Editorial

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Open AccessEditorial

Editorial for the Special Issue of Monitoring Anticoagulants

by Jean Amiral

Biomedicines 2022, 10(1), 155; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10010155 - 12 Jan 2022

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This Special Issue focuses on monitoring anticoagulant therapies and presents all the most recent updates introduced for laboratory practice, which benefit anticoagulated patients [...] Full article

(This article belongs to the Special Issue Monitoring Anticoagulant)

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Research

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16 pages, 2089 KiB

Open AccessArticle

Optimization of Heparin Monitoring with Anti-FXa Assays and the Impact of Dextran Sulfate for Measuring All Drug Activity

by Jean Amiral, Cédric Amiral and Claire Dunois

Biomedicines 2021, 9(6), 700; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9060700 - 21 Jun 2021

Cited by 6 | Viewed by 2902

Abstract

Heparins, unfractionated or low molecular weight, are permanently in the spotlight of both clinical indications and laboratory monitoring. An accurate drug dosage is necessary for an efficient and safe therapy. The one-stage kinetic anti-FXa assays are the most widely and universally used with [...] Read more.

Heparins, unfractionated or low molecular weight, are permanently in the spotlight of both clinical indications and laboratory monitoring. An accurate drug dosage is necessary for an efficient and safe therapy. The one-stage kinetic anti-FXa assays are the most widely and universally used with full automation for large series, without needing exogenous antithrombin. The WHO International Standards are available for UFH and LMWH, but external quality assessment surveys still report a high inter-assay variability. This heterogeneity results from the following: assay formulation, designed without or with dextran sulfate to measure all heparin in blood circulation; calibrators for testing UFH or LMWH with the same curve; and automation parameters. In this study, various factors which impact heparin measurements are reviewed, and we share our experience to optimize assays for testing all heparin anticoagulant activities in plasma. Evidence is provided on the usefulness of low molecular weight dextran sulfate to completely mobilize all of the drug present in blood circulation. Other key factors concern the adjustment of assay conditions to obtain fully superimposable calibration curves for UFH and LMWH, calibrators’ formulations, and automation parameters. In this study, we illustrate the performances of different anti-FXa assays used for testing heparin on UFH or LMWH treated patients’ plasmas and obtained using citrate or CTAD anticoagulants. Comparable results are obtained only when the CTAD anticoagulant is used. Using citrate as an anticoagulant, UFH is underestimated in the absence of dextran sulfate. Heparin calibrators, adjustment of automation parameters, and data treatment contribute to other smaller differences. Full article

(This article belongs to the Special Issue Monitoring Anticoagulant)

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15 pages, 3289 KiB

Open AccessArticle

Functional Flow Cytometric Assay for Reliable and Convenient Heparin-Induced Thrombocytopenia Diagnosis in Daily Practice

by Brigitte Tardy-Poncet, Aurélie Montmartin, Michele Piot, Martine Alhenc-Gelas, Philippe Nguyen, Ismail Elalamy, Andreas Greinacher, Emmanuel De Maistre, Dominique Lasne, Marie-Hélène Horellou, Grégoire Le Gal, Thomas Lecompte, Bernard Tardy and on behalf of the GFHT-HIT Study Group

Biomedicines 2021, 9(4), 332; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9040332 - 25 Mar 2021

Cited by 9 | Viewed by 2510

Abstract

Reliable laboratory diagnosis of heparin-induced thrombocytopenia (HIT) remains a major clinical concern. Immunoassays are highly sensitive, while confirmatory functional tests (based on heparin-dependent platelet activation) lack standardization. We evaluated the diagnostic performance of a functional flow cytometric assay (FCA) based on the detection [...] Read more.

Reliable laboratory diagnosis of heparin-induced thrombocytopenia (HIT) remains a major clinical concern. Immunoassays are highly sensitive, while confirmatory functional tests (based on heparin-dependent platelet activation) lack standardization. We evaluated the diagnostic performance of a functional flow cytometric assay (FCA) based on the detection of heparin-dependent platelet activation with an anti-p-selectin. A total of 288 patients were included (131 HIT-positive and 157 HIT-negative) with a HIT diagnosis established by expert opinion adjudication (EOA) considering clinical data and local laboratory results. The FCA was centrally performed in a single laboratory on platelet-rich plasma, using a very simple four-color fluorometer. The results were standardized according to the Heparin Platelet Activation (HEPLA) index. The serotonin release assay (SRA) was performed in the four French reference laboratories. Based on the final HIT diagnosis established by EOA, the sensitivity and specificity of the FCA were 88 and 95%, respectively, values very similar to those of the SRA (88 and 97%, respectively). This study showed that the FCA, based on easily implementable technology, may be routinely used as a reliable confirmatory test for HIT diagnosis. Full article

(This article belongs to the Special Issue Monitoring Anticoagulant)

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15 pages, 1544 KiB

Open AccessArticle

An Optimized and Standardized Rapid Flow Cytometry Functional Method for Heparin-Induced Thrombocytopenia

by Anne Runser, Caroline Schaning, Frédéric Allemand and Jean Amiral

Biomedicines 2021, 9(3), 296; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9030296 - 13 Mar 2021

Cited by 7 | Viewed by 2852

Abstract

Heparin-induced thrombocytopenia (HIT) is a thrombocytopenia caused by heparin and mediated by an atypical immune mechanism leading to a paradoxical high thrombotic risk, associated with severe morbidity or death. The diagnosis of HIT combines a clinical scoring of pretest probability and laboratory testing. [...] Read more.

Heparin-induced thrombocytopenia (HIT) is a thrombocytopenia caused by heparin and mediated by an atypical immune mechanism leading to a paradoxical high thrombotic risk, associated with severe morbidity or death. The diagnosis of HIT combines a clinical scoring of pretest probability and laboratory testing. First-line routine tests are antigen binding assays detecting specific antibodies. The most sensitive of these tests have a high HIT-negative predictive value enabling HIT diagnosis to be ruled out when negative. However, HIT-positive predictive value is low, and a functional assay evaluating the pathogenicity of the antibodies should be performed to exclude false-positive results. In contrast to screening assays, functional assays are highly specific but technically challenging, and are thus performed in referral laboratories, where platelet activation is detected using radioactive serotonin (serotonin release assay, SRA) or visually (heparin-induced platelet activation, HIPA). Flow cytometry is a possible alternative. It is, however, currently not widely used, mostly because of the lack of standardization of the published assays. This article describes and discusses the standardization of a HIT flow cytometry assay (HIT-FCA) method, which subsequently led to the development and commercialization of a CE-marked assay (HIT Confirm^®, Emosis, France) as a suitable rapid HIT functional test. Full article

(This article belongs to the Special Issue Monitoring Anticoagulant)

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14 pages, 2719 KiB

Open AccessArticle

The Lectin-Like Domain of Thrombomodulin Inhibits β1 Integrin-Dependent Binding of Human Breast Cancer-Derived Cell Lines to Fibronectin

by Eiji Kawamoto, Nodoka Nago, Takayuki Okamoto, Arong Gaowa, Asami Masui-Ito, Yuichi Akama, Samuel Darkwah, Michael Gyasi Appiah, Phyoe Kyawe Myint, Gideon Obeng, Atsushi Ito, Siqingaowa Caidengbate, Ryo Esumi, Takanori Yamaguchi, Eun Jeong Park, Hiroshi Imai and Motomu Shimaoka

Biomedicines 2021, 9(2), 162; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9020162 - 07 Feb 2021

Cited by 4 | Viewed by 2464

Abstract

Thrombomodulin is a molecule with anti-coagulant and anti-inflammatory properties. Recently, thrombomodulin was reported to be able to bind extracellular matrix proteins, such as fibronectin and collagen; however, whether thrombomodulin regulates the binding of human breast cancer-derived cell lines to the extracellular matrix remains [...] Read more.

Thrombomodulin is a molecule with anti-coagulant and anti-inflammatory properties. Recently, thrombomodulin was reported to be able to bind extracellular matrix proteins, such as fibronectin and collagen; however, whether thrombomodulin regulates the binding of human breast cancer-derived cell lines to the extracellular matrix remains unknown. To investigate this, we created an extracellular domain of thrombomodulin, TMD123-Fc, or domain deletion TM-Fc proteins (TM domain 12-Fc, TM domain 23-Fc) and examined their bindings to fibronectin in vitro by ELISA. The lectin-like domain of thrombomodulin was found to be essential for the binding of the extracellular domain of thrombomodulin to fibronectin. Using a V-well cell adhesion assay or flow cytometry analysis with fluorescent beads, we found that both TMD123-Fc and TMD12-Fc inhibited the binding between β1 integrin of human breast cancer-derived cell lines and fibronectin. Furthermore, TMD123-Fc and TMD12-Fc inhibited the binding of activated integrins to fibronectin under shear stress in the presence of Ca²⁺ and Mg²⁺ but not under strong integrin-activation conditions in the presence of Mg²⁺ without Ca²⁺. This suggests that thrombomodulin Fc fusion protein administered exogenously at a relatively early stage of inflammation may be applied to the development of new therapies that inhibit the binding of β1 integrin of breast cancer cell lines to fibronectin. Full article

(This article belongs to the Special Issue Monitoring Anticoagulant)

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Review

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10 pages, 491 KiB

Open AccessReview

What Do We Know about Thromboprophylaxis and Its Monitoring in Critically Ill Patients?

by Philippe Cauchie and Michael Piagnerelli

Biomedicines 2021, 9(8), 864; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9080864 - 22 Jul 2021

Cited by 6 | Viewed by 2412

Abstract

Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, is an important complication in patients hospitalized in intensive care units (ICU). Thromboprophylaxis is mainly performed with Low Molecular Weight Heparin (LMWH) and, in some specific patients, with Unfractionated Heparin (UFH). These intensive [...] Read more.

Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, is an important complication in patients hospitalized in intensive care units (ICU). Thromboprophylaxis is mainly performed with Low Molecular Weight Heparin (LMWH) and, in some specific patients, with Unfractionated Heparin (UFH). These intensive units are an environment where individual patient variability is extreme and where traditional antithrombotic protocols are frequently ineffective. This was known for a long time, but the hospitalization of many patients with COVID-19 inflammatory storms suddenly highlighted this knowledge. It is therefore reasonable to propose variable antithrombotic prevention protocols based initially on a series of individual criteria (weight, BMI, and thrombotic risks). Secondly, they should be adjusted by the monitoring of anticoagulant activity, preferably by measuring the anti-Xa activity. However, we still face unresolved questions, such as once- or twice-daily LMWH injections, monitoring at the peak and/or trough, and poorly defined therapeutic targets. Equally surprisingly, we observed a lack of standardization of the anti-Xa activity kits. Full article

(This article belongs to the Special Issue Monitoring Anticoagulant)

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15 pages, 1353 KiB

Open AccessReview

Laboratory Monitoring of Direct Oral Anticoagulants (DOACs)

by Claire Dunois

Biomedicines 2021, 9(5), 445; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9050445 - 21 Apr 2021

Cited by 39 | Viewed by 6960

Abstract

The introduction of direct oral anticoagulants (DOACs), such as dabigatran, rivaroxaban, apixaban, edoxaban, and betrixaban, provides safe and effective alternative to previous anticoagulant therapies. DOACs directly, selectively, and reversibly inhibit factors IIa or Xa. The coagulation effect follows the plasma concentration–time profile of [...] Read more.

The introduction of direct oral anticoagulants (DOACs), such as dabigatran, rivaroxaban, apixaban, edoxaban, and betrixaban, provides safe and effective alternative to previous anticoagulant therapies. DOACs directly, selectively, and reversibly inhibit factors IIa or Xa. The coagulation effect follows the plasma concentration–time profile of the respective anticoagulant. The short half-life of a DOAC constrains the daily oral intake. Because DOACs have predictable pharmacokinetic and pharmacodynamic responses at a fixed dose, they do not require monitoring. However in specific clinical situations and for particular patient populations, testing may be helpful for patient management. The effect of DOACs on the screening coagulation assays such as prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT) is directly linked to reagent composition, and clotting time can be different from reagent to reagent, depending on the DOAC’s reagent sensitivity. Liquid chromatography–mass spectrometry (LC-MS/MS) is considered the gold standard method for DOAC measurement, but it is time consuming and requires expensive equipment. The general consensus for the assessment of a DOAC is clotting or chromogenic assays using specific standard calibrators and controls. This review provides a short summary of DOAC properties and an update on laboratory methods for measuring DOACs. Full article

(This article belongs to the Special Issue Monitoring Anticoagulant)

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20 pages, 2727 KiB

Open AccessReview

Updates on Anticoagulation and Laboratory Tools for Therapy Monitoring of Heparin, Vitamin K Antagonists and Direct Oral Anticoagulants

by Osamu Kumano, Kohei Akatsuchi and Jean Amiral

Biomedicines 2021, 9(3), 264; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9030264 - 07 Mar 2021

Cited by 14 | Viewed by 7286

Abstract

Anticoagulant drugs have been used to prevent and treat thrombosis. However, they are associated with risk of hemorrhage. Therefore, prior to their clinical use, it is important to assess the risk of bleeding and thrombosis. In case of older anticoagulant drugs like heparin [...] Read more.

Anticoagulant drugs have been used to prevent and treat thrombosis. However, they are associated with risk of hemorrhage. Therefore, prior to their clinical use, it is important to assess the risk of bleeding and thrombosis. In case of older anticoagulant drugs like heparin and warfarin, dose adjustment is required owing to narrow therapeutic ranges. The established monitoring methods for heparin and warfarin are activated partial thromboplastin time (APTT)/anti-Xa assay and prothrombin time – international normalized ratio (PT-INR), respectively. Since 2008, new generation anticoagulant drugs, called direct oral anticoagulants (DOACs), have been widely prescribed to prevent and treat several thromboembolic diseases. Although the use of DOACs without routine monitoring and frequent dose adjustment has been shown to be safe and effective, there may be clinical circumstances in specific patients when measurement of the anticoagulant effects of DOACs is required. Recently, anticoagulation therapy has received attention when treating patients with coronavirus disease 2019 (COVID-19). In this review, we discuss the mechanisms of anticoagulant drugs—heparin, warfarin, and DOACs and describe the methods used for the measurement of their effects. In addition, we discuss the latest findings on thrombosis mechanism in patients with COVID-19 with respect to biological chemistry. Full article

(This article belongs to the Special Issue Monitoring Anticoagulant)

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15 pages, 916 KiB

Open AccessReview

Updates in Anticoagulation Therapy Monitoring

by Hannah L. McRae, Leah Militello and Majed A. Refaai

Biomedicines 2021, 9(3), 262; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9030262 - 06 Mar 2021

Cited by 28 | Viewed by 7652

Abstract

In the past six decades, heparin and warfarin were the primary anticoagulants prescribed for treatment and prophylaxis of venous thromboembolism worldwide. This has been accompanied by extensive clinical knowledge regarding dosing, monitoring, and reversal of these anticoagulants, and the resources required to do [...] Read more.

In the past six decades, heparin and warfarin were the primary anticoagulants prescribed for treatment and prophylaxis of venous thromboembolism worldwide. This has been accompanied by extensive clinical knowledge regarding dosing, monitoring, and reversal of these anticoagulants, and the resources required to do so have largely been readily available at small and large centers alike. However, with the advent of newer oral and parenteral anticoagulants such as low molecular weight heparins, factor Xa inhibitors, and direct thrombin inhibitors in recent years, new corresponding practice guidelines have also emerged. A notable shift in the need for monitoring and reversal agents has evolved as well. While this has perhaps streamlined the process for physicians and is often desirable for patients, it has also left a knowledge and resource gap in clinical scenarios for which urgent reversal and monitoring is necessary. An overview of the currently available anticoagulants with a focus on the guidelines and available tests for anticoagulant monitoring will be discussed in this article. Full article

(This article belongs to the Special Issue Monitoring Anticoagulant)

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