Differential Contributions of Intrinsic and Extrinsic Pathways to Thrombin Generation in Adult, Maternal and Cord Plasma Samples

• Authors: Nicklaus T. Rice, Vanderbilt University; Fania Szlam, Emory University; Jeffrey D. Varner, Purdue University; Peter S. Bernstein, Albert Einstein College of Medicine; Arthur D. Szlam, City College of New York; Kenichi A. Tanaka, University of Maryland
• Journal Title: PLoS ONE
• Volume: Volume 11, Number 5
• Publisher: Public Library of Science | 2016-05-19, Pages e0154127-e0154127
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1371/journal.pone.0154127
• Subjects: Health Sciences, Obstetrics and Gynecology; Health Sciences, General; Biology, Bioinformatics
• Keywords: Multidisciplinary Sciences; FACTOR-IXA; CARDIOPULMONARY BYPASS; LOW ANTITHROMBIN; INHIBITOR TFPI; APTAMER BAX499; FACTOR VIIA; TISSUE; BLOOD; MECHANISM; Blood plasma; Thrombin; Coagulation factors; Pregnancy; Adults; Serine proteases; Platelets; Mathematical models

Abstract

BACKGROUND: Thrombin generation (TG) is a pivotal process in achieving hemostasis. Coagulation profiles during pregnancy and early neonatal period are different from that of normal (non-pregnant) adults. In this ex vivo study, the differences in TG in maternal and cord plasma relative to normal adult plasma were studied. METHODS: Twenty consented pregnant women and ten consented healthy adults were included in the study. Maternal and cord blood samples were collected at the time of delivery. Platelet-poor plasma was isolated for the measurement of TG. In some samples, anti-FIXa aptamer, RB006, or a TFPI inhibitor, BAX499 were added to elucidate the contribution of intrinsic and extrinsic pathway to TG. Additionally, procoagulant and inhibitor levels were measured in maternal and cord plasma, and these values were used to mathematically simulate TG. RESULTS: Peak TG was increased in maternal plasma (393.6±57.9 nM) compared to adult and cord samples (323.2±38.9 nM and 209.9±29.5 nM, respectively). Inhibitory effects of RB006 on TG were less robust in maternal or cord plasma (52% vs. 12% respectively) than in adult plasma (81%). Likewise the effectiveness of BAX499 as represented by the increase in peak TG was much greater in adult (21%) than in maternal (10%) or cord plasma (12%). Further, BAX499 was more effective in reversing RB006 in adult plasma than in maternal or cord plasma. Ex vivo data were reproducible with the results of the mathematical simulation of TG. CONCLUSION: Normal parturient plasma shows a large intrinsic pathway reserve for TG compared to adult and cord plasma, while TG in cord plasma is sustained by extrinsic pathway, and low levels of TFPI and AT.