(Stroke. 1999;30:2547.)
© 1999 American Heart Association, Inc.
Original Contributions |
Markers of Thrombin and Platelet Activity in Patients With Atrial Fibrillation
Correlation With Stroke Among 1531 Participants in the Stroke Prevention in Atrial Fibrillation III Study
From the Department of Neurology, the University of Arizona, Tucson, Ariz (W.M.F.); Axio Research Corporation, Seattle, Wash (L.A.P.); University of Texas at San Antonio (R.G.H.); Laboratory for Clinical Biochemical Research, Department of Pathology, University of Vermont, Burlington, Vt (M.C., E.S.C., E.G.B.); and Haemostasis Thrombosis and Vascular Biology Unit, City Hospital, Birmingham, UK (G.Y.H.L.).
Correspondence to Robert G. Hart, MD, Department of Medicine (Neurology), University of Texas HSC, 7703 Floyd Curl Dr, San Antonio, TX 78284. E-mail HartR{at}uthscsa.edu
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Abstract |
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Background and Purpose—Markers of thrombin generation and platelet activation are often elevated in patients with nonvalvular atrial fibrillation, but it is unclear whether such markers usefully predict stroke. Therefore, we undertook the present study to assess the relationship between prothrombin fragment F1.2 (F1.2), ß-thromboglobulin (BTG), fibrinogen, and the factor V Leiden mutation with stroke in atrial fibrillation.
Methods—Specimens were obtained from 1531 participants in the Stroke Prevention in Atrial Fibrillation III study. The results were correlated with patient features, antithrombotic therapy, and subsequent thromboembolism (ischemic stroke and systemic embolism) by multivariate analysis.
Results—Increased F1.2 levels were associated with age (P<0.001), female sex (P<0.001), systolic blood pressure (P=0.006), and heart failure (P=0.001). F1.2 were not affected by aspirin use and were not associated with thromboembolism after adjustment for age (P=0.18). BTG levels were higher with advanced age (P=0.006), coronary artery disease (P=0.05), carotid disease (P=0.005), and heart failure (P<0.001), lower in regular alcohol users (P=0.05), and not significantly associated with thromboembolism. Fibrinogen levels were not significantly related to thromboembolism but were associated with elevated BTG levels (P<0.001). The factor V Leiden mutation was not associated with thromboembolism (relative risk 0.5, 95% CI 0.1 to 3.8).
Conclusions—Elevated F1.2 levels were associated with clinical risk factors for stroke in atrial fibrillation, whereas increased BTG levels were linked to manifestations of atherosclerosis. In this large cohort of patients with atrial fibrillation who were receiving aspirin, F1.2, BTG, fibrinogen, and factor V Leiden were not independent, clinically useful predictors of stroke.
Key Words: atrial fibrillation • coagulation • fibrinogen • platelet activation • thrombin
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Atrial fibrillation (AF) results in stasis of blood flow in the left atrial appendage, leading to thrombus formation and embolic stroke. Although AF is associated with a 6-fold increase in stroke, most patients with AF never suffer stroke, which suggests that factors in addition to the dysrhythmia contribute to the formation of atrial appendage thrombi.1 Hemostasis conditions favoring thrombosis could be important in the pathogenesis of AF-associated stroke, but this has not been firmly established.
Previous studies have demonstrated elevation of markers of thrombin and
platelet activity in patients with AF.2 3 4 5 6 7 8 9 10
Prothrombin fragment 1+2 (F1.2) reflects in vivo thrombin generation,
is reported to be elevated in AF,8 10 and is suppressed by
anticoagulation in a dose-dependent manner.11 Elevation of
ß-thromboglobulin (BTG), a protein fragment
released from 
-granules during the second phase of platelet
activation, has also been reported in AF patients.3 4 5 7 9
In addition, people with a genetic abnormality leading to
activated protein C resistance (ie, factor V Leiden, G1691A
mutation) have an increased risk of venous thrombosis,12
but this has not been systematically assessed as a predictor of stroke
in patients with AF.
To explore hemostatic markers in patients with atrial fibrillation, we measured F1.2, fibrinogen, and BTG in participants in the Stroke Prevention in Atrial Fibrillation (SPAF) III study, correlating these markers with patient features and subsequent thromboembolism. Our hypothesis was that increased levels of F1.2 and BTG would predict subsequent stroke.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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All patients were participants in the SPAF III study, which was performed at 20 clinical sites in the United States and Canada between 1993 and 1997; the design and main results have been reported previously.13 14 15 In brief, participants were adults with sustained or intermittent AF without mitral stenosis or prosthetic cardiac valves and were stratified as either low risk or high risk for stroke based on associated clinical features (Figure 1
). Those with any of 4 high-risk
criteria were randomized to receive either adjusted-dose warfarin
(target international normalized ratio [INR] 2 to 3) or fixed,
low-dose warfarin (target INR 1.2 to 1.5) plus aspirin 325 mg/d (termed
combination therapy). Participants without any of the 4 specific risk
factors were all given aspirin 325 mg/d alone. Primary thromboembolic
events included all ischemic strokes and non–central nervous
system (CNS) systemic cardiogenic emboli. Strokes were secondarily
categorized by use of a clinical classification scheme as probably
cardioembolic, probably noncardioembolic, or of uncertain cause by a
central events committee whose members were unaware of
treatment.16 Cardioembolic events consisted of
cardioembolic strokes and non-CNS emboli.
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Specimens for hemostatic markers were collected from a convenience
sample of 1531 participants. Samples were initially collected within 30
days of enrollment from all participants; after the first year of
recruitment, this was limited to those not receiving anticoagulation.
Subsequently, samples were collected after 3 months, 12 months, and
annually thereafter, as well as at the time of thromboembolic events.
Participants enrolled and followed up at outlying clinics at which
specimens could not be adequately processed were not included; 79%
(1531/1936) of SPAF III participants had 
1 sample collected for these
analyses (Figure 1
). Correlations between F1.2 levels
and INR have been reported previously.11
Blood Collection and Laboratory Analysis
Blood collection materials were prepared at the Laboratory
for Clinical Biochemistry Research, Department of
Pathology, University of Vermont. Blood for determination of F1.2 and
fibrinopeptide A (FPA) was drawn into SCAT-I special
coagulation tubes (Hematologic Technologies Inc), which yielded
a final concentration of 4.5 mmol/L EDTA, 0.15 kallikrein
inhibitor units of aprotinin per liter, and 20 mol/L
DE-Phe-Pro-Arg-chloromethyl ketone. Blood for BTG determination was
drawn into a Diatube H special coagulation tube (American
Bioproducts) containing 3.8% sodium citrate and a proprietary
antiplatelet agent. Blood for fibrinogen assays was drawn into
3.8% sodium citrate tubes (Becton Dickinson), and for DNA extraction,
blood was drawn into 4.5-mmol/L EDTA tubes (Becton Dickinson). All
samples were immediately mixed by gentle inversion, stored on melting
ice, and centrifuged at 4°C for 30 000g-minutes
within 1 hour of phlebotomy. Plasma was separated for F1.2, FPA, and
fibrinogen assays. Plasma from the Diatube H was additionally passed
through a 0.2-µm filter (Gelman Sciences) to prepare
platelet-free plasma for BTG assay. Buffy coat was collected from
the EDTA tube for DNA extraction. Samples were separated into aliquots
into color-coded 0.5-mL cryovials (USA Scientific) and frozen at
-70°C until shipped on dry ice to the core laboratory.
Research personnel participating in blood collection received phlebotomy training and recorded venipuncture quality. Samples were categorized as obtained by satisfactory phlebotomy in the absence of hematoma formation, multiple needle punctures, vein collapse, leakage at the site, tourniquet time >2 minutes, or difficult phlebotomy noted by the phlebotomist. Blood was collected with a 21-gauge butterfly needle. FPA assays were used as a measure of phlebotomy quality control and measured in a convenience sample of 625 participants. Unsatisfactory venipunctures (see criteria above) correlated significantly with FPA levels: FPA levels >22 ng/mL occurred in 32% of unsatisfactory venipunctures versus 5% of others (P<0.001).
All assays were performed on samples that had been stored at -70°C. F1.2 was measured with an ELISA assay (Dade Behring Inc) according to the manufacturer’s specifications as previously described.17 The interassay coefficient of variation (CV) was 8%. The FPA assay was measured with a radioimmunoassay (Byk-Sangtec) according to the manufacturer’s instructions, with an interassay CV of 18%. The fibrinogen assay was performed according to the method of Clauss,18 19 with an interassay CV of 3%. BTG was measured with an ELISA (American Bioproducts); the interassay CV was 9%. The factor V Leiden G1691A mutation was assessed by genotyping with polymerase chain reaction amplification and restriction-enzyme digestion.20
Data Analysis
Analyses for F1.2 were performed in the subgroup of
patients who had not received warfarin in the prior 2
weeks.11 The upper limit of normal for F1.2 was chosen as
2.8 nmol/L.21 22 All analyses were done with the
natural log transform for F1.2 and BTG levels because the distributions
were heavily skewed (Figures 2 and 3). Differences in markers (transformed
values) between independent groups were evaluated with 2-sample
t tests and ANOVA for continuous marker levels and a
2 test for dichotomized levels. Changes over
time in transformed values were evaluated with a paired t
test. Forward and backward stepwise linear regression analyses
were used to identify features independently associated with marker
levels. The relative risk of a thromboembolic event associated with a
marker level was estimated with a Cox proportional hazards model
(likelihood ratio test). Statistical significance was accepted at the
0.05 level (2-sided). Analyses were done with SPSS
software.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Prothrombin Activation Fragment 1.2
F1.2 levels were determined at study entry in 553 participants (mean age 70 years); none were taking warfarin, whereas 488 took aspirin, and 65 received no antithrombotic therapy (Table 1
). F1.2 levels ranged from 0.5 to
7.2 nmol/L (excluding 2 patients with values >3 SDs above the
transformed mean), with a median of 1.9 nmol/L. In 8%, F1.2 levels
were 
1.0 nmol/L, and 18% of F1.2 levels exceeded 2.8 nmol/L (Figure 2). The mean ln-transformed level (F1.2ln)
was 0.6±0.4 nmol/L (anti-ln of mean=1.8 nmol/L) and was identical for
those taking versus those not taking aspirin. The influence of aspirin
was further assessed by examination of 32 patients who had an initial
measurement while receiving no antithrombotic therapy and then had a
second determination while taking aspirin 325 mg/d; there was no
significant difference in mean F1.2ln levels
(mean difference 0.05 nmol/L, P=0.5). Among the 553
patients, 42 were recorded as having unsatisfactory
venipuncture; mean F1.2ln levels were
identical with satisfactory venipunctures
(P=0.95), and these patients were included in all subsequent
analyses.
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Increased F1.2 levels were strongly associated with older age
(P<0.001) and female sex (P<0.001) (Table 2). Women >75 years of age (mean age 81
years) had a mean F1.2ln level of 0.9 versus 0.7
nmol/L for men older than 75 years (mean age 80 years,
P=0.003). Dense spontaneous echo contrast, present in 23
of the subset of 206 participants who underwent
transesophageal echocardiography,
was not associated with F1.2 levels (P=0.8).
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In addition to age and sex, other independent correlates of elevated
F1.2 levels were systolic blood pressure >160 mm Hg
(P=0.006), a history of congestive heart failure
(P=0.001), and the absence of diabetes (P=0.01),
with the independent contribution of each of these features being of
similar magnitude (Table 3).
Postmenopausal hormone replacement therapy (n=46) was not independently
associated with F1.2 (P=0.1). The 5 features independently
associated with increased F1.2 levels (Table 3) predicted 23%
of the variability in measured levels (ie, adjusted
r2=23%).
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When an additional 263 participants who took aspirin or aspirin plus
low, inefficacious doses of warfarin and who also had F1.2 levels
measured 3 months after study entry but not before were considered, 21
thromboembolic events occurred in 726 patients over the subsequent 2
years (rate of 2.1% per year). F1.2 levels measured at study entry or
at the 3-month follow-up were higher in those with subsequent
thromboembolic events, but differences were small and of marginal
statistical significance (Table 4). When
analysis was restricted to cardioembolic events, the
differences increased (relative risk [RR] associated with F1.2 >2.8
nmol/L=3.0, P=0.03; Table 4). Adjustment for age
resulted in a relative risk of thromboembolism associated with F1.2
>2.8 nmol/L of 1.9 (95% CI 0.8 to 4.9; P=0.18).
Multivariate analysis to assess the predictive
value of F1.2 levels when considered with other clinical predictors of
thromboembolic events could not be performed owing to the small number
of events.
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To assess the relationship between F1.2 levels and thromboembolic events among high-risk AF patients, the last measured F1.2 levels preceding the primary thromboembolic event (a median of 57 days, range 6 to 289 days) in 21 high-risk AF patients assigned to combination therapy were compared with 126 high-risk participants without thromboembolism matched on the basis of age, sex, body surface area, and interval between study entry and sample collection. Mean F1.2ln did not differ significantly between those with stroke and control subjects (0.8 versus 0.6 nmol/L, respectively; P=0.12). The frequency of F1.2ln >2.8 nmol/L was similar in those with stroke and controls (RR=1.1, 95% CI 0.4 to 3.3).
ß-Thromboglobulin
BTG levels were measured at study entry or at the initial 3-month
follow-up visit in 1338 participants (Table 1); 646 were taking
aspirin, 467 were taking adjusted-dose warfarin, 160 were taking both
warfarin and aspirin, and 65 were not taking antithrombotic therapy.
BTG levels ranged from 1.5 to 266 ng/mL, with a median of 26 ng/mL
(Figure 3). Mean BTGln was 3.3±0.8 ng/mL
and was not affected by antithrombotic therapy (P=0.5) or by
the exclusion of patients recorded as having unsatisfactory
venipuncture (n=113, mean BTGln=3.5
ng/mL). Serial measurement of BTG at 3 and 12 months after entry during
treatment with aspirin was done in 252 participants; the mean
BTGln difference was -0.08±1.0 ng/mL, with an
intermeasurement correlation coefficient of 0.25.
The influence of antithrombotic therapies on BTG levels was further explored by comparison of BTG levels obtained at entry with those from the 3-month follow-up on a different therapy. Among those who initially received no antithrombotic therapy and were then given aspirin (n=32), there was no significant change in mean BTGln (mean difference -0.009±0.7, P=0.95, 95% CI for relative change at mean BTGln -42% to 41%.). For those who were initially taking adjusted-dose warfarin who subsequently were given aspirin alone or aspirin plus low-dose warfarin (n=164), there was also no significant change in mean BTGln (mean difference 0.06±0.8, P=0.35, 95% CI for relative change at mean BTGln -48% to 52%).
By multivariate analysis, BTG levels were
associated with age (P=0.006), heart failure
(P<0.001), and coronary artery disease
(P=0.05) (Table 5), but
together these accounted for only 2% of the observed variability (ie,
adjusted r2=2%). In addition, carotid
bruit/surgery and regular alcohol consumption were independently
associated with higher and lower levels of BTG, respectively (Table 5). Antithrombotic therapy, sex, mitral
regurgitation, mitral annular calcification, and dense
spontaneous echo contrast were not associated with BTG levels. There
was no association between BTG and F1.2 levels (P=0.2,
r=0.05).
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When the patients who were assigned to adjusted-dose warfarin were excluded, 40 thromboembolic events occurred over 2 years among 1004 patients who had BTG levels measured (annualized rate of 3.0% with aspirin or combination therapy). BTG levels were not predictive of thromboembolic events either when analyzed as a continuous variable (P=0.8) or when those with BTG levels >42 ng/mL were compared with others (RR=1.0, 95% CI 0.5 to 2.1). The restriction of the analysis to events classified as cardioembolic (n=24) did not appreciably alter these results.
Fibrinogen Levels
Fibrinogen levels were measured in 621 participants within 6
months of study entry; the mean level was 319±70 mg/dL after 8
participants with extreme values (3 <50 mg/dL, 5 >640 mg/dL) were
excluded. Features independently associated with fibrinogen levels
included hypertension (P=0.003), diabetes
(P=0.03), current tobacco smoking (P=0.02), and
heart failure (P=0.003); age was marginally significant in
this model (P=0.07) (Table 6).
Treatment with aspirin, warfarin, or hormone replacement therapy was
not associated with fibrinogen levels. The 5 associated features (Table 6) accounted for 5% of the variability (ie, adjusted
r2=5%). Fibrinogen levels were not
associated with F1.2ln levels (P=0.4)
but were independently related to BTGln levels
(P<0.001, r=0.25).
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When patients who were assigned to aspirin or aspirin plus low, inefficacious doses of warfarin (n=461) were considered, 23 thromboembolic events occurred within 2 years (annualized rate 3.4%). Fibrinogen levels were not significantly associated with thromboembolic events (P=0.5 for continuous data). The relative risk of a thromboembolic event associated with fibrinogen levels >362 mg/dL was likewise not statistically significantly increased, although confidence intervals were wide: RR=2.1, 95% CI 0.9 to 4.9, P=0.11; after adjustment for hypertension, RR=1.9, 95% CI 0.8 to 4.5, P=0.17. Multivariate analysis to assess the predictive value of fibrinogen levels when considered with clinical predictors of thromboembolism could not be performed owing to the limited number of events.
Factor V Leiden
Among 752 low-risk AF patients, the factor V Leiden mutation was
present in 6% (n=46). During follow-up while patients were
receiving aspirin, the occurrence of 29 thromboembolic events
(annualized rate of 1.9%) was not associated with the mutation (RR
0.5, 95% CI 0.1 to 3.8, P=0.5). The presence of the factor
V Leiden mutation was independently associated with higher levels of
F1.2 (an increase of 
40%; P<0.001).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We sought to identify markers of coagulation and platelet activity that were independently associated with stroke in AF patients. These selected markers, which were assessed in the setting of a multicenter clinical trial, were not useful predictors of stroke when analyzed with age and other clinical features.
F1.2 levels were independently associated with advanced age, female sex, systolic blood pressure, and heart failure and were not influenced by aspirin use. Advanced age and female sex have been consistently associated with higher F1.2 levels.17 21 23 24 25 Thus, patient features predictive of a high risk of stroke in AF according to the SPAF analysis14 (ie, older women, systolic blood pressure >160 mm Hg, and heart failure) were independently associated with increased levels of F1.2.
Previous case-control studies suggest that AF patients have increased F1.2 levels compared with those in sinus rhythm.8 10 This issue cannot be addressed directly by the present study, because all participants had AF. The geometric (ie, antilog of the mean of ln-transformed values) mean F1.2 in young and middle-aged healthy cohorts has been reported as 0.5 to 0.7 nmol/L21 25 compared with 1.8 nmol/L in these elderly AF patients. However, it is difficult to compare F1.2 levels directly between studies owing to differences in specimen collection, processing, and analysis and in the reporting of results.22 26 A higher frequency of systolic hypertension and heart failure could explain higher observed levels of F1.2 in cohorts of AF patients.
F1.2 levels measured near study entry were higher in participants who
subsequently suffered thromboembolic events, but differences were only
marginally statistically significant (Table 4) and were even
less so after adjustment for age. Hence, F1.2 does not appear to be a
useful independent predictor of stroke in AF patients, although the
analyses did not have sufficient power to definitively exclude
such a relationship. Too few events were observed to reliably compare
F1.2 levels with INR as predictors of stroke during
anticoagulation.
The range and SD of BTG levels from this cohort were wider than those from most other studies.5 7 9 27 28 29 30 31 32 The correlation coefficient comparing 2 BTG levels from the same individual was only 0.25, and the relatively weak relationships with patient features accounted for only 3% of the observed large variance. Taken together, these findings suggest that BTG levels in this clinical trial cohort were either not assessed accurately or were inherently unstable.
BTG levels were associated with age, as found in several previous studies,29 33 34 and with coronary artery disease and carotid bruit/surgery, both of which are manifestations of atherosclerosis. Regular alcohol consumption was an independent predictor of reduced stroke risk in these AF patients35 and also was independently associated with lower BTG levels. Antithrombotic therapy with aspirin had no detectable effect on BTG levels, consistent with most previous studies,3 28 36 with exceptions.27 BTG levels did not predict stroke in this cohort of AF patients, but this finding must be considered in light of the caveats regarding the intrasubject variability.
The presence of the mutation for factor V Leiden was not associated with thromboembolism. The cohort for this assessment was restricted to low-risk AF patients, who may have fewer cardioembolic relative to noncardioembolic strokes than high-risk patients14 15 ; all were given aspirin, and confidence intervals were wide. Whether the factor V Leiden mutation is associated with formation of stasis-precipitated left atrial appendage thrombi in high-risk AF patients is an important, unresolved issue.37
Several potential limitations may apply. The participants, on average, had lower rates of thromboembolism (2% to 3% per year) than most published cohorts of AF patients, because all received some type of antithrombotic therapy. The limited number of events resulted in wide confidence intervals that did not exclude clinically important associations and prohibited multivariate analysis to adjust for other influences.
We were unable to identify hemostatic markers that were independently predictive of subsequent stroke in AF patients. The markers assessed in the present study were associated with advanced age, hypertension, heart failure, and other features associated with an increased stroke risk in AF. Whether the hemostasis abnormalities contribute directly to stroke or are epiphenomena is unclear. The potential role of prothrombotic diatheses as contributors to the formation of atrial thrombi in patients with AF remains elusive.
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Acknowledgments |
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This study was supported by a grant (RO1 NS24224) from the Division of Stroke and Trauma, National Institute of Neurological Disorders and Stroke.
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Footnotes |
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1 Deceased.
Received August 11, 1999; revision received September 22, 1999; accepted September 22, 1999.
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References |
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