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Blood, Vol. 91 No. 4 (February 15), 1998:
pp. 1325-1331
Screening for von Willebrand Disease With a New Analyzer Using
High Shear Stress: A Study of 60 Cases
By
Edith Fressinaud,
Agnès Veyradier,
Florence Truchaud,
Isabelle Martin,
Catherine Boyer-Neumann,
Marc Trossaert, and
Dominique Meyer
From the Laboratoire d'Hématologie, CHU Hôtel Dieu,
Nantes; and the Laboratoire d'Hématologie, Hôpital
Antoine-Béclère, Clamart, and INSERM U.143, Hôpital
de Bicêtre, Kremlin-Bicêtre, France.
 |
ABSTRACT |
We have evaluated the performance of a new analyzer using high shear
stress, the PFA-100 (Platelet Function Analyzer, Dade International,
Massy, France), for screening of patients with von Willebrand disease
(vWD). Whole citrated blood is aspirated through a capillary to the
central aperture of a membrane coated with collagen and with a platelet
agonist (either epinephrine or adenosine diphosphate
[ADP]). The time required to obtain occlusion of the
aperture by a platelet plug is defined as the closure time (CT). We
studied 60 patients with different types of vWD and 96 normal subjects.
Fourteen subjects with hemophilia and 15 patients with a platelet
disorder were also analyzed. When omitting results from two patients
with type 2N, the 58 other patients with type 1, type 2A, type 2B, type
3, or acquired vWD all exhibited an abnormal occlusion with
collagen-ADP (sensitivity, 100%) and 56 of 58 had an abnormal CT with
collagen-epinephrine (sensitivity, 96.5%). Only two patients with mild
type 1 were not detected with collagen-epinephrine. In comparison, the
bleeding time (BT) was normal in 20 patients: 17 with type 1, two with
type 2A, and one with acquired vWD (sensitivity, 65.5%). The
specificity of the PFA-100 was over 95% with both types of cartridges.
Thus, the analyzer is well adapted to routine testing, as it has the
advantages of simplicity and ease of execution, and demonstrates a high
sensitivity, clearly superior to that of BT, for the screening of
patients with vWD.
| |
INTRODUCTION |
VON WILLEBRAND DISEASE (vWD), which is
the most common inherited bleeding disorder with an incidence as high
as 1%,1 results from quantitative or qualitative defects
of von Willebrand factor (vWF).2 vWF is a large multimeric
glycoprotein and its degree of polymerization and integrity of specific
domains are essential for function of the protein.3,4 vWF
is involved in platelet adhesion to the injured vessel wall, platelet
spreading, and platelet-platelet interactions under conditions of high
shear.3,4 These functions require interaction of vWF with
two platelet receptors, glycoprotein (GP) Ib/IX, and
GPIIb/IIIa.5-8 vWF also serves to transport factor VIII
(F.VIII) and to protect it from proteolytic degradation.3,4
Recently, a pathophysiologic classification for vWD was introduced by
Sadler.9 Quantitative defects of vWF may either be classified as partial (type 1) or total (type 3). vWD type 2 (subtypes 2A, 2M, 2B, and 2N) corresponds to a qualitative defect, and distinct mutations have been found in the vWF gene corresponding to different functional domains of vWF.10,11 Type 2A is characterized by both a decreased interaction of vWF with platelets and lack of the
highest sized multimers. In contrast, type 2M corresponds to a
decreased interaction of vWF with platelets, which is not associated
with a loss of high molecular weight multimers. Type 2B is
characterized by an increased affinity of vWF for GPIb/IX. Type 2N is
due to a qualitative abnormality of vWF causing defective interaction
with F.VIII, which is not anymore protected from rapid proteolysis.
At present, the diagnosis of vWD relies on the determination of the
bleeding time (BT) and assessment of vWF antigen (vWFAg), vWF
ristocetin cofactor activity (vWFRCo), and F. VIII activity. Ristocetin-induced platelet agglutination (RIPA) and distribution of
vWF multimers allow for further diagnosis and classification.
Historically, the BT has been considered as an essential screening test
for primary hemostasis disorders and particularly for vWD, except in
type 2N, probably because of the lack of a better alternative. However,
the accuracy, validity, predictibility, and reproducibility of the BT
have frequently been questioned.12 As a result, the BT is
usually replaced by assays such as vWFRCo and/or vWFAg that
require more time and skill to perform. In this study, we tested a new
instrument, the PFA-100 (Platelet Function Analyzer, Dade
International, Massy, France), that allows a rapid and simple
determination of platelet function in primary hemostasis. We used the
PFA-100 to screen 60 patients with different types of vWD. The present
study shows that the PFA-100 is strikingly more sensitive than the BT
in screening patients with vWD type 1, type 2A, type 2B or type 3, and
acquired forms of the disease.
| |
MATERIALS AND METHODS |
Patients.
Sixty patients with vWD were included in the study after obtaining
appropriate consent. Twenty-six men and thirty-four women, with a mean
age of 32.4 years (range, 2 to 77) were investigated. These patients
had not received vWF concentrates or DDAVP for at least 1 month. vWD had been previously diagnosed by a personal or familial
bleeding history and results of laboratory tests such as vWFAg, vWFRCo,
F.VIII, RIPA, and multimeric composition of vWF. For this study, all
parameters were retested and patients were classified according to the
revised classification of vWD.9 The following vWD types
were represented in the 60 patients: type 1, n = 36; type 2A, n = 10;
type 2B, n = 3; type 3, n = 4; and type 2N, n = 2. Among the 36 patients with type 1, 32 of them exhibited all criteria for
"definite" type 1 vWD, ie, a personal history of significant
mucocutaneous bleeding, results of vWFRCo and vWFAg <2 standard
deviation (SD) below the mean of the normal population
when adjusted to the blood type and a positive family history of vWD.
The four other patients had "possible" type 1 vWD, ie, positive
personal history and laboratory criteria, but no evidence of familial
vWD. We also studied five patients with acquired vWD associated with
benign (n = 3) or malignant (n = 2) B-cell disorders.
Fifteen patients with a previously well-defined platelet disorder were
also investigated: two with Glanzmann thrombasthenia, three with
pseudo- or platelet-type vWD, four with congenital storage pool
disease, and six with aspirin-like defect.
Control group.
One hundred and ten subjects devoid of any primary hemostasis disorder
were used as controls. They had not taken any medication for at least 2 weeks. Ninety-six healthy volunteers (31 men and 65 women) served as
the first control group. Their mean age was 34.5 years (range, 15 to
65). These individuals had no history of bleeding. Fourteen subjects
with hemophilia A (n = 12) or B (n = 2) were used as the second control
group. Informed consent was obtained from each of them.
Laboratory tests.
Hematocrit and platelet counts were performed with a Coulter STKS cell
counter (Coulter Corporation, Coultronics, France). Blood samples were
also collected for blood group. Citrated whole blood (1 vol of 3.8%
sodium citrate mixed with 9 vol of blood) was obtained by clean
venipuncture. The activated partial thromboplastin time (APTT) was
measured with PTT-LT (Diagnostica Stago, Asnieres, France) using an STA
analyzer (Diagnostica Stago). F.VIII activity was performed by a
one-stage clotting assay based on the APTT using F.VIII-deficient
plasma (Diagnostica Stago) on the STA. vWFAg was measured by
enzyme-linked immunosorbent assay (ELISA) with a commercial kit
(Asserachrom vWF, Diagnostica Stago). vWFRCo was assayed by
aggregometry using a commercially available kit from Behring (Marburg,
Germany), which consists of lyophilized platelets and ristocetin A. All
results are the mean of two determinations and expressed as IU/dL of
plasma. The Second International Reference Preparation for Factor
VIII-related activities (National Institute for Biological Standards
and Control, London, UK) was used as a standard. Multimeric composition
of plasma vWF was estimated by sodium dodecyl sulfate gel
electrophoresis as previously described.13 RIPA was
performed in platelet-rich plasma on an aggregometer (Thrombo-Agregametre, Regulest, France) with ristocetin (Diagnostica Stago) at three final concentrations: 0.5, 1.0, and 1.5 mg/mL. Platelet
aggregation was performed at 37°C in platelet-rich plasma on the
same aggregometer using 2.5 and 5 µmol/L of
adenosine-5 -diphosphate (ADP), 5 µmol/L of epinephrine from
Diagnostica Stago, 1.0 and 4.0 µg/mL of equine collagen from Hormon
Chemie, Munich, Germany, or 1.5 mmol/L of arachidonic acid from Helena
Laboratories, Beaumont, TX.
BT was determined by a modified Ivy technique using the Simplate
sterile disposable device (Organon Teknika Corp, Durham, NC) according
to the instructions of the manufacturer.
PFA-100 system.
The PFA-100 is a high shear-inducing device that simulates primary
hemostasis after injury to a small vessel.14-16 The system consists of a microprocessor-controlled instrument and a disposable test cartridge. The test cartridge contains a reservoir for citrated whole blood and a capillary (200 µm internal diameter) surmounted by
a cup containing a biologically active membrane with a central aperture
(approximately 150 µm diameter). The membrane is coated with
fibrillar type I equine tendon collagen. Additionally, either epinephrine (10 µg) or ADP (50 µg) is present on the membrane. These agents provide a controlled stimulation of platelets as the blood
sample passes through the aperture. The analyzer provides a constant
negative pressure that aspirates whole blood (800 µL) through the
capillary into the cup where it comes into contact with the membrane
and then passes through the aperture. In response to stimulation by
collagen, in conjunction with either epinephrine or ADP, as well as by
high shear rates (5,000 to 6,000 second-1), platelets
adhere and aggregate on the membrane surface at the area surrounding
the aperture. During the course of measurement, a platelet plug forms
that ultimately occludes the aperture and blood flow is stopped. The
time required to obtain occlusion of the aperture is defined as the
closure time (CT).
All normal subjects and patients were tested with both types of
cartridges (collagen/epinephrine or collagen/ADP). For each cartridge
type, results were based on the mean of duplicate testing. If results
of duplicate tests deviated by more than 20%, a third test was
performed. Citrated whole blood was stored at room temperature less
than 4 hours before testing.
Statistical analysis.
Mean, SD, and reference ranges were determined for all parameters. The
normal range for the PFA-100 was calculated as mean ± 2 SD of the
healthy volunteers group. Sensitivity was calculated as the percentage
of correctly detected vWD patients, using the formula: sensitivity (%) = true positive × 100/true positive + false negative. Specificity
was calculated as the percentage of values within the normal range
among the total control group (healthy volunteers and hemophiliacs),
using the formula: specificity (%) = true negative × 100/true
negative + false positive. Positive predictive value (PPV) was
estimated as the percentage of patients with vWD among the subjects
whose CT is prolonged, using the formula: PPV = true positive × 100/true positive + false positive. Negative predictive
value (NPV) was estimated as the percentage of subjects devoid of any
primary hemostasis disorder among the subjects whose CT is in the
normal range, using the formula: NPV = true negative × 100/true
negative + false negative. The analysis of correlations was performed
with statgraphics (Statview; Abacus Concepts, Berkeley, CA) as simple regression.
| |
RESULTS |
Blood group, hematocrit, and platelet count.
Blood group type O was found in 32 healthy volunteers (33.3%), non-O
in 64 (66.7%). Blood group O was found in seven subjects with
hemophilia (50%), non-O in three (21.4%), and was unknown in four
(28.6%). In vWD patients, 27 (45%) were of group O, 30 (50%) of
group non-O, the blood group being unknown for three (5%). In all
controls and patients, the hematocrit was > 35% and platelet count
was > 150 × 109/L, except in one patient with type
2B vWD (90 × 109/L).
vWF assays.
Table 1 shows the extreme values, mean, and
SD of vWF levels in the 96 healthy volunteers.
Table 2 indicates the results in the 14 hemophiliacs. Table 3 shows vWFAg and
vWFRCo levels in the 36 patients with type 1 vWD. Among these patients,
18 had vWFRCo levels between 26 and 39 UI/dL, 10 between 11 and 25 IU/dL, and eight between 1 and 10 IU/dL. Results in patients with type 2 (2A, 2B, 2N), type 3, and acquired vWD are reported in
Table 4. One patient with type 2B was
tested during pregnancy, with a normal vWFRCo level (88 IU/dL) and a
high vWFAg level (208 IU/dL).
BT.
For evident ethical reasons, BT was not performed in the control group.
The values in vWD patients are indicated in Tables 3 and 4. The BT was
normal in the two patients with type 2N vWD. Only 38 of 58 patients
with other types of vWD showed a prolonged BT (> 8.5 minutes)
(Fig 1). Twenty patients had a normal BT:
two with type 2A, one with an acquired form, and 17 with type 1 (Fig 1). When excluding results in type 2N vWD, the sensitivity of the BT,
calculated from these results, was 65.5%.
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| Fig 1.
Comparison of BT (Simplate) and measurement of CT with
collagen-ADP and collagen-epinephrine cartridges in the PFA-100 in patients with von Willebrand disease (n = 60). Each type of vWD is
identified by the following symbol: ( ) type 1, ( ) type 2A, ( )
type 2B, ( ) type 2N, ( ) type 3, and ( ) acquired vWD. The interrupted lines represent the upper limit of the normal range (8.5 minutes) for the BT and the mean value + 2 SD of the control group
for CT (120 seconds with collagen-ADP and 160 seconds with collagen-epinephrine).
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CT with collagen-epinephrine test cartridges.
The extreme values of CT obtained in 96 normal subjects (Table 1) were
77 to 186 seconds, with a mean value of 120 seconds and a mean CV of
5.4%. This control group was used to calculate the normal range,
indicating an upper limit of 160 seconds (mean + 2 SD). Four healthy
volunteers had a slightly prolonged CT (167, 169, 174, and 186 seconds,
respectively). The 14 hemophiliacs had a normal CT (Table 2). Among the
110 controls without any primary hemostasis disorder, the frequency of
prolonged CT was 3.6%, indicating a specificity of 96.4%. Type 2N
patients exhibited normal occlusion ( Fig 2). Fifty-six
of the remaining 58 patients showed abnormal occlusion (Tables 3 and
4). All patients with type 3 and type 2A vWD had infinite CT, that is
greater than 250 seconds (Fig 2). All patients with type 2B had a
prolonged CT, even the patient with a normal vWFRCo level. Among the 41 patients with acquired or type 1 vWD, 28 showed an infinite CT (Fig 2). Only two patients with type 1 had a normal CT (137 and 159 seconds) and
their level of vWFRCo was 39 and 36 IU/dL, respectively (Table 3). When
excluding results from type 2N vWD, the sensitivity of the test with
collagen-epinephrine cartridges was 96.5%. The CT with
collagen-epinephrine exhibited a PPV of 93.3% and an NPV of 98.2%.
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| Fig 2.
Measurement of CT with collagen-epinephrine cartridges in
the PFA-100 in normal subjects and in patients with vWD disease. Each
closed circle is the mean of duplicate testing in an individual. The
solid line represents the mean value in the normal subjects (120 seconds); the interrupted line across the figure represents the upper
limit of normal (160 seconds), which was calculated as the mean (m) + 2 SD.
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CT with collagen-ADP test cartridges.
In the normal subjects (Table 1), the extreme values of CT were 66 to
126 seconds with a mean value of 89 seconds (mean CV of 4.5%),
indicating an upper limit of 120 seconds (mean + 2 SD). Only one
healthy volunteer had a slightly prolonged CT (126 seconds). All of the
hemophiliacs had a normal CT (Table 2). Thus, less than 1% of the
control group showed a prolonged CT, indicating a specificity of 99%.
The CT was normal in type 2N vWD. All other patients exhibited abnormal
occlusion (Fig 3). The CT was infinite (> 250 seconds) in all patients with type 3 and type 2A vWD, in two with
type 2B, in 18 with type 1, and in three with acquired vWD (Fig 3). In
the pregnant patient with type 2B, the CT could not be estimated
because of rapid flow obstruction of the capillary. When omitting
results from type 2N patients, the sensitivity of the test with
collagen-ADP cartridges was 100%. The CT collagen-ADP exhibited a PPV
of 98.3% and an NPV of 100%.
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| Fig 3.
Measurement of CT with collagen-ADP cartridges in the
PFA-100 in normal subjects and in patients with vWD. Each closed circle is the mean of duplicate testing in an individual. The solid line represents the mean value in the normal subjects (89 seconds); the
interrupted line across the figure represents the upper limit of normal
(120 seconds), which was calculated as the mean (m) + 2 SD.
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Correlations.
Figure 4 shows the correlation between CT and vWFRCo
levels in the 96 healthy volunteers: R = 0.62 with ADP and R = 0.56 with epinephrine. The correlation between CT and vWFRCo levels in
patients with vWD could not be calculated because a large number of
patients had an infinite CT (> 250 seconds): n = 37 with collagen-ADP
cartridges and n = 44 with collagen-epinephrine cartridges (Tables 3
and 4). However, results in type 1 vWD indicated that on the whole the
prolongation of the CT was inversely proportional to the level of
vWFRCo (Table 3).
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| Fig 4.
Correlation between vWFRCo levels and CT with either
collagen-epinephrine or collagen-ADP in 96 normal subjects.
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| |
DISCUSSION |
The detection of vWD is still a challenge, especially in the mild
forms. Because there is an abnormal interaction of platelets with the
subendothelium in all types of vWD except type 2N,17 the BT
has been considered in the past as a useful screening tool to detect
these patients. Due to poor sensitivity, lack of reproducibility and
large variability, the BT is however not a suitable method for
screening of vWD. The poor sensitivity of the BT has been illustrated
by the Italian working group,12 showing that about 20% of
patients with moderate vWD have a normal BT. Our study confirms these
findings and indicates that 47% of patients with type 1 vWD, 20% with
type 2A, and 20% with acquired vWD, have a normal BT.
An optimal screening procedure to detect patients with a primary
hemostasis disorder needs to be reproducible, sensitive, and specific.
The PFA-100 shows excellent reproducibility as results of duplicate
tests deviated by more than 20% in only 2% of controls and 0% of
patients.
The sensitivity of the PFA-100 is also highly satisfactory. When
omitting results in type 2N vWD (showing as expected a normal CT), the
PFA-100 detected all patients with vWD using the collagen-ADP cartridges and all but two patients using the collagen-epinephrine cartridges. The latter two patients had a positive history of mild
bleeding and laboratory criteria (vWFRCo levels of 39 and 36 IU/dL) in
favor of vWD, but no evidence for an inherited form. According to the
recent recommendations of the Standardization and Scientific Committee
(SSC) of the International Society on Thrombosis and Haemostasis
(ISTH), both patients had "possible" and not "definite"
type 1 vWD. In addition, it is well known that individuals with group O
have lower levels of vWF18 than those of other groups and
may have a very mild bleeding tendency or none at all. Knowing that
these two subjects were of group O, they may also be considered as
borderline normal subjects and do not really limit the excellent
sensitivity of the PFA-100 in detecting patients with vWD.
The specificity of the PFA-100 was assessed by studying a large control
group devoid of any primary hemostasis disorder (healthy volunteers and
hemophiliacs); we detected four of 96 normal subjects whose CT with
epinephrine was either slightly prolonged or prolonged, and one whose
CT was borderline with ADP. A forgotten medication with any drug
interacting with primary hemostasis may have explained the four
prolonged CT with epinephrine, although the platelet aggregation tests
were found to be normal. As expected, results in hemophilia showed that
the CT was not affected by coagulation abnormalities. The good
specificity of CT was confirmed by the estimation of predictive values.
Positive and negative predictive values were excellent, the latter
being essential for a screening test used to exclude the diagnosis of
vWD.
The relationship between BT and plasma vWFRCo levels has been analyzed
by several investigators and Weiss,19 in particular, reported a good correlation between both tests. In the present study,
we analyzed the correlation between the CT measured in the PFA-100 and
the plasma vWFRCo levels. The correlation was fair in normal subjects,
but could not be calculated in vWD patients because a large number
exhibited an infinite CT due to the high sensitivity of the method.
A recent study16 has shown the involvement of vWF in
platelet adhesion and aggregation under the high shear stress
conditions of the PFA-100 by demonstrating that monoclonal antibodies
to vWF, specific for the collagen-, GPIb/IX-, or GPIIb/IIIa-binding sites of vWF, caused a dose-dependent prolongation of the CT. In
contrast, a polyclonal antibody to fibrinogen did not affect the
CT.16 In fact, we tested a patient with afibrinogenemia and
found a normal CT with both types of cartridges (results not shown).
These results are in agreement with those of perfusion studies6 indicating that under high shear stress flow
conditions, vWF is the only protein to play a role in platelet adhesion
and aggregation. This has been corroborated by experiments of
shear-induced platelet aggregation.20
Interestingly, the PFA-100 was capable of detecting patients with type
2B vWD. This is in agreement with our results of perfusion studies21 and with experiments using the blood filtration
test showing defective platelet retention and aggregation in all vWD patients tested.22 On the contrary, 2B variants are not
detected by shear-induced platelet aggregation measured in the
cone-and-plate viscometer23 where there is an increased
aggregation, paradoxically masking the defective platelet adhesion and
thrombus formation in these patients. In vivo, binding of abnormal vWF
to platelet GPIb results in occupation of the receptor so that it is no
longer available for mediating platelet adhesion. The PFA-100 system appears to detect a decreased ability of platelets to adhere rather than an increased tendency of platelets to aggregate. Therefore, this
system may mirror the defective hemostatic function of vWF in type 2B
as well as in all other types of vWD, except type 2N. Thus, the PFA-100
reflects vWF-dependent adhesive interactions as they occur in vivo and
is a global predictor of vWF-dependent platelet function under high
shear stress.
The PFA-100 may be used in a more general setting to predict the
bleeding tendency resulting from functional platelet alterations in
patients with defects other than vWD and to monitor vWD patients treated by deamino-8-D-arginine vasopressin (DDAVP). Studies using monoclonal antibodies to GPIb or to GPIIb/IIIa, and
aspirin14-16 have shown the usefulness of the the PFA-100
for detecting patients with inherited or acquired platelet dysfunction.
Indeed, we tested patients with various platelet disorders and found
that the PFA-100 is an excellent analyzer for their screening. All
patients showed prolonged CT using epinephrine and ADP, except three
with an aspirin-like defect whose CT was normal with ADP
(Table 5). However, ADP is known not to be
discriminating for the diagnosis of aspirin-like defects.15
In regard to the therapeutic monitoring of vWD patients, we found that
DDAVP completely corrected the CT with both types of cartridges in the
11 cases with type 1 vWD that we tested (results not shown),
emphasizing the usefulness of the PFA-100 as compared with the other
tests (BT, vWFRCo, and vWFAg).
In conclusion, the PFA-100 is well adapted to routine testing, as it
has the advantage of simplicity and ease of execution. It provides fast
results and uses the same citrated blood that is routinely drawn for
other coagulation testing; the latter is particularly useful in
emergency situations, especially before surgery. The test can be safely
delayed for up to 4 hours from the time of blood sampling, provided
that the blood is kept at room temperature. When expressed by its
sensitivity, specificity, and predictive values, the clinical
performance of the test is excellent in vWD with both types of
cartridges, possibly slightly better in the presence of ADP. The high
sensitivity demonstrated by the PFA-100 analyzer is clearly superior to
that of BT for the detection of patients with vWD. This leads to the
proposal of the following strategy: if the CT is within the normal
range, one may exclude the diagnosis of vWD (except type 2N) and
probably of a hereditary or acquired platelet disorder; if the CT is
abnormal, a medical questioning should first search for any medication
capable of interacting with platelet aggregation. Secondly, the CT
should be retested before measuring vWFRCo and/or vWFAg levels
and investigating for platelet function defects.
| |
FOOTNOTES |
Submitted January 29, 1997;
accepted October 8, 1997.
Address reprint requests to Prof Dominique Meyer, MD, INSERM U143,
Hôpital Bicêtre, Secteur Violet, Porte 19, 94275 Le
Kremlin-Bicêtre Cedex, France.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely
to indicate this fact.
| |
ACKNOWLEDGMENT |
We are most grateful to Marlies Ledford for her helpful comments. We
also thank Christine Euzen and Anne-Lise Marville-Gigot for expert
secretarial assistance.
| |
REFERENCES |
1.
Rodeghiero F,
Castaman G,
Dini E:
Epidemiological investigation of the prevalence of von Willebrand's disease.
Blood
69:454,
1987[Abstract/Free Full Text]
2. Gralnick HR, Ginsburg D: von Willebrand disease, in Beutler A,
Lichtman MA, Coller BS, Kipps TJ (eds): Williams Hematology, (ed 5).
New York, NY, McGraw-Hill, 1995, p 1458
3.
Ruggeri ZM,
Ware J:
The structure and function of von Willebrand factor.
Thromb Haemost
67:594,
1992[Medline]
[Order article via Infotrieve]
4.
Meyer D,
Girma JP:
von Willebrand factor: Structure and function.
Thromb Haemost
70:99,
1993[Medline]
[Order article via Infotrieve]
5.
Weiss HJ,
Turitto VT,
Baumgartner HR:
Effect of shear rate on platelet interaction with subendothelium in citrated and native blood. I. Shear rate-dependant decrease of adhesion in von Willebrand's disease and the Bernard-Soulier syndrome.
J Lab Clin Med
92:750,
1978[Medline]
[Order article via Infotrieve]
6.
Weiss HJ,
Hawiger J,
Ruggeri ZM,
Turitto VT,
Thiagarajan P,
Hoffmann T:
Fibrinogen-independent platelet adhesion and thrombus formation on subendothelium mediated by glycoprotein IIb-IIIa complex at high shear rate.
J Clin Invest
83:288,
1989
7.
Savage B,
Shattil SJ,
Ruggeri ZM:
Modulation of platelet function through adhesion receptors: A dual role for glycoprotein IIb-IIIa (integrin  IIb  3) mediated by fibrinogen and glycoprotein Ib-von Willebrand factor.
J Biol Chem
267:11300,
1992[Abstract/Free Full Text]
8. Goto S, Salomon Dr, Ikeda Y, Ruggeri ZM: Characterization of the
unique mechanism mediating the shear-dependent binding of soluble von
Willebrand factor to platelets. J Biol Chem 270:23352, 1995
9.
Sadler JE:
A revised classification of von Willebrand disease. For the Subcommittee on von Willebrand factor of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis.
Thromb Haemost
71:520,
1994[Medline]
[Order article via Infotrieve]
10.
Ginsburg D,
Sadler JE:
von Willebrand disease: A database of point mutations, insertions and deletions.
Thromb Haemost
69:177,
1993[Medline]
[Order article via Infotrieve]
11. Mazurier C, Meyer D: Molecular basis of von Willebrand disease,
in Haemophilia, Baillière's Clinical Haematology (vol 9).
London, UK, 1996, p 229
12. Italian Working Group: Spectrum of von Willebrand's disease: A
study of 100 cases. Br J Haematol 35:101, 1977
13.
Meyer D,
Obert B,
Pietu G,
Lavergne JM,
Zimmerman TS:
Multimeric structure of factor VIII/von Willebrand factor in von Willebrand's disease.
J Lab Clin Med
95:590,
1980[Medline]
[Order article via Infotrieve]
14. (suppl 2)
Kundu SK,
Heilmann EJ,
Sio R,
Garcia C,
Davidson RM,
Ostgaard RA:
Description of an "in vitro" platelet function analyzer PFA-100TM.
Semin Thromb Hemost
21:106,
1995[Medline]
[Order article via Infotrieve]
15. (suppl 2)
Mammen EF,
Alshameeri RS,
Comp PC:
Preliminary data from a field trial of the PFA-100TM system.
Semin Thromb Hemost
21:113,
1995
16.
Kundu SK,
Heilmann E,
Sio R,
Garcia C,
Ostgaart R:
Characterization of an in vitro platelet function analyzer, PFA-100TM.
Clin Appl Thromb Hemost
2:241,
1996
17. Meyer D, Fressinaud E, Gaucher C, Lavergne JM, Hilbert L, Ribba
AS, Jorieux S, Mazurier C and the INSERM Network on molecular
abnormalities in von Willebrand disease: Gene defects in 150 unrelated
French cases with type 2 von Willebrand disease: From the patient to
the gene. Thromb Haemost 78:451, 1997
18.
Gill JC,
Endres-Brooks J,
Bauer PJ,
Marks WJ,
Montgomery RR:
The effect of ABO blood group on the diagnosis of von Willebrand disease.
Blood
69:1691,
1987[Abstract/Free Full Text]
19. (letter)
Weiss HJ:
Relation of von Willebrand factor to bleeding time.
N Engl J Med
291:420,
1974
20.
Ikeda Y,
Handa M,
Kawano K,
Kamata T,
Murata M,
Araki Y,
Anbo H,
Kawai Y,
Watanabe K,
Itagaki I,
Sakai K,
Ruggeri ZM:
The role of von Willebrand factor and fibrinogen in platelet aggregation under varying shear stress.
J Clin Invest
87:1234,
1991
21. Fressinaud E, Federici AB, Castaman G, Mannucci PM, Meyer D: Ex
vivo experimental thrombosis in variants of von Willebrand disease. C R
Acad Sci Paris, Sciences de la vie/Life Sci 316:1260, 1993
22.
O'Brien JR,
Salmon GP:
Shear stress activation of platelet glycoprotein IIb-IIIa plus von Willebrand factor causes aggregation, filter blockage and the long bleeding time in von Willebrand's disease.
Blood
70:1354,
1987[Abstract/Free Full Text]
23.
Pareti IF,
Cattaneo M,
Carpinelli L,
Zighetti ML,
Bressi C,
Mannucci PM,
Ruggeri ZM:
Evaluation of the abnormal platelet function in von Willebrand disease by the blood filtration test.
Thromb Haemost
75:460,
1996[Medline]
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Abstract
Introduction
Abstract