Perturbations in kinetics of the thrombin generation assay identify women at risk of preeclampsia in the first trimester and provide the rationale for a preventive approach
Issued Date
2023-05-01
Resource Type
ISSN
00029378
eISSN
10976868
Scopus ID
2-s2.0-85145271543
Pubmed ID
36368431
Journal Title
American Journal of Obstetrics and Gynecology
Volume
228
Issue
5
Start Page
580.e1
End Page
580.e17
Rights Holder(s)
SCOPUS
Bibliographic Citation
American Journal of Obstetrics and Gynecology Vol.228 No.5 (2023) , 580.e1-580.e17
Suggested Citation
Erez O., Gotsch F., Jung E., Chaiworapongsa T., Gudicha D.W., Suksai M., Gallo D.M., Chaemsaithong P., Bosco M., Al Qasem M., Meyyazhagan A., Than N.G., Romero R. Perturbations in kinetics of the thrombin generation assay identify women at risk of preeclampsia in the first trimester and provide the rationale for a preventive approach. American Journal of Obstetrics and Gynecology Vol.228 No.5 (2023) , 580.e1-580.e17. 580.e17. doi:10.1016/j.ajog.2022.11.1276 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/82063
Title
Perturbations in kinetics of the thrombin generation assay identify women at risk of preeclampsia in the first trimester and provide the rationale for a preventive approach
Author's Affiliation
Ramathibodi Hospital
University of Michigan Medical School
Detroit Medical Center
Michigan State University
Emek Medical Center
Semmelweis Egyetem
Wayne State University School of Medicine
National Institute of Child Health and Human Development (NICHD)
Institute of Enzymology
Maternity Private Clinic of Obstetrics and Gynecology
University of Michigan Medical School
Detroit Medical Center
Michigan State University
Emek Medical Center
Semmelweis Egyetem
Wayne State University School of Medicine
National Institute of Child Health and Human Development (NICHD)
Institute of Enzymology
Maternity Private Clinic of Obstetrics and Gynecology
Other Contributor(s)
Abstract
Background: Activation of the coagulation system and increased thrombin generation have been implicated in the pathophysiology of preeclampsia, and this rationale supports the administration of low-molecular-weight heparin to prevent this syndrome in patients at risk. Yet, randomized trials of this prophylactic measure have yielded contradictory results. A possible explanation is that only a subset of patients with preeclampsia have excessive thrombin generation and would benefit from the administration of low-molecular-weight heparin. Therefore, the key questions are whether and when patients who subsequently develop preeclampsia present evidence of abnormal thrombin generation. Objective: This study aimed to determine (1) the kinetics of thrombin generation throughout gestation in women with a normal pregnancy and in those with early and late preeclampsia, and (2) the diagnostic performance of in vivo thrombin generation parameters to predict the development of preeclampsia. Study Design: This retrospective, nested case–control study was based on a prospective longitudinal cohort of singleton gestations. Cases comprised women who developed preeclampsia (n=49), and controls consisted of patients with a normal pregnancy (n=45). Preeclampsia was classified into early-onset (n=24) and late-onset (n=25). Longitudinal changes in the parameters of the thrombin generation assay (lag time, time to peak thrombin concentration, peak thrombin concentration, endogenous thrombin generation, and velocity index) throughout gestation were compared between the study groups, and normal pregnancy percentiles were derived from the control group. We tested whether a single parameter or a combination of parameters, derived from the kinetics of thrombin generation, could identify patients who subsequently developed preeclampsia. Time-related parameters <10th percentile were considered short, and concentration-related parameters >90th percentile were considered high. Results: (1) Patients who developed preeclampsia (early- and late-onset) had abnormal thrombin generation kinetics as early as 8 to 16 weeks of pregnancy; (2) patients with a combination of a short lag time and high peak thrombin concentration at 8 to 16 weeks of pregnancy had an odds ratio of 43.87 for the subsequent development of preeclampsia (area under the curve, 0.79; sensitivity, 56.8%; specificity, 92.7%; positive likelihood ratio, 7.76); (3) at 16 to 22 weeks of gestation, patients with a combination of a short lag time and a high velocity index had an odds ratio of 16 for the subsequent development of preeclampsia (area under the curve, 0.78; sensitivity, 62.2%; specificity, 92.5%; positive likelihood ratio, 8.29). Conclusion: During early pregnancy, the thrombin generation assay can identify the subset of patients at a greater risk for the development of preeclampsia owing to accelerated and enhanced production of thrombin. This observation provides a rationale for testing the efficacy of low-molecular-weight heparin in this subset of patients. We propose that future research on the efficacy of low-molecular-weight heparin and other interventions targeting the coagulation system to prevent preeclampsia should be focused on patients with abnormal kinetics of thrombin generation.