Acquired von Willebrand Syndrome in Aortic Stenosis

Abstract

Aortic-valve stenosis can be complicated by bleeding that is associated with acquired type 2A von Willebrand syndrome. However, the prevalence and cause of the hemostatic abnormality in aortic stenosis are unknown.
We enrolled 50 consecutive patients with aortic stenosis, who completed a standardized screening questionnaire to detect a history of bleeding. Forty-two patients with severe aortic stenosis underwent valve replacement. Platelet function under conditions of high shear stress, von Willebrand factor collagen-binding activity and antigen levels, and the multimeric structure of von Willebrand factor were assessed at base line and one day, seven days, and six months postoperatively.
Skin or mucosal bleeding occurred in 21 percent of the patients with severe aortic stenosis. Platelet-function abnormalities under conditions of high shear stress, decreased von Willebrand factor collagen-binding activity and the loss of the largest multimers, or a combination of these was present in 67 to 92 percent of patients with severe aortic stenosis and correlated significantly with the severity of valve stenosis. Primary hemostatic abnormalities were completely corrected on the first day after surgery but tended to recur at six months, especially when there was a mismatch between patient and prosthesis (with an effective orifice area of less than 0.8 cm2 per square meter of body-surface area).
Type 2A von Willebrand syndrome is common in patients with severe aortic stenosis. Von Willebrand factor abnormalities are directly related to the severity of aortic stenosis and are improved by valve replacement in the absence of mismatch between patient and prosthesis.

Full text

n engl j med
349;4
www.nejm.org july
24, 2003
The
new england journal
of
medicine
343
original article
Acquired von Willebrand Syndrome
in Aortic Stenosis
André Vincentelli, M.D., Sophie Susen, M.D., Thierry Le Tourneau, M.D., Ph.D.,
Isabelle Six, Ph.D., Olivier Fabre, M.D., Francis Juthier, Anne Bauters,
Christophe Decoene, M.D., Jenny Goudemand, M.D., Ph.D.,
Alain Prat, M.D., and Brigitte Jude, M.D., Ph.D.
From the Equipe d’Accueil 2693, University
of Lille II, Faculté de Médecine (A.V., S.S.,
T.L., O.F., F.J., A.B., J.G., A.P., B.J.), the Cli-
nique de Chirurgie Cardiovasculaire (A.V.,
O.F., F.J., C.D., A.P.), the Institut d’Héma-
tologie Biologique et d’Hémobiologie–
Transfusion (S.S., I.S., A.B., J.G., B.J.), and
the Service d’Explorations Fonctionnelles
Cardiologiques (T.L.) — all in Lille, France.
Address reprint requests to Dr. Jude at the
Institut d’Hématologie Biologique et d’Hé-
mobiologie–Transfusion, Hôpital Cardiolo-
gique, 59037 Lille CEDEX, France.
Drs. Vincentelli and Susen contributed
equally to this article.
N Engl J Med 2003;349:343-9.
Copyright © 2003 Massachusetts Medical Society.
background
Aortic-valve stenosis can be complicated by bleeding that is associated with acquired
type 2A von Willebrand syndrome. However, the prevalence and cause of the hemostatic
abnormality in aortic stenosis are unknown.
methods
We enrolled 50 consecutive patients with aortic stenosis, who completed a standard-
ized screening questionnaire to detect a history of bleeding. Forty-two patients with se-
vere aortic stenosis underwent valve replacement. Platelet function under conditions of
high shear stress, von Willebrand factor collagen-binding activity and antigen levels,
and the multimeric structure of von Willebrand factor were assessed at base line and
one day, seven days, and six months postoperatively.
results
Skin or mucosal bleeding occurred in 21 percent of the patients with severe aortic steno-
sis. Platelet-function abnormalities under conditions of high shear stress, decreased
von Willebrand factor collagen-binding activity and the loss of the largest multimers, or
a combination of these was present in 67 to 92 percent of patients with severe aortic ste-
nosis and correlated significantly with the severity of valve stenosis. Primary hemostatic
abnormalities were completely corrected on the first day after surgery but tended to recur
at six months, especially when there was a mismatch between patient and prosthesis
(with an effective orifice area of less than 0.8 cm
2
per square meter of body-surface area).
conclusions
Type 2A von Willebrand syndrome is common in patients with severe aortic stenosis.
Von Willebrand factor abnormalities are directly related to the severity of aortic stenosis
and are improved by valve replacement in the absence of mismatch between patient and
prosthesis.
abstract
Downloaded from www.nejm.org by RONALD R. JONES MD on July 14, 2004.
Copyright © 2003 Massachusetts Medical Society. All rights reserved.

n engl j med
349;4
www.nejm.org july
24
,
2003
The
new england journal
of
medicine
344
ortic-valve stenosis can be com-
plicated by bleeding, particularly that
due to gastrointestinal angiodysplasia
(Heyde’s syndrome).
1-3
This hemorrhagic syn-
drome is associated with acquired type 2A von Wil-
lebrand syndrome, which is characterized by the
loss of the largest multimers of von Willebrand fac-
tor.
4-7
Proteolysis of von Willebrand factor as it pass-
es through the stenotic valve is one of the proposed
causes of the bleeding. High shear forces can induce
structural changes in the shape of the von Wille-
brand factor molecule, leading to exposure of the
bond between amino acids 842 and 843, which is
sensitive to the action of a specific von Willebrand
protease.
8-10
This results in proteolysis of the high-
est-molecular-weight multimers of von Willebrand
factor, which are the most effective in platelet-medi-
ated hemostasis under conditions of high shear
stress.
11
This concept is further supported by the
recent demonstration that the biologic abnormali-
ties can be corrected by valve replacement.
12-14
Given these facts, we hypothesized that acquired
von Willebrand syndrome could be a common fea-
ture in patients with aortic stenosis. The present
study was designed to evaluate the prevalence and
the determinants of hemostatic abnormalities in pa-
tients with aortic stenosis and their clinical conse-
quences.
patients
Between March and July 2001, 50 consecutive pa-
tients (20 women and 30 men) referred for evalua-
tion of aortic stenosis were enrolled in the study. Pa-
tients were excluded if they were under 18 years of
age or not competent to give consent, had active en-
docarditis, had multivalvular disease, had associat-
ed coronary disease, or were receiving antiplatelet
treatment that could not be stopped 10 days before
surgery. Written informed consent was obtained
from each patient, and the local ethics committee
approved the study.
Forty-two patients (18 women and 24 men, mean
[
±
SD] age, 70
±
10 years) had severe aortic stenosis
(a mean gradient of >50 mm Hg or an indexed ef-
fective orifice area of <0.5 cm
2
per square meter of
body-surface area) and subsequently underwent
aortic-valve replacement. Eight patients (mean age,
66
±
11 years) had only moderate aortic stenosis and
did not undergo surgery.
screening for bleeding diathesis
Each patient’s bleeding symptoms were evaluated
by the use of a standardized screening question-
naire, adapted from those of Rapaport
15
and Blery
and colleagues.
16
Only bleeding during the six
months preceding evaluation was taken into ac-
count. The same evaluation was repeated six months
postoperatively in the group undergoing surgery.
echocardiographic evaluation
Using a Vingmed Five or an Acuson Sequoia echo-
cardiographic system, one investigator assessed the
hemodynamic performance of the aortic valve by
transthoracic echocardiography at base line and at
six months postoperatively in the surgical group.
The mean and peak transvalvular pressure gradients
were calculated with the modified Bernoulli equa-
tion, and the effective orifice area (EOA) was cal-
culated by the continuity equation. The wall shear
stress was calculated as 4µ¬V
m
÷r, where µ is the
blood viscosity, estimated at 0.035 poise; V
m
is the
mean transvalvular blood velocity; and r is the radius
of the stenosis, with r=(EOA÷
p
)
1/2
. At six months
postoperatively, a mismatch between the patient and
prosthesis was defined as an indexed EOA of less
than 0.8 cm
2
per square meter of body-surface
area. The echocardiographic data are presented in
Table 1.
blood collection and laboratory assays
In patients with severe aortic stenosis, blood sam-
ples were collected the day before surgery and one
day, seven days, and six months after surgery. In pa-
tients with moderate aortic stenosis, blood samples
were collected on the day of echocardiography.
Platelet-related hemostasis was tested with a
platelet-function analyzer (PFA-100, Dade Inter-
national) by determining closure time of adenine
diphosphate cartridges (normal value, less than 114
seconds). The platelet-function analyzer is a high-
shear system for in vitro testing of platelet function
that simulates primary hemostasis after injury to a
small vessel. It is a highly sensitive way to screen pa-
tients for von Willebrand factor defect.
17,18
Plasma
von Willebrand factor antigen was measured by im-
munoturbidimetry, and factor VIII coagulant activity
by a one-stage clotting assay with factor VIII–defi-
cient plasma. Functional analysis of von Willebrand
factor was performed by measuring its collagen-
binding activity with an enzyme-linked immunosor-
bent assay, as previously described,
19
with the use of
a
methods
Downloaded from www.nejm.org by RONALD R. JONES MD on July 14, 2004.
Copyright © 2003 Massachusetts Medical Society. All rights reserved.

n engl j med
349;4
www.nejm.org july
24, 2003
aortic stenosis and von willebrand syndrome
345
equine type 1 collagen (Horm, Nycomed). The ratio
between collagen binding and von Willebrand fac-
tor antigen was calculated (the normal value is great-
er than 0.7).
The multimeric structure of plasma von Wille-
brand factor was analyzed by electrophoresis with
0.1 percent sodium dodecyl sulfate and 1.5 percent
agarose gel.
20
The percentage of multimers of the
highest molecular weight (more than 15 mers) was
determined after densitometric scanning, as previ-
ously described.
20-22
A pool of normal platelet-poor
plasma was used as a reference in each gel electro-
phoresis. The lower limit of the normal range for
the percentage of highest-molecular-weight multi-
mers, which is defined as 2 SD below the mean value
for normal plasma samples, was 10.5 percent.
Flow-cytometric analysis of platelet surface anti-
gens was performed on an XL flow cytometer (Beck-
man Coulter) with the use of anti-CD61 (glycopro-
tein IIIa) antigen (Immunotech), antihuman von
Willebrand factor antibody (WAK-Chemie Medical),
and antihuman P selectin antibody (WAK-Chemie
Medical).
statistical analysis
Statistical analysis was performed with Statview
(SAS Institute), with the Mann–Whitney U test used
to determine significant differences (P<0.05) be-
tween groups and the Wilcoxon signed-rank test
used to compare the different time points in each
group. Discrete variables were compared by Fisher’s
exact test. Correlations between variables were as-
sessed by Spearman’s rank-correlation test.
prevalence of bleeding
Among the 42 patients with severe aortic stenosis,
11 had episodes of bleeding in the six months be-
fore surgery. In two, the bleeding episode occurred
during oral anticoagulant treatment and was not
taken into account in further analysis. Thus, 9 of 42
patients (21.4 percent) had at least one episode of
bleeding, most frequently skin or mucosal bleeding
(Table 2). Among these, one patient had a history of
major bleeding (epistaxis) that needed transfusion.
Among the eight patients with moderate aortic ste-
nosis, two had a history of hemorrhagic syndrome,
both while receiving antiplatelet agents. There was
no difference between patients with O and non-O
blood types with respect to the occurrence of bleed-
ing episodes.
results
base-line biologic data
The closure time determined by the platelet-func-
tion analyzer (which measures platelet function un-
der conditions of high shear stress) was prolonged
in 92 percent of the patients with severe aortic ste-
nosis and in 50 percent of those with moderate aor-
tic stenosis. The ratio of collagen-binding activity to
antigen and the percentage of highest-molecular-
weight multimers were decreased in 67 and 79 per-
cent of the patients with severe aortic stenosis and
in 25 and 75 percent of the patients with moderate
aortic stenosis, respectively. All patients with pro-
longed closure time according to the platelet-func-
tion analyzer had decreased percentages of highest-
molecular-weight multimers. Patients with severe
and moderate aortic stenosis had significantly dif-
ferent values for closure time according to the plate-
let-function analyzer and the ratio of collagen-
binding activity to antigen (medians, 173 and 107
seconds [P=0.007] and 0.64 and 0.80 seconds
Table 1. Mean (±SD) Echocardiographic Data.
Variable
Moderate
Aortic Stenosis
(N=8)
Severe
Aortic Stenosis
(N=42) P Value
Mean gradient (mm Hg)
30.8±11.1 57.3±12.7 <0.001
Effective orifice area (cm
2
)
1.1±0.1 0.6±0.1 <0.001
Indexed effective orifice area
(cm
2
/m
2
of body-surface area)
0.58±0.15 0.38±0.15 <0.001
Wall shear stress (dyn/cm
2
)
64.8±12.2 118.0±25.9 <0.001
Table 2. Hemorrhagic Disorders That Occurred
in the Patients.
Disorder No. of Events
Spontaneous bleeding
Epistaxis 10
Ecchymosis 6
Menorrhagia or metrorrhagia 1
Gastrointestinal hemorrhage 4
Hematuria 1
Gingivorrhagia 3
Induced bleeding
Dental extraction 2
Downloaded from www.nejm.org by RONALD R. JONES MD on July 14, 2004.
Copyright © 2003 Massachusetts Medical Society. All rights reserved.

n engl j med
349;4
www.nejm.org july
24
,
2003
The
new england journal
of
medicine
346
[P=0.006], respectively). They did not differ in the
percentage of highest-molecular-weight multimers,
which was low in both groups (median, 8 percent in
patients with severe aortic stenosis and 9 percent in
those with moderate aortic stenosis). The results did
not differ in patients with O and non-O blood types.
The levels of factor VIII coagulant activity and von
Willebrand antigen were normal in all patients
(more than 0.5 IU per milliliter).
Platelet-function–analyzer values were positively
correlated, and percentages of highest-molecular-
weight multimers were negatively correlated, with
the mean transvalvular gradient (r=0.58 [P<0.001]
and r=–0.56 [P<0.001], respectively) and stenosis-
induced shear stress (r=0.65 [P<0.001] and r=–0.59
[P<0.001], respectively) (Fig. 1). The ratio of col-
lagen-binding activity to antigen was also weakly
correlated with the mean transvalvular gradient and
stenosis-induced shear stress (r=0.37 [P=0.021]
and r=0.49 [P=0.007], respectively).
The platelet count was within the normal range
in all but two patients (one with severe and one with
moderate aortic stenosis). Flow-cytometric analysis
found no difference between patients and controls
in platelet membrane–associated glycoprotein IIIa,
von Willebrand factor, or P selectin.
No significant differences in hemostatic values
were observed between patients with and patients
without a preoperative history of bleeding.
surgical treatment
Eleven patients 65 years of age or younger received
a mechanical bileaflet prosthetic device (Mira, Ed-
wards, or Regent, St. Jude Medical), and 31 patients
over 65 years of age received a biologic device (29
pericardial valves [Perimount, Carpentier-Edwards],
1 stentless porcine aortic valve [Toronto, St. Jude
Medical], and 1 cryopreserved aortic homograft
[European Homograft Bank]). Mechanical devices
were implanted in three patients with a preoperative
history of bleeding.
immediate postoperative course
The median blood loss 24 hours after valvular re-
placement was 415 ml (range, 120 to 1580). One
patient underwent reoperation for bleeding on the
day after surgery. One other patient died from ven-
tricular fibrillation 10 days after surgery.
The platelet-function–analyzer values were cor-
rected in all patients on days one and seven. The lev-
els of factor VIII coagulant activity and of von Wille-
brand factor antigen increased significantly by six
months after surgery, as compared with the preop-
erative values (P<0.001 and P=0.002, respectively).
The percentage of highest-molecular-weight mul-
timers was corrected (i.e., was at least 10.5 percent)
in all patients on days 1 and 7. The multimeric pat-
tern of von Willebrand factor determined in one pa-
tient three hours after surgery was also normalized
(Fig. 2).
The postoperative blood loss was significantly
higher in patients with preoperative bleeding than
in those without preoperative bleeding (median,
565 ml [range, 195 to 1580] vs. 370 ml [120 to 700];
P=0.04). Six patients, all with a preoperative history
of bleeding, had a blood loss greater than 700 ml.
In these patients, the base-line percentage of high-
est-molecular-weight multimers was significantly
lower than in those with no excessive blood loss
(P=0.007).
follow-up at six months in the patients
who underwent surgery
Two patients were lost to follow-up at six months.
One patient presented with early homograft valve
stenosis that required reoperation at six months. In
this patient, repeated epistaxis was observed at the
onset of restenosis. The other 38 patients were
asymptomatic at six months, without bleeding ep-
isodes, even those who had a preoperative history of
bleeding and had a mechanical prosthesis requiring
oral anticoagulant therapy. A mismatch between pa-
tient and prosthesis was observed in 10 cases.
Figure 1. Relation between Von Willebrand Factor Abnor-
malities and Severity of Stenosis, Represented as the
Mean Transvalvular Gradient Plotted against the Per-
centage of Highest-Molecular-Weight Von Willebrand
Factor Multimers (r=¡0.56, P<0.001).
The line is the regression line.
Mean Transvalvular Gradient (mm Hg)
0 20 40
80
60
100
Von Willebrand Factor High-
Molecular-Weight Multimers (%)
16
14
12
10
8
6
4
2
0
Downloaded from www.nejm.org by RONALD R. JONES MD on July 14, 2004.
Copyright © 2003 Massachusetts Medical Society. All rights reserved.

n engl j med
349;4
www.nejm.org july
24, 2003
aortic stenosis and von willebrand syndrome
347
At six months, the platelet counts were nor-
mal, and platelet flow-cytometric analysis found
no change from base line. The platelet-function–
analyzer values, although significantly lower than
at base line (P<0.001), were abnormal in 66 percent
of the patients (median, 189 seconds; range, 73 to
300). The percentage of highest-molecular-weight
multimers was below the normal range in 74 per-
cent of the patients (median, 8.7 percent; range, 3.9
to 13). Figure 3 shows the time course of the per-
centage of multimers of highest molecular weight
according to the presence or absence of a mismatch
between patient and prosthesis. The percentage
was significantly lower in patients with a mismatch
(P=0.01). The lowest percentage of highest-molec-
ular-weight multimers was observed in the patient
with severe homograft stenosis. There was no effect
of the type of prosthesis (mechanical or biologic) on
the changes in hemostatic values.
This study evaluated the frequency and determi-
nants of acquired von Willebrand syndrome and
bleeding in consecutive patients with aortic steno-
sis. Careful investigation showed that bleeding
(mostly from the skin or mucosa) was present in
about 20 percent of the patients with severe aortic
stenosis. Moreover, prolongation of the platelet-
function–analyzer closure time (a measure of plate-
let function under conditions of high shear stress),
abnormalities of von Willebrand factor, or both
were common in severe aortic stenosis. We also
demonstrated that von Willebrand factor abnor-
malities increased with the pressure gradient and
the stenosis-induced shear stress, indicating that
von Willebrand factor abnormalities are related to
the severity of aortic stenosis. Together, these data
suggest that the hemostatic defect is related mostly
to direct proteolysis of the largest multimers of von
Willebrand factor.
Veyradier and colleagues have shown that vascu-
lar malformations, such as angiodysplasia, are at
high risk of bleeding in patients with aortic stenosis,
since effective hemostasis in these high-shear-stress
lesions requires the presence of high-molecular-
weight multimers of von Willebrand factor.
6
We
found no differences in the biologic features that we
measured between patients with and without a pre-
operative history of bleeding, suggesting that bleed-
ing depends on the presence of bleeding-prone le-
sions.
All patients with major postoperative bleeding
also had preoperative bleeding and had very low per-
centages of highest-molecular-weight multimers
before surgery. All patients with severe aortic steno-
sis without valve replacement are probably also at
discussion
Figure 3. Mean (±SE) Evolution of Highest-Molecular-
Weight Von Willebrand Factor Multimers after Valvular
Replacement in Patients with and Patients without a
Mismatch between Patient and Prosthesis.
Day 1 Day 7 Mo 6Before
Replacement
17
16
15
14
13
12
11
10
9
8
7
6
0
Patient–prosthesis
mismatch
No patient–prosthesis
mismatch
Von Willebrand Factor High-
Molecular-Weight Multimers (%)
P=0.01
Figure 2. Analysis of Highest-Molecular-Weight Von Willebrand Factor Multi-
mers in One Patient, before and 3 Hours, 24 Hours, and Seven Days after Val-
vular Replacement.
Arrows indicate the area where the highest-molecular-weight multimers
migrate.
High-Molecular-
Weight Multimers
Low-Molecular-
Weight Multimers
7 Days 1 Day 3 Hours Base Line
Downloaded from www.nejm.org by RONALD R. JONES MD on July 14, 2004.
Copyright © 2003 Massachusetts Medical Society. All rights reserved.

n engl j med
349;4
www.nejm.org july
24
,
2003
The
new england journal
of
medicine
348
high risk for bleeding during noncardiac surgery.
However, the therapeutic possibilities for the con-
trol of bleeding are limited.
23
As previously suggest-
ed, the best correction is probably achieved by valve
replacement.
13
Early correction of the percentage
of highest-molecular-weight multimers was ob-
served after surgery, suggesting that the risk of hem-
orrhage in the first hours after surgery is probably
limited.
Warkentin and colleagues recently reported long-
lasting correction (lasting more than 10 years) of
clinical and biologic hemostatic abnormalities in
two patients who had undergone surgical treatment
of severe aortic stenosis with acquired von Wille-
brand syndrome and bleeding.
24
In our study, a sig-
nificant improvement in biologic values was ob-
served at six months. However, all patients did not
have a complete, sustained correction. A recur-
rence of prolonged platelet-function–analyzer val-
ues and a decreased percentage of highest-molec-
ular-weight multimers occurred in some patients,
especially those with a mismatch between patient
and prosthesis, which appears to be one of the de-
terminants of relapse of von Willebrand syndrome.
Other determinants, such as residual flow disturb-
ances through the implanted prosthesis, could also
interfere with the outcome.
No patient who had a mechanical prosthesis and
was receiving oral anticoagulant therapy had a re-
currence of bleeding. Whether mechanical prosthe-
ses can be safely implanted in patients who have a
history of severe bleeding remains debatable. Ad-
ditional studies are required to confirm that preop-
erative hemorrhagic syndrome does not have to be
considered in deciding between a biologic and a
mechanical valve substitute in patients with aortic
stenosis, as long as a mismatch between patient and
prosthesis is avoided.
At the present time, it is well accepted that pa-
tients with severe aortic stenosis who become symp-
tomatic require aortic-valve replacement.
25
How-
ever, only cardiac symptoms are considered in the
evaluation of the indications for valve replace-
ment.
26
The present study demonstrates that ac-
quired von Willebrand syndrome is a consequence
of the mechanical obstruction of blood flow and that
hemostatic abnormalities and bleeding are symp-
toms of severe stenosis. Further prospective studies
are needed to determine whether hemostatic dis-
turbances should be taken into account in the indi-
cations for valve replacement.
Supported by grants (EA 2693 and IFR 114) from the University of
Lille II and from St. Jude Medical and Edwards Life Science.
We are indebted to Olivier Fouquet, Claudine Caron, Claudine
Mazurier, and Bruno Jegou for their help in the performance of the
study.
references
1.
Heyde EC. Gastrointestinal bleeding in
aortic stenosis. N Engl J Med 1958;259:196.
2.
Greenstein RJ, McElhinney AI, Reuben
D, Greenstein AJ. Colonic vascular ectasias
and aortic stenosis: coincidence or casual
relationship? Am J Surg 1986;151:347-51.
3.
King RM, Pluth JR, Giuliani ER. The as-
sociation of unexplained gastrointestinal
bleeding with calcific aortic stenosis. Ann
Thorac Surg 1987;44:514-6.
4.
Warkentin TE, Moore JC, Morgan DG.
Aortic stenosis and bleeding gastrointesti-
nal angiodysplasia: is acquired von Wille-
brand’s disease the link? Lancet 1992;340:
35-7.
5.
Gill JC, Wilson AD, Endres-Brooks J,
Montgomery RR. Loss of the largest von
Willebrand factor multimers from the plas-
ma of patients with congenital cardiac de-
fects. Blood 1986;67:758-61.
6.
Veyradier A, Balian A, Wolf M, et al. Ab-
normal von Willebrand factor in bleeding
angiodysplasias of the digestive tract. Gas-
troenterology 2001;120:346-53.
7.
Federici AB, Rand JH, Bucciarelli P, et al.
Acquired von Willebrand syndrome: data
from an international registry. Thromb Hae-
most 2000;84:345-9. [Erratum, Thromb
Haemost 2000;84:739.]
8.
Tsai HM, Sussman II, Nagel RL. Shear
stress enhances the proteolysis of von Wille-
brand factor in normal plasma. Blood 1994;
83:2171-9.
9.
Dent JA, Berkowitz SD, Ware J, Kasper
CK, Ruggeri ZM. Identification of a cleavage
site directing the immunochemical detec-
tion of molecular abnormalities in type IIA
von Willebrand factor. Proc Natl Acad Sci
U S A 1990;87:6306-10.
10.
Siediecki CA, Lestini BJ, Kottke-Mar-
chant KK, Eppell SJ, Wilson DL, Marchant
RE. Shear-dependent changes in the three-
dimensional structure of human von Wille-
brand factor. Blood 1996;88:2939-50.
11.
Sugimoto M, Matsui H, Mizuno T, et al.
Mural thrombus generation in type 2A and
2B von Willebrand disease under flow con-
ditions. Blood 2003;101:915-20.
12.
Cappell MS, Lebwohl O. Cessation of
recurrent bleeding from gastrointestinal an-
giodysplasias after aortic valve replacement.
Ann Intern Med 1986;105:54-7.
13.
Anderson RP, McGrath K, Street A. Re-
versal of aortic stenosis, bleeding gastroin-
testinal angiodysplasia, and von Willebrand
syndrome by aortic valve replacement. Lan-
cet 1996;347:689-90.
14.
Pareti FI, Lattuada A, Bressi C, et al. Pro-
teolysis of von Willebrand factor and shear
stress-induced platelet aggregation in pa-
tients with aortic valve stenosis. Circulation
2000;102:1290-5.
15.
Rapaport SI. Preoperative hemostatic
evaluation: which tests, if any? Blood 1983;
61:229-31.
16.
Blery C, Charpak Y, Szatan M, et al. Eval-
uation of a protocol for selective ordering of
preoperative tests. Lancet 1986;1:139-41.
17.
Mammen EF, Alshameeri RS, Comp PC.
Preliminary data from a field trial of the PFA-
100 system. Semin Thromb Hemost 1995;
21:Suppl 2:113-21.
18.
Fressinaud E, Veyradier A, Truchaud F,
et al. Screening for von Willebrand disease
with a new analyzer using high shear stress:
a study of 60 cases. Blood 1998;91:1325-31.
19.
Favaloro EJ, Henniker A, Facey D,
Hertzberg M. Discrimination of von Wille-
brand’s disease (VWD) subtypes: direct com-
parison of von Willebrand factor:collagen
binding assay (VWF:CBA) with monoclonal
antibody (MAB) based von Willebrand fac-
tor-capture systems. Thromb Haemost 2000;
84:541-7.
20.
Ruggeri ZM, Zimmerman TS. Variant
von Willebrand’s disease: characterization of
two subtypes by analysis of multimeric com-
Downloaded from www.nejm.org by RONALD R. JONES MD on July 14, 2004.
Copyright © 2003 Massachusetts Medical Society. All rights reserved.

n engl j med
349;4
www.nejm.org july
24, 2003
aortic stenosis and von willebrand syndrome
349
position of factor VIII/von Willebrand factor
in plasma and platelets. J Clin Invest 1980;
65:1318-25.
21.
Mazurier C. In vitro evaluation of the
haemostatic value of the LFB-von Wille-
brand factor concentrate. Haemophilia
1998;4:Suppl 3:40-3.
22.
Zimmerman TS, Dent JA, Ruggeri ZM,
et al. Subunit composition of plasma von
Willebrand factor: cleavage is present in
normal individuals, increased in IIA and IIB
von Willebrand disease, but minimal in vari-
ants with aberrant structure of individual
oligomers (types IIC, IID and IIE). J Clin In-
vest 1986;77:947-51.
23.
Veyradier A, Jenkins CS, Fressinaud E,
Meyer D. Acquired von Willebrand syn-
drome: from pathophysiology to manage-
ment. Thromb Haemost 2000;84:175-82.
24.
Warkentin TE, Moore JC, Morgan DG.
Gastrointestinal angiodysplasia and aortic
stenosis. N Engl J Med 2002;347:858-9.
25.
Carabello BA. Aortic stenosis. N Engl J
Med 2002;346:677-82.
26.
Bonow RO, Carabello B, de Leon AC, et
al. ACC/AHA guidelines for the manage-
ment of patients with valvular heart disease:
executive summary: a report of the Ameri-
can College of Cardiology/American Heart
Association Task Force on Practice Guide-
lines (Committee on Management of Pa-
tients with Valvular Heart Disease). J Heart
Valve Dis 1998;7:672-707.
Copyright © 2003 Massachusetts Medical Society.
Downloaded from www.nejm.org by RONALD R. JONES MD on July 14, 2004.
Copyright © 2003 Massachusetts Medical Society. All rights reserved.