Von Willebrand Factor Drives the Association Between
Elevated Factor VIII and Poor Outcomes in Patients With
Ischemic Stroke
Alyana Samai, BHS; Dominique Monlezun, BA; Amir Shaban, MD; Alexander George, BS;
Lauren Dowell, MS; Rebecca Kruse-Jarres, MD, MPH; Laurie Schluter, RN, MSN, FNP;
Ramy El Khoury, MD; Sheryl Martin-Schild, MD, PhD
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Background and Purpose—Despite clear roles of factor VIII (FVIII) and von Willebrand factor (vWF) in thrombosis, few
studies have examined the relationship of these factors with acute ischemic stroke (AIS). We sought to determine whether
concurrent elevation in FVIII and vWF was associated with adverse events and outcomes.
Methods—From our prospective stroke registry, patients consecutively admitted with AIS between July 2008 and October
2013 were included if both FVIII and vWF were measured during admission. The primary outcome was the modified
Rankin Scale score on discharge.
Results—Among 1453 cases in our stroke registry, 148 patients with AIS met inclusion criteria; 62 patients (41.9%) had
FVIII−/vWF−, 16 patients (10.8%) had FVIII+/vWF−, and 51 patients (34.5%) had FVIII+/vWF+. In the fully adjusted
model, patients with FVIII+/vWF+ had increased odds of inpatient complications (odds ratio, 8.6; 95% confidence
interval, 1.58–46.85; P=0.013) and neuroworsening (odds ratio, 3.2; 95% confidence interval, 1.18–8.73; P=0.022) than
patients with FVIII−/vWF−. Adjusted for age, baseline stroke severity, and glucose, patients with FVIII+/vWF+ had
increased odds of poor functional outcome (modified Rankin Scale>2; odds ratio, 2.87; 95% confidence interval, 1.16–
7.06; P=0.021) than patients with FVIII−/vWF−.
Conclusions—Concurrent FVIII/vWF elevation predicts higher odds of inpatient complications, neuroworsening, and
worse functional outcomes for patients with AIS compared with patients with normal levels. Our findings suggest that
FVIII and vWF levels may serve as clinically useful stroke biomarkers by providing risk profiles for patients with AIS. (Stroke. 2014;45:2789-2791.)
Key Words: blood coagulation factors ◼ factor VIII ◼ stroke ◼ thrombosis ◼ von Willebrand factor
F
singular elevation in FVIII or combined elevation in both
FVIII and vWF. In addition, we explored the relationship of
singular elevation in vWF with these variables.
actor VIII (FVIII), a protein heavily involved in clot
formation, is biochemically stabilized in plasma by von
Willebrand Factor (vWF). The FVIII–vWF complex supports
FVIII binding and cleavage with other components of the
coagulation cascade and mediates platelet attachment to damaged subendothelium.1 A relationship between levels of FVIII
and vWF has been demonstrated.2,3
Several studies support the association between elevation
in either FVIII or vWF and increased risk of venous thrombosis and recurrent thromboembolic events.4–7 Elevated FVIII
is a risk factor for acute ischemic stroke (AIS) and coronary
artery disease.4,8,9 However, no evidence exists for the combined effect of FVIII and vWF in the context of AIS. In this
study, we sought to determine differences in stroke severity,
in-hospital complications, and outcomes between patients
with normal serum values of FVIII and vWF and those with
Methods
Patients who presented to our stroke center with AIS between July
2008 and October 2013 were identified consecutively from our prospective registry. Patients <18 years or who did not have FVIII and
vWF levels obtained during admission were excluded.
Laboratory tests for hypercoagulability were ordered at the discretion of the treating physician, typically when no obvious cause of
stroke was identified. The laboratory reference range for both FVIII
and vWF is 50% to 150%. We defined elevated levels at the 200%
threshold based on our previous research.4
Patients were divided into 4 groups: both FVIII and vWF within
normal range (FVIII−/vWF−); FVIII within normal range, but elevated vWF (FVIII−/vWF+); elevated FVIII, but normal vWF (FVIII+/
vWF−); and elevation of both FVIII and vWF (FVIII+/vWF+).
Received June 6, 2014; final revision received June 6, 2014; accepted June 16, 2014.
From the Stroke Program, Department of Neurology (A. Samai, D.M., A. Shaban, A.G., L.D., L.S., R.E.K., S.M.-S.) and Section of Hematology/
Oncology, Department of Medicine (R.K.-J.) Tulane University School of Medicine, New Orleans, LA; and Department of Epidemiology, Tulane School
of Public Health and Tropical Medicine, New Orleans, LA (A. Samai).
Correspondence to Sheryl Martin-Schild, MD, PhD, Stroke Program, Department of Neurology, Tulane University School of Medicine, 1440 Canal St,
TB-52, Suite 1000, New Orleans, LA 70112. E-mail [email protected]
© 2014 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.114.006394
2789
2790 Stroke September 2014
Table 1. Demographic and Baseline Characteristics of Patients According to Factor VIII and vWF Levels
Normal Factor VIII
Normal Factor VIII
Elevated Factor VIII
(>200%)
Elevated Factor VIII
(>200%)
Normal vWF
Elevated vWF (>200%)
Normal vWF
Elevated vWF (>200%)
n=62 (41.9%)
n=19 (12.8%)
n=16 (10.8%)
n=51 (34.5%)
P Value
Age, median (range)
53 (26–83)
54 (19–85)
56 (23–77)
54 (22–78)
0.317
Black, n (%)
43 (69.4)
15 (79.0)
10 (62.5)
41 (80.4)
0.520
Female, n (%)
23 (37.1)
9 (47.4)
9 (56.3)
32 (62.8)*
0.052
Prior h/o stroke
20.0 (32.3)
8.0 (42.1)
10.0 (62.5)*
17.0 (34.0)
0.143
Hyperlipidemia
10.0 (16.1)
10.0 (52.6)*
8.0 (50.0)*
12.0 (24.0)
0.002
History of DM
12.0 (19.4)
9.0 (47.4)*
7.0 (46.7)*
24.0 (49.0)*
0.005
History of hypertension
41.0 (66.1)
37.0 (74.0)
0.247
Demographic info
Past medical history, n (%)
17.0 (89.5)
12.0 (75.0)
Admission information/visit history (baseline values)
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NIHSS, median (range)
Glucose, median (range)
4 (0–20)
6 (0–19)
5 (0–18)
5 (0–33)*
0.013
109 (75–435)
124 (83–338)*
148 (83–831)
137 (70–447)*
0.006
HbA1c, median (range)
6.0 (4.5–11.8)
6.2 (5.0–9.8)
7.6 (3.5–13.9)
6.3 (3.5–14.7)
0.006
Cholesterol, median (range)
168 (101–329)
182 (91–261)
179 (90–257)
170 (91–304)
0.456
WBC, median (range)
7.5 (4.0–18.7)
9.3 (3.1–16.4)
8.2 (4.0–14.6)
9.7 (4.2–26.9)*
0.018
tPA, %
38.7
57.9
0*
25.5
0.001
DM indicates diabetes mellutis; FVIII, factor VIII; HbA1c, hemoglobin A1c; h/o, history of; NIHSS, National Institute of Health Stroke Scale; tPA, tissuetype plasminogen activator; vWF, von Willebrand factor; and WBC, white blood cell count.
*P<0.05 compared with FVIII−/vWF−.
Appropriate statistical tests and multivariate logistic regression
analyses were conducted, including adjustment for age, National
Institute of Health Stroke Scale (NIHSS), glucose level on admission,
and administration of intravenous tissue-type plasminogen activator.
Our institutional review board approved this study.
Results
Patient Demographics and Baseline Characteristics
Among 1453 AIS cases, 148 patients met criteria; 62 patients
(41.9%) had FVIII−/vWF−, 19 patients (12.8%) had FVIII−/
Table 2. Laboratory/Outcome Characteristics of Patients by Factor VIII and vWF Levels
Elevated Factor VIII
(>200%)
Elevated Factor VIII
(>200%)
Elevated vWF (>200%)
Normal vWF
Elevated vWF (>200%)
n=19 (12.8%)
n=16 (10.8%)
n=51 (34.5%)
P Value
2.3 (0.3–8.8)
4.7 (1.0–11.1)*
2.3 (0.3–12.1)*
0.010
10 (0–106)
13 (2–56)
18 (6–151)
28 (2–139)
0.009
Neuroworsening, n (%)
8.0 (13.1)
4.0 (21.1)
3.0 (18.8)
17.0 (35.4)*
0.052
Inpatient complications, n (%)
3.0 (4.8)
2.0 (10.5)
1.0 (6.3)
15.0 (29.4)*
0.002
Recurrent thrombotic events, n (%)
8.0 (12.9)
4.0 (21.1)
3.0 (18.8)
22.0 (43.1)*
0.003
mRS on discharge, median (range)
1 (0–6)
3 (0–4)*
2 (0–5)
3 (0–7)*
0.000
Length of stay, median (range)
4 (0–81)
6 (1–52)
6 (1–28)
6 (1–56)*
0.042
NIHSS at 24 h, median (range)
2 (0–19)
3 (0–16)
2 (0–23)
5 (0–25)*
0.007
Normal Factor VIII
Normal Factor VIII
Normal vWF
n=62 (41.9%)
Laboratory values (only significant values reported)
CRP value, median (range)
ESR rate, median (range)
0.40 (0.03–2.20)
In-hospital course/discharge info
NIHSS at d/c, median (range)
1 (0–42)
2 (0–14)
1 (0–9)
4 (0–42)*
0.167
Unfavorable d/c disposition, n (%)
15.0 (25.0)
10.0 (52.6)*
4.0 (25.0)
26.0 (52.0)*
0.010
Poor functional outcome, n (%)
17.0 (27.9)
11.0 (57.9)*
7.0 (43.8)
30.0 (60.0)*
0.004
CRP indicates C-reactive protein; d/c, discharge; ESR, erythrocyte sedimentation rate; FVIII, factor VIII; mRS, modified Rankin Scale; NIHSS, National
Institute of Health Stroke Scale; and vWF, von Willebrand factor.
*P<0.05 compared with FVIII−/vWF−.
Samai et al vWF, FVIII, and Outcomes After AIS 2791
vWF+, 16 patients (10.8%) had FVIII+/vWF−, and 51 patients
(34.5%) had FVIII+/vWF+. Demographic and baseline characteristics are shown in Table 1.
FVIII+/vWF+ Compared With FVIII−/vWF−
Table 2 demonstrates in-hospital events and discharge outcomes
for the groups. After adjusting for age, NIHSS, and glucose,
FVIII+/vWF+ patients were at increased odds of having poor
functional outcome (odds ratio [OR]=2.87; 95% confidence
interval [CI], 1.17–7.06; P=0.021). After additional adjustment
for tissue-type plasminogen activator, patients with FVIII+/
vWF+ were more likely to experience inpatient complications
(OR=8.6; 95% CI, 1.57–46.85; P=0.013), neuroworsening
(OR=3.21; 95% CI, 1.18–8.72; P=0.022), and recurrent thrombotic events (OR=4.21; 95% CI, 1.57–11.28; P=0.004).
FVIII−/vWF+ Compared With FVIII−/vWF−
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Patients with FVIII−/vWF+ were at increased likelihood of
experiencing poor functional outcome (OR=3.43; 95% CI,
1.04–11.34; P=0.043) and unfavorable discharge disposition
(OR=3.46; 95% CI, 1.00–11.92; P=0.049) than those in the
FVIII−/vWF− group after adjusting for age, NIHSS at baseline,
baseline glucose level, and tissue-type plasminogen activator.
Discussion
Our study is the first to examine the relationship between
FVIII and vWF with respect to patient characteristics and outcomes in the setting of AIS.
Almost half of our sample had either elevated FVIII or
vWF, and over one third had concurrent elevation, suggesting
that elevation in these factors is not rare among patients with
AIS and merits exploration.
Groups of patients with FVIII+, regardless of vWF, had
elevated erythrocyte sedimentation rate and C-reactive protein
compared with those in the FVIII−/vWF− group, suggesting
that FVIII may be driving this association and supporting
elevation in FVIII as an acute phase response.4 Given that the
FVIII−/vWF+ group was not associated with higher inflammatory markers, but was associated with worse outcomes, the
results suggest that vWF elevation is clinically relevant, independent of inflammation.
Patients in the FVIII+/vWF+ group experienced recurrent
thrombotic events and neuroworsening with significantly
greater frequency. Isolated FVIII+ is associated with patient
baseline characteristics and may be related to stroke onset
and the acute phase of stroke. Groups of patients with vWF+,
regardless of FVIII, had higher median discharge modified
Rankin Scale scores. Taken together, our results suggest that
elevation of FVIII and vWF relate to different stages of AIS
progression. Combined elevation of FVIII and vWF seems
to be related to in-hospital events, suggesting a cooperative
effect on AIS progression.
This study is limited by single measurement of FVIII/
vWF, cross-sectional design, and relatively small sample size.
Testing of FVIII/vWF was not random or universal, which
likely results in selection bias and limits generalizability. Our
results require validation in a prospective study using serial
measurements to determine whether concurrent FVIII/vWF
elevation is related exclusively to the acute phase of stroke or
is more broadly related to both stroke risk and recovery.
Sources of Funding
The author(s) disclose an uncompensated pilot funds grant from
Tulane University School of Medicine.
Disclosures
None.
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Von Willebrand Factor Drives the Association Between Elevated Factor VIII and Poor
Outcomes in Patients With Ischemic Stroke
Alyana Samai, Dominique Monlezun, Amir Shaban, Alexander George, Lauren Dowell,
Rebecca Kruse-Jarres, Laurie Schluter, Ramy El Khoury and Sheryl Martin-Schild
Downloaded from http://stroke.ahajournals.org/ by guest on June 15, 2017
Stroke. 2014;45:2789-2791; originally published online July 15, 2014;
doi: 10.1161/STROKEAHA.114.006394
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