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Application of a plasmin generation assay to define pharmacodynamic effects of tranexamic acid in women undergoing cesarean delivery.

ABSTRACT: Essentials Tranexamic acid (TXA) is an antifibrinolytic drug used to reduce bleeding. Assaying plasmin generation (PG) in plasma detects clinically relevant TXA levels in vitro and ex vivo. 3.1-16.2 µg/mL TXA half-maximally inhibits PG in plasma from women undergoing cesarean delivery. PG velocity shows the strongest dose-relationship at low TXA concentrations (?10 µg/mL). ABSTRACT: Background Tranexamic acid (TXA) is used to reduce bleeding. TXA inhibits plasmin(ogen) binding to fibrin and reduces fibrinolysis. TXA antifibrinolytic activity is typically measured by clot lysis assays; however, effects on plasmin generation (PG) are unclear due to a lack of tools to measure PG in plasma. Aims Develop an assay to measure PG kinetics in human plasma. Determine effects of TXA on PG and compare with fibrinolysis measured by rotational thromboelastometry (ROTEM). Methods We characterized effects of plasminogen, tissue plasminogen activator, fibrinogen, and ?₂ -antiplasmin on PG in vitro. We also studied effects of TXA on PG in plasma from 30 pregnant women administered intravenous TXA (5, 10, or 15 mg/kg) during cesarean delivery. PG was measured by calibrated fluorescence. PG parameters were compared with TXA measured by mass spectrometry and ROTEM of whole blood. Results The PG assay is specific for plasmin and sensitive to tissue plasminogen activator, fibrin(ogen), and ?₂ -antiplasmin. Addition of TXA to plasma in vitro dose dependently prolonged the clot lysis time and delayed and reduced PG. For all doses of TXA administered intravenously, the PG assay detected delayed time-to-peak (?3 hours) and reduced the velocity, peak, and endogenous plasmin potential (?24 hours) in plasma samples obtained after infusion. The PG time-to-peak, velocity, and peak correlated significantly with TXA concentration and showed less variability than the ROTEM lysis index at 30 minutes or maximum lysis. Conclusions The PG assay detects pharmacologically relevant concentrations of TXA administered in vitro and in vivo, and demonstrates TXA-mediated inhibition of PG in women undergoing cesarean delivery.

SUBMITTER: Miszta A

PROVIDER: S-EPMC7875467 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Application of a plasmin generation assay to define pharmacodynamic effects of tranexamic acid in women undergoing cesarean delivery.

Miszta Adam A Ahmadzia Homa K HK Luban Naomi L C NLC Li Shuhui S Guo Dong D Holle Lori A LA Berger Jeffrey S JS James Andra H AH Gobburu Jogarao V S JVS van den Anker John J de Laat Bas B Wolberg Alisa S AS

Journal of thrombosis and haemostasis : JTH 20201226 1

Essentials Tranexamic acid (TXA) is an antifibrinolytic drug used to reduce bleeding. Assaying plasmin generation (PG) in plasma detects clinically relevant TXA levels in vitro and ex vivo. 3.1-16.2 µg/mL TXA half-maximally inhibits PG in plasma from women undergoing cesarean delivery. PG velocity shows the strongest dose-relationship at low TXA concentrations (≤10 µg/mL). ABSTRACT: Background Tranexamic acid (TXA) is used to reduce bleeding. TXA inhibits plasmin(ogen) binding to fibrin and redu ...[more]

PMID: 33001565

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Project description:PurposeGiving birth is the most common reason for hospital admission, with Cesarean delivery being the most frequently performed inpatient surgery. Through a needs assessment and iterative design process involving patients and obstetric anesthesiologists, we previously developed a mobile application, C-Care, for patients undergoing Cesarean delivery. The focus of C-Care is perioperative education and self-monitoring of potential anesthetic complications. This study aimed to obtain feedback on patient engagement with C-Care.MethodWe conducted a prospective cohort study of patients ≥ 18 yr (n = 36) undergoing elective Cesarean delivery. Anonymous usage data were recorded for 30 days. On postoperative days 1-5, participants received daily self-monitoring questionnaires within C-Care. Fourteen days after surgery, participants received an online survey regarding satisfaction and use of C-Care.ResultsThirty-five out of 36 participants visited the application after orientation, with a median [interquartile range (IQR)] age of 32 [31-36] yr. Each participant visited the application a median of 15 [9-31] times over 30 days and completed a median of 3 [2-4] out of five self-monitoring questionnaires. Each participant viewed a median of 4 [2-7] out of eight education topics, with the most viewed patient education topics being "Controlling Pain" and "The First Few Days". Visits to the application were highest in the first week postpartum. Of the 18 respondents who completed the day 14 survey, 83% (n = 15) participants would recommend C-Care to other women, and the median participant satisfaction score was 7.5 out of 10 (range, 2-10).ConclusionMost participants used this mobile application for patient education and self-monitoring after elective Cesarean delivery. Insights into patient engagement with C-Care after Cesarean delivery could help design more effective perioperative mobile telehealth programs.Trial registrationwww.ClinicalTrials.gov (NCT03746678); registered 5 November 2018.

Project description:BACKGROUND:An antifibrinolytic agent that blocks lysine-binding sites on plasminogen molecules, tranexamic acid reduces bleeding-related mortality in women with postpartum hemorrhage (PPH), especially administered fairly soon after delivery. According to the randomized controlled trials thus far reported for PPH prevention after cesarean deliveries (n?=?16), women who received tranexamic acid had significantly less postpartum blood loss and no increase in severe adverse effects. These were, however, primarily small single-center studies that had fundamental methodological flaws. Multicenter randomized controlled trials with adequate power are necessary to demonstrate its value persuasively before tranexamic acid goes into widespread use for the prevention of PPH after cesarean deliveries. METHODS/DESIGN:This study will be a multicenter, double-blind, randomized controlled trial with two parallel groups including 4524 women with cesarean deliveries before or during labor, at a term ?34?weeks, modeled on our previous study of tranexamic acid administered after vaginal deliveries. Treatment (either tranexamic acid 1?g or placebo) will be administered intravenously just after birth. All women will also receive a prophylactic uterotonic agent. The primary outcome will be the incidence of PPH, defined by a calculated estimated blood loss >?1000?mL or a red blood cell transfusion before day 2 postpartum. This study will have 80% power to show a 20% reduction in the incidence of PPH, from 15.0 to 12.0%. DISCUSSION:As an, inexpensive, easy to administer drug that can be add to the routine management of cesarean births in delivery rooms, tranexamic acid is a promising candidate for preventing PPH after these births. This large, adequately powered, multicenter randomized placebo-controlled trial seeks to determine if the benefits of the routine prophylactic use of tranexamic acid after cesarean delivery significantly outweigh its risks. TRIAL REGISTRATION:ClinicalTrials.gov NCT03431805 (February 12, 2018).

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Application of a plasmin generation assay to define pharmacodynamic effects of tranexamic acid in women undergoing cesarean delivery.

Publications

Application of a plasmin generation assay to define pharmacodynamic effects of tranexamic acid in women undergoing cesarean delivery.

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