P1698: increased complement activation and decreased adamts13 activity in patients with pre-eclampsia compared to healthy pregnancies

Background: Preeclampsia is a progressive multi systemic disorder, characterized by either proteinuria or critical organ damage in addition to new-onset hypertension. Although ADAMTS13 (A Disintegrin And Metalloprotease with ThromboSpondin type 1 repeats) and the complement system have been implicated in the pathogenesis of the disease, there are currently no specific biomarkers for diagnosis and severity prediction of preeclampsia. Aims: We investigated whether ADAMTS13 and the complement system could play a role in the development of preeclampsia. Methods: We studied consecutive preeclamptic and control pregnant women of similar age and gestational weeks that provided a written informed consent. Preeclampsia was diagnosed according to American College of Obstetricians and Gynaecologists criteria: one instance of systolic blood pressure (SBP)>160 or diastolic blood pressure (DBP)>110 or two instances of SBP>140 or DBP>90 with proteinuria or evidence of end-organ damage. Patients with pre-existing hypertensive conditions or a history of pre-eclampsia, HELLP syndrome, antiphospholipid syndrome, or other autoimmune disorders and complement-mediated disease were excluded. Peripheral blood samples were collected to perform genetic sequencing of complement regulatory genes (Complement factor H/CFH, CFH-related, CFI, CFB, CFD, C3, CD55, C5, MCP, thombomodulin/THBD, ADAMTS13, MiniSeq System, Illumina). The modified Ham test was used as a functional in vitro assay to test for complement activation. ADAMTS13 activity and soluble C5b-9 were measured with commercially available ELISA kits. Results: We studied 22 Caucasian preeclamptic pregnant women aged 34±7 years, at median 32 gestational weeks, as well as a control group of 15 healthy pregnancies aged 31±6 years, at median 30 gestational weeks. Healthy pregnancies had similar baseline characteristics and otherwise uncomplicated pregnancies with no sign of gestational hypertension until normal birth. As expected, serum creatinine and urine protein excretion were significantly increased in preeclampsia (p=0.029 and p:0.025). Interestingly, patients with preeclampsia had decreased ADAMTS13 activity (median 70%, range 1-96% versus 92% [54-104%], p=0.012) and increased C5b-9 (311[25-1909] versus 35[11-22], p=0.007), with a trend toward significant association between them (p=0.058). Importantly, the modified HAM test was found to be positive only in preeclamptic women (8/22, 36%) with a statistically significant difference between the two groups (p=0.008). Regarding the genetic analysis, risk-factor variants were found in ADAMTD13 (rs2301612), C3 (rs2230199), and CFH (rs800292). Double heterozygocity in these genes was found only in preeclamptic women (12/22, 54%, p<0.001). Focusing on patients with worse outcomes, only one patient with a positive mHam assay (C5b-9 1232 ng/ml, ADAMTS13 31%) and double heterozygous variants had renal failure. Summary/Conclusion: Our study indicates that a portion of patients with preeclampsia has increased complement activation and decreased ADAMTS13 activity. Given the potential association of these markers with worse outcomes, further studies are needed to determine whether they can serve as reliable biomarkers or predictive factors of the disease course.