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Gustafsson, Kerstin
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Publications (8 of 8) Show all publications
Alfredsson, J., Swahn, E., Gustafsson, K., Janzon, M., Jonasson, L., Logander, E., . . . Lindahl, T. (2019). Individual long-term variation of platelet reactivity in patients with dual antiplatelet therapy after myocardial infarction.. Platelets, 30(5), 572-578
Open this publication in new window or tab >>Individual long-term variation of platelet reactivity in patients with dual antiplatelet therapy after myocardial infarction.
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2019 (English)In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 30, no 5, p. 572-578Article in journal (Refereed) Published
Abstract [en]

There is a large inter-individual variation in response to clopidogrel treatment, and previous studies have indicated higher risk of thrombotic events in those with high residual platelet reactivity (HPR). Less is known about individual variation over time. The aim of this prospective cohort study was to investigate intra-individual variation in platelet reactivity. Platelet aggregation in whole blood was assessed in 77 patients, at 3 days, 8 days and 6 months after admission for acute myocardial infarction and loading dose of clopidogrel. All patients were treated with aspirin and clopidogrel through 6-month follow-up. We found a significant increase in median ADP-stimulated aggregation from third to eighth day (195 vs. 250 AU*min, p-value = 0.001) but not from day 8 to 6 months (250 vs. 223 AU*min, p-value = 0.666). There was no significant change in the overall rate of HPR (15.6% vs 20.8%, p-value 0.503) or low platelet reactivity (LPR) (37.7% vs 33.8%, p-value = 0.609) from day 8 to 6-month follow-up. In contrast, more than one in four changed HPR status, 15.6% from non-HPR to HPR and 10.4% HPR to non-HPR. A shift in LPR status appeared even more frequent, occurring in about one of three patients. In spite of similar median aggregation and rate of HPR during 6-month follow-up, about one in four of the patients changed HPR status and one in three changed LPR status. This may be important information for a concept of risk stratification based on a single aggregation value early after an acute coronary syndromes.

Keywords
High residual platelet reactivity, myocardial infarction, platelet
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:liu:diva-149564 (URN)10.1080/09537104.2018.1479519 (DOI)000469424700004 ()29869923 (PubMedID)
Available from: 2018-07-06 Created: 2018-07-06 Last updated: 2019-07-18
Hillarp, A., Strandberg, K., Baghaei, F., Blixter, I. F., Gustafsson, K. & Lindahl, T. (2018). Effects of the oral, direct factor Xa inhibitor edoxaban on routine coagulation assays, lupus anticoagulant and anti-Xa assays. Scandinavian Journal of Clinical and Laboratory Investigation, 78(7-8), 575-583
Open this publication in new window or tab >>Effects of the oral, direct factor Xa inhibitor edoxaban on routine coagulation assays, lupus anticoagulant and anti-Xa assays
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2018 (English)In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 78, no 7-8, p. 575-583Article in journal (Refereed) Published
Abstract [en]

Edoxaban is an oral direct factor Xa inhibitor for prophylaxis and treatment of thromboembolic disorders. The effects on common coagulation assays are clinically valuable information and in certain clinical situations a quick assessment of the anticoagulant is wanted. Our aim was to investigate the effect of edoxaban on routine coagulation methods and evaluate anti-Xa assays, commonly used for other direct factor Xa inhibitors, for estimation of the drug concentration. Edoxaban was spiked to plasma samples from healthy subjects in the concentration range 0-742 mu g/L and analyzed using different reagents for activated partial thromboplastin time (APTT) and prothrombin time (PT). Assays for antithrombin, activated protein C resistance, lupus anticoagulant (LA) and chromogenic anti-Xa assays were also included. Edoxaban displayed similar effects in vitro to other oral direct Xa inhibitors. The concentration needed to double the coagulation time varied between assays and reagents; 539-758 mu g/L for the APTT and between 329 and 2505 mu g/L for the PT. Edoxaban gave false high antithrombin activities in assays based on Xa-inhibition. Two integrated assays for LA, both based on activation with dilute Russells viper venom, displayed different results. Chromogenic anti-Xa assays displayed linear dose-response curves with edoxaban up to approximately 500 mu g/L. In conclusion, therapeutic concentrations of edoxaban variably affect different coagulation assays, and even different reagents within an assay group. In comparison with other oral Xa-inhibitors, the in vitro effects of edoxaban were more similar to rivaroxaban than apixaban. For measurement of edoxaban concentration in plasma, it is possible to use the chromogenic anti-Xa assays.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2018
Keywords
Anticoagulants; blood coagulation analysis; edoxaban; lupus coagulation inhibitor; activated partial thromboplastin time; prothrombin time
National Category
Clinical Laboratory Medicine
Identifiers
urn:nbn:se:liu:diva-153979 (URN)10.1080/00365513.2018.1522664 (DOI)000454770900009 ()30278787 (PubMedID)
Available from: 2019-01-21 Created: 2019-01-21 Last updated: 2019-05-02
Venetsanos, D., Lindahl, T., Sederholm Lawesson, S., Gustafsson, K., Wallen, H., Erlinge, D., . . . Alfredsson, J. (2018). Pretreatment with ticagrelor may offset additional inhibition of platelet and coagulation activation with bivalirudin compared to heparin during primary percutaneous coronary intervention. Thrombosis Research, 171, 38-44
Open this publication in new window or tab >>Pretreatment with ticagrelor may offset additional inhibition of platelet and coagulation activation with bivalirudin compared to heparin during primary percutaneous coronary intervention
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2018 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 171, p. 38-44Article in journal (Refereed) Published
Abstract [en]

Background

It remains unknown if bivalirudin compared to heparin confers any additional inhibition of platelet and coagulation activation during primary percutaneous coronary intervention(PPCI) after pretreatment with ticagrelor.

Methods

In this substudy of VALIDATE-SWEDEHEART trial, 103 patients pretreated with ticagrelor were randomized before PPCI to heparin or bivalirudin. Blood samples were collected before and 1 and 12 h after PPCI. We measured platelet reactivity (PR) using Multiplate, soluble P-selectin, thrombin-antithrombin complexes (TAT) and prothrombin fragments 1 + 2 (F1 + 2) as markers of platelet and coagulation activation.

Results

The median (IQR) time from ticagrelor administration to randomization was 63 (29) vs 60 (24) minutes, p = 0.28. ADP-induced PR did not significantly differ between groups over time (heparin vs bivalirudin, AUC 73 (62) vs 74 (68), p = 0.74, 32 (42) vs 43 (51), p = 0.38, 15 (15) vs 19 (15), p = 0.29, before, 1 and 12 h after PPCI). Soluble P-selectin did not significantly differ between groups. At 1 h TAT significantly increased with bivalirudin (3.0 (1.3) to 4.3 (4.2) ug/L; p < 0.01), but not with UFH (3.1 (2.1) to 3.5 (1.6) ug/L, p = 0.24). F1 + 2 increased in both groups but the rise was numerically higher with bivalirudin (170 (85) to 213 (126) pmol/L vs 168 (118) to 191 (103) pmol/L). At 12 h, a comparable significant increase in thrombin generation was observed in both groups.

Conclusion

In patients treated with ticagrelor, we found no major differences between bivalirudin and heparin in platelet aggregation or coagulation markers, which is in agreement with the neutral clinical results of the VALIDATE-SWEDEHEART study.

Place, publisher, year, edition, pages
Pergamon Press, 2018
Keywords
Bivalirudin; Heparin; Coagulation; Platelet; Aggregation; Thrombin
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:liu:diva-153386 (URN)10.1016/j.thromres.2018.09.046 (DOI)000450362200006 ()30248659 (PubMedID)2-s2.0-85053795837 (Scopus ID)
Note

Funding Agencies|AstraZeneca

Available from: 2018-12-13 Created: 2018-12-13 Last updated: 2019-05-02Bibliographically approved
Alfredsson, J., Lindahl, T. L., Gustafsson, K. M., Janzon, M., Jonasson, L., Logander, E., . . . Swahn, E. (2015). Large early variation of residual platelet reactivity in Acute Coronary Syndrome patients treated with clopidogrel: Results from Assessing Platelet Activity in Coronary Heart Disease (APACHE).. Thrombosis Research, 136(2), 335-340
Open this publication in new window or tab >>Large early variation of residual platelet reactivity in Acute Coronary Syndrome patients treated with clopidogrel: Results from Assessing Platelet Activity in Coronary Heart Disease (APACHE).
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2015 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 136, no 2, p. 335-340Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: There is a large inter-individual variation in response to clopidogrel treatment and previous studies have indicated higher risk of thrombotic events in patients with high residual platelet reactivity (HRPR), but the optimal time-point for testing is not established. The aim of this study was to investigate the optimal time-point for aggregometry testing and the risk of major adverse cardiac events associated with HRPR.

METHOD AND RESULTS: We included 125 patients with ACS (73 with STEMI, and 71 received abciximab). The prevalence of HRPR varied substantially over time. The rate of HRPR in patients treated and not treated with abciximab were 43% vs 67% (p=0.01) before, 2% vs 23% (p=0.001) 6-8h after, 8% vs 9% (p=0.749) 3days after, and 23% vs 12% (p=0.138) 7-9 days after loading dose of clopidogrel. We found HRPR in 18% of the patients but only four ischemic events during 6months follow-up, with no significant difference between HRPR patients compared to the rest of the population. There were 3 TIMI major bleedings, all of which occurred in the low residual platelet reactivity (LRPR) group.

CONCLUSION: There is a large variation in platelet reactivity over time, also depending on adjunctive therapy, which has a large impact on optimal time-point for assessment. We found HRPR in almost 1 in 5 patients, but very few MACE, and not significantly higher in HRPR patients. In a contemporary ACS population, with low risk for stent thrombosis, the predictive value of HRPR for ischemic events will probably be low.

Place, publisher, year, edition, pages
Pergamon Press, 2015
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:liu:diva-119644 (URN)10.1016/j.thromres.2015.05.021 (DOI)000363953000026 ()26033398 (PubMedID)
Note

Funding agencies: Linkoping University; County Council of Ostergotland

Available from: 2015-06-24 Created: 2015-06-23 Last updated: 2019-02-11
Lindahl, T., Wallstedt, M., Gustafsson, K., Persson, E. & Hillarp, A. (2015). More efficient reversal of dabigatran inhibition of coagulation by activated prothrombin complex concentrate or recombinant factor VIIa than by four-factor prothrombin complex concentrate. Thrombosis Research, 135(3), 544-547
Open this publication in new window or tab >>More efficient reversal of dabigatran inhibition of coagulation by activated prothrombin complex concentrate or recombinant factor VIIa than by four-factor prothrombin complex concentrate
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2015 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 135, no 3, p. 544-547Article in journal (Refereed) Published
Abstract [en]

The number of patients on antithrombotic treatment due to atrial fibrillation and venous thromboembolism is increasing fast due to an aging population. A growing proportion will be treated with novel oral anticoagulants, the first in clinical use was the direct oral thrombin inhibitor dabigatran (Pradaxa (R)). A small percentage of the patients on dabigatran will experience serious bleeding or be in need of urgent surgery. The aim of this study was to test the effects of different hemostatic agents in potentially reversing the anticoagulant effects in vitro in blood or platelet-rich plasma (PRP) spiked with dabigatran. Whole blood or PRP was spiked with the active substance dabigatran, 200 mu g/L. We measured clotting time being induced by 1.4 pmol/L tissue factor using the instrument ReoRox2 (TM) and initial clot growth velocity from a tissue factor covered surface using the instrument Thrombodynamics Analyzer T-2 (TM). Dabigatran prolonged clotting time 5-fold but reduced clot growth velocity only slightly. The reversing effects of prothrombin complex concentrates (PCC), activated PCC (APCC) and recombinant activated factor VII (rFVIIa) were then tested. APCC (1.8 U/mL) reduced the prolonged clotting time by 1/3, rFVIIa (2 mu g/L) only slightly (n = 10-20). The reduction was not significant using Mann-Whitney test but significant using t-test with Bonferronis correction for multiple comparisons, whereas PCC (0.56 U/mL) had no effect on clotting time. APCC doubled initial clot growth velocity, although even more in the absence of dabigatran. In conclusion, APCC and rFVIIa, but not PCC, seem to reverse, at least partially, some effects of dabigatran on coagulation parameters. Systematic evaluation of case reports, registries and, ultimately, randomized clinical trials are needed to elucidate potential benefit for patients. (C) 2014 Elsevier Ltd. All rights reserved.

Place, publisher, year, edition, pages
Elsevier, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-115816 (URN)10.1016/j.thromres.2014.12.019 (DOI)000349633800019 ()25596769 (PubMedID)
Note

Funding Agencies|Boehringer-Ingelheim; County Council of Ostergotland

Available from: 2015-03-20 Created: 2015-03-20 Last updated: 2017-12-04
Hillarp, A., Gustafsson, K., Faxälv, L., Strandberg, K., Baghaei, F., Fagerberg Blixter, I., . . . Lindahl, T. (2014). Effects of the oral, direct factor Xa inhibitor apixaban on routine coagulation assays and anti-FXa assays. Journal of Thrombosis and Haemostasis, 12(9), 1545-1553
Open this publication in new window or tab >>Effects of the oral, direct factor Xa inhibitor apixaban on routine coagulation assays and anti-FXa assays
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2014 (English)In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 12, no 9, p. 1545-1553Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION:

Apixaban is an oral direct factor Xa inhibitor developed for the prophylaxis and treatment of thromboembolic disorders. Laboratory monitoring is not necessary, but the effects on common coagulation reagents and assays constitute clinically valuable information.

OBJECTIVES:

To investigate the effects of apixaban on commonly used coagulation methods, and to evaluate anti-FXa assays for specific determination of the drug concentration.

MATERIALS AND METHODS:

Apixaban was added to plasma from healthy subjects in the concentration range 0-1000 μg L(-1) , and analyses were performed with different reagents for activated partial thromboplastin time (APTT), prothrombin time (PT), antithrombin, protein C, and protein S. A lupus anticoagulant assay and an APTT assay with varying phospholipid concentrations were used to study the phospholipid dependence.

RESULTS:

In general, apixaban showed fewer effects in vitro than have been shown for rivaroxaban, another direct FXa inhibitor. The concentration needed to double the APTT varied between 2200 and 4700 μg L(-1) , and the concentration needed to double the PT varied between 700 and 3900 μg L(-1) . The effects on antithrombin, protein C and protein S assays were dependent on the type of reagent. Apixaban did not cause false-positive lupus anticoagulant results. Chromogenic anti-FXa assays showed linear dose-response curves with apixaban.

CONCLUSIONS:

Therapeutic concentrations of apixaban variably affect different assay groups, and even different reagents within an assay group. The effects were much smaller than with rivaroxaban. The use of APTT and/or PT assays to screen the anticoagulant activity of apixaban cannot be recommended. A chromogenic anti-FXa assay can be used for reliable measurements of apixaban concentration.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2014
Keywords
analysis; anticogaulants; apixaban; blood coagulation tests; factorXa
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-111458 (URN)10.1111/jth.12649 (DOI)000342143900023 ()24965851 (PubMedID)
Note

Funding Agencies|Bristol Meyers Squibb

Available from: 2014-10-21 Created: 2014-10-17 Last updated: 2017-12-05Bibliographically approved
Lindahl, T., Baghaei, F., Fagerberg Blixter, I., Gustafsson, K., Stigendal, L., Sten-Linder, M., . . . Hillarp, A. (2011). Effects of the oral, direct thrombin inhibitor dabigatran on five common coagulation assays. THROMBOSIS AND HAEMOSTASIS, 105(2), 371-378
Open this publication in new window or tab >>Effects of the oral, direct thrombin inhibitor dabigatran on five common coagulation assays
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2011 (English)In: THROMBOSIS AND HAEMOSTASIS, ISSN 0340-6245, Vol. 105, no 2, p. 371-378Article in journal (Refereed) Published
Abstract [en]

Dabigatran is an oral, reversible thrombin inhibitor that has shown promising results in large clinical trials. Laboratory monitoring is not needed but the effects on common coagulation assays are incompletely known. Dabigatran was added to plasma from healthy subjects in the concentration range 0-1,000 mu g/l and analysed using several reagents for activated thromboplastin time (APTT), prothrombin time (PT), fibrinogen, antithrombin, and activated protein C resistance. Typical trough concentrations are about 50 mu g/l, peak concentrations 100-300 mu g/l. At 100 mu g/l all APTT-results were prolonged. The concentration required to double APTT ranged between 227 and 286 mu g/l, the responses for all five reagents were similar. PT-reagents were much less affected with almost no samples above INR 1.2 at 100 mu g/l. The effect was sample dilution dependent with PT Quick type more sensitive than PT Owren type methods. If a patient on dabigatran has prolonged APTT, andgt; 90 seconds, and Quick PT INR andgt; 2 or Owren PT INR andgt; 1.5 over-dosing or accumulation of dabigatran should be considered. Two of four fibrinogen reagents underestimated the fibrinogen concentration considerably at expected peak concentration. Methods based on inhibition of thrombin over-estimated the antithrombin concentration, but not Xa-based. The APC-resistance methods over-estimated the APC-ratio, which may lead to miss-classification of factory Leiden patients as being normal. Different coagulation assays, and even different reagents within an assay group, display variable effects at therapeutic concentrations of dabigatran. Some of these assay variations are of clinical importance, thus knowledge is needed for a correct interpretation of results.

Place, publisher, year, edition, pages
F K Schattauer Verlagsgesellschaft MBH, 2011
Keywords
Dabigatran, thrombin inhibitor, interference, anticoagulant, coagulation assays
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-66845 (URN)10.1160/TH10-06-0342 (DOI)000287943600023 ()
Note
This article is not an exact copy of the original published article in THROMBOSIS AND HAEMOSTASIS. The definitive publisher-authenticated version is available:: Tomas Lindahl, Fariba Baghaei, Inger Fagerberg Blixter, Kerstin Gustafsson, Lennart Stigendal, Margareta Sten-Linder, Karin Strandberg and Andreas Hillarp, Effects of the oral, direct thrombin inhibitor dabigatran on five common coagulation assays, 2011, THROMBOSIS AND HAEMOSTASIS, (105), 2, 371-378. http://dx.doi.org/10.1160/TH10-06-0342Available from: 2011-03-22 Created: 2011-03-21 Last updated: 2012-03-25
Dudek, M. M., Kent, N., Gustafsson, K., Lindahl, T. & Killard, A. J. (2011). Fluorescence-Based Blood Coagulation Assay Device for Measuring Activated Partial Thromboplastin Time. ANALYTICAL CHEMISTRY, 83(1), 319-328
Open this publication in new window or tab >>Fluorescence-Based Blood Coagulation Assay Device for Measuring Activated Partial Thromboplastin Time
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2011 (English)In: ANALYTICAL CHEMISTRY, ISSN 0003-2700, Vol. 83, no 1, p. 319-328Article in journal (Refereed) Published
Abstract [en]

The measurement of blood clotting time is important in a range of clinical applications such as assessing coagulation disorders and controlling the effect of various anticoagulant drug therapies. Clotting time tests essentially measure the onset of clot formation which results from the formation of fibrin fibers in the blood sample. However, such assays are inherently imprecise due to the highly variable nature of the clot formation process and the sample matrix. This work describes a clotting time measurement assay which uses a fluorescent probe to very precisely detect the onset of fibrin clot formation. It uses a microstructured surface which enhances the formation of multiple localized clot loci and which results in the abrupt redistribution of the fluorescent label at the onset of clot formation in both whole blood and plasma. This methodology was applied to the development of an activated partial thromboplastin time (aPTT) test in a lateral flow microfluidic platform and used to monitor the effect of heparin dosage where it showed linearity from 0 to 2 U/mL in spiked plasma samples (R-2=0.996, n = 3), correlation against gold standard coagulometry of 0.9986, and correlation against standard hospital aPTT in 32 patient samples of 0.78.

Place, publisher, year, edition, pages
ACS American Chemical Society, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-65961 (URN)10.1021/ac102436v (DOI)000285570600045 ()
Note
Original Publication: Magdalena M Dudek, Nigel Kent, Kerstin Gustafsson, Tomas Lindahl and Anthony J Killard, Fluorescence-Based Blood Coagulation Assay Device for Measuring Activated Partial Thromboplastin Time, 2011, ANALYTICAL CHEMISTRY, (83), 1, 319-328. http://dx.doi.org/10.1021/ac102436v Copyright: ACS American Chemical Society http://pubs.acs.org/Available from: 2011-02-28 Created: 2011-02-28 Last updated: 2012-03-25
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