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A novel prothrombin time method to measure all non-vitamin K-dependent oral anticoagulants (NOACs)
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine and Geriatrics.ORCID iD: 0000-0003-1068-6168
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
Zafena AB, Borensberg, Sweden.
2017 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 3, p. 171-176Article in journal (Refereed) Published
Abstract [en]

Background: There is a clinical need for point-of-care (POC) methods for non-vitamin K-dependent oral anticoagulants (NOACs). We modified a routine POC procedure: Zafena’s Simple Simon™ PT-INR, a room-temperature, wet-chemistry prothrombin time method of the Owren-type.

Methods: To either increase or decrease NOAC interference, two assay variants were devised by replacing the standard 10 µL end-to-end capillary used to add the citrated plasma sample to 200 µL of prothrombin time (PT) reagent by either a 20 µL or a 5 µL capillary. All assay variants were calibrated to show correct PT results in plasma samples from healthy and warfarin-treated persons.

Results: For plasmas spiked with dabigatran, apixaban, or rivaroxaban, the 20 µL variant showed markedly higher PT results than the 5 µL. The effects were even more pronounced at room temperature than at +37 °C. In plasmas from patients treated with NOACs (n = 30 for each) there was a strong correlation between the PT results and the concentration of NOACs as determined by the central hospital laboratory. For the 20 µL variant the PT response of linear correlation coefficient averaged 0.90. The PT range was INR 1.1–2.1 for dabigatran and apixaban, and INR 1.1–5.0 for rivaroxaban. Using an INR ratio between the 20 µL and 5 µL variants (PTr20/5) made the NOAC assay more robust and independent of the patient sample INR value in the absence of NOAC. Detection limits were 80 µg/L for apixaban, 60 µg/L for dabigatran, and 20 µg/L for rivaroxaban.

Conclusions: A wet-chemistry POC PT procedure was modified to measure the concentrations of three NOACs using a single reagent.

Place, publisher, year, edition, pages
Taylor & Francis Group, 2017. Vol. 122, no 3, p. 171-176
Keywords [en]
Anticoagulant, apixaban, dabigatran, prothrombin time, rivaroxaban
National Category
Clinical Medicine
Identifiers
URN: urn:nbn:se:liu:diva-141178DOI: 10.1080/03009734.2017.1370040ISI: 000414107800003PubMedID: 28891412OAI: oai:DiVA.org:liu-141178DiVA, id: diva2:1144161
Note

Funding agencies: county of Ostergotland research funds [LIO-609911]

Available from: 2017-09-25 Created: 2017-09-25 Last updated: 2023-10-31
In thesis
1. Two worlds, one goal: A Clinician’s Perspective on Laboratory Analyses in Anticoagulant Treatment
Open this publication in new window or tab >>Two worlds, one goal: A Clinician’s Perspective on Laboratory Analyses in Anticoagulant Treatment
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Almost precisely a century ago, in the 1920s and 1930s, cattle bled to death in North America after being fed moldy hay containing sweet clover, the yellow Melilotus officinalis, and the white Melilotus albus. The toxic substance in the hay inhibiting blood coagulation was identified and named dicumarol. Further development resulted in warfarin, an oral anticoagulant that has been used for over 70 years and still is, even though newer direct-acting oral anticoagulants (DOACs) are mainly replacing it. For some patients, warfarin is still the drug of choice. A safe warfarin treatment needs repeated blood sample analysis (PT-INR), and with the new DOACs come new laboratory challenges. The aim of this thesis was to investigate ways laboratory methods can contribute to improving oral anticoagulant treatment. 

Paper I explores genetic variants of the enzyme targeted by warfarin, VKORC1. The result shows that the haplotype VKORC1*2 is the most important of the VKORC1 haplotypes for warfarin dosage, with a lower dose requirement. The VKORC1*2 haplotype was also related to more unstable PT-INR levels. 

Paper II describes a cross-section study comparing warfarin treatment control, as PT-INRs within the intended therapeutic range, in primary health care centers (PHCCs) and specialized anticoagulation clinics (ACCs). Both settings showed good therapeutic control, with at least as good therapeutic control in the PHCCs as in the ACCs. Today, almost all warfarin treatment in our region is centralized to ACCs. 

Paper III focuses on the modification of a point-of-care PT method. A ratio of PT from two different dilutions of each patient sample was calculated and used as an indirect measure of DOAC activity. There were close correlations between the PT ratio and drug concentrations measured at the hospital laboratory. The detection level varies between DOACs and may limit its use in some situations. 

Paper IV evaluated the MRX PT DOAC, an assay based on the PT ratio principle. It was found to be able to detect potentially interfering DOAC levels in plasma samples. Confirmatory testing is recommended, as is sensitivity improvement for the detection of specific interferences.   

Abstract [sv]

För nästan exakt 100 år sedan dog boskap i Nordamerika av stora blödningar. Det skulle visa sig att det berodde på att de utfodrats med mögligt hö innehållande gul och vit sötväppling, Melilotus officinalis och Melilotus albus. Den giftiga substans som bildas hindrar blodet från att koagulera. Forskare lyckades identifiera och renframställa substansen, och en vidareutveckling av den gav upphov till warfarin, ett “blodförtunnande” läkemedel (antikoagulantia) i tablettform. Warfarin används än idag, även om nya antikoagulantialäkemedel används allt oftare. För vissa patienter är warfarin ännu det bästa läkemedlet. Warfarinbehandlade patienter kontrolleras regelbundet med analys PK-prov på laboratorium för att behandlingen ska vara säker, och med de nya läkemedlen kommer nya analysutmaningar. Målsättningen med den här avhandlingen har varit att undersöka olika sätt som laboratoriemetoder kan bidra till att förbättra antikoagulantiabehandling.

I delarbete I har vi sett att det finns en koppling mellan vissa genetiska varianter och ett lägre behov av warfarin, och likaså en mer svårinställd behandling.

I delarbete II undersökte vi kvaliteten på warfarinbehandlingen i primärvård jämfört med specialiserade antikoagulantia(AK-)mottagningar genom jämförelse av hur PK-proven under en viss vecka förhöll sig till önskade värden. Båda vårdformerna visade god kvalitet på warfarinbehandlingen, minst lika bra i primärvården som på AK-mottagningarna. Sedan studien gjordes har nästan all warfarinbehandling centraliserats till AK-mottagningar.

I delarbete III modifierade vi en analysmetod som vanligen används för analys av PK-prov, med sikte på att också kunna använda den för analys av effekt av de nya antikoagulantialäkemedlen. Vi såg en god överensstämmelse mellan den modifierade metodens resultat och ordinarie analys.

I delarbete IV utvärderade vi MRX PT DOAC, en analysmetod som bygger på den princip som beskrivs i delarbete III. Vi använde MRX PT DOAC för att upptäcka prover med läkemedel som kan störa andra analyser. Vi såg goda resultat men också förbättringspotential.  

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2023. p. 76
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1875
Keywords
Anticoagulants, Warfarin, DOAC, PT-INR, VKORC1
National Category
Basic Medicine
Identifiers
urn:nbn:se:liu:diva-198901 (URN)10.3384/9789180753470 (DOI)9789180753463 (ISBN)9789180753470 (ISBN)
Public defence
2023-11-28, Hugo Theorell, Building 440, Campus US, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2023-10-31 Created: 2023-10-31 Last updated: 2023-11-02Bibliographically approved

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