Validation of a modified thromboelastometry approach to detect changes in fibrinolytic activity

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Background

Thus far, validated whole blood assays used in in vitro fibrinolysis experiments using thromboelastometry (ROTEM) are lacking or have yet to be tested in humans.

The objective was first, to establish a standardized modified ROTEM approach to detect both hypo- and hyperfibrinolysis. And second, to perform a technical and clinical validation of the assay.

Methods

Blood was used of healthy volunteers, patients with sepsis, patients after cardiothoracic surgery, pregnant women, and cirrhotic liver disease patients. A whole blood tissue factor (TF) activated ROTEM assay with and without the addition of recombinant tissue plasminogen activator (rTPA) was developed. Plasma fibrinolysis determinants were measured in all volunteers and patients.

Results

Thirty five pM TF and additions of 125 and 175 ng/ml rTPA resulted in full lysis within 60 min in healthy volunteers. Coefficients of variation were below 10 % without and below 20 % with rTPA addition. In sepsis the hypofibrinolytic ROTEM profiles with 175 ng/ml rTPA were in line with the plasma determinants (high PAI-1, high fibrinogen, low tPA activity, and high d-dimers). After cardiothoracic surgery, reduced fibrinogen and platelet levels accounted for the reduced maximum clot firmness. The hypofibrinolytic profile is attributed to tranexamic acid use and elevated PAI-1 levels. The lowest rTPA concentration in cirrhosis resulted in hyperfibrinolysis in only few of the patients. In pregnancy normal profiles were found.

Discussion

Our high rTPA concentration demonstrates hypofibrinolytic profiles adequately in sepsis and after cardiothoracic surgery. Our low rTPA concentration of 125 ng/ml seems too high for demonstrating hyperfibrinolysis in cirrhotic liver disease.

Conclusions

We were able to present a validated whole blood ROTEM approach to fibrinolysis testing using added rTPA, which can be of added value next to classical plasma based fibrinolysis assays.

Related collections

Most cited references 43

Record: found
Abstract: found
Article: not found

Septic shock.

Djillali Annane, Eric Bellissant, Jean-Marc Cavaillon (2005)

Septic shock, the most severe complication of sepsis, is a deadly disease. In recent years, exciting advances have been made in the understanding of its pathophysiology and treatment. Pathogens, via their microbial-associated molecular patterns, trigger sequential intracellular events in immune cells, epithelium, endothelium, and the neuroendocrine system. Proinflammatory mediators that contribute to eradication of invading microorganisms are produced, and anti-inflammatory mediators control this response. The inflammatory response leads to damage to host tissue, and the anti-inflammatory response causes leucocyte reprogramming and changes in immune status. The time-window for interventions is short, and treatment must promptly control the source of infection and restore haemodynamic homoeostasis. Further research is needed to establish which fluids and vasopressors are best. Some patients with septic shock might benefit from drugs such as corticosteroids or activated protein C. Other therapeutic strategies are under investigation, including those that target late proinflammatory mediators, endothelium, or the neuroendocrine system.

0 comments Cited 282 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

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

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.

0 comments Cited 169 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial.

Ian Roberts, Haleema Shakur, Adefemi O. Afolabi … (2011)

The aim of the CRASH-2 trial was to assess the effects of early administration of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage. Tranexamic acid significantly reduced all-cause mortality. Because tranexamic acid is thought to exert its effect through inhibition of fibrinolysis, we undertook exploratory analyses of its effect on death due to bleeding. The CRASH-2 trial was undertaken in 274 hospitals in 40 countries. 20,211 adult trauma patients with, or at risk of, significant bleeding were randomly assigned within 8 h of injury to either tranexamic acid (loading dose 1 g over 10 min followed by infusion of 1 g over 8 h) or placebo. Patients were randomly assigned by selection of the lowest numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Both participants and study staff (site investigators and trial coordinating centre staff ) were masked to treatment allocation. We examined the effect of tranexamic acid on death due to bleeding according to time to treatment, severity of haemorrhage as assessed by systolic blood pressure, Glasgow coma score (GCS), and type of injury. All analyses were by intention to treat. The trial is registered as ISRCTN86750102, ClinicalTrials.gov NCT00375258, and South African Clinical Trial Register/Department of Health DOH-27-0607-1919. 10,096 patients were allocated to tranexamic acid and 10,115 to placebo, of whom 10,060 and 10,067, respectively, were analysed. 1063 deaths (35%) were due to bleeding. We recorded strong evidence that the effect of tranexamic acid on death due to bleeding varied according to the time from injury to treatment (test for interaction p<0.0001). Early treatment (≤1 h from injury) significantly reduced the risk of death due to bleeding (198/3747 [5.3%] events in tranexamic acid group vs 286/3704 [7.7%] in placebo group; relative risk [RR] 0.68, 95% CI 0.57-0.82; p<0.0001). Treatment given between 1 and 3 h also reduced the risk of death due to bleeding (147/3037 [4.8%] vs 184/2996 [6.1%]; RR 0.79, 0.64-0.97; p=0.03). Treatment given after 3 h seemed to increase the risk of death due to bleeding (144/3272 [4.4%] vs 103/3362 [3.1%]; RR 1.44, 1.12-1.84; p=0.004). We recorded no evidence that the effect of tranexamic acid on death due to bleeding varied by systolic blood pressure, Glasgow coma score, or type of injury. Tranexamic acid should be given as early as possible to bleeding trauma patients. For trauma patients admitted late after injury, tranexamic acid is less effective and could be harmful. UK NIHR Health Technology Assessment programme, Pfizer, BUPA Foundation, and J P Moulton Charitable Foundation. Copyright © 2011 Elsevier Ltd. All rights reserved.

0 comments Cited 119 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Gerhardus J. A. J. M. Kuiper: +31 43 3877455 , g.kuiper@mumc.nl

Marie-Claire F. Kleinegris: m-c.kleinegris@maastrichtuniversity.nl

René van Oerle: rene.vanoerle@maastrichtuniversity.nl

Henri M. H. Spronk: henri.spronk@maastrichtuniversity.nl

Marcus D. Lancé: marcus.lance@mumc.nl

Hugo ten Cate: h.ten.cate@mumc.nl

Yvonne M. C. Henskens: yvonne.henskens@mumc.nl

Journal

Journal ID (nlm-ta): Thromb J

Journal ID (iso-abbrev): Thromb J

Title: Thrombosis Journal

Publisher: BioMed Central (London )

ISSN (Electronic): 1477-9560

Publication date (Electronic): 14 January 2016

Publication date PMC-release: 14 January 2016

Publication date Collection: 2016

Volume: 14

Electronic Location Identifier: 1

Affiliations

[ ]Department of Anaesthesiology and Pain Treatment, Maastricht University Medical Center (MUMC+), P. Debyelaan 25, PO Box 5800, 6202 AZ Maastricht, The Netherlands

[ ]Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Laboratory for Clinical Thrombosis and Haemostasis, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands

[ ]Central Diagnostic Laboratory, Cluster for Hemostasis and transfusion, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands

Article

Publisher ID: 76

DOI: 10.1186/s12959-016-0076-2

PMC ID: 4712545

PubMed ID: 26770073

SO-VID: 6313c790-d092-45e5-92c7-d25ab3476fb1

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 5 August 2015

Date accepted : 10 January 2016

Custom metadata

ScienceOpen disciplines: Cardiovascular Medicine

Keywords: blood coagulation tests,fibrinolysis,thrombelastography,tissue plasminogen activator,validation studies

Data availability:

ScienceOpen disciplines: Cardiovascular Medicine

Keywords: blood coagulation tests, fibrinolysis, thrombelastography, tissue plasminogen activator, validation studies

Validation of a modified thromboelastometry approach to detect changes in fibrinolytic activity

Read this article at

Abstract

Background

Methods

Results

Discussion

Conclusions

Related collections

Cardiovascular Innovations and Applications

Most cited references 43

Septic shock.

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

The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial.

Author and article information

Contributors

Journal

Affiliations

Article

History

Categories

Custom metadata

Comments

Comment on this article

Similar content 134

Cited by 27

Most referenced authors 575