Depressed Kallikrein Generation in Women With Preeclampsia: A Matched Cross-Sectional Study

Abstract

ObjectiveThe pathophysiology of preeclampsia is not fully understood. Disturbances in the contact system are associated with preeclampsia. Few studies have investigated the association between preeclampsia and alterations in the contact system in plasma. This study aims to elucidate whether this basic biological system is affected in preeclampsia using new methods focusing on the dynamic interactions and total capacity of the contact system in blood.DesignCross-sectional study matching women with preeclampsia and controls without preeclampsia regarding age, pregestational body mass index, and gestational age at onset of the disease.SettingTwo Danish University hospitals.SampleA cohort of 117 women with preeclampsia and 117 controls.MethodsThe turnover and capacity of the contact system were determined with new methods. Paired t-test, Wilcoxon signed-pairs signed rank test, Mann-Whitney or Chi2-test were applied, as appropriate.Main Outcome MeasurementsKallikrein generation (peak kallikrein concentration and endogenous kallikrein potential), coagulation factor XII, prekallikrein, H-kininogen, cleaved H-kininogen, and complement C1 esterase inhibitor.ResultsThe endogenous kallikrein potential, peak kallikrein concentration, prekallikrein and cleaved H-kininogen were significantly lower in women with preeclampsia compared to the controls, p ≤ 0.005, whereas the concentration of coagulation factor XII, H-kininogen and complement C1 esterase inhibitor was not significantly different, p > 0.05.ConclusionThis study demonstrates significant reduction in kallikrein generating capacity, prekallikrein and cleaved H-kininogen indicating that the contact system is affected in preeclampsia suggesting a link to the pathophysiology of the disease.

Increased contact activated endogenous thrombin potential in pregnant women with preeclampsia

“…Despite the delay in thrombin formation, the thrombin-generating capacity of CAS, in terms of ETP and peak thrombin concentration, is significantly higher in women with preeclampsia than controls. We have previously demonstrated that the plasma concentration of FXII and HK are comparable in our patients with preeclampsia and controls, whereas prekallikrein is lower in the patients with preeclampsia [10]. Hence, differences in the concentration of the CAS proteins are presumably not responsible for the observed differences in thrombin generation.…”

“…A prolonged lag time may in general be related to increased C1inh, the major inhibitor of CAS. But C1inh is reduced in both controls and women with preeclampsia, and the concentration of C1inh is not significantly different between the two groups [10]. These results suggest that C1inh is not responsible for the prolonged lag time observed in women with preeclampsia.…”

“…In addition, both AT and protein C are reduced in women with preeclampsia, hereby supporting the hyper-coagulability characterizing preeclampsia. In a former study [10], we reported a decreased kallikrein generation as an expression for the depressed inflammatory pathway of CAS in women with preeclampsia compared with controls. Combined, the studies suggest a depressed inflammatory pathway but an increased CAS-mediated coagulation in women with preeclampsia compared with controls.…”

“…The surface-induced pathway is initiated by the contact system (CAS), by activating coagulation factor XII (FXII) to activated FXII (FXIIa). The interaction of CAS and an activating surface determines the propagation of CAS [9], and may lead to initiation of coagulation, fibrinolysis or inflammation [10]. FXIIa can activate coagulation factor XI (FXI) to an activated form (FXIa) and proceed to the common pathway of coagulation resulting in thrombin formation.…”

Fibrinolytic Changes in Women with Preeclampsia

“…The patient cohort is described previously. 11 In brief, the Preeclampsia and ContAct System study (PreCAS) is a matched cross-sectional trial conducted from January 2020 to October 2021. Patients were included at Departments of Obstetrics and Gynecology at University Hospital of Southern Denmark, Esbjerg and Odense.…”