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Biomarkers and risk of intracerebral hemorrhage: population-based studies in northern Sweden
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
2021 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background

Intracerebral hemorrhage (ICH) is a disease associated with a high morbidity and mortality and treatment options for the condition are limited. Even though an ICH event usually comes as a surprise to the affected individual, pathogenetic processes often have occurred before the sudden ICH event and may have preceded disease onset by years. It is possible that individuals at increased risk of ICH could be identified using biomarkers, for example markers of hemostasis and fibrinolysis. Even if these biomarkers are not part of the causal chain, they could be used as risk indicators to better define high-risk groups. Another approach could be to measure already established risk markers for ICH, such as self-reported alcohol consumption, using a blood biomarker. That could increase measurement reliability and consequently the accuracy of the estimates of ICH risk.

Aims

The aim of this thesis was to investigate potential biomarkers and risk of ICH. Specific aims were to evaluate the associations between factor XII, D-dimer, von Willebrand factor (VWF), ABO blood groups with focus on blood group O, phosphatidylethanol (PEth), and risk of ICH.

Methods

In our first study, aiming to investigate the association between factor XII and risk of hemorrhagic stroke, we followed participants of the health examination northern Sweden MONItoring trends and determinants in CArdiovascular disease (MONICA) performed in 1994 as a cohort until 2011. Factor XII concentrations were measured in blood samples drawn at the baseline health examination where the participants also answered a questionnaire regarding lifestyle factors and medical history. Diagnosis codes from the National Patient Register and the Swedish Cause of Death Register were used to find cases of hemorrhagic stroke, defined as ICH or subarachnoid hemorrhage. 

 

In the subsequent studies, the associations between biomarkers (factor XII, D-dimer, VWF, ABO blood groups, and PEth) and risk of ICH were investigated using a matched, nested case-referent design including individuals that had participated in the Västerbotten Intervention Programme, the MONICA and the Mammography Screening Project in 1985–2007. The participants donated blood samples at baseline for future research which were stored at -80 degrees C until biomarker analyses. The majority of the participants also underwent a baseline health examination including a questionnaire. First-ever ICH diagnoses during the study period 1985–2007 were validated using medical records and autopsy reports. To each case, two referents were matched for age, sex, geographical region, health examination date and health examination setting. 

 

Results

In the cohort study of the association between factor XII concentrations and risk of hemorrhagic stroke, 1,852 participants were included among which 30 experienced a hemorrhagic stroke event. There was an association between high factor XII and risk of hemorrhagic stroke in a multivariable model (hazard ratio 1.51; 95% confidence interval [CI] 1.03–2.21 per standard deviation [SD] of factor XII). In the case-referent study of the association between factor XII and risk of ICH, 70 cases with ICH and 137 matched referents were included. We found no association between factor XII and risk of ICH in a multivariable model (odds ratio [OR] 1.06; 95% CI 0.57–1.97 per SD of factor XII).

 

The study of the association between D-dimer and risk of ICH included 141 cases and 255 matched referents. We found an association between D-dimer and risk of ICH in a multivariable model (OR 1.36; 95% CI 1.05–1.77 per SD of D-dimer). When stratifying the analysis for time between blood sampling and ICH event in tertiles, the association remained significant in the cases with the shortest time between blood sampling and ICH event in a multivariable model (OR 1.78; 95% CI 1.05–3.05 per SD of D-dimer).

 

The study investigating the association between VWF and risk of ICH included 139 cases and 276 referents. We found no association between VWF and risk of ICH in a multivariable model (OR 0.85; 95% CI 0.54–1.34 per SD of VWF). In the analysis investigating the associations between ABO blood groups and risk of ICH, 162 cases and 317 referents were included. We found no association between blood group O compared to non-O blood groups and risk of ICH (OR 0.96; 95% CI 0.65–1.42). 

In the study of the association between PEth concentrations and risk of ICH, 97 cases and 180 referents were included. There was an association between PEth concentrations > 0.30 µmol/L compared to < 0.01 µmol/L and risk of ICH in a multivariable model (OR 4.64; 95% CI 1.49–14.40).

Conclusions

High concentrations of D-dimer and PEth are associated with an increased risk of ICH. Our conclusion of the two studies investigating the association between factor XII and risk of hemorrhagic stroke and ICH respectively is that there is no association between factor XII and risk of ICH. We found no association between VWF or blood group O and risk of ICH.

Abstract [sv]

Stroke är en sjukdom som kan bero på antingen en blodpropp eller en hjärnblödning. Vid en stroke dör hjärnceller till följd av syrebrist och personen som drabbas kan få symptom som till exempel påverkan på tal, syn eller svårigheter att röra arm eller ben. Hjärnblödning sker på grund av att ett blodkärl i hjärnan brister. Genom att öka vår kunskap om vad som händer i kroppen under tiden innan en person insjuknar i hjärnblödning kan vi bli bättre på att hitta personer med hög risk för att få sjukdomen. Förhoppningsvis leder detta till att vi i framtiden kan bli bättre på att förebygga sjukdomen.

Ett sätt att undersöka detta är att använda biomarkörer. Biomarkörer kan till exempel vara proteiner och andra ämnen man mäter i blodprover. De kan användas till att uppskatta hur hög risk en person har att drabbas av en sjukdom. Det finns idag inga etablerade biomarkörer för att uppskatta risken att insjukna i hjärnblödning.

I den här avhandlingen har vi studerat fem olika biomarkörer som mäts i blodprover. Fyra av biomarkörerna (koagulationsfaktor XII, D-dimer, von Willebrandfaktor och blodgrupp O) tänker vi skulle kunna spegla processer i blodkärlen som sker före en hjärnblödning eller ha att göra med blodets levringsförmåga och förmåga att lösa upp blodproppar. Tidigare forskning har visat att personer som dricker mycket alkohol tycks ha en högre risk att få hjärnblödning. Den femte biomarkören vi har studerat, fosfatidyletanol, visar hur mycket alkohol en person har druckit veckorna innan blodprovet tas. Syftet med den här avhandlingen var att undersöka om de fem biomarkörena skulle kunna användas för att uppskatta en persons risk för hjärnblödning. 

Vi har studerat personer som deltagit i hälsoundersökningar i Västerbotten och Norrbotten mellan 1985 och 2007. Hälsoundersökningarna heter MONICA, Västerbottens hälsoundersökning och mammografiscreeningsprojektet. Vid hälsoundersökningarna har personerna lämnat blodprover som skulle få användas för framtida forskning. Blodproverna frystes ned i samband med hälsoundersökningen. Vi har sedan tinat dem och analyserat nivåerna av de olika biomarkörerna. Majoriteten av personerna som är med i våra studier har i samband med att de lämnade blodproverna också svarat på en enkät om tidigare sjukdomar och levnadsvanor samt mätt längd, vikt, blodtryck, blodsocker och blodfetter. 

Vi har sedan jämfört nivåerna av olika biomarkörer i blodproven mellan personer som fick en hjärnblödning under studieperioden och en grupp personer som inte fick någon hjärnblödning.  Det finns en del faktorer, till exempel högt blodtryck och hög ålder som vi sedan tidigare vet att har samband med ökad risk att få en hjärnblödning. Sådana kända faktorer tog vi hänsyn till i vår jämförelse.

I vår första och andra studie undersökte vi biomarkören koagulationsfaktor XII. I den första studien såg vi ett möjligt samband mellan höga nivåer av koagulationsfaktor XII och ökad risk för hjärnblödning. När vi undersökte sambandet mellan koagulationsfaktor XII och risk för hjärnblödning i en ytterligare studie där fler personer med hjärnblödning deltog kunde vi inte se något sådant samband. Vi fann ett samband mellan höga nivåer av D-dimer och ökad risk för att få en hjärnblödning. Sambandet var tydligast hos personer för vilka det inte gått så lång tid mellan att blodproverna togs och att hjärnblödningen inträffade. Vi fann inget samband mellan von Willebrandfaktor eller blodgrupp O och risk för hjärnblödning.

Vår sista studie visade att personer med förhöjda nivåer av fosfatidyletanol, en biomarkör för alkoholintag, hade en ökad risk att få en hjärnblödning. Personer med ett fosfatidyletanol-värde som motsvarar ett intag av ungefär fyra standardglas alkoholhaltig dryck per dag hade en nästan fem gånger ökad risk att drabbas av hjärnblödning jämfört med personer med inget eller mycket lågt alkoholintag.

Vår tolkning av resultaten av våra studier är att D-dimer och fosfatidyletanol i framtiden kanske skulle kunna användas som biomarkörer för att hitta personer med hög risk för hjärnblödning. Innan detta kan bli verklighet krävs dock mer forskning.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2021. , p. 89
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2115
Keywords [en]
Intracerebral hemorrhage, hemorrhagic stroke, factor XII, D-dimer, von Willebrand factor, ABO blood groups, phosphatidylethanol, alcohol, risk markers, biomarkers
National Category
Other Clinical Medicine
Research subject
Medicine
Identifiers
URN: urn:nbn:se:umu:diva-180312ISBN: 978-91-7855-465-2 (electronic)ISBN: 978-91-7855-464-5 (print)OAI: oai:DiVA.org:umu-180312DiVA, id: diva2:1529610
Public defence
2021-03-17, Arenan, Campus Skellefteå, Skellefteå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2021-02-24 Created: 2021-02-18 Last updated: 2021-02-22Bibliographically approved
List of papers
1. Factor XII as a Risk Marker for Hemorrhagic Stroke: A Prospective Cohort Study
Open this publication in new window or tab >>Factor XII as a Risk Marker for Hemorrhagic Stroke: A Prospective Cohort Study
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2017 (English)In: Cerebrovascular diseases extra, ISSN 1664-5456, Vol. 7, no 1, p. 84-94Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Coagulation factor XII (FXII) is involved in pathological thrombus formation and is a suggested target of anticoagulants. It is unclear whether FXII levels are correlated with cardiovascular risk factors and whether they are associated with myocardial infarction or ischemic or hemorrhagic stroke. The aim of this study was to investigate the correlation between FXII and cardiovascular risk factors in the general population. We also aimed to study the associations between FXII levels and future myocardial infarction and ischemic and hemorrhagic stroke.

METHODS: This prospective cohort study measured FXII levels in 1,852 randomly selected participants in a health survey performed in northern Sweden in 1994. Participants were followed until myocardial infarction, stroke, death, or until December 31, 2011.

RESULTS: During the median follow-up of 17.9 years, 165 individuals were diagnosed with myocardial infarction, 108 with ischemic stroke, and 30 with hemorrhagic stroke. There were weak correlations between FXII and body mass index, cholesterol, and hypertension. There was no association between FXII and myocardial infarction or ischemic stroke, neither in univariable Cox regression analysis nor after adjustment for age, sex, smoking, body mass index, cholesterol, hypertension, and diabetes. In univariable Cox regression analysis, the hazard ratio for the association between FXII levels and hemorrhagic stroke was 1.42 per SD (95% confidence interval: 0.99-2.05). In the multivariable model, higher levels of FXII were associated with increased risk of hemorrhagic stroke (hazard ratio 1.51 per SD; 95% confidence interval: 1.03-2.21).

CONCLUSION: We found an independent association between FXII levels and the risk of hemorrhagic stroke, but not between FXII levels and ischemic stroke or myocardial infarction.

Place, publisher, year, edition, pages
S. Karger, 2017
Keywords
Coagulation, Biomarkers, Intracranial hemorrhage, Cohort study, Cardiovascular disease
National Category
Cardiology and Cardiovascular Disease
Identifiers
urn:nbn:se:umu:diva-136401 (URN)10.1159/000468994 (DOI)000405098500004 ()28433996 (PubMedID)2-s2.0-85018360509 (Scopus ID)
Available from: 2017-06-16 Created: 2017-06-16 Last updated: 2025-02-10Bibliographically approved
2. Factor XII Concentrations and Risk of Intracerebral Haemorrhage: A Prospective Case-Referent Study
Open this publication in new window or tab >>Factor XII Concentrations and Risk of Intracerebral Haemorrhage: A Prospective Case-Referent Study
2021 (English)In: Journal of Stroke & Cerebrovascular Diseases, ISSN 1052-3057, E-ISSN 1532-8511, Vol. 30, no 3, article id 105565Article in journal (Refereed) Published
Abstract [en]

Objectives: In a previous pilot study, we found an association between high factorXII levels and risk of haemorrhagic stroke suggesting that factor XII is a risk markerfor intracerebral haemorrhage (ICH). The aim of this study was to further investigate the association between factor XII and risk of ICH in a larger population.

Materials and Methods:This study was conducted as a prospective nested case-referent study. All participants underwent a health examination and blood sampling for factor XII analysis at baseline. Cases were defined as participants who were diagnosed with a first-ever ICH between 1985 and 2000. Two referents were matched to eachcase.

Results:We identified 70 individuals withfirst-ever ICH and 137 matchedreferents who had undergone a health examination and donated blood samples Factor XII Concentrations and Risk of Intracerebral Haemorrhage. A Prospective Case-Referent Studybefore the ICH event. The mean age was 54 years, and 33% were women. The median time-to-event was 3.5 years (range 0.04 to 10.2 years). Conditional logistic regression showed no association between factor XII and risk of ICH, (odds ratio1.06 per SD; [95% confidence interval: 0.57–1.97] in a multivariable model).

Conclusions: A previous finding of an association between high concentration of factor XII and risk of ICH could not be replicated in this larger study

Place, publisher, year, edition, pages
Elsevier, 2021
Keywords
Intracerebral haemorrhage, Factor XII, Haemostasis, Biomarkers, Intracranial bleeding
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-180311 (URN)10.1016/j.jstrokecerebrovasdis.2020.105565 (DOI)000620676300033 ()2-s2.0-85098886681 (Scopus ID)
Funder
Region Västerbotten
Available from: 2021-02-16 Created: 2021-02-16 Last updated: 2023-09-05Bibliographically approved
3. D-Dimer is associated with first-ever intracerebral hemorrhage: a nested case-control study
Open this publication in new window or tab >>D-Dimer is associated with first-ever intracerebral hemorrhage: a nested case-control study
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2018 (English)In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 49, no 9, p. 2034-2039Article in journal (Refereed) Published
Abstract [en]

Background and Purpose - Hypertension is the most important risk factor for intracerebral hemorrhage (ICH), but further characterization is needed for groups at high risk of ICH. One way to predict the risk of developing a disease is with plasma biomarkers. This study aimed to investigate the association between the biomarker, D-dimer, and ICH risk.

Methods - This population-based, nested case-control study was conducted using data from 2 population-based surveys; the Vasterbotten Intervention Programme and MONICA Northern Sweden (Monitoring Trends and Determinants in Cardiovascular Disease). All participants underwent a health examination and blood sampling at baseline before the event. Cases (n=141) were diagnosed with a first-ever ICH between 1985 and March 2007. One or 2 controls (n=255) were matched to each case.

Results - The median age was 60 years; 39% of participants were women; and the median time from blood sampling to ICH was 5.2 years. When D-dimer was evaluated as a continuous variable, it was significantly associated with ICH. After multivariable adjustment (for hypertension, body mass index, cholesterol levels, diabetes mellitus, and smoking), the odds ratio was 1.36 per SD of D-dimcr (95% CI, 1.05-1.77). When participants were stratified in 3 groups according to time from blood sampling at health examination to ICH, we found that the association between D-dimer levels and ICH was most pronounced in individuals with the shortest time from blood sampling to ICH event (<3.5 years; odds ratio, 1.78; 95% CI, 1.05-3.05).

Conclusions - High plasma concentrations of D-dimer were associated with increased risk of a future ICH, after adjusting for cardiovascular risk factors. This association was predominantly driven by the cases with the shortest time from blood sampling to ICH event.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2018
Keywords
biomarkers, case-control studies, cerebral hemorrhage, fibrin fragment, fibrinolysis
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-153829 (URN)10.1161/STROKEAHA.118.021751 (DOI)000442858100014 ()30354971 (PubMedID)2-s2.0-85055599118 (Scopus ID)
Funder
Västerbotten County CouncilNorrbotten County Council
Available from: 2018-12-11 Created: 2018-12-11 Last updated: 2023-03-23Bibliographically approved
4. Von Willebrand factor, ABO blood group, and risk of first-ever intracerebral hemorrhage: A prospective nested case-control study
Open this publication in new window or tab >>Von Willebrand factor, ABO blood group, and risk of first-ever intracerebral hemorrhage: A prospective nested case-control study
Show others...
2020 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 195, p. 77-80Article in journal (Refereed) Published
Abstract [en]

Background and purpose: Low levels of von Willebrand factor (VWF) were associated with intracerebral hemorrhage (ICH) in a previous study. Persons with blood group O have lower VWF levels than other ABO blood groups. This study aimed to investigate the association between VWF and the risk of ICH in adults, as well as the association between ABO blood group and risk of ICH.

Methods: This population-based, nested case-control study was conducted using data and blood samples from health examinations between 1985 and 2007. All participants were followed, and cases with first-ever ICH were identified and validated. One or two controls were matched to each case.

Results: During a median follow-up time from blood sampling to ICH of 5.6 years, 176 cases with ICH were identified. The mean age at health examination was 57 years; 50% of participants were women. There was an association between hypertension and risk of ICH, but there was no association between VWF level and risk of ICH. There was no association between blood group O and risk of ICH.

Conclusions: To our knowledge this is the largest prospective study investigating the association between VWF, ABO blood group and ICH. We found no association between VWF or blood group O and risk of future ICH.

Place, publisher, year, edition, pages
Elsevier, 2020
Keywords
Biomarker Risk factor, ABO blood group, von Willebrand factor, Intracerebral hemorrhage
National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-177170 (URN)10.1016/j.thromres.2020.07.003 (DOI)000583278500015 ()32673959 (PubMedID)2-s2.0-85087760249 (Scopus ID)
Available from: 2020-12-08 Created: 2020-12-08 Last updated: 2023-03-23Bibliographically approved
5. Phosphatidylethanol Levels, As a Marker of Alcohol Consumption, Are Associated With Risk of Intracerebral Hemorrhage
Open this publication in new window or tab >>Phosphatidylethanol Levels, As a Marker of Alcohol Consumption, Are Associated With Risk of Intracerebral Hemorrhage
Show others...
2020 (English)In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 51, no 7, p. 2148-2152Article in journal (Refereed) Published
Abstract [en]

Background and Purpose: Previous observational studies have shown a moderately increased risk of intracerebral hemorrhage (ICH) with high self-reported alcohol consumption. However, self-reported data tend to underestimate alcohol consumption. Phosphatidylethanol is a specific biomarker reflecting alcohol intake during the last month and correlates with the amount of alcohol consumed. The present study aimed to investigate the association between phosphatidylethanol levels and the risk of future ICH.

Methods: This population-based nested case-referent study was conducted within the Northern Sweden Health and Disease Cohort. At baseline, all participants underwent a health examination, including a questionnaire with questions about alcohol consumption. A blood sample was collected and stored at −80°C, and phosphatidylethanol 16:0/18:1 levels were measured in packed erythrocytes. Cases (n=97) were diagnosed with a first-ever ICH between 1985 and 2007. Two referents (n=180) were matched to each case.

Results: The mean age at baseline was 55 years, 39% of participants were women, and the mean time from blood sampling to ICH was 7.3 years. Only phosphatidylethanol and hypertension remained independently associated with ICH in a multivariable model. Participants with phosphatidylethanol >0.30 μmol/L had an increased risk of ICH compared with those with phosphatidylethanol <0.01 μmol/L (odds ratio, 4.64 [95% CI, 1.49–14.40]).

Conclusions: High blood concentrations of phosphatidylethanol were associated with an increased risk of future ICH. This association was independent of hypertension and other risk factors for ICH. Our findings suggest that phosphatidylethanol, as a marker of alcohol consumption, may be used as a risk marker of future ICH.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2020
Keywords
alcoholic beverages, alcoholism, biomarkers, case-control study, cerebral hemorrhage, intracranial hemorrhages, stroke
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-173632 (URN)10.1161/STROKEAHA.120.029630 (DOI)000544979200045 ()32543974 (PubMedID)2-s2.0-85087114871 (Scopus ID)
Funder
Region VästerbottenNorrbotten County Council
Available from: 2020-07-21 Created: 2020-07-21 Last updated: 2024-07-02Bibliographically approved

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