(Circulation. 1999;100:736-742.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Prospective Study of Markers of Hemostatic Function With Risk of Ischemic Stroke
From the Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis (A.R.F., E.S., M.L.R.); Collaborative Studies Coordinating Center, Department of Biostatistics, University of North Carolina at Chapel Hill (W.D.R.); Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, Bethesda, Md (L.S.C.); Division of Hematology, University of Texas Medical School, Houston (N.A., K.K.W.); and Department of Epidemiology, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Md (F.J.N.).
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background—Several markers of hemostatic function and inflammation have been associated with increased risk of coronary heart disease, but prospective evidence for their role in ischemic stroke is scant.
Methods and Results—The Atherosclerosis Risk in Communities (ARIC) Study measured several of these markers in more than 14 700 participants 45 to 64 years old who were free of cardiovascular disease and were followed up for 6 to 9 years for occurrence of ischemic stroke (n=191). There was no apparent association between ischemic stroke incidence and factor VIIc, antithrombin III, platelet count, or activated partial thromboplastin time. After adjustment for multiple cardiovascular risk factors, von Willebrand factor, factor VIIIc, fibrinogen, and white blood cell count were positively associated and protein C was negatively but nonsignificantly associated with ischemic stroke incidence in regression analyses based on either continuous variables or fourths of the variable distributions. The adjusted relative risk (and 95% CI) for ischemic stroke in those in the highest versus lowest fourth were: von Willebrand factor, 1.71 (1.1 to 2.7); factor VIIIc, 1.93 (1.2 to 3.1); white blood cell count, 1.50 (0.9 to 2.4); fibrinogen, 1.26 (0.8 to 2.0); and protein C, 0.65 (0.4 to 1.0).
Conclusions—This study offers modest support for the hypothesis that some markers of hemostatic function and inflammation can identify groups of middle-aged adults at increased risk of stroke. These factors may play a role in the pathogenesis of ischemic stroke.
Key Words: stroke • ischemia • hemostasis
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Prospective studies have linked hemostatic factors (eg, fibrinogen,1 2 3 4 5 factor VII,1 and von Willebrand factor5 6 ) or markers of inflammation (eg, white blood cell [WBC] count4 5 7 and C-reactive protein4 8 9 10 ) with risk of coronary heart disease (CHD). Yet, few prospective studies link these factors to risk of ischemic stroke.2 3 8 9 11 12 13 14 15 There appear to be no prospective data on the associations of factor VIII, antithrombin III (AT-III), protein C, or platelet count with incidence of ischemic stroke.
Additional prospective studies are needed to clarify these potential new risk factors for stroke and to perhaps offer clues to stroke prevention. We therefore examined the association of plasma levels of several coagulation and anticoagulation proteins as well as the WBC count (for simplicity, referred to here collectively as "hemostatic factors") with risk of incident ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) Study.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Study Population
The ARIC Study16 included a cohort totaling 15 792 persons between 45 and 64 years of age at recruitment in 1987 through 1989, probability sampled from Forsyth County, North Carolina; Jackson, Miss (blacks only); the northwest suburbs of Minneapolis, Minn; and Washington County, Maryland. Participants underwent reexamination in 1990 through 1992, in 1993 through 1995, and in 1996 through 1998.
Baseline Measurements
Blood was drawn after an 8-hour fasting period with minimal
trauma from an antecubital vein. Samples were processed by a
standardized protocol and stored at –70°C until assayed at the ARIC
Hemostasis Laboratory at the University of Texas Medical School,
Houston. Detailed methods for blood processing and measurement
of hemostatic variables have been published.17 18
Fibrinogen was measured by the thrombin-time titration method; factor
VII activity (VIIc) and factor VIII activity (VIIIc) by clotting
assays; von Willebrand factor antigen and protein C antigen by
ELISA; AT-III activity by a chromogenic substrate method;
and activated partial thromboplastin time (aPTT) on an
automated coagulometer. Reliability coefficients obtained from repeated
testing of individuals over several weeks were 0.72 for fibrinogen,
0.78 for factor VIIc, 0.86 for factor VIIIc, 0.68 for von
Willebrand factor, 0.56 for protein C, 0.42 for AT-III, and
0.92 for aPTT.19
Plasma total cholesterol and triglycerides were
measured by an enzymatic method, and LDL cholesterol was
calculated.20 HDL cholesterol was measured
after dextran-magnesium precipitation of non-HDL lipoproteins.
Prevalent diabetes mellitus was defined as a fasting glucose level
126 mg/dL, nonfasting glucose level 200 mg/dL, and/or a history of
or treatment for diabetes. Platelet counts and WBCs were measured
by Coulter counters.
The ratio of waist (umbilical level) and hip (maximum buttocks)
circumferences was calculated as a measure of fat distribution. Three
blood pressure measurements were taken with a random-zero
sphygmomanometer; the last 2 measurements were averaged. Hypertension
was defined as systolic blood pressure 140 mm Hg,
diastolic blood pressure 90 mm Hg, or use of
antihypertensive medication. Physical activity was expressed as a sport
index ranging from 1 (low) to 5 (high).21 Left
ventricular hypertrophy was determined by
Cornell voltage criteria for the resting ECG.22
Ascertainment of Incident Ischemic Stroke
Strokes were identified and classified according to published
criteria based on the occurrence and duration of neurological signs and
symptoms, the results of neuroimaging and other diagnostic
procedures, and treatments provided.23 Strokes secondary
to trauma, neoplasm, hematological abnormality, infection, or
vasculitis were not counted, and a focal deficit lasting <24 hours was
not considered a stroke. Over the 6 to 9 years of follow-up, there were
274 definite, probable, or possible incident strokes among participants
with no history of stroke at baseline. CT or MRI was available for 83%
of them. The strokes included 221 definite or probable ischemic
strokes, which were the focus of this analysis.
Data Analysis
After those with prevalent CHD, prevalent stroke, and unknown
baseline stroke status were excluded, 14 713 of the 15 792 ARIC
participants were included in the analysis. The exclusion of
participants with prevalent CHD decreased the number of
ischemic strokes for analysis from 221 to 191.
Follow-up went from baseline to whichever of the following occurred
first: ischemic stroke, death, last contact, or December 31,
1995.
Age-, race-, sex-, and ARIC community–adjusted means and SEMs of baseline continuous hemostatic variables for incident stroke cases and noncases were computed by ANCOVA. Relative risks (RR) (95% CI) of incident stroke in relation to the baseline variables were computed by proportional hazards regression. First, continuous hemostatic variables were used to compute standardized RRs (ie, per 1 SD increment). Hemostatic variable distributions were also divided into fourths, and proportional hazards regression was used to determine RRs (hazard rate ratios) and 95% CIs for the second, third, and highest fourth, with the lowest fourth used as the reference, and the linear trend across categories was tested by inclusion of a variable with values of 1, 2, 3, or 4 to designate the successive categories. The multivariable models adjusted initially for age (continuous), sex, race (black, white), and ARIC community; then sequentially for systolic blood pressure (continuous) and antihypertensive medications (yes/no), diabetes (yes/no), smoking (former, current, never, and pack-years), HDL cholesterol and LDL cholesterol (both continuous), waist-to-hip ratio (continuous), and education (<high school, high school, >high school).
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
In a previous report,5 we noted correlations among the hemostasis variables: factor VIIIc with von Willebrand factor (Pearson r=0.71); factor VIIIc and von Willebrand factor with aPTT (r=-0.31 and -0.46); factor VIIIc and von Willebrand factor with fibrinogen (r=0.26 and 0.29); WBC count with fibrinogen (r=0.29); WBC with platelet count (r=0.24); and factor VIIc with protein C (r=0.40).
Over the median of 7.2 years of follow-up, there were 94 incident
ischemic strokes in men and 97 in women; there were 88 in
blacks and 103 in whites. These latter numbers correspond to rates per
1000 person-years of 3.6 in blacks and 1.5 in whites. The age-, sex-,
race-, and community-adjusted baseline mean values of fibrinogen,
factor VIIc, factor VIIIc, von Willebrand factor, and WBC count
were higher (P<0.05) for those who experienced an
ischemic stroke than for those who did not (Table 1
). The RRs of ischemic stroke
per SD increment for these variables ranged from 1.19 to 1.36.
There was little evidence of an association for protein C, AT-III,
aPTT, and platelet count, so they are not presented
further.
|
When the standardized RRs (Table 1
) were
multivariately adjusted (Table 2), the RRs for fibrinogen, factor VIIIc,
von Willebrand factor, and WBC count decreased to 1.13 to 1.26
but were still statistically significant (P
0.05). However,
factor VIIc (RR=1.03) was no longer significant. There was no obvious
difference in the association of incident ischemic stroke with
these hemostasis variables between men and women, blacks and
whites, hypertensives and nonhypertensives (Table 2), or current
smokers and nonsmokers (not shown) or between participants with carotid
intima-media thickness above versus below the median (not shown). In
the multivariable model, protein C proved to be weakly inversely
associated with incident ischemic stroke, with a standardized
RR of 0.89 (Table 2).
|
Because several of these factors are known to be interrelated, another
multivariable model was run including von Willebrand
factor, factor VIIIc, fibrinogen, WBC count, and protein C adjusted for
the same covariates as in Table 2. In this
simultaneous model, only von Willebrand factor (RR
per SD=1.22, 95% CI=1.03 to 1.44) remained statistically significantly
associated with ischemic stroke incidence.
As Table 3 shows, from the lowest to the
highest fourths, the adjusted RR of stroke rose 1.93-fold and 1.71-fold
for factor VIIIc and von Willebrand factor, respectively. It
rose 1.26-fold for fibrinogen and 1.50-fold for WBC. The RR for the
highest versus lowest fourth of protein C was 0.65. Although several of
the associations depicted in Table 3 appeared to be nonlinear,
quadratic terms in the continuous variable models proved to be not
statistically significant.
|
For comparison, in the Figure we
present RRs for incident ischemic stroke versus incident
CHD in the ARIC cohort.5 In general, fibrinogen and WBC
were more strongly associated with CHD, whereas von Willebrand
factor, factor VIIIc, and protein C were more strongly associated with
stroke, although the confidence limits for both end points
consistently overlapped.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The ARIC Study assessed whether levels of several markers of hemostatic function or inflammation in middle-aged adults free of cardiovascular disease predict the incidence of ischemic stroke during an average of 7.2 years of follow-up. Ischemic stroke incidence was positively and moderately strongly associated with factor VIIIc and von Willebrand factor and was positively and more weakly associated with WBC count and fibrinogen. There was a negative but statistically nonsignificant association with protein C after adjustment for other risk factors. Ischemic stroke was not independently associated with aPTT, factor VIIc, AT-III, or platelet count, as was also true for CHD incidence in the ARIC cohort.5
The most novel findings of this study were the associations for von
Willebrand factor and factor VIII, which were somewhat stronger
for ischemic stroke than for CHD incidence in ARIC
(Figure). ARIC participants in the upper fourth of von
Willebrand factor values had a 1.7-fold higher risk of
developing ischemic stroke than did those in the lowest fourth.
Other prospective studies have linked von Willebrand factor or
factor VIIIc with CHD incidence or
recurrence1 5 6 24 25 and with mortality after
stroke.15 However, only the Edinburgh Artery Study has
prospectively examined von Willebrand factor and stroke
incidence.11 The Edinburgh study, however, had only 45
stroke cases, and although the median von Willebrand factor
concentration was 20% higher in stroke cases than in those remaining
free of cardiovascular disease (similar to our
difference in means), the difference was not statistically significant.
Plasma von Willebrand factor, which is synthesized primarily by
vascular endothelial cells, has 3 major activities: (1)
mediating platelet adhesion to damaged arterial walls,
(2) mediating platelet aggregation at high shear stress, and (3)
binding and stabilizing factor VIIIc.26 Vascular injury or
stress increases von Willebrand factor synthesis, so an
elevated plasma von Willebrand factor level may reflect
excessive endothelial stress.27 Increased
von Willebrand factor levels therefore may augment platelet
adhesion, enhance shear stress–induced platelet aggregation, and
increase plasma factor VIIIc levels, thereby increasing risk of
cerebral thrombosis when atherosclerotic plaques rupture.
To the best of our knowledge, ARIC is the first study to report a positive association of plasma VIIIc levels with ischemic stroke incidence. Plasma factor VIIIc levels are closely related to von Willebrand factor levels (r=0.71 in ARIC), because free factor VIII is unstable, and its stability is greatly increased by binding to von Willebrand factor. It is unknown whether increased plasma VIIIc levels are simply due to high levels of von Willebrand factor or to other causes and whether an increased level of factor VIIIc enhances thrombus formation. Factor VIII serves as a cofactor for IXa. On activated platelet surfaces and in the presence of calcium, factor IXa and VIIIa catalyze the conversion of factor X to Xa, which in turn catalyzes the formation of thrombin. It is conceivable that an increased plasma VIIIc level may accelerate thrombin generation and consequently increase fibrin and platelet aggregate formation.
The positive associations of fibrinogen and WBC count with ischemic stroke were weaker than for CHD in this cohort. The fibrinogen association with ischemic stroke was also weaker than in other prospective studies of stroke.2 3 11 Fibrinogen is an acute-phase reactant, whose plasma level is increased by inflammation. Recent prospective studies have shown that the level of C-reactive protein, another major acute-phase reactant and a marker of inflammation, is a risk factor for CHD8 9 10 and stroke.8 9 Insofar as fibrinogen and WBC count reflect inflammation, our finding of a weaker association of plasma fibrinogen levels and WBC count with ischemic stroke than CHD suggests that inflammation may be less important in the pathogenesis of ischemic stroke than CHD. Nevertheless, there are direct mechanisms by which elevated fibrinogen could increase stroke risk. Fibrinogen mediates platelet aggregation, is a major contributor to blood viscosity and fibrin thrombi, and may be involved in smooth muscle migration and proliferation.1
WBC count was associated with ischemic stroke in a previous prospective study of atomic bomb survivors, but potential confounding by smoking was not explored.13 In a prospective study of US adults, Gillum found WBC count to be weakly associated with stroke, but not after adjustment for smoking.14 Oxidant-generating stimuli (eg, smoking) raise the WBC count, and WBC counts contribute to blood viscosity, inflammation, and vascular injury through endothelial adhesion and by release of oxygen radicals and proteolytic enzymes.7
We found the associations of hemostatic factors with ischemic
stroke incidence to be similar in blacks and whites (Table 2).
Yet, compared with whites, blacks in ARIC have 15% to 20% higher von
Willebrand factor and factor VIIIc levels, 3% higher
fibrinogen levels, but 10% to 15% lower WBC counts. Whether
differences in these factors could explain racial differences in stroke
is unclear. Statistical adjustment for von Willebrand factor or
factor VIIIc tended to reduce the association between race and
ischemic stroke, whereas adjustment for WBC count strengthened
it (data not shown).
The negative association of plasma protein C level with ischemic stroke, although not statistically significant with this sample size, contrasts with the lack of any association between protein C and CHD in this cohort.5 Plasma protein C exists as a zymogen, and after activation by thrombomodulin-bound thrombin, activated protein C in the presence of protein S degrades factor Va and VIIIa, thereby inhibiting the coagulation reaction. Although a reduced protein C level in hereditary protein C deficiency is an established risk factor for venous thromboembolism, low protein C level has not been reported previously to be a prospective risk factor for arterial thrombosis. The inverse association between protein C and ischemic stroke was apparent only after multivariable adjustment and therefore should be interpreted cautiously, especially in light of the protein C measurement variability.19
Although the Northwick Park Heart Study reported a strong positive association between factor VIIc and CHD mortality,1 several other studies have failed to replicate this.5 28 29 We know of no previous studies of factor VIIc and stroke incidence. Our findings do not suggest that factor VII plays a role in the pathogenesis of ischemic stroke.
Potential limitations of this study warrant consideration. ARIC made a
single assessment of hemostatic factors, which may lead to
misclassification of the habitual hemostatic factor levels of some
individuals. Correction for measurement unreliability19
strengthens the standardized RR estimates shown in Table 1 (eg,
fibrinogen to RR=1.50, von Willebrand factor to RR=1.57, and
factor VIIIc to RR=1.41). We had no baseline measure of fibrinolytic
capacity, although studies are planned on stored samples. Others have
shown that impaired fibrinolytic capacity is a strong risk factor for
stroke.11 30 The interpretation of the weaker associations
of hemostatic factors with stroke after multivariable adjustment is
complicated. The adjusting factors may be confounding variables, at
least in part, but several stroke risk factors (eg, smoking) may also
operate through hemostatic mechanisms. Thus, the true RRs probably lie
between the minimally adjusted and fully adjusted values.
Taken together with previous evidence, our study suggests that to a modest degree, these markers of hemostatic function or inflammation can identify groups of people at increased risk of ischemic stroke. These factors also may play a pathophysiological role in stroke by enhancing atherosclerosis or thrombosis of the carotid or cerebral arteries, by reducing blood flow in the cerebral microvasculature, or by enhancing tissue injury from ischemic infarction. In the ARIC Study, fibrinogen was cross-sectionally associated with carotid intima-media thickness, but von Willebrand factor, factor VIIIc, and protein C were not31 ; this suggests that increased carotid atherosclerosis is not an important mechanism by which these factors increase risk of stroke.
Interestingly, aspirin is more efficacious in preventing myocardial infarction in men with high C-reactive protein values.8 Aspirin might also prevent ischemic stroke better in the setting of increased hemostatic factors. Nevertheless, none of the RRs observed here was as large as the >2-fold elevated RRs for potentially modifiable major stroke risk factors, such as hypertension, diabetes, and cigarette smoking. Thus, the value of screening for and modifying these new risk markers as an additional means to prevent stroke clearly remains to be established.
|
Acknowledgments |
|---|
The ARIC Study was funded by contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022 from the National Heart, Lung, and Blood Institute.
|
Footnotes |
|---|
Reprint requests to Dr Kenneth K. Wu, Division of Hematology, University of Texas Medical School, 6431 Fannin, MSB 5.234, Houston, TX 77030.
Guest Editor for this article was Carl J. Pepine, MD, University of Florida College of Medicine, Gainesville.
Received November 17, 1998; revision received May 14, 1999; accepted May 20, 1999.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR, North WR, Haines AP, Stirling Y, Imeson JD, Thompson SG. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet. 1986;2:533–537.[Medline] [Order article via Infotrieve]
2. Wilhelmsen L, Svardsudd K, Korsan-Bengtsen K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med. 1984;311:501–505.[Abstract]
3.
Kannel WB, Wolf PA, Castelli WP, D'Agostino RB.
Fibrinogen and risk of cardiovascular disease: the
Framingham Study. JAMA. 1987;258:1183–1186.
4.
Danesh J, Collins R, Appleby P, Peto R. Association of
fibrinogen, C-reactive protein, albumin, or leukocyte count
with coronary heart disease: meta-analyses of
prospective studies. JAMA. 1998;279:1477–1482.
5.
Folsom AR, Wu KK, Rosamond WD, Sharrett AR, Chambless
LE. Prospective study of hemostatic factors and incidence of
coronary heart disease: the Atherosclerosis
Risk in Communities (ARIC) Study. Circulation. 1997;96:1102–1108.
6.
Jansson J-H, Nilsson TK, Johnson O. von
Willebrand factor in plasma: a novel risk factor for recurrent
myocardial infarction and death. Br Heart J. 1991;66:351–355.
7.
Ernst E, Hammerschmidt DE, Bagge U, Matrai A, Dormandy
JA. Leukocytes and the risk of ischemic diseases.
JAMA. 1987;257:2318–2324.
8.
Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens
CH. Inflammation, aspirin, and the risk of
cardiovascular disease in apparently healthy men.
N Engl J Med. 1997;336:973–979.
9.
Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH.
Prospective study of C-reactive protein and the risk of future
cardiovascular events among apparently healthy women.
Circulation. 1998;98:731–733.
10.
Koenig W, Sund M, Fröhlich M, Fischer HG,
Löwel H, Döring A, Hutchinson WL, Pepys MB. C-reactive
protein, a sensitive marker of inflammation, predicts future risk of
coronary heart disease in initially healthy middle-aged men:
results from the MONICA (Monitoring Trends and Determinants in
Cardiovascular Disease) Augsburg Cohort Study, 1984 to
1992. Circulation. 1999;99:237–242.
11.
Smith FB, Lee AJ, Fowkes FGR, Price JF, Rumley A, Lowe
GDO. Hemostatic factors as predictors of ischemic heart disease
and stroke in the Edinburgh Artery Study. Arterioscler Thromb
Vasc Biol. 1997;17:3321–3325.
12. Resch KL, Ernst E, Matrai A, Paulsen HF. Fibrinogen and viscosity as risk factors for subsequent cardiovascular events in stroke survivors. Ann Intern Med. 1992;117:371–375.
13. Prentice RL, Szatrowski TP, Kato H, Mason MW. Leukocyte counts and cerebrovascular disease. J Chronic Dis. 1982;35:703–714.[Medline] [Order article via Infotrieve]
14.
Gillum RF, Ingram DD, Makuc DM. White blood cell count
and stroke incidence and death: the NHANES I Epidemiologic Follow-up
Study. Am J Epidemiol. 1994;139:894–902.
15. Catto AJ, Carter AM, Barrett JH, Bamford J, Rice PJ, Grant PJ. von Willebrand factor and factor VIIIc in acute cerebrovascular disease: relationship to stroke subtype and mortality. Thromb Haemost. 1997;77:1104–1108.[Medline] [Order article via Infotrieve]
16.
The ARIC Investigators. The
Atherosclerosis Risk in Communities (ARIC) Study:
design and objectives. Am J Epidemiol. 1989;129:687–702.
17. Papp AC, Hatzakis H, Bracey A, Wu KK. ARIC hemostasis study, I: development of blood collection and processing system suitable for multicenter hemostatic studies. Thromb Haemost. 1989;61:15–19.[Medline] [Order article via Infotrieve]
18. Atherosclerosis Risk in Communities Study Manual 9: Hemostasis Determinations. Chapel Hill, NC: National Heart, Lung, and Blood Institute of the National Institutes of Health, Collaborative Studies Coordinating Center, University of North Carolina; 1987.
19. Chambless LE, McMahon R, Wu K, Folsom A, Finch A, Shen Y-L. Short-term intraindividual variability in hemostasis factors: the ARIC Study. Ann Epidemiol. 1992;2:723–733.[Medline] [Order article via Infotrieve]
20. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499–502.[Abstract]
21.
Baecke JAH, Burema J, Frijters JER. A short
questionnaire for the measurement of habitual physical activity in
epidemiological studies. Am J Clin Nutr. 1982;36:936–942.
22. Crow RS, Prineas RJ, Rautaharju P, Hannan P, Liebson PR. Relation between electrocardiography and echocardiography for left ventricular mass in mild systemic hypertension (results from Treatment of Mild Hypertension Study). Am J Cardiol. 1995;75:1233–1238.[Medline] [Order article via Infotrieve]
23.
Rosamond WD, Folsom AR, Chambless LE, Wang C-H,
McGovern PG, Howard G, Cooper LS, Shahar E. Stroke incidence and
survival among middle-aged adults: 9-year follow-up of the
Atherosclerosis Risk in Communities (ARIC) cohort.
Stroke. 1999;30:736–743.
24.
Thompson SG, Kienast J, Pyke SDM, Haverkate F, van de
Loo JC. Hemostatic factors and the risk of myocardial infarction or
sudden death in patients with angina pectoris. N Engl J
Med. 1995;332:635–641.
25. Meade TW, North WRS, Chakrabarti R, Stirling Y, Haines AP, Thompson SG, Brozovie M. Haemostatic function and cardiovascular death: early results of a prospective study. Lancet. 1980;1:1050–1054.[Medline] [Order article via Infotrieve]
26. Ruggeri ZM, Ware J. The structure and function of von Willebrand factor. Thromb Haemost. 1992;67:594–599.[Medline] [Order article via Infotrieve]
27. Blann A. von Willebrand factor and the endothelium in vascular disease. Br J Biomed Sci. 1993;50:125–134.[Medline] [Order article via Infotrieve]
28.
Tracy RP, Bovill EG, Yanez D, Psaty BM, Fried LP, Heiss
G, Lee M, Polak JF, Savage PJ. Fibrinogen and factor VIII, but not
factor VII, are associated with measures of subclinical
cardiovascular disease in the elderly: results from the
Cardiovascular Health Study. Arterioscler Thromb
Vasc Biol. 1995;15:1269–1279.
29.
Yarnell JWG, Baker IA, Sweetnam PM, Bainton D, O'Brien
JR, Whitehead PJ, Elwood PC. Fibrinogen, viscosity, and white blood
cell count are major risk factors for ischemic heart disease:
the Caerphilly and Speedwell Collaborative Heart Disease Studies.
Circulation. 1991;83:836–844.
30. Ridker PM, Hennekens CH, Stampfer MJ, Manson JE, Vaughan DE. Prospective study of endogenous tissue plasminogen activator and risk of stroke. Lancet. 1994;343:940–943.[Medline] [Order article via Infotrieve]
31.
Folsom AR, Wu KK, Shahar E, Davis CE. Association of
hemostatic variables with prevalent cardiovascular
disease and asymptomatic carotid artery
atherosclerosis. Arterioscler Thromb. 1993;13:1829–1836.
This article has been cited by other articles:
 |
|
 |
|
  L. Wu, Y. Shen, X. Liu, X. Ma, B. Xi, J. Mi, K. Lindpaintner, X. Tan, and X. Wang The 1425G/A SNP in PRKCH Is Associated With Ischemic Stroke and Cerebral Hemorrhage in a Chinese Population Stroke, September 1, 2009; 40(9): 2973 - 2976. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. E. Tietjen, N. A. Herial, L. White, C. Utley, J. M. Kosmyna, and S. A. Khuder Migraine and Biomarkers of Endothelial Activation in Young Women Stroke, September 1, 2009; 40(9): 2977 - 2982. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Ohira, J. M. Peacock, H. Iso, L. E. Chambless, W. D. Rosamond, and A. R. Folsom Serum and Dietary Magnesium and Risk of Ischemic Stroke: The Atherosclerosis Risk in Communities Study Am. J. Epidemiol., June 15, 2009; 169(12): 1437 - 1444. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-Y. Chuang, C.-H. Bai, W.-H. Chen, L.-M. Lien, and W.-H. Pan Fibrinogen Independently Predicts the Development of Ischemic Stroke in a Taiwanese Population: CVDFACTS Study Stroke, May 1, 2009; 40(5): 1578 - 1584. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. K. Mahmoodi, J.-L. P. Brouwer, N. J.G.M. Veeger, and J. van der Meer Hereditary Deficiency of Protein C or Protein S Confers Increased Risk of Arterial Thromboembolic Events at a Young Age: Results From a Large Family Cohort Study Circulation, October 14, 2008; 118(16): 1659 - 1667. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Sturgeon, A. R. Folsom, W.T. Longstreth Jr, E. Shahar, W. D. Rosamond, and M. Cushman Hemostatic and Inflammatory Risk Factors for Intracerebral Hemorrhage in a Pooled Cohort Stroke, August 1, 2008; 39(8): 2268 - 2273. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Reich, G. Heiss, L. L. Boland, A. T. Hirsch, K. Wu, and A. R. Folsom Ankle brachial index and hemostatic markers in the Atherosclerosis Risk in Communities (ARIC) study cohort Vascular Medicine, November 1, 2007; 12(4): 267 - 273. [Abstract] [PDF]
|
|
|
|
 |
|
 F. Bilora, E. Zanon, A. Casonato, A. Bertomoro, F. Petrobelli, M. Cavraro, E. Campagnolo, and A. Girolami Type IIB von Willebrand Disease: Role of Qualitative Defects in Atherosclerosis and Endothelial Dysfunction Clinical and Applied Thrombosis/Hemostasis, October 1, 2007; 13(4): 384 - 390. [Abstract] [PDF]
|
|
|
|
 |
|
 K. G. Moulakakis, G. Sfyroeras, P. Pavlidis, N. Besias, D. Maras, and V. Andrikopoulos Hypercoagulable State Due to Alcohol-Paracetamol Syndrome Producing Acute Limb Ischemia Vascular and Endovascular Surgery, September 1, 2007; 41(4): 362 - 365. [Abstract] [PDF]
|
|
|
|
|
|
I. Tzoulaki, G. D. Murray, A. J. Lee, A. Rumley, G. D.O. Lowe, and F. G. R. Fowkes Relative Value of Inflammatory, Hemostatic, and Rheological Factors for Incident Myocardial Infarction and Stroke: The Edinburgh Artery Study Circulation, April 24, 2007; 115(16): 2119 - 2127. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. O. Mosnier, B. V. Zlokovic, and J. H. Griffin The cytoprotective protein C pathway Blood, April 15, 2007; 109(8): 3161 - 3172. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. N. Bongers, M. P.M. de Maat, M.-L. P.J. van Goor, V. Bhagwanbali, H. H.D.M. van Vliet, E. B. Gomez Garcia, D. W.J. Dippel, and F. W.G. Leebeek High von Willebrand Factor Levels Increase the Risk of First Ischemic Stroke: Influence of ADAMTS13, Inflammation, and Genetic Variability Stroke, November 1, 2006; 37(11): 2672 - 2677. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ohira, E. Shahar, L. E. Chambless, W. D. Rosamond, T. H. Mosley Jr, and A. R. Folsom Risk Factors for Ischemic Stroke Subtypes: The Atherosclerosis Risk in Communities Study Stroke, October 1, 2006; 37(10): 2493 - 2498. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Sato, H. Iso, H. Noda, A. Kitamura, H. Imano, M. Kiyama, T. Ohira, T. Okada, M. Yao, T. Tanigawa, et al. Plasma Fibrinogen Concentrations and Risk of Stroke and Its Subtypes Among Japanese Men and Women Stroke, October 1, 2006; 37(10): 2488 - 2492. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Y. Wong, R. Klein, C. Sun, P. Mitchell, D. J. Couper, H. Lai, L. D. Hubbard, A. R. Sharrett, and for the Atherosclerosis Risk in Communities Study Age-Related Macular Degeneration and Risk for Stroke Ann Intern Med, July 18, 2006; 145(2): 98 - 106. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. A. Meyer, G. Kundt, M. Steiner, P. Schuff-Werner, and W. Kienast Impaired Flow-Mediated Vasodilation, Carotid Artery Intima-Media Thickening, and Elevated Endothelial Plasma Markers in Obese Children: The Impact of Cardiovascular Risk Factors Pediatrics, May 1, 2006; 117(5): 1560 - 1567. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Vorchheimer and R. Becker Platelets in Atherothrombosis Mayo Clin. Proc., January 1, 2006; 81(1): 59 - 68. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. H. Jee, J. Y. Park, H.-S. Kim, T. Y. Lee, and J. M. Samet White Blood Cell Count and Risk for All-Cause, Cardiovascular, and Cancer Mortality in a Cohort of Koreans Am. J. Epidemiol., December 1, 2005; 162(11): 1062 - 1069. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Smith, C. Patterson, J. Yarnell, A. Rumley, Y. Ben-Shlomo, and G. Lowe Which Hemostatic Markers Add to the Predictive Value of Conventional Risk Factors for Coronary Heart Disease and Ischemic Stroke?: The Caerphilly Study Circulation, November 15, 2005; 112(20): 3080 - 3087. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W.H. L. Kao, W.-C. Hsueh, D. L. Rainwater, D. H. O'Leary, I. G. Imumorin, M. P. Stern, and B. D. Mitchell Family History of Type 2 Diabetes Is Associated With Increased Carotid Artery Intimal-Medial Thickness in Mexican Americans Diabetes Care, August 1, 2005; 28(8): 1882 - 1889. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. L. Margolis, J. E. Manson, P. Greenland, R. J. Rodabough, P. F. Bray, M. Safford, R. H. Grimm Jr, B. V. Howard, A. R. Assaf, R. Prentice, et al. Leukocyte Count as a Predictor of Cardiovascular Events and Mortality in Postmenopausal Women: The Women's Health Initiative Observational Study Arch Intern Med, March 14, 2005; 165(5): 500 - 508. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Stuveling, S. J. L. Bakker, H. L. Hillege, P. E. de Jong, R. O. B. Gans, and D. de Zeeuw Biochemical risk markers: a novel area for better prediction of renal risk? Nephrol. Dial. Transplant., March 1, 2005; 20(3): 497 - 508. [Full Text] [PDF]
|
|
|
|
 |
|
 M P J van Goor, E B Gomez-Garcia, F W G Leebeek, G J Brouwers, P J Koudstaal, and D W J Dippel The - 148 C/T fibrinogen gene polymorphism and fibrinogen levels in ischaemic stroke: a case-control study J. Neurol. Neurosurg. Psychiatry, January 1, 2005; 76(1): 121 - 123. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Rothwell, S. C. Howard, D. A. Power, S. A. Gutnikov, A. Algra, J. van Gijn, T. G. Clark, M. F.G. Murphy, C. P. Warlow, and for the Cerebrovascular Cohort Studies Collaborati Fibrinogen Concentration and Risk of Ischemic Stroke and Acute Coronary Events in 5113 Patients With Transient Ischemic Attack and Minor Ischemic Stroke Stroke, October 1, 2004; 35(10): 2300 - 2305. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. E. Chambless, G. Heiss, E. Shahar, M. J. Earp, and J. Toole Prediction of Ischemic Stroke Risk in the Atherosclerosis Risk in Communities Study Am. J. Epidemiol., August 1, 2004; 160(3): 259 - 269. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Santamaria, J. Mateo, I. Tirado, A. Oliver, R. Belvis, J. Marti-Fabregas, R. Felices, J. M. Soria, J. C. Souto, and J. Fontcuberta Homozygosity of the T Allele of the 46 C->T Polymorphism in the F12 Gene Is a Risk Factor for Ischemic Stroke in the Spanish Population Stroke, August 1, 2004; 35(8): 1795 - 1799. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. F Viles-Gonzalez, V. Fuster, and J. J Badimon Atherothrombosis: A widespread disease with unpredictable and life-threatening consequences Eur. Heart J., July 2, 2004; 25(14): 1197 - 1207. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Haim, V. Boyko, U. Goldbourt, A. Battler, and S. Behar Predictive Value of Elevated White Blood Cell Count in Patients With Preexisting Coronary Heart Disease: The Bezafibrate Infarction Prevention Study Arch Intern Med, February 23, 2004; 164(4): 433 - 439. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Patel and R. Arya Tests for Hereditary Thrombophilia Are of Limited Value in the Black Population Stroke, December 1, 2003; 34 (12): e236 - e236. [Full Text] [PDF]
|
|
|
|
 |
|
 D. G. Hackam and S. S. Anand Emerging Risk Factors for Atherosclerotic Vascular Disease: A Critical Review of the Evidence JAMA, August 20, 2003; 290(7): 932 - 940. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. H Reinhart Fibrinogen - marker or mediator of vascular disease? Vascular Medicine, August 1, 2003; 8(3): 211 - 216. [Abstract] [PDF]
|
|
|
|
|
|
E. Domotor, O. Benzakour, J. H. Griffin, D. Yule, K. Fukudome, and B. V. Zlokovic Activated protein C alters cytosolic calcium flux in human brain endothelium via binding to endothelial protein C receptor and activation of protease activated receptor-1 Blood, June 15, 2003; 101(12): 4797 - 4801. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. Smith, H. A. Lane, J. Lewis, S. Dann, J. Goodfellow, P. Collins, L. M. Evans, M. F. Scanlon, and J. S. Davies Endothelial Function and Coagulant Factors in Growth Hormone-Treated Hypopituitary Adults Receiving Desmopressin J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 2152 - 2156. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W.-H. Chen, M.-Y. Lan, Y.-Y. Chang, S.-S. Chen, and J.-S. Liu The Prevalence of Protein C, Protein S, and Antithrombin III Deficiency in non-APS/SLE Chinese Adults with Noncardiac Cerebral Ischemia Clinical and Applied Thrombosis/Hemostasis, April 1, 2003; 9(2): 155 - 162. [Abstract] [PDF]
|
|
|
|
|
|
S.C. Kofoed, H.H. Wittrup, H. Sillesen, and B.G. Nordestgaard Fibrinogen predicts ischaemic stroke and advanced atherosclerosis but not echolucent, rupture-prone carotid plaques: The Copenhagen City Heart Study Eur. Heart J., March 2, 2003; 24(6): 567 - 576. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Shahar, L. E. Chambless, W. D. Rosamond, L. L. Boland, C. M. Ballantyne, P. G. McGovern, and A. R. Sharrett Plasma Lipid Profile and Incident Ischemic Stroke: The Atherosclerosis Risk in Communities (ARIC) Study Stroke, March 1, 2003; 34(3): 623 - 631. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Soria, L. Almasy, J. C. Souto, A. Buil, E. Martinez-Sanchez, J. Mateo, M. Borrell, W. H. Stone, M. Lathrop, J. Fontcuberta, et al. A new locus on chromosome 18 that influences normal variation in activated protein C resistance phenotype and factor VIII activity and its relation to thrombosis susceptibility Blood, January 1, 2003; 101(1): 163 - 167. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Sandusky, D. T. Berg, M. A. Richardson, L. Myers, and B. W. Grinnell Modulation of Thrombomodulin-dependent Activation of Human Protein C through Differential Expression of Endothelial Smads J. Biol. Chem., December 13, 2002; 277(51): 49815 - 49819. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Lindhoff-Last, B. Wenning, M. Stein, F. Gerdsen, R. Bauersachs, and R. Wagnert Risk Factors and Long-term Follow-up of Patients with the Immune Type of Heparin-Induced Thrombocytopenia Clinical and Applied Thrombosis/Hemostasis, October 1, 2002; 8(4): 347 - 352. [Abstract] [PDF]
|
|
|
|
 |
|
 C. G.C. Spencer, D. Gurney, A. D. Blann, D. G. Beevers, and G. Y.H. Lip Von Willebrand Factor, Soluble P-Selectin, and Target Organ Damage in Hypertension: A Substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Hypertension, July 1, 2002; 40(1): 61 - 66. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. M. Ananyeva, D. V. Kouiavskaia, M. Shima, and E. L. Saenko Intrinsic pathway of blood coagulation contributes to thrombogenicity of atherosclerotic plaque Blood, May 29, 2002; 99(12): 4475 - 4485. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Deguchi, J. A. Fernandez, and J. H. Griffin Neutral Glycosphingolipid-dependent Inactivation of Coagulation Factor Va by Activated Protein C and Protein S J. Biol. Chem., March 8, 2002; 277(11): 8861 - 8865. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. B. Braunstein, D. W. Kershner, P. Bray, G. Gerstenblith, S. P. Schulman, W. S. Post, and R. S. Blumenthal Interaction of Hemostatic Genetics With Hormone Therapy : New Insights To Explain Arterial Thrombosis in Postmenopausal Women Chest, March 1, 2002; 121(3): 906 - 920. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Rizos and D. P Mikhailidis Are high density lipoprotein (HDL) and triglyceride levels relevant in stroke prevention? Cardiovasc Res, November 1, 2001; 52(2): 199 - 207. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Sramek, J.H.C. Reiber, W.B.J. Gerrits, and F.R. Rosendaal Decreased Coagulability Has No Clinically Relevant Effect on Atherogenesis: Observations in Individuals With a Hereditary Bleeding Tendency Circulation, August 14, 2001; 104(7): 762 - 767. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. W. Tsai, A. R. Folsom, W. D. Rosamond, and D. W. Jones Ankle-Brachial Index and 7-Year Ischemic Stroke Incidence: The ARIC Study Stroke, August 1, 2001; 32(8): 1721 - 1724. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. J. Hankey, J. W. Eikelboom, F. M. van Bockxmeer, E. Lofthouse, N. Staples, and R. I. Baker Inherited Thrombophilia in Ischemic Stroke and Its Pathogenic Subtypes Stroke, August 1, 2001; 32(8): 1793 - 1799. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G.E. Tietjen, M.M. Al-Qasmi, K. Athanas, R.M. Dafer, and S.A. Khuder Increased von Willebrand factor in migraine Neurology, July 24, 2001; 57(2): 334 - 336. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Bloomfield Rubins, J. Davenport, V. Babikian, L. M. Brass, D. Collins, L. Wexler, S. Wagner, V. Papademetriou, G. Rutan, and S. J. Robins Reduction in Stroke With Gemfibrozil in Men With Coronary Heart Disease and Low HDL Cholesterol : The Veterans Affairs HDL Intervention Trial (VA-HIT) Circulation, June 12, 2001; 103(23): 2828 - 2833. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. W. Kamphuisen, J. C. J. Eikenboom, and R. M. Bertina Elevated Factor VIII Levels and the Risk of Thrombosis Arterioscler Thromb Vasc Biol, May 1, 2001; 21(5): 731 - 738. [Full Text] [PDF]
|
|
|
|
|
|
M. Shibata, S. R. Kumar, A. Amar, J. A. Fernandez, F. Hofman, J. H. Griffin, and B. V. Zlokovic Anti-Inflammatory, Antithrombotic, and Neuroprotective Effects of Activated Protein C in a Murine Model of Focal Ischemic Stroke Circulation, April 3, 2001; 103(13): 1799 - 1805. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Morrison, P. A. Doris, A. R. Folsom, F. J. Nieto, E. Boerwinkle, and R. A. Hegele G-Protein {beta}3 Subunit and {{alpha}}-Adducin Polymorphisms and Risk of Subclinical and Clinical Stroke Editorial Comment : Candidate Genes for Stroke: If Elected, Will They Serve? Stroke, April 1, 2001; 32(4): 822 - 829. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. L. Feigin, C. S. Anderson, N. E. Anderson, J. B. Broad, M. J. Pledger, and R. Bonita Is There a Temporal Pattern in the Occurrence of Subarachnoid Hemorrhage in the Southern Hemisphere? : Pooled Data From 3 Large, Population-Based Incidence Studies in Australasia, 1981 to 1997 Stroke, March 1, 2001; 32(3): 613 - 619. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. B. Goldstein, R. Adams, K. Becker, C. D. Furberg, P. B. Gorelick, G. Hademenos, M. Hill, G. Howard, V. J. Howard, B. Jacobs, et al. Primary Prevention of Ischemic Stroke : A Statement for Healthcare Professionals From the Stroke Council of the American Heart Association Circulation, January 2, 2001; 103(1): 163 - 182. [Full Text] [PDF]
|
|
|
|
|
|
R. Shurtz-Swirski, S. Sela, A. T. Herskovits, S. M. Shasha, G. Shapiro, L. Nasser, and B. Kristal Involvement of Peripheral Polymorphonuclear Leukocytes in Oxidative Stress and Inflammation in Type 2 Diabetic Patients Diabetes Care, January 1, 2001; 24(1): 104 - 110. [Abstract] [Full Text]
|
|
|
|
|
|
L. B. Goldstein, R. Adams, K. Becker, C. D. Furberg, P. B. Gorelick, G. Hademenos, M. Hill, G. Howard, V. J. Howard, B. Jacobs, et al. Primary Prevention of Ischemic Stroke : A Statement for Healthcare Professionals From the Stroke Council of the American Heart Association Stroke, January 1, 2001; 32(1): 280 - 299. [Full Text] [PDF]
|
|
|
|
|
|
M. R. Di Tullio, R. L. Sacco, M. T. Savoia, R. R. Sciacca, and S. Homma Gender Differences in the Risk of Ischemic Stroke Associated With Aortic Atheromas Stroke, November 1, 2000; 31(11): 2623 - 2627. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Pinotti, R. Toso, D. Girelli, D. Bindini, P. Ferraresi, M. L. Papa, R. Corrocher, G. Marchetti, and F. Bernardi Modulation of factor VII levels by intron 7 polymorphisms: population and in vitro studies Blood, June 1, 2000; 95(11): 3423 - 3428. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||