Placental sFLT1 is associated with complement activation and syncytiotrophoblast damage in preeclampsia

ABSTRACT

The immune complement system protects against pathogens; however, excess activation results in disease like hemolytic uremic syndrome, a clinical imitator of preeclampsia. Vascular endothelial factor (VEGF) protects against aberrant complement activation and is inhibited by soluble fms-like tyrosine kinase-1 (sFLT1) in other organs. We hypothesize that sFLT1 promotes complement-mediated placental damage through VEGF inhibition in preeclampsia.

Objective: Quantify placental complement activity and sFLT1 expression in preeclampsia, and the subgroup of preeclampsia with hemolysis elevated liver enzymes low platelets (HELLP) syndrome.

Methods: Placental complement activation marker C4d, membrane attack complex (MAC), and sFLT1 expression was quantified using immunofluores cence microscopy.

Results: Placentas from 18 controls, 25 preeclampsia, including 6 cases of HELLP syndrome were identified. Placental C4d expression was greater in PE (median 6.4 [IQR: 5.1, 8.3]) compared to controls (4.4 [3.6, 5.5]; p = 0.003). MAC expression was also increased in preeclampsia compared to controls (6.5 [5.8, 8.7]; 5.4 [2.9, 5.9], p = 0.001). Placental sFLT1 expression was also higher in preeclampsia (p <0.0001). C4d and MAC were strongly correlated with sFLT1 levels in the placenta (R = 0.72; p < 0.0001 and R = 0.59; p = 0.01, respectively). Complement and sFLT1 expression was elevated in HELLP compared to preeclampsia without laboratory abnormalities, but this difference did not reach statistical significance.

Conclusion: Increased placental complement activation and damage was seen in preeclampsia and correlates with sFLT1 expression. Our findings support the importance of the complement pathway in preeclampsia.

KEYWORDS:

• Preeclampsia
• complement
• sFLT1
• HELLP

Acknowledgments

We thank Ms. Lena Ellezian for cryosectioning the placental tissue samples.

Disclosure statement

S. A. K. is co-listed as a coinventor on patents related to preeclampsia biomarkers and therapies that are held at Beth Israel Deaconess Medical Center. S.A.K. has a financial interest in Aggamin, LLC and also reports serving as a consultant to Thermo Fisher Scientific and Roche. S.A.K. has received research funding from Siemens. Z. Z. reports financial interests in Radikal Therapeutics. The remaining authors do not have any conflicts to disclose.

Additional information

Funding

This study was supported by funds from the BIDMC OB/GYN foundation. A. Y. C. was supported by the Reproductive Scientist Development Program (K12HD000849) by the Eunice Kennedy Shriver National Institute of Child Health & Human Development and Burroughs Wellcome Fund, as part of the Reproductive Scientist Development Program.