Germline mutations in the alternative pathway of complement predispose to HELLP syndrome

Area of Science:

• Reproductive Medicine
• Immunology
• Genetics

Background:

• HELLP syndrome, a severe pregnancy complication, affects 1% of pregnancies with significant maternal and fetal risks.
• Previous research indicated a role for the alternative pathway of complement (APC) in HELLP syndrome.
• A two-hit model, involving genetic susceptibility and environmental factors, is hypothesized for HELLP syndrome, similar to atypical hemolytic uremic syndrome (aHUS).

Purpose of the Study:

• To comparatively analyze the frequency of APC activation and germline mutations in women with HELLP syndrome.
• To develop a predictive model for identifying HELLP syndrome.

Main Methods:

• Recruitment of pregnant women with HELLP syndrome and healthy controls (gestation > 23 weeks).
• Inclusion of participants with aHUS and thrombotic thrombocytopenic purpura for comparison.
• Performance of a functional assay (mHam) and targeted genetic sequencing across all groups.

Main Results:

• A higher prevalence of rare germline mutations in APC genes was observed in the HELLP cohort compared to controls (46% vs. 8%, P = 0.01).
• More HELLP participants tested positive for the mHam assay than controls (62% vs. 16%, P = 0.009).
• Combined positivity for germline mutation and mHam assay was highly predictive of HELLP syndrome diagnosis.

Conclusions:

• HELLP syndrome is characterized by both APC activation and frequent germline mutations in APC genes.
• Complement inhibition, a strategy used for aHUS, may be a potential treatment to reduce maternal and fetal morbidity and mortality in HELLP syndrome.