High von Willebrand Factor Levels Increase the Risk of Stroke: The Rotterdam Study
Abstract
Background and Purpose—Many studies have investigated the role of plasma von Willebrand factor level in coronary heart disease, but few have investigated its role in stroke. The aim of this study was to determine if von Willebrand factor levels are associated with the risk of stroke.
Methods—The study was part of the Rotterdam Study, a large population-based cohort study among subjects aged ≥55 years. We included 6 250 participants who were free from stroke at baseline (1997 to 2001) and for whom blood samples were available. Follow-up for incident stroke was complete up to January 1, 2005. Data were analyzed with Cox proportional hazards models adjusted for age and sex and additionally with models adjusted for other potential confounders including ABO blood group. A subgroup analysis was performed in participants without atrial fibrillation. Effect modification by sex was tested on a multiplicative and on an additive scale.
Results—During an average follow-up time of 5.0 years, 290 first-ever strokes occurred, of which 197 were classified as ischemic. The risk of stroke increased with increasing von Willebrand factor levels (age- and sex-adjusted hazard ratios per SD increase in von Willebrand factor level: 1.12 [95% CI, 1.01 to 1.25] for stroke, 1.13 [95% CI, 0.99 to 1.29] for ischemic stroke). Adjustments for additional confounders slightly attenuated the association. The association was also present in subjects without atrial fibrillation and did not differ between sexes.
Conclusion—High von Willebrand factor levels are associated with stroke risk in the general population.
The plasma glycoprotein von Willebrand factor (vWF) has an essential role in hemostasis because it promotes platelet adhesion and aggregation at sites of vascular injury and acts as a carrier protein for Factor VIII.1 vWF is almost exclusively synthesized, stored, and secreted by endothelial cells.2 The release of vWF is increased when endothelial cells are activated or damaged.3 Therefore, plasma vWF level is considered a marker of endothelial dysfunction, a condition that predisposes to atherosclerosis and thrombosis.4 Because of its direct role in hemostasis, and its indirect role as a marker of endothelial dysfunction, vWF is a potential risk indicator for cerebrovascular disease.
Although many investigators have studied the relationship between plasma vWF levels and coronary heart disease,5 little is known about the association between vWF levels and stroke. Several case-control studies did report an association with stroke, but vWF levels were measured after the stroke was diagnosed. Therefore, it remains debatable whether high levels are a cause or a consequence of stroke.6–10 Results from longitudinal studies are limited. Thus far, only 1 longitudinal study of a stroke-free cohort with a sufficiently large number of incident stroke cases has investigated the relationship between vWF levels and stroke in the general population.11 Because the population of this study was relatively young (45 to 64 years old at baseline), it needs to be investigated if these findings also apply to elderly people, who are at the highest risk of stroke.
We investigated whether plasma vWF levels are associated with the risk of stroke and its subtype ischemic stroke in a large population-based cohort study among elderly subjects. We further examined if the association was different in men and women and whether it could be attributed to the effect of atrial fibrillation on vWF levels.
Methods
Source Population
This study is part of the Rotterdam Study, an ongoing prospective population-based cohort study, which started in 1990.12 Initially, 7983 persons (of 10 215 invitees) who were aged ≥55 years and living in Ommoord, a district in the city of Rotterdam in The Netherlands, were enrolled in the cohort. In the Year 2000, the cohort was expanded by 3011 persons (of 4472 invitees) who had reached the age of 55 years or moved into the study district since the start of the study. Baseline examinations consisted of an interview at home and 2 visits to the research center for physical examination and blood sampling. These examinations were repeated every 3 to 4 years. All participants were continuously monitored for disease.
For the present study, we included participants of the third examination cycle of the original cohort (baseline 1997 to 1999) and participants of the first examination cycle of the extension of the cohort (baseline 2000 to 2001).
The study was approved by the Medical Ethics Committee of the Erasmus University Medical Center in Rotterdam. Written informed consent was obtained from all participants.
Assessment of Stroke
History of stroke at baseline was assessed during the baseline interview and verified by reviewing medical records (n=419). After enrollment in the Rotterdam Study, participants were continuously monitored for incident strokes through automated linkage of the study database with files from general practitioners, the municipality, and nursing home physicians’ files. Additional information was obtained from hospital records. Potential strokes were reviewed by research physicians and verified by an experienced stroke neurologist (P.J.K.). Subarachnoid hemorrhages and retinal strokes were excluded.
Strokes were further classified as ischemic or hemorrhagic based on the following criteria: ischemic stroke was diagnosed if a CT or MRI scan carried out within 4 weeks after the event ruled out other diagnoses or if indirect evidence (neurological deficit limited to 1 limb or completely recovered within 72 hours or atrial fibrillation in the absence of anticoagulant therapy) indicated that the stroke was of an ischemic nature; a hemorrhagic stroke was diagnosed if a relevant hemorrhage was shown on CT or MRI scan or if the person lost consciousness permanently or died within hours after the onset of focal signs. If a stroke did not match any of these criteria, it was classified as unspecified.
Participants were followed from baseline to stroke, death, last health status update when they were known to be free of stroke, or January 1, 2005, whichever came first. For the analysis of ischemic stroke, we censored participants who were diagnosed with hemorrhagic or unspecified stroke at the date of the event. Follow-up was complete up to January 1, 2005, for 98.6% of potential person-years.13
Blood Sampling Procedure and vWF Plasma Measurement
Fasting venous blood samples were taken at the research center and collected in citrated tubes. Samples were stored at −80°C. vWF antigen was determined with an in-house enzyme-linked immunosorbent assay using polyclonal rabbit antihuman vWF antibodies (DakoCytomation, Glostrop, Denmark) for catching and tagging. The intra-assay coefficient of variation was 5.8% and the interassay coefficient of variation was 7.8%.
Baseline Measurements
Smoking behavior and current medication use were assessed during the interview at home. Clinical measurements were obtained during 2 visits to the research center. Blood pressure was calculated as the mean of 2 measurements with the random-zero sphygmomanometer at the right brachial artery as the subject was in a sitting position. Hypertension was defined as a diastolic blood pressure of ≥90 mm Hg and/or a systolic blood pressure of ≥140 mm Hg and/or the use of antihypertensive medication indicated for the treatment of high blood pressure (≥Grade 1 hypertension according to World Health Organization criteria).14 Total cholesterol and high-density lipoprotein cholesterol were measured with an automated enzymatic procedure. Diabetes mellitus was defined as the use of serum glucose-lowering medication and/or a fasting serum glucose level ≥7.0 mmol/L. The waist-to-hip ratio was calculated by dividing the waist circumference (in centimeters) by the hip circumference (in centimeters). Body mass index was calculated as weight (in kilograms) divided by the square of height (in meters). History of myocardial infarction was determined during the baseline interview and verified in medical records. History of coronary heart disease was positive if the participant underwent a revascularization procedure or fulfilled the criteria of myocardial infarction. Prevalent and incident atrial fibrillation were ascertained using the following methods: (1) an electrocardiogram was recorded during baseline visits and follow-up rounds; and (2) information was obtained from general practitioners files, hospital records, and the national registration system of hospital discharge diagnoses.15 The presence of peripheral arterial disease was evaluated by measuring the systolic blood pressure level of the posterior tibial artery at both legs using a Doppler probe and a random-zero sphygmomanometer with the subject in a supine position. The ratio of the systolic blood pressure at the ankle to the systolic blood pressure at the brachial artery was calculated for each leg. Peripheral arterial disease was considered present if the ankle-brachial index was <0.9 in at least 1 leg.16 Blood group antigen phenotypes were reconstructed by haplotype analysis of 4 single nucleotide polymorphisms, rs687289, rs507666, rs8176704, and rs8176749, which collectively serve as tagging single nucleotide polymorphisms for the O, A1, A2, and B allele.17
Population for Analysis
A total of 8517 persons were free from stroke at baseline and eligible to participate. Of these, 2267 persons were not included in the analyses because they did not visit the research center (n=1869) or because blood draw or storage failed (n=398). In total, 6250 participants were included in the analyses.
Statistical Analysis
vWF levels were truncated at the mean±4 SDs to remove outliers. Age- and sex-adjusted mean values (SD) or percentages of stroke risk factors across vWF quartiles were computed by analysis of covariance. We used Cox proportional hazards regression to determine hazard ratios with 95% CIs for the association between plasma vWF levels and stroke. Only first-ever strokes were included in the analyses. Hazard ratios were expressed per SD increase in vWF level and in strata of vWF quartile (relative to the lowest quartile). The linear trend across quartiles was tested by including the quartile categories as a continuous variable in the model. All hazard ratios were adjusted for age and sex (Model 1) and additionally for other putative confounders (systolic blood pressure, diabetes mellitus, total serum cholesterol level, high-density lipoprotein cholesterol level, lipid-lowering medication use, current cigarette smoking, waist-to-hip ratio, atrial fibrillation, coronary heart disease, peripheral arterial disease, and antithrombotic medication use; Model 2) and ABO blood group (Model 3). Missing values in covariates were imputed by using a linear regression model based on age and sex.
Subsequently, we analyzed if the association between vWF and stroke was different in men and women. Interaction, or effect modification, is usually determined by entering a product term in the regression model. Because the Cox regression model is a multiplicative model, adding a product term results in a measure of interaction as a departure from multiplicity. However, the preferred approach to examine biological interaction rather than statistical interaction is to estimate interaction as a departure from additivity.18 In this study, we examined both types of interaction. We tested for interaction on a multiplicative scale by adding a product term to the model, and we tested for biological interaction or effect measure modification on an additive scale by estimating the relative excess risk due to interaction and its 95% CI.19–21
Finally, we performed a subgroup analysis among participants who were free from atrial fibrillation at baseline (n=5959). Subjects who developed atrial fibrillation during follow-up were censored at the date of onset of atrial fibrillation.
Results
During 31 489 person-years of follow-up (mean 5.0 years), 290 participants developed a stroke (153 women), of which 197 were ischemic, 28 hemorrhagic, and 65 unspecified. CT or MRI imaging reports were available for 72.4% of strokes and for 92.4% of ischemic strokes.
Baseline characteristics of the study population are shown in Table 1. At baseline, the mean age was 69.1 years, and 57.2% of the participants were female.Table 1. Baseline Characteristics of the Study Population (n=6250)
| Values are means (SD) or percentages. | |
| HDL indicates high-density lipoprotein. | |
| Age, years | 69.1 (8.2) |
| Female sex, % | 57.2 |
| Systolic blood pressure, mm Hg | 143.2 (21.3) |
| Diastolic blood pressure, mm Hg | 76.8 (11.2) |
| Hypertension, % | 62.5 |
| Antihypertensive medication, % | 23.6 |
| Glucose, mmol/L | 6.0 (1.6) |
| Diabetes mellitus, % | 12.8 |
| Current cigarette smoking, % | 17.4 |
| Total cholesterol, mmol/L | 5.81 (0.98) |
| HDL cholesterol, mmol/L | 1.39 (0.40) |
| Lipid-lowering medication, % | 12.8 |
| Waist-to-hip ratio | 0.92 (0.10) |
| Body mass index, kg/m2 | 27.0 (4.0) |
| History of cardiovascular disease, % | 26.7 |
| Atrial fibrillation, % | 4.6 |
| Myocardial infarction, % | 8.0 |
| Coronary heart disease, % | 10.5 |
| Peripheral arterial disease, % | 15.3 |
| Antithrombotic medication, % | 19.1 |
| ABO blood group, % | |
| O | 45.6 |
| A | 42.3 |
| B | 8.8 |
| AB | 3.3 |
| vWF, IU/mL | 1.31 (0.54) |
Table 2 describes the baseline characteristics across quartiles of the vWF distribution. vWF levels rose with age. ABO blood group was strongly related to vWF level. Diabetes mellitus and cardiovascular disease were more prevalent in subjects with higher vWF levels.Table 2. Baseline Characteristics of the Study Population Across vWF Quartiles
| vWF Quartile (Range, IU/mL) | 1 (0.24–0.92) | 2 (0.92–1.20) | 3 (1.20–1.59) | 4 (1.60–3.64) | P |
|---|---|---|---|---|---|
| Mean values (SD) or percentages. Values are adjusted for age and sex when applicable. | |||||
| HDL indicates high-density lipoprotein. | |||||
| No. | 1563 | 1556 | 1557 | 1554 | |
| Age, years | 66.7 (7.3) | 68.0 (7.9) | 69.7 (8.1) | 71.9 (8.4) | <0.001 |
| Female sex, % | 59.2 | 56.9 | 55.8 | 56.9 | 0.26 |
| Systolic blood pressure, mm Hg | 142.9 (21.1) | 143.6 (20.9) | 144.0 (20.9) | 142.2 (21.2) | 0.10 |
| Diastolic blood pressure, mm Hg | 76.8 (11.1) | 77.0 (11.0) | 77.1 (11.0) | 76.1 (11.1) | 0.06 |
| Hypertension, % | 61.4 | 62.7 | 63.8 | 62.0 | 0.55 |
| Antihypertensive medication, % | 24.6 | 22.7 | 23.6 | 23.4 | 0.65 |
| Glucose, mmol/L | 5.8 (1.6) | 5.9 (1.6) | 6.0 (1.5) | 6.2 (1.6) | <0.001 |
| Diabetes mellitus, % | 11.2 | 10.9 | 13.3 | 15.9 | <0.001 |
| Current cigarette smoking, % | 17.2 | 16.8 | 17.9 | 18.0 | 0.79 |
| Total cholesterol, mmol/L | 5.85 (0.95) | 5.81 (0.95) | 5.81 (0.95) | 5.77 (0.94) | 0.15 |
| HDL cholesterol, mmol/L | 1.41 (0.39) | 1.41 (0.35) | 1.39 (0.36) | 1.36 (0.39) | <0.001 |
| Lipid-lowering medication, % | 11.0 | 12.2 | 13.2 | 14.8 | 0.02 |
| Waist-to-hip ratio | 0.91 (0.08) | 0.92 (0.08) | 0.92 (0.08) | 0.92 (0.08) | 0.04 |
| Body mass index, kg/m2 | 26.5 (4.0) | 26.6 (3.9) | 27.2 (3.9) | 27.5 (4.0) | <0.001 |
| History of cardiovascular disease, % | 25.7 | 25.0 | 26.1 | 29.8 | 0.01 |
| Atrial fibrillation, % | 3.9 | 3.9 | 4.2 | 6.5 | <0.001 |
| Myocardial infarction, % | 7.0 | 7.2 | 7.7 | 10.2 | 0.01 |
| Coronary heart disease, % | 9.6 | 9.5 | 9.7 | 13.1 | <0.001 |
| Peripheral arterial disease, % | 15.3 | 15.5 | 15.7 | 14.7 | 0.87 |
| Antithrombotic medication, % | 18.5 | 17.7 | 18.8 | 21.4 | 0.05 |
| ABO blood group, % | |||||
| O | 70.7 | 52.3 | 37.0 | 22.2 | <0.001 |
| A | 25.3 | 38.0 | 47.5 | 58.6 | <0.001 |
| B | 3.3 | 6.8 | 12.0 | 13.2 | <0.001 |
| AB | 0.8 | 3.0 | 3.6 | 5.9 | <0.001 |
Table 3 shows the association between plasma vWF level and risk of stroke and ischemic stroke. After adjustment for age and sex, higher vWF levels were associated with an increased risk of stroke. Additional adjustment for multiple putative confounders, including ABO blood group, had only a minor effect on the association. Effect estimates for the association between vWF level and ischemic stroke were of similar magnitude, although not statistically significant.Table 3. Association Between Plasma vWF Level and Stroke
| vWF | HR (95% CI)* | ||
|---|---|---|---|
| Model 1 | Model 2 | Model 3 | |
| *Hazard ratios (95% CIs). | |||
| †vWF quartiles (IU/mL): 0.24–0.92; 0.92–1.20; 1.20–1.59; 1.60–3.64. | |||
| Model 1: adjusted for age and sex. | |||
| Model 2: adjusted for age, sex, systolic blood pressure, diabetes mellitus, total cholesterol, HDL cholesterol, lipid-lowering medication, current cigarette smoking, waist-to-hip ratio, atrial fibrillation, coronary heart disease, peripheral arterial disease, and antithrombotic medication. | |||
| Model 3: like Model 2, additionally adjusted for ABO blood group. | |||
| All strokes (n=290) | |||
| per SD increase | 1.12 (1.01–1.25) | 1.11 (1.00–1.24) | 1.12 (1.00–1.25) |
| Quartile 1† | 1 (referent) | 1 (referent) | 1 (referent) |
| Quartile 2 | 1.03 (0.70–1.51) | 1.02 (0.69–1.49) | 1.02 (0.70–1.50) |
| Quartile 3 | 1.29 (0.91–1.84) | 1.26 (0.88–1.79) | 1.27 (0.89–1.81) |
| Quartile 4 | 1.37 (0.97–1.93) | 1.32 (0.93–1.87) | 1.33 (0.93–1.91) |
| P trend | 0.035 | 0.056 | 0.061 |
| Ischemic strokes (n=197) | |||
| per SD increase | 1.13 (0.99–1.29) | 1.12 (0.98–1.27) | 1.10 (0.95–1.26) |
| Quartile 1† | 1 (referent) | 1 (referent) | 1 (referent) |
| Quartile 2 | 1.00 (0.64–1.58) | 0.99 (0.63–1.55) | 0.96 (0.61–1.52) |
| Quartile 3 | 1.26 (0.83–1.93) | 1.23 (0.80–1.87) | 1.19 (0.77–1.82) |
| Quartile 4 | 1.38 (0.91–2.09) | 1.32 (0.87–2.00) | 1.25 (0.81–1.92) |
| P trend | 0.066 | 0.108 | 0.194 |
Sex was not a significant effect modifier of the association between vWF and stroke either on a multiplicative scale (P=0.33) or on an additive scale (P=0.69), indicating that the association between vWF and stroke was not different in men and women.
The association between plasma vWF level and stroke in the subgroup of participants without atrial fibrillation was similar to the association we found in the total cohort. Age- and sex-adjusted hazard ratios per SD increase in vWF level were 1.15 (95% CI, 1.03 to 1.18) for stroke and 1.15 (1.01 to 1.32) for ischemic stroke.
Discussion
In the present study among subjects aged ≥55 years who were free from stroke at baseline, we found that plasma vWF levels were associated with the risk of stroke. The association was only slightly attenuated after adjustment for multiple potential confounders and was similar in subjects without atrial fibrillation. There was no evidence for effect modification by sex.
Before interpreting the results, some methodological issues need to be considered. The strengths of our study are its prospective and population-based design, the large number of participants, and the long and nearly complete follow-up (loss of potential person-years only 1.4%). Thorough stroke monitoring procedures allowed us to include also patients with stroke who had not been referred to a neurologist. A disadvantage of this procedure was that neuroimaging had not been performed in 28% of patients with stroke. However, 92% of ischemic strokes had been confirmed by CT or MRI. We used single imputation methods to replace missing values in covariates. Single imputation methods are considered to produce unbiased results but too much precision compared with multiple imputation methods.22 However, because the overall number of missing values in our data set was small, we think the method we used did not have a strong influence on the results.
This is the first study that shows an association between vWF levels and stroke in an elderly population independent from conventional cardiovascular risk factors and ABO blood group. Previous studies have investigated the relationship between vWF level and stroke. The majority of these studies used a case-control design in which vWF levels were determined after the stroke was diagnosed.6–10 Results from these studies are likely to be biased by poststroke changes in vWF levels. Four longitudinal studies have reported on the association between vWF and stroke in the general population.11,23–26 In a matched case-control study among subjects with atrial fibrillation nested within the Rotterdam Study, no association was found between vWF level and stroke.23 The Caerphilly Study among middle-aged men also did not find an association between vWF and stroke after a median follow-up period of 13 years.24 The Edinburgh Artery Study found a modest, nonsignificant association when participants were followed for a maximum of 5 years,25 but the association disappeared when the average follow-up period was extended to 17 years.26 The lack of an association in the Caerphilly Study and the prolonged Edinburgh Artery Study might be explained by interindividual variability in vWF levels in the long-term, resulting in dilution of the presumed effect. Furthermore, the results of these studies have to be interpreted carefully because they were small or had not excluded participants with prevalent stroke at baseline. Results of the Atherosclerosis Risk in Communities (ARIC) Study, the only prospective study of a cohort free of stroke at baseline with a large number of incident stroke cases, were very much in line with the results of our study.11 Because ARIC Study participants were younger (45 to 64 years of age at baseline), our study is the first to provide information about vWF level and stroke risk in the elderly population (aged ≥55 years).
ABO blood group is a strong determinant of plasma vWF levels. Blood group A and B antigens, which are located on the surface of vWF molecules, decrease vWF clearance. As a result, vWF levels are approximately 25% higher in individuals with blood group non-O than in individuals with blood group O.27 Because several studies have linked ABO blood group to stroke risk,28 blood group may be a confounder of the association between vWF level and stroke. However, adjustment for ABO blood group did not alter the association between vWF and stroke, suggesting that the association between vWF and stroke is independent from ABO blood group.
We performed a subgroup analysis among participants without atrial fibrillation and found that the association between vWF level and stroke was also present in this subgroup and of similar magnitude as the association we found in the total cohort. Unfortunately, we were not able to examine this association in subjects with atrial fibrillation, because the number of stroke cases in the subpopulation with atrial fibrillation was low. However, our findings in participants without atrial fibrillation suggest that the association between vWF and stroke is not principally driven by the presence of atrial fibrillation.
Recently, there has been increasing awareness of sex differences in stroke. Several studies have shown that the risk factor profile is different in male and female patients with stroke. Men with stroke are more likely to have a history of heart disease, myocardial infarction, peripheral arterial disease, diabetes, and alcohol and tobacco use, whereas women with stroke are older at onset and more likely to have atrial fibrillation and hypertension.29–34 Furthermore, it has been suggested that risk factors may have a different effect on stroke risk in men and women.34 This motivated us to investigate if sex differences influenced the association between vWF and stroke risk. However, we did not detect any evidence for the presence of effect modification by sex in our study.
The association we found between vWF levels and the subtype ischemic stroke was of similar magnitude as the association we found with any stroke. However, probably due to the smaller number of events, the association was no longer statistically significant at the conventional α=0.05 level. Further studies and systematic reviews are required to establish the nature of the association with confidence.
In conclusion, plasma vWF levels are associated with the risk of stroke in the general population, independent from cardiovascular risk factors and ABO blood group. The association is also present in subjects without atrial fibrillation and does not differ between men and women.
Acknowledgments
The contribution of inhabitants, general practitioners, and pharmacists of the Ommoord district to the Rotterdam Study is gratefully acknowledged.
Sources of Funding
The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam, The Netherlands Organization for Scientific Research (NWO), The Netherlands Organization for Health Research and Development (ZonMW), the Research Institute for Diseases in the Elderly (RIDE), The Netherlands Genomics Initiative, the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. This study was supported by The Netherlands Heart Foundation (grant 2007B159, F.W.G.L.) and the Erasmus Medical Center (MRACE grant 2006, F.W.G.L.).
Disclosures
None.
Footnote
*R.G.W. and M.C.v.S. contributed equally to this work.
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Received: 2 April 2010
Revision received: 11 June 2010
Accepted: 28 July 2010
Published online: 26 August 2010
Published in print: 1 October 2010
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