Von Willebrand Disease

Stacy Cooper and Clifford Takemoto

Pediatrics in Review 2014;35;136
DOI: 10.1542/pir.35-3-136

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/content/35/3/136

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2014 by the American Academy of
Pediatrics. All rights reserved. Print ISSN: 0191-9601.
in brief
In Brief
Von Willebrand Disease
Stacy Cooper, MD
Clifford Takemoto, MD
Charlotte Bloomberg Children’s Center,
Johns Hopkins Hospital
Baltimore, MD
Author Disclosure
Dr Cooper has disclosed no financial
relationships relevant to this article.
Dr Takemoto has disclosed a research
grant from Novo Nordisk for
hemophilia factor trials at Johns
Hopkins University. This commentary
does not contain discussion of
unapproved/investigative use of
a commercial product/device.
Von Willebrand Disease (VWD):
Evidence-Based Diagnosis and
Management Guidelines, The
National Heart, Lung, and Blood
Institute (NHLBI) Expert Panel
Report (USA). Nichols W, Hultin MB,
James AH, et al. Haemophilia. 2008;
14(2):171–232
Bleeding Scores: Are They Really Useful?
O’Brien SH. Am Soc Hematol Educ
Program. 2012;2012(1):152–156
Von Willebrand Disease. Montgomery G,
Cox JG. In: Orkin SH, Nathan DG,
Ginsburg D, Look AT, Fisher DE, Lux SE,
Lantigua CJ. Nathan and Oski’s
Hematology of Infancy and Childhood.
7th ed. Philadelphia, PA: Saunders;
2009:1487–1524
Von Willebrand disease (vWD) is an in-
herited bleeding diathesis. It is caused
by quantitative or qualitative defects
in von Willebrand factor (vWF), which
functions to bind platelets to damaged
endothelium and to stabilize factor VIII
(FVIII). A range of mutations have been
136 Pediatrics in Review Vol.35 No.3 March 2014
identified in this protein, encompassing
the spectrum of single missense muta-
tions to large deletions. Because of var-
iation in the diagnostic criteria for vWD,
debate exists regarding the prevalence;
however, some studies estimate it to be
as high as 1% to 2% of the population
when including children and adults.
There are 3 major categories of vWD,
classified as partial deficiency of vWF
(type 1), functional defects (type 2),
and complete deficiency of vWF (type
3). Type 2 can be further subcategorized
based on the 4 subtypes of specific
qualitative defects of the multimers
(types 2A, 2B, 2M, and 2N). The differ-
ent types of vWD vary in severity. Type 1
is the most common, an autosomal dom-
inant disorder that comprises approxi-
mately 75% of vWD patients, and is
usually confined to mild bleeding. Type
2 may demonstrate either dominant or
recessive inheritance, and type 3 is au-
tosomal recessive, with types 2 and 3
often involved in more serious bleeding
presentations.
Most often vWD presents with muco-
cutaneous bleeding. Common symptoms
include epistaxis, easy bruising, and
menorrhagia. Bleeding episodes are usu-
ally mild and self-resolving but in some
cases may be significant and require in-
tervention. Type 3 vWD and other more
severe forms may present with less com-
mon serious bleeds, such as hemarthrosis
or gastrointestinal bleeding.
When evaluating a child with con-
cern for abnormal bleeding, it is impor-
tant to detail the age at onset, location
of bleeding, and whether the bleeding
occurs spontaneously or is trauma in-
duced. Additional assessments include
the duration of bleeding, whether inter-
vention was needed, and any concurrent
medications taken (with nonsteroidal
anti-inflammatory drugs the most
common pediatric culprits but aspi-
rin-containing products also worthy
of consideration). Other important in-
formation to obtain is the patient’s
history of bleeding with hemostatic
challenges (such as operations and
minor trauma). However, young chil-
dren with vWD may have an unremark-
able bleeding history because of their
young age and not yet having experi-
enced any bleeding challenges or past
surgical history. Thus, a comprehensive
family history is also an essential part
of the workup for suspected bleeding
disorders.
The evaluation and diagnosis of a
child with vWD are complicated by the
mild bleeding symptoms encountered
in the healthy population. Several bleed-
ing scoring systems have been developed
to determine the likelihood of vWD in
adults; however, many of these have
not been validated in children. Further-
more, although these bleeding scores
may be useful to identify individuals
who have a low likelihood of vWD, asymp-
tomatic children with a positive family his-
tory may still deserve a workup because of
the lack of hemostatic challenges.
The initial workup for all children with
a suspected bleeding disorder should in-
clude a complete blood cell count with
a blood smear to evaluate for anemia or
thrombocytopenia and prothrombin time
and activated partial thromboplastin time
to screen for coagulation factor deficien-
cies. The activated partial thromboplastin
time may be prolonged in some patients
with vWD but is most often normal. Thus,
a directed vWD workup may still be ap-
propriate based on clinical assessment
even if the initial screen result is normal.
Specific vWD testing begins with 3
laboratory tests: vWF antigen (vWF:
 in brief

Ag), vWF activity (vWF ritocetin cofac-
tor [vWF:RCo] activity), and FVIII level.
The most common type of vWD, type
1, is characterized by a quantitative re-
duction of both vWF:Ag and vWF:RCo.
The rarer vWD type 2 mutations usually
exhibit discordance between vWF:Ag
and vWF:RCo, with reduced activity
for antigen. vWD type 3 has no detect-
able vWF antigen, and activity of FVIII
levels may be markedly decreased be-
cause of the role of vWF in stabilizing
FVIII.
Additional evaluation may also in-
clude platelet function testing, the re-
sults of which may be abnormal in
vWD. Bleeding time can be abnormal
in some patients with vWD; however,
this test has been largely abandoned
because of poor specificity and variabil-
ity in execution and interpretation. Fur-
ther testing for the vWF multimers is
helpful to distinguish the various sub-
classes of type 2 vWD.
Repeat testing may be needed if
clinical suspicion is high but results
were normal because numerous factors
can affect vWF levels, such as estro-
gens, active bleeding, and stress. It is
also important to recognize that many
individuals may have borderline low
levels of vWF but not meet criteria
for vWD. However, these patients
may have bleeding symptoms that
warrant treatment or intervention if
significant.
Treatment of vWD is reserved for ac-
tive bleeding symptoms or prophylaxis
for surgical procedures. Desmopressin,
a synthetic vasopressin analog, is com-
monly used to promote release of vWF
from endothelial storage, also resulting
in an improved FVIII half-life. Patients
with type 1 often respond well to desmo-
pressin; however, this treatment results
in a variable response in type 2 and inad-
equate response in type 3. Desmopressin
is generally well tolerated, but an impor-
tant adverse effect to be aware of is
hyponatremia. Hyponatremia is usually
avoided with water restriction, but in rare
cases, seizures have been reported, par-
ticularly in young children. When desmo-
pressin is insufficient or contraindicated,
plasma-derived vWF and FVIII purified
concentrates can be given. When con-
centrate is not available, cryoprecipitate
may be used; however, this is usually re-
served for life-threatening bleeds, given
infectious risks with this product. Ad-
junctive measures include antifibri-
nolytic agents, such as aminocaproic
acid and tranexamic acid, which help
clot stabilization.
As a common bleeding disorder,
vWD should be considered in patients
with a concerning personal or family
bleeding history, with several treatment
options available for active bleeding
and surgical prophylaxis.
Comments: Drs Cooper and Takemoto
summarize the challenges of diagnosing
vWD. A patient can present at any age
and may have negative laboratory results,
yet a primary care clinician may still want
to pursue the diagnosis and repeat testing
if the bleeding history is significant. Use of
bleeding scores may be helpful for primary
care clinicians because the high negative
predictive value may identify those for
whom further testing or referral is not
warranted. Several factors may influence
the levels of vWFs, such as the presence
of lower plasma levels in those with O
blood type, whereas levels may be elevated
in those with increased estrogen, such as
during pregnancy or while taking an estro-
gen-containing oral contraceptive. vWF is
also an acute-phase reactant, so it can be
elevated in those with an acute inflamma-
tory process. Because different laboratories
may use different assays, it is important to
interpret results in consultation with a he-
matologist. Consultation is also helpful for
patients with a concerning bleeding his-
tory and for assistance in patients with di-
agnosed conditions who are experiencing
significant bleeding.
Janet Serwint, MD
Consulting Editor, In Brief

Corrections
• In the February 2014 Pediatrics in Review article “Muscle Disease” (Tsao, C-Y. Pediatr Rev. 2014;35(2):49–61.
doi: 10.1542/pir.35-2–49), answer option “D” for quiz question 4 should read “Dermatomyositis.” This correction has
been made in the online quiz and the online version of the journal. The journal regrets the error.
• In the February 2014 article “Congenital Torticollis and Positional Plagiocephaly” (Kuo AA, Tritasavit S, and Graham Jr JM.
Pediatr Rev. 2014 ;35(2):79–87. doi:10.1542/pir.35-2–79), one of the images in Figure 3 is mislabeled. The second row of
printed headings should read, from left to right, “Prom Lrot¼ 86 . Prom Rrot¼78.” The Journal regrets the error.

Pediatrics in Review Vol.35 No.3 March 2014 137

 Von Willebrand Disease
Stacy Cooper and Clifford Takemoto
Pediatrics in Review 2014;35;136
DOI: 10.1542/pir.35-3-136

Updated Information & including high resolution figures, can be found at:
Services http://pedsinreview.aappublications.org/content/35/3/136
References This article cites 2 articles, 0 of which you can access for free at:
http://pedsinreview.aappublications.org/content/35/3/136#BIBL
Subspecialty Collections This article, along with others on similar topics, appears in the
following collection(s):
Genetics
http://pedsinreview.aappublications.org/cgi/collection/genetics_sub
Epigenetics
http://pedsinreview.aappublications.org/cgi/collection/epigenetics_su
b
Hematology/Oncology
http://pedsinreview.aappublications.org/cgi/collection/hematology:o
ncology_sub
Blood Disorders
http://pedsinreview.aappublications.org/cgi/collection/blood_disorde
rs_sub
Permissions & Licensing Information about reproducing this article in parts (figures, tables) or
in its entirety can be found online at:
http://pedsinreview.aappublications.org/site/misc/Permissions.xhtml
Reprints Information about ordering reprints can be found online:
http://pedsinreview.aappublications.org/site/misc/reprints.xhtml