Quantitative Alterations in Complement Alternative Pathway and Related Genetic Analysis in Severe Phenotype Preeclampsia.

Background: Preeclampsia and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome share many clinical and biologic features with thrombotic microangiopathy syndromes caused by complement abnormalities. Our hypothesis was that similar functional and genetic alterations in the complement alternative pathway (CAP) are present in these disorders of pregnancy.
Methods: We conducted quantitative analysis of proteins involved in CAP using ELISA and nephelometry on prospectively collected blood samples from patients with severe phenotype preeclampsia (defined as delivery ≤34 weeks due to preeclampsia), HELLP syndrome, or eclampsia, and matched normotensive controls ( n =25 in each arm) between 2011 and 2016. Sequencing was performed to interrogate 14 genes encoding CAP components.
Results: Both groups were similar in age, gravidity, parity, marital status, and race. The study group had a higher BMI (mean±SD, 32±8 versus 25±4 kg/m ² ; P =0.002) and earlier gestational age at delivery (32.5±3.6 versus 40.3±1 weeks; P <0.001). Serologic studies demonstrated elevated Bb subunit (median [range], 1.2 [0.5-4.3] versus 0.6 [0.5-1] μ g/ml; P<0.001), complement C5 concentration (28 [18-33] versus 24 [15-34] mg/dl; P =0.03), and sMAC (371 [167-761] versus 184 [112-249] ng/ml; P<0.001) concentrations in patients with preeclampsia. Two thirds of patients with preeclampsia had at least one nonsynonymous sequence variant in CAP genes.
Conclusion: Patients with severe phenotype preeclampsia manifest functional alterations in CAP activation. Genetic variants in the CAP genes were detected in several patients, but a larger population study is necessary to fully evaluate genetic risk. Genetic screening and complement-targeted treatment may be useful in risk stratification and novel therapeutic approaches.
Competing Interests: V.D. Garovic reports being the inventor of the technology “Markers for preeclampsia.” The technology has not been licensed. M.L. Gonzalez Suarez reports receiving research funding from Gilead. M.J. Wick reports serving on the board of Informed DNA. M.A.V. Willrich reports serving on the Clinical Chemistry and Laboratory Medicine (published by De Gruyter) editorial board, as chair of the Clinical Diagnostic Immunology Division of the American Association for Clinical Chemistry, and as vice-chair of the Diagnostic Immunology and Flow Cytometry Committee of the College of American Pathologists; having consultancy agreements with Sebia Inc.; and receiving research funding from Sebia Inc., Siemens Healthineers, and The Binding Site. All remaining authors have nothing to disclose.
(Copyright © 2021 by the American Society of Nephrology.)