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Determinants of adverse events during oral anticoagulant treatment
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Treament with oral anticoagulation is highly effective in reducing the burden of thromboembolic complications in several clinical conditions. The number of patients receiving oral anticoagulation is growing steadily. InSwedenabout 1.5 percent of the population receives treatment. Although the treatment is highly effective in preventing thromboembolic complications, it is also associated with a substantial increase in the risk of bleeding. In clinical practice every physician has to balance the potential benefit of treatment against the risk of bleeding complications in the individual patient.

To aid in this decision making, risk scores addressing the likelihood of thromboembolic events, as well as the risk of bleeding complications, have been developed. These scores are imperfect and, to some degree limited by the fact that the risk factors predictive of thromboembolic events are also often associated with bleeding complications. The addition of biomarkers has the potential to increase the predictive ability of risk scores and further enhance the net benefit of oral anticoagulant treatment in the individual patient. In this thesis several potential biomarkers for thromoboembolic and haemorrhagic complications of anticoagulant therapy have been investigated in a longitudinal cohort study of 719 patients with a median follow-up time of 4.2 years.

Thrombomodulin is a key component in the generation of activated protein C and hence, a coagulation inhibitor. Conversely, it is also a key component in the inhibition of fibrinolysis by activation of trombin-activated fibrinolysis inhibitor. In warfarin-treated patients we demonstrate that thrombomodulin predicts an increased risk of bleeding complications, but not cardiovascular events. Thus, thrombomodulin has potential as a biomarker specifically for bleeding complications.

Von Willebrand factor plays a central and intricate role in the aggregation of platelets and low levels of VWF have been associated with bleeding as a manifestation of von Willebrand’s disease. In our study we noted that high levels of von Willebrand factor predict an increased risk of cardiovascular as well as all-cause mortality, possibly as an expression of endothelial dysfunction. We also noted that high levels of WVF seem to be associated with serious bleeding complications.

Decreased renal function is usually measured by an increase in the levels of creatinine and cystatin C, or a decrease in the calculated glomerular filtration rate. A decrease in kidney function is regarded as a marker of an increased risk of bleeding complications. We investigated all the mentioned markers of kidney function and no association with bleeding complications became apparent. However, a clear association between a decrease in kidney function and mortality was noted. Our findings indicate that the emphasis on impaired kidney function as a risk marker needs to be shifted from bleeding complications toward thromboembolic events.

Fibrinolysis is important in containing coagulation and several constituents of the fibrinolytic pathway have been shown to predict cardiovascular events and mortality. We found that fibrinolytic factors seem to predict cardiovascular events in patients with oral anticoagulation and that D-dimer also predicts bleeding complications.

In conclusion, we have found several biomarkers which exhibit different predictive abilities in patients with oral anticoagulation. It is likely that biomarkers, either alone, in combination, or as ancillary components of risk scores, can contribute to improved risk stratification in patients with oral anticoagulation.

Place, publisher, year, edition, pages
Umeå: Umeå University , 2012. , 88 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1483
Keyword [en]
Oral anticoagulants, warfarin, mortality, bleeding, biomarkers
National Category
Hematology
Research subject
Medicine
Identifiers
URN: urn:nbn:se:umu:diva-53431ISBN: 978-91-7459-380-8 (print)OAI: oai:DiVA.org:umu-53431DiVA: diva2:512021
Public defence
2012-04-27, Forumsalen, Campus, Skellefteå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2012-04-05 Created: 2012-03-26 Last updated: 2012-04-05Bibliographically approved
List of papers
1. Thrombomodulin as a marker for bleeding complications during warfarin treatment.
Open this publication in new window or tab >>Thrombomodulin as a marker for bleeding complications during warfarin treatment.
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2009 (English)In: Archives of Internal Medicine, ISSN 0003-9926, E-ISSN 1538-3679, Vol. 169, no 13, 1210-1215 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The major adverse effect of warfarin treatment is hemorrhage. Several risk factors for bleeding complications are also risk factors for thromboembolic events, making the clinical decision to initiate or withhold anticoagulant treatment difficult. Specific markers that solely identify patients at high risk of bleeding would have great clinical impact. This study aimed to test if thrombomodulin (TM) concentrations were associated with bleeding complications, cardiovascular events, or mortality in long-term anticoagulant-treated patients. METHODS: In a longitudinal cohort study we followed up 719 patients receiving warfarin treatment for a mean duration of 4.2 years. All bleeding complications causing hospitalization were registered and classified. Soluble TM antigen (sTM) concentration in plasma was measured with an enzyme-linked immunosorbent assay method. RESULTS: During the follow-up time, 113 clinically relevant bleeding events and 73 major bleeding events occurred. Increased concentration of sTM was associated with both clinically relevant bleeding and major bleeding events after adjustment for age. In the multivariable models, hazard ratios for the highest tertiles compared with the lowest were 2.29 (95% confidence interval, 1.35-3.89) and 2.33 (95% confidence interval, 1.21-4.48), respectively. No association between sTM concentration and nonfatal ischemic cardiovascular events or all-cause mortality was found. CONCLUSIONS: Increased levels of sTM are associated with bleeding complications during warfarin treatment but not with cardiovascular events or all-cause mortality. Soluble TM antigen concentration has potential as a new specific marker to identify patients at high risk of bleeding during warfarin treatment.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-32937 (URN)10.1001/archinternmed.2009.170 (DOI)19597070 (PubMedID)
Available from: 2010-03-31 Created: 2010-03-31 Last updated: 2017-12-12Bibliographically approved
2. Von Willebrand factor predicts major bleeding and mortality during oral anticoagulant treatment
Open this publication in new window or tab >>Von Willebrand factor predicts major bleeding and mortality during oral anticoagulant treatment
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2012 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 271, no 3, 239-246 p.Article in journal (Refereed) Published
Abstract [en]

Aims.  Oral anticoagulation (OAC), predominantly with warfarin, is an effective treatment to prevent thromboembolic events. Serious bleeding is a frequent and feared treatment complication. In this longitudinal cohort study of OAC-treated patients, we aimed to evaluate the relationship between von Willebrand factor (VWF) levels and risk of bleeding complications, cardiovascular mortality and all-cause mortality.

Methods and results.  A total of 719 patients receiving warfarin treatment were observed for a mean duration of 4.2 years. All bleeding complications causing hospitalization were registered and classified into clinically relevant bleeding (CRB) and major bleeding. Ischaemic stroke, peripheral arterial embolism, myocardial infarction, and death were also recorded. We identified 113 cases of CRB and 73 of major bleeding. In total, 161 deaths occurred during follow-up with cardiovascular disease identified as the cause of death in 110 patients. Patients in the highest tertile of VWF had a significantly increased risk of bleeding complications: hazard ratio (HR) 2.53 (95% CI 1.41-4.56) for major bleeding and HR 2.19 (95% CI 1.38-3.48) for CRB. VWF, expressed either in tertiles or as a continuous variable, showed a significant association with cardiovascular mortality (HR 1.68, 95% CI 1.40-2.01) and all-cause mortality (HR 1.77, 95% CI 1.52-2.05). In multivariate Cox regression analysis, the findings remained significant after adjusting for age, high-sensitivity C-reactive protein and creatinine.

Conclusions.  Patients with high levels of VWF had an increased risk of bleeding complications, cardiovascular mortality and all-cause mortality during OAC treatment. Our findings imply that the use of VWF as a risk marker for thromboembolic events is complicated by the association of VWF with bleeding complications.

Keyword
bleeding;mortality;oral anticoagulation;von Willebrand factor
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-45877 (URN)10.1111/j.1365-2796.2011.02418.x (DOI)000300836300004 ()21707795 (PubMedID)
Available from: 2011-08-19 Created: 2011-08-19 Last updated: 2017-12-08Bibliographically approved
3. Cystatin C and creatinine as markers of bleeding and mortality during oral anticoagulant treatment
Open this publication in new window or tab >>Cystatin C and creatinine as markers of bleeding and mortality during oral anticoagulant treatment
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2012 (English)Manuscript (preprint) (Other academic)
Publisher
88 p.
Keyword
Oral anticoagulants, warfarin, mortality, bleeding, biomarkers
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:umu:diva-53424 (URN)978-91-7459-380-8 (ISBN)
Available from: 2012-03-26 Created: 2012-03-26 Last updated: 2012-05-16Bibliographically approved
4. Impact of fibrinolytic factors on bleeding, morbidity and mortality during warfarin treatment
Open this publication in new window or tab >>Impact of fibrinolytic factors on bleeding, morbidity and mortality during warfarin treatment
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-53430 (URN)
Projects
Determinants of adverse events during oral anticoagulant treatment
Available from: 2012-03-26 Created: 2012-03-26 Last updated: 2012-04-05

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