Computational model of tranexamic acid on urokinase mediated fibrinolysis

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Abstract

Understanding the coagulation process is critical to developing treatments for trauma and coagulopathies. Clinical studies on tranexamic acid (TXA) have resulted in mixed reports on its efficacy in improving outcomes in trauma patients. The largest study, CRASH-2, reported that TXA improved outcomes in patients who received treatment prior to 3 hours after the injury, but worsened outcomes in patients who received treatment after 3 hours. No consensus has been reached about the mechanism behind the duality of these results. In this paper we use a computational model for coagulation and fibrinolysis to propose that deficiencies or depletions of key anti-fibrinolytic proteins, specifically antiplasmin, a1-antitrypsin and a2-macroglobulin, can lead to worsened outcomes through urokinase-mediated hyperfibrinolysis.

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Tranexamic acid: a review of its use in the treatment of hyperfibrinolysis.

Paul L McCormack (2012)

Tranexamic acid, a synthetic derivative of the amino acid lysine, is an antifibrinolytic agent that acts by binding to plasminogen and blocking the interaction of plasmin(ogen) with fibrin, thereby preventing dissolution of the fibrin clot. Tranexamic acid (Transamin®) is indicated in Japan for use in certain conditions with abnormal bleeding or bleeding tendencies in which local or systemic hyperfibrinolysis is considered to be involved. This article reviews the efficacy and tolerability of tranexamic acid in conditions amenable to antifibrinolytic therapy and briefly overviews the pharmacological properties of the drug. In large, randomized controlled trials, tranexamic acid generally significantly reduced perioperative blood loss compared with placebo in a variety of surgical procedures, including cardiac surgery with or without cardiopulmonary bypass, total hip and knee replacement and prostatectomy. In many instances, tranexamic acid also reduced transfusion requirements associated with surgery. It also reduced blood loss in gynaecological bleeding disorders, such as heavy menstrual bleeding, postpartum haemorrhage and bleeding irregularities caused by contraceptive implants. Tranexamic acid significantly reduced all-cause mortality and death due to bleeding in trauma patients with significant bleeding, particularly when administered early after injury. It was also effective in traumatic hyphaema, gastrointestinal bleeding and hereditary angioneurotic oedema. While it reduces rebleeding in subarachnoid haemorrhage, it may increase ischaemic complications. Pharmacoeconomic analyses predicted that tranexamic acid use in surgery and trauma would be very cost effective and potentially life saving. In direct comparisons with other marketed agents, tranexamic acid was at least as effective as ε-aminocaproic acid and more effective than desmopressin in surgical procedures. It was more effective than desmopressin, etamsylate, flurbiprofen, mefenamic acid and norethisterone, but less effective than the levonorgestrel-releasing intra-uterine device in heavy menstrual bleeding and was as effective as prednisolone in traumatic hyphaema. Tranexamic acid was generally well tolerated. Most adverse events in clinical trials were of mild or moderate severity; severe or serious events were rare. Therefore, while high-quality published evidence is limited for some approved indications, tranexamic acid is an effective and well tolerated antifibrinolytic agent.

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Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis.

Karim Brohi, Mitchell J Cohen, Michael T Ganter … (2008)

Coagulopathy is present at admission in 25% of trauma patients, is associated with shock and a 5-fold increase in mortality. The coagulopathy has recently been associated with systemic activation of the protein C pathway. This study was designed to characterize the thrombotic, coagulant and fibrinolytic derangements of trauma-induced shock. This was a prospective cohort study of major trauma patients admitted to a single trauma center. Blood was drawn within 10 minutes of arrival for analysis of partial thromboplastin and prothrombin times, prothrombin fragments 1 + 2 (PF1 + 2), fibrinogen, factor VII, thrombomodulin, protein C, plasminogen activator inhibitor-1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI), tissue plasminogen activator (tPA), and D-dimers. Base deficit was used as a measure of tissue hypoperfusion. Two hundred eight patients were studied. Systemic hypoperfusion was associated with anticoagulation and hyperfibrinolysis. Coagulation was activated and thrombin generation was related to injury severity, but acidosis did not affect Factor VII or PF1 + 2 levels. Hypoperfusion-induced increase in soluble thrombomodulin levels was associated with reduced fibrinogen utilization, reduction in protein C and an increase in TAFI. Hypoperfusion also resulted in hyperfibrinolysis, with raised tPA and D-Dimers, associated with the observed reduction in PAI-1 and not alterations in TAFI. Acute coagulopathy of trauma is associated with systemic hypoperfusion and is characterized by anticoagulation and hyperfibrinolysis. There was no evidence of coagulation factor loss or dysfunction at this time point. Soluble thrombomodulin levels correlate with thrombomodulin activity. Thrombin binding to thrombomodulin contributes to hyperfibrinolysis via activated protein C consumption of PAI-1.

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The WOMAN Trial (World Maternal Antifibrinolytic Trial): tranexamic acid for the treatment of postpartum haemorrhage: an international randomised, double blind placebo controlled trial

Haleema Shakur, Diana Elbourne, Ahmet Metin Gülmezoglu … (2010)

Background Each year, worldwide about 530,000 women die from causes related to pregnancy and childbirth. Of the deaths 99% are in low and middle income countries. Obstetric haemorrhage is the leading cause of maternal mortality, most occurring in the postpartum period. Systemic antifibrinolytic agents are widely used in surgery to prevent clot breakdown (fibrinolysis) in order to reduce surgical blood loss. At present there is little reliable evidence from randomised trials on the effectiveness of tranexamic acid in the treatment of postpartum haemorrhage. Methods The Trial aims to determine the effect of early administration of tranexamic acid on mortality, hysterectomy and other morbidities (surgical interventions, blood transfusion, risk of non-fatal vascular events) in women with clinically diagnosed postpartum haemorrhage. The use of health services and safety, especially thromboembolic effect, on breastfed babies will also be assessed. The trial will be a large, pragmatic, randomised, double blind, placebo controlled trial among 15,000 women with a clinical diagnosis of postpartum haemorrhage. All legally adult women with clinically diagnosed postpartum haemorrhage following vaginal delivery of a baby or caesarean section will potentially be eligible. The fundamental eligibility criterion is the responsible clinician's 'uncertainty' as to whether or not to use an antifibrinolytic agent in a particular woman with postpartum haemorrhage. Treatment will entail a dose of tranexamic acid (1 gram by intravenous injection) or placebo (sodium chloride 0.9%) will be given as soon as possible after randomisation. A second dose may be given if after 30 minutes bleeding continues, or if it stops and restarts within 24 hours after the first dose. The main analyses will be on an 'intention to treat' basis, irrespective of whether the allocated treatment was received or not. Subgroup analyses for the primary outcome will be based on type of delivery; administration or not of prophylactic uterotonics; and on whether the clinical decision to consider trial entry was based primarily on estimated blood loss alone or on haemodynamic instability. A study with 15,000 women will have over 90% power to detect a 25% reduction from 4% to 3% in the primary endpoint of mortality or hysterectomy. Trial registration Current Controlled Trials: ISRCTN76912190 and Clinicaltrials.gov ID: NCT00872469

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Author and article information

Contributors

Tie Bo Wu:

ORCID: http://orcid.org/0000-0001-9522-3626

Role: Formal analysisRole: MethodologyRole: VisualizationRole: Writing – original draftRole: Writing – review & editing

Thomas Orfeo: Role: ConceptualizationRole: ResourcesRole: Writing – review & editing

Hunter B. Moore: Role: ConceptualizationRole: InvestigationRole: Resources

Joshua J. Sumislawski: Role: ConceptualizationRole: Investigation

Mitchell J. Cohen: Role: ConceptualizationRole: Project administrationRole: Supervision

Linda R. Petzold:

ORCID: http://orcid.org/0000-0001-6251-6078

Role: Project administrationRole: SupervisionRole: Writing – review & editing

Raghavan Raju: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2020

Publication date (Electronic): 26 May 2020

Volume: 15

Issue: 5

Electronic Location Identifier: e0233640

Affiliations

[1 ] Department of Mechanical Engineering, University of California Santa Barbara, Santa Barbara, California, United States of America

[2 ] Department of Biochemistry, University of Vermont, Burlington, Vermont, United States of America

[3 ] Department of Surgery, Denver Health and Hospital Authority, Denver, Colorado, United States of America

Medical College of Georgia, Augusta, UNITED STATES

Author notes

Competing Interests: The authors have declared that no competing interests exist.

* E-mail: tiebo@ 123456ucsb.edu

Author information

Tie Bo Wu http://orcid.org/0000-0001-9522-3626

Linda R. Petzold http://orcid.org/0000-0001-6251-6078

Article

Publisher ID: PONE-D-20-03512

DOI: 10.1371/journal.pone.0233640

PMC ID: 7250412

PubMed ID: 32453766

SO-VID: 9e60b61e-9abc-466f-bc0f-2db668c0f844

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 6 February 2020

Date accepted : 9 May 2020

Page count

Figures: 6, Tables: 0, Pages: 11

Funding

Funded by: funder-id http://dx.doi.org/10.13039/100010459, Research, Development and Engineering Command;

Award ID: W911QY-15-C-0026

Award Recipient :

ORCID: http://orcid.org/0000-0001-6251-6078

Linda R. Petzold

This material is based upon work supported by the US Army Contracting Command, Aberdeen Proving Ground, Natick Contracting Division under Contract No. W911QY-15-C-0026. Funding was granted to Linda Petzold (LP). The funders had no role in study design, analysis, decision to publish, or preparation of the manuscript.

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Computational model of tranexamic acid on urokinase mediated fibrinolysis

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Most cited references 26

Tranexamic acid: a review of its use in the treatment of hyperfibrinolysis.

Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis.

The WOMAN Trial (World Maternal Antifibrinolytic Trial): tranexamic acid for the treatment of postpartum haemorrhage: an international randomised, double blind placebo controlled trial

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