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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 4, July/August 2016
226
AFRICA
structure. Rauch
et al
. reported four cases of VWD in 12 patients
with patent ductus arteriosus, and six months after closure of
the defect, the abnormal levels of von Willebrand factor had
returned to within normal limits.
15
The prevalence of bleeding episodes in patients with
congenital heart disease is controversial. Several studies reported
that at least 20% of patients with aortic stenosis have a history
of bleeding.
16-18
In the study by Gill
et al.
,
14
66% of patients
with ventricular septal defect and 50% with aortic stenosis had
bleeding episodes; however, patients with atrial septal defect did
not have bleeding episodes. Most of these episodes were excessive
bleeding after injury or epistaxis, and easy bruising.
In our study, two of seven patients (28.5%) with a diagnosis
of AVWS had episodes of bleeding. These two patients had
aortic stenosis, and PFA-100 collagen epinephrine closure time
was prolonged in both.
Although Froom
et al
.
19
reported a relationship between
frequent epistaxis episodes and low VWF:Ag, Rauch
et al
.
15
did
not find any association between bleeding episodes and the von
Willebrand deficiency in patients with patent ductus arteriosus.
We also could not find any relationship between low VWF:Ag
levels and bleeding. In our study, it was noteworthy that 33% of
patients with pulmonary stenosis with prolonged PFA-100 ADP
collagen closure times had bleeding episodes.
The PFA-100 closure time has been suggested to be useful
in screening for disorders of primary haemostasis, including
VWD.
9
In a study by Vincentelli
et al
.,
17
92% of patients with
severe aortic stenosis and 50% of patients with moderate aortic
stenosis had prolonged PFA-100 ADP collagen closure times.
However, in our study, 67% of the patients with severe aortic
stenosis and 50% of those with moderate aortic stenosis had
prolonged PFA-100 ADP collagen closure times.
In our study, PFA-100 collagen epinephrine closure time was
prolonged in all seven patients with impaired haematological
parameters matching AVWS. Only one of seven patients had
a bleeding history, which suggests that absence of a history
of bleeding episodes is not enough to exclude AVWS. For this
reason, patients with heart disease should be screened with
PFA-100 closure time before any intervention or surgery, even in
the absence of a history of bleeding.
Yoshida
et al
.
16
reported a positive correlation between
VWF:Ag levels and effective valvular area in patients with
aortic stenosis. However, we were unable to show any correlation
between degree of valvular stenosis and VWF:Ag and VWF:RCo
levels.
Routine coagulation tests and thrombo-elastometric
measurements are not enough to exclude a diagnosis of AVWS.
Laboratory investigations for AVWS include patient’s history of
bleeding (lifelong mucocutaneous, postoperative bleeding) and
a family history of bleeding, screening procedures [e.g. platelet
count, PTT, concentration of factor VIII (FVIII:C), PFA-100],
and confirming tests [e.g. VWF:Ag, VWF:RCo, VWF collagen-
binding activity (VWF:CB), RIPA, and analysis of VWF
multimers by gel electrophoresis].
20
Most of these tests are time
consuming and available only in specific centres.
In some studies, the VWF:Ag levels were normal, while in
others, they were low.
13, 15,17,20
In our study, VWF:Ag levels were
normal in all the healthy children and in the patients with aortic
stenosis, but they were low in 5% of patients with pulmonary
stenosis. The VWFR:RCo level was low in one of three patients
with low VWF:Ag levels. In a study by Gill
et al
.,
14
VWF:RCo
levels were low in seven of 12 patients with acyanotic congenital
heart disease. Only 6% of our patients had low VWF:Ag levels.
Early diagnosis of AVWS is difficult, due to a lack of
sensitivity of the tests used. Tiede
et al
.
5
found that the sensitivity
of PFA-100 was 80% for the diagnosis of AVWS. In our study,
the sensitivity of VWF:Ag (23%) and VWF:RCo/VWF:Ag
<
0.7
(26%) was too low to rule out this disease. We agree with Tiede
et
al
.
5
They suggested that a substantial number of patients present
with normal or abnormal test results. The analysis of VWF
multimers should always be part of the diagnostic workup.
5
There were some study limitations; first, the low number
of patients in each group, and second, for financial reasons,
we could not perform VWF multimer analysis, which is the
gold-standard test for the diagnosis of acquired VWD. Finally,
patients in the control group did not undergo PFA-100 closure
time tests.
Conclusion
We suggest that a history of bleeding must be evaluated carefully
in patients with stenotic obstructive heart disease, due to the
increased risk of AVWS. Furthermore, even in the absence of
bleeding episodes, PFA-100 closure time should be evaluated
routinely before any intervention or surgery. If any abnormality
is detected, VWF:Ag, VWF:RCo and platelet aggregation tests
should be performed. Although the gold-standard test for
AVWS is detection of structural abnormalities of VWF, it is a
time-consuming assay and not available in most centres.
References
1.
Succer C, Michiels JJ, Zotz RB. Causes, etiology and diagnosis of
acquired von Willebrand disease: a prospective diagnostic workup to
establish the most effective therapeutic strategies.
Acta Haematol
2009;
121
: 177–182.
2.
Federici AB, Rand JH, Bucciarelli P,
et al
. Acquired von Willebrand
syndrome: Data from an international registry.
Thromb Haemost
2000;
84
: 345–349.
3.
Steinlechner B, Zeidler P, Base E,
et al
. Patients with severe aortic
valve stenosis and impaired platelet function benefit from preoperative
desmopressin infusion.
Ann Thorac Surg
2011;
91
: 1420–1426.
4.
Kumar S, Pruthi RK, Nichols WL. Acquired von Willebrand disease.
Mayo Clin Proc
2002;
77
: 181–187.
5.
Tiede A, Priesack J, Werwitzke S,
et al.
Diagnostic workup of patients
with acquired von Willebrand syndrome: a retrospective single-centre
cohort study.
J Thrombosis Haemostasis
2008;
6
: 569–576.
6.
Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka
PA,
et al
. Chamber Quantification Writing Group; American Society of
Echocardiography’s Guidelines and Standards Committee; European
Association of Echocardiography. Recommendations for chamber quan-
tification: a report from the American Society of Echocardiography’s
Guidelines and Standards Committee and the Chamber Quantification
Writing Group, developed in conjunction with the European Association
of Echocardiography, a branch of the European Society of Cardiology
.
J Am Soc Echocardiogr
2005;
18
: 1440–1463.
7.
Latson LA. Aortic stenosis: valvular, supravalvular, and fibromus-
cular subralvular. In: Garson A, Bricker JT, McNamara DG (eds).
The Science and Practice of Pediatric Cardiology
. Philadelphia: Lea &
Febiger, 1990: 1134–1352.