The Interrelationship of Complement-Activation Fragments and Angiogenesis-related Factors in Early Pregnancy and Their Association With Preeclampsia

Abstract

Objective-To determine the interrelationships during early pregnancy of complement-activation fragments Bb, C3a and sC5b-9, and angiogenesis-related factors placental growth factor (PiGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), and their associations with pre-eclampsia. Design-Prospective cohort study. Setting-Denver complement study (June 2005-June 2008).Population-A total of 668 pregnant women with singleton gestations, recruited between 10 and 15 weeks of gestation.Methods-Using univariable and multivariable logistic regression analysis, concentrations of complement-activation fragments and angiogenesis-related factors were compared between 10 and Correspondence: Dr A Lynch, Department of Obstetrics and Gynecology, University of Colorado Denver School of Medicine, Mail Stop B198, 12631 East 17th Avenue, Aurora, CO 80045, USA. anne.lynch@ucdenver.edu. Disclosure of interestsThe authors have nothing to disclose. Contribution to authorshipAML designed and oversaw the study, conducted the data analysis, obtained the funding and wrote the manuscript; JRM provided statistical consultation; PCG provided consultation on the interpretation of complement results; RJL contributed his expertise in the area of angiogenesis-related factors; RSG contributed his expertise in maternal-fetal medicine. VMH and JES contributed their expertise in the area of complement research, and VMH served as mentor to AML on her NICHD K23 grant. Details of ethics approvalThe Colorado Multiple Institutional Review Board approved the study (COMIRB protocol number 07-0960). Interrelationships between these variables were tested using the non-parametric Spearman rank correlation coefficient. HHS Public AccessMain outcome measure-Pre-eclampsia. The association of complement-activation fragments and angiogenesis-related factors with obesity was also examined.Results-The mean (±SD) levels of complement Bb in early pregnancy among women who did and did not develop pre-eclampsia were 0.84 (±0.26) µg/ml and 0.69 (±0.2) µg/ml, respectively (P = 0.001). Concentrations of PiGF were significantly (P = 0.01) lower (31 ± 12 pg/ml) in early pregnancy in the pre-eclamptic group of women, as compared with the normotensive group (39 ± 32 pg/ml). The adjusted odds ratio (AOR) of Bb and PiGF were 2.1 (CI = 1.4-3.1, P < 0.0003) and 0.2 (CI = 0.07-0.7, P = 0.01), respectively. There was no significant difference in the levels of C3a, sC5b-9, sFlt-1 and sEng in early pregnancy among women who developed pre-eclampsia, compared with women who remained normotensive during pregnancy. Higher levels of Bb (P = 0.0001) and C3a (P = 0.03), and lower levels of sFlt-1 (P = 0.0002) and sEng (P = 0.0001) were found among women with obesity, compared with non-obese controls. No meaningful relationships were found between the complement-activation fragments and the angiogenesisrelated factors.Conclusions-In this cohort during early pregnancy, increased concentrations of complementactivation factor Bb and lower concentrations of PiGF were ...

Complement activation and regulation in preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome

“…In contrast, soluble C5b-9 levels were not increased in early gestation (10e15 weeks) among women who developed preeclampsia. 72 Taken together, these results show that the activation of the alternative complement pathway, but not the terminal complement pathway, is increased in early pregnancy among women who develop preeclampsia.…”

An observational study of haemostatic changes, leptin and soluble endoglin during pregnancy in women with different BMIs

“…A significant reduction of sEng in obese pregnant compared to nonobese pregnant was demonstrated in a study by Lynch et al [23]. They postulated it may have been because of expansion of the vascular bed in adipose tissue of obese women.…”

“…Overexpression of soluble endoglin (sEng) and another angiogenic factor, fms-like tyrosine kinase-1 in rodents results in a syndrome similar to human HELLP (Haemolysis, Elevated Liver enzymes, Low platelets); consisting of proteinuria, hypertension, intrauterine growth restriction, low platelets and elevated LDH [22]. Interestingly, sEng has been found to be significantly lower in obese, compared with nonobese, women in early pregnancy [23].…”

The evaluation of some serum immunochemical markers in early onset pre‐eclamptic women from Algeria

“…Thus, it seems that the needed theory for PE is the one that can assemble biological phenomena in maternal blood, that is, circulating markers of inflammation, with placental oxidative stress (OS). Notably, one of the theories that best fits the pathophysiological puzzle of preeclampsia with clear link to antiangiogenic factors was “the complement system” that has been already translated into the clinic by introducing C5 blockade as an effective strategy, owing to the hyperactivation of the alternative complement pathway (ACP), but not the terminal nor the classical pathway, as it seems to exceed the complement regulation and consequently prompting antiangiogenic state in women who develop preeclampsia 2,6,7 …”

“…Notably, one of the theories that best fits the pathophysiological puzzle of preeclampsia with clear link to antiangiogenic factors was "the complement system" that has been already translated into the clinic by introducing C5 blockade as an effective strategy, owing to the hyperactivation of the alternative complement pathway (ACP), but not the terminal nor the classical pathway, as it seems to exceed the complement regulation and consequently prompting antiangiogenic state in women who develop preeclampsia. 2,6,7 In this work, using samples from patients with established early onset PE, we have focused on biomarkers originating from the principal theories framing the pathogenesis of the condition: AP 50 and complement factor H (CFH) reflecting the alternative complement pathway status, soluble fms-like tyrosine kinase 1 (sFlt-1) and placenta growth factor (PlGF) to assesses the angiogenic approach, malondialdehyde (MDA) for oxidative stress, and finally interleukin 6 (IL-6) and procalcitonin (PCT) as indicators of the maternal circulating inflammation.…”