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  • 1.
    Arbring, Kerstin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Internmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Medicinska akutkliniken.
    Chaireti, Roza
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Medicinska akutkliniken.
    Janzon, Magnus
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Kardiologiska kliniken US.
    Uppugunduri, Srinivas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Jansson, Kjell
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Fysiologiska kliniken US.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    First experience of structured introduction of new oral anticoagulants in a Swedish health care district: dabigatran as an alternative to warfarin in atrial fibrillation2013Konferensbidrag (Refereegranskat)
  • 2.
    Arbring, Kerstin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Internmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Medicinska akutkliniken.
    Uppugunduri, Srinivas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Comparison of prothrombin time (INR) results and main characteristics of patients on warfarin treatment in primary health care centers and anticoagulation clinics2013Ingår i: BMC Health Services Research, ISSN 1472-6963, E-ISSN 1472-6963, Vol. 13Artikel i tidskrift (Refereegranskat)
    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.

  • 3.
    Chaireti, Roza
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Arbring, Kerstin
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Hälsouniversitetet.
    Olsen, Ole H.
    Novo Nordisk A/S, Novo Nordisk Park, Måløv, Danmark.
    Persson, Egon
    Novo Nordisk A/S, Novo Nordisk Park, Måløv, Danmark.
    Lindahl, Tomas L.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för klinisk kemi.
    Thrombin generation and levels of factor VII activity measured in the presence of rabbit and human thromboplastins in patients with mild factor VII deficiency – effects of mutations in factor VIIManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Background/Aim: It is known that spontaneous prolonged prothrombin time-international normalized ratio may be caused by deficiency of factor VII (FVII). The activity of FVII in the presence of thromboplastins of different origin is affected by the presence of specific mutations in the F7 gene. The present study aims to evaluate patients with mild FVII deficiency and somewhat discrepant FVII activity depending on the use of human or rabbit thromboplastin in relation to mutations in the FVII gene and markers of thrombin generation.

    Patients and methods: A cohort of 10 patients with mild deficiency of FVII and discrepant FVII activity was investigated. The median ratio of the FVII activity in the presence of human/rabbit thromboplastin was 1.4. All but 1 patient had mild to no bleeding symptoms. A genetic analysis of the F7 gene was performed. Thrombin generation was measured by the calibrated automated thrombogram in platelet poor plasma in the presence of human recombinant and different dilutions of rabbit thromboplastin and compared with thrombin generation in healthy controls (n=12). Thrombin generation was measured in 9 patients as 1 was treated with warfarin at the time of the blood sampling.

    Results: Six previously described mutations were found. Two of those (FVII Padua and FVII Shinjo) are known to affect the results for FVII activity dependent on the species origin of the thromboplastin. Nine out of 10 patients had one mutation in common (Arg353Gln), which however does not affect the binding site of FVII to tissue factor. Lagtime and ttpeak increased with decreasing concentrations of thromboplastin and total and maximum thrombin concentrations increased with increasing thromboplastin concentrations in the patients with FVII deficiency. ETP in patients with FVII deficiency was 86% of ETP in controls.

    Discussion: The Arg353Gln mutation was very common, however it does not appear to affect the reactivity towards thromboplastins of different origins. Although ETP was higher in the healthy controls, thrombin generation in FVII deficient patients was enough to sustain normal haemostasis. The expected thrombin generation patterns with increasing thromboplastin concentrations were confirmed for the patients in this study.

  • 4.
    Lindahl, Tomas
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Arbring, Kerstin
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Medicinska och geriatriska akutkliniken.
    Wallstedt, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Rånby, Mats
    Zafena AB, Borensberg, Sweden.
    A novel prothrombin time method to measure all non-vitamin K-dependent oral anticoagulants (NOACs)2017Ingår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, nr 3, s. 171-176Artikel i tidskrift (Refereegranskat)
    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.

  • 5.
    Nelson, Nina
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Arbring, Kerstin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Internmedicin.
    Theodorsson, Elvar
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi.
    Neonatal salivary cortisol in response to heelstick: Method modifications enable analysis of low concentrations and small sample volumes2001Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 61, nr 4, s. 287-291Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Measuring cortisol in saliva offers important advantages compared to measurement in plasma or serum. However, the sampling procedure and also the detection limit cause problems, especially in paediatric and neonatal care. We describe a simple and efficient sampling procedure, together with a modification of a radioimmunoassay, which enables analysis of low (down to 1 nmol/L) concentrations of salivary cortisol (10 times lower detection limit than in the original procedure). This setting was used in studying salivary cortisol concentrations before and after heelstick on healthy newborn infants. A significant rise (median 81%, p <0.01) in salivary cortisol as response to this invasive stressor was noted.

  • 6.
    Osman, Abdimajid
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk kemi.
    Arbring, Kerstin
    Linköpings universitet, Institutionen för medicin och hälsa, Internmedicin. Linköpings universitet, Hälsouniversitetet.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    A new high-performance liquid chromatographic method for determination of warfarin enantiomers.2005Ingår i: Journal of Chromatography B, ISSN 1570-0232, Vol. 826, nr 1-2, s. 75-80Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Warfarin is the most common agent used for control and prevention of venous as well as arterial thromboembolism. Although warfarin is administered as a racemic mixture of two stereoisomers (S and R), the S-form is mainly responsible for the anticoagulant effect. The anticoagulant effect of the drug is monitored by analysis of prothrombin complex (International Normalised Ratio,INR). In some cases, however, the measurements of plasma warfarin concentration are needed. Here, we present a new, rapid, sensitive and cost-effective HPLC-method for the determination of warfarin enantiomers in plasma. The chromatographic system consisted of Waters 616 gradient pump, Waters 996 photo diode array detector, Gilson 230 autoinjector and Pirkle (R,R) Whelk-O1 column (25 cm × 4.6 mm I.D., 5 μm). An isocratic mobile phase of methanol/acetonitrile/water (50/10/40, v/v) with 0.1% glacial acetic acid was used. The follow rate was 1 mL/min. Data analysis was carried out with Waters Millennium32. The absorbance at 305 nm was measured with a total run-time of 15 min. Method linearity was studied by establishing regression data containing eight points over the range 0.08–10 μg/mL. In this range, warfarin showed to be linear (r2 = 0.9997 for S-warfarin and r2 = 0.9998 for R-warfarin). The limit of detection in plasma was 16 ng/mL for S-warfarin and 18 ng/mL for R-warfarin. Limit of quatitation was defined as 10 × LOD. The extraction recovery was approximately 80%. Also the relation between INR and warfarin concentration was investigated. As expected, there was a low correlation between these two variables (r = 0.23, y = 0.3044x + 0.9712). This method offers a rapid and cost-effective determination of warfarin enantiomers in human plasma.

  • 7.
    Osman, Abdimajid
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk kemi.
    Enström, Camilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Arbring, Kerstin
    Linköpings universitet, Institutionen för medicin och hälsa, Internmedicin. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Main haplotypes and mutational analysis of vitamin K epoxide reductase (VKORC1) in a Swedish population: A retrospective analysis of case records2006Ingår i: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, Vol. 4, nr 8, s. 1723-1729Artikel i tidskrift (Refereegranskat)
    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.

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