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Two worlds, one goal: A Clinician’s Perspective on Laboratory Analyses in Anticoagulant Treatment
Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi och farmakologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Medicinska och geriatriska akutkliniken.ORCID-id: 0000-0003-1068-6168
2023 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.  

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2023. , s. 76
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1875
Emneord [en]
Anticoagulants, Warfarin, DOAC, PT-INR, VKORC1
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-198901DOI: 10.3384/9789180753470ISBN: 9789180753463 (tryckt)ISBN: 9789180753470 (digital)OAI: oai:DiVA.org:liu-198901DiVA, id: diva2:1808517
Disputas
2023-11-28, Hugo Theorell, Building 440, Campus US, Linköping, 09:00 (svensk)
Opponent
Veileder
Tilgjengelig fra: 2023-10-31 Laget: 2023-10-31 Sist oppdatert: 2023-11-02bibliografisk kontrollert
Delarbeid
1. Main haplotypes and mutational analysis of vitamin K epoxide reductase (VKORC1) in a Swedish population: A retrospective analysis of case records
Åpne denne publikasjonen i ny fane eller vindu >>Main haplotypes and mutational analysis of vitamin K epoxide reductase (VKORC1) in a Swedish population: A retrospective analysis of case records
Vise andre…
2006 (engelsk)Inngår i: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, Vol. 4, nr 8, s. 1723-1729Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Background: Vitamin K epoxide reductase (VKORC1) is the site of inhibition by coumarins. Several reports have shown that mutations in the gene encoding VKORC1 affect the sensitivity of the enzyme for warfarin. Recently, three main haplotypes of VKORC1; *2, *3 and *4 have been observed, that explain most of the genetic variability in warfarin dose among Caucasians.

Objectives: We have investigated the main haplotypes of the VKORC1 gene in a Swedish population. Additional objective was to screen the studied population for mutations in the coding region of VKORC1 gene.

Patients/methods: Warfarin doses and plasma S- and R-warfarin of 98 patients [with a target International Normalized Ratio (INR) of 2.0–3.0] have been correlated to VKORC1 haplotypes. Controls of 180 healthy individuals have also been haplotyped. Furthermore, a retrospective analysis of case records was performed to find any evidence indicating influence of VKORC1 haplotypes on warfarin response in the first 4 weeks (initiation phase) and the latest 12 months of warfarin treatment.

Results and conclusions: Our result shows that VKORC1*2 is the most important haplotype for warfarin dosage. Patients with VKORC1*2 haplotype had more frequent visits than patients with VKORC1*3 or *4 haplotypes, higher coefficient of variation (CV) of prothrombin time-INR and higher percentage of INR values outside the therapeutic interval (i.e. 2.0–3.0) than patients with VKORC1*3 or *4 haplotypes. Also, there was a statistically significant difference in warfarin dose (P < 0.001) and R-warfarin plasma levels (P < 0.01) between VKORC1*2 and VKORC1*3 or 4 haplotypes. Patients with VKORC1*2 haplotype seem to require much lower warfarin doses than other patients.

Emneord
INR, VKORC1, warfarin
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-14488 (URN)10.1111/j.1538-7836.2006.02039.x (DOI)
Tilgjengelig fra: 2007-05-21 Laget: 2007-05-21 Sist oppdatert: 2023-10-31
2. Comparison of prothrombin time (INR) results and main characteristics of patients on warfarin treatment in primary health care centers and anticoagulation clinics
Åpne denne publikasjonen i ny fane eller vindu >>Comparison of prothrombin time (INR) results and main characteristics of patients on warfarin treatment in primary health care centers and anticoagulation clinics
2013 (engelsk)Inngår i: BMC Health Services Research, E-ISSN 1472-6963, Vol. 13Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Background

Oral anticoagulant therapy is used to prevent thrombosis in patients with atrial fibrillation (AF), venous thrombosis and prosthetic heart valves. The introduction of new therapies emphasizes the need to discern the best practice for the patients remaining on warfarin treatment. This study compares patient characteristics and therapeutic control in two settings managing warfarin treatment: Swedish primary health care centers (PHCC) and specialized anticoagulation clinics (ACC).

Methods

Prothrombin time (PT) test results reported as International Normalized Ratio (INR) were collected for five consecutive days from patients on warfarin treatment; 564 PHCC and 927 ACC patients. Therapeutic control was calculated as PT test results in relation to intended therapeutic range (TR). Mann–Whitney Rank Sum Test and Chi2 test were used for statistical comparisons.

Results

The PHCC patients were older than the ACC patients, 76 v. 70 years (p<0.01) with a predominance of men in both groups. The reasons for treating differed between the groups. Seventy-two percent of PHCC patients and 66% of ACC patients had a PT-INR within the intended TR (p<0.05). Men generally had better results than women (72% v. 63%, p<0.001) and particularly in the PHCC group v. the ACC group (78% v. 69%, p<0.01).

PT-INR above intended TR was significantly more common in the ACC setting, (p<0.05), for women overall (p<0.01), for women in the PHCC setting, and for ACC men (p<0.05).

Conclusions

In this study both settings achieved good therapeutic control of warfarin treatment with a minor advantage for PHCC over ACC, and better results for men, especially in the PHCC setting. As patient characteristics differ between the PHCC and ACC, it is important to conduct further randomized studies to discern the best practice locally for warfarin management also after the introduction of new drugs.

sted, utgiver, år, opplag, sider
BioMed Central, 2013
Emneord
Oral anticoagulants, Treatment, Quality control, Warfarin
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-90753 (URN)10.1186/1472-6963-13-85 (DOI)000315994100001 ()
Merknad

Funding Agencies|Medical Research Council of Southeast Sweden (FORSS)||

Tilgjengelig fra: 2013-04-08 Laget: 2013-04-05 Sist oppdatert: 2023-10-31bibliografisk kontrollert
3. A novel prothrombin time method to measure all non-vitamin K-dependent oral anticoagulants (NOACs)
Åpne denne publikasjonen i ny fane eller vindu >>A novel prothrombin time method to measure all non-vitamin K-dependent oral anticoagulants (NOACs)
2017 (engelsk)Inngår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, nr 3, s. 171-176Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
Taylor & Francis Group, 2017
Emneord
Anticoagulant, apixaban, dabigatran, prothrombin time, rivaroxaban
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-141178 (URN)10.1080/03009734.2017.1370040 (DOI)000414107800003 ()28891412 (PubMedID)
Merknad

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

Tilgjengelig fra: 2017-09-25 Laget: 2017-09-25 Sist oppdatert: 2023-10-31

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