUS, and autoimmune TTP, primarily in the third trimester. Eight patients had postpartum hemorrhage (mean blood loss 1312 ml) with normal activated partial thromboplastin times but reduced fibrinogen levels. Genetic findings included two mutations in the C3 gene in one patient, one DGKE mutation, one factor V Leiden mutation, and CFHR3-1 gene deletions (two homozygous, one heterozygous). ADAMTS13 autoantibodies were detected in the TTP case.

Conclusion: The rarity and overlapping criteria of pTMA with other syndromes complicate diagnosis. Early recognition of coagulation abnormalities, hemorrhage, and cardiovascular disorders can help identify at-risk patients. Genetic mutations indicating complement dysregulation suggest that targeted therapies could improve outcomes. Comprehensive diagnostics, timely management, and close follow-up are crucial for optimizing the maternal and fetal health.

Key message: Pregnancy-associated thrombotic microangiopathy is a rare life-threatening condition that requires prompt diagnosis and treatment. This study helps obstetricians to identify at-risk patients. In a proportion of cases rare complement gene variants can be identified. The broad spectrum on underlying causes highlights the need for comprehensive diagnostic testing to improve management and outcomes.

Keywords: Complement; Factor H; HELLP; Preeclampsia; Pregnancy; TTP; Thrombotic Microangiopathy; aHUS.