Quantitative alterations in complement alternative pathway and related genetic analysis in severe phenotype preeclampsia
Background: Preeclampsia and HELLP (hemolysis, elevated liver enzymes, low platelets) 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: Quantitative analysis of proteins involved in CAP using ELISA and nephelometry was conducted on prospectively collected blood samples from cases of 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 vs 25±4 kg/m2; p=0.002) and earlier gestational age at delivery (32.5±3.6 vs 40.3±1 weeks; p<0.001). Serological studies demonstrated elevated Bb subunit (median [range]; 1.2 [0.5-4.3] vs 0.6 [0.5-1] mcg/mL; p<0.001), complement C5 concentration (28 [18-33] vs 24 [15-34] mg/dL; p=0.03) and sMAC (371 [167-761] vs 184 [112-249] ng/mL; p<0.001) concentrations in patients with preeclampsia. Two-thirds had at least 1 non-synonymous 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, 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.