Pediatr Clin N Am 55 (2008) 377–392

von Willebrand Disease

Jeremy Robertson, MDa, David Lillicrap, MDb,
Paula D. James, MDc,*
a
Division of Hematology/Oncology, Hospital for Sick Children, 555 University Avenue,
Toronto, ON M5G 1X8, Canada
b
Department of Pathology and Molecular Medicine, Richardson Labs, Queen’s University,
108 Stuart Street, Kingston, ON K7L 3N6, Canada
c
Department of Medicine, Queen’s University, Room 2025, Etherington Hall,
94 Stuart Street, Kingston, ON K7l 2V6, Canada

History
von Willebrand disease (VWD) first was described in 1926 by a Finnish
physician named Dr. Erik von Willebrand. In the original publication [1]
he described a severe mucocutaneous bleeding problem in a family living
on the Åland archipelago in the Baltic Sea. The index case in this family,
a young woman named Hjördis, bled to death during her fourth menstrual
period. At least four other family members died from severe bleeding and,
although the condition originally was referred to as ‘‘pseudohemophilia,’’
Dr. von Willebrand noted that in contrast to hemophilia, both genders
were affected. He also noted that affected individuals exhibited prolonged
bleeding times despite normal platelet counts.
In the mid-1950s, it was recognized that the condition usually was accom-
panied by a reduced level of factor VIII (FVIII) activity and that the bleed-
ing phenotype could be corrected by the infusion of normal plasma. In the
early 1970s, the critical immunologic distinction between FVIII and von
Willebrand factor (VWF) was made and since that time significant progress
has been made in understanding the molecular pathophysiology of this
condition.

JR is the 2007/2008 recipient of the Baxter BioScience Pediatric Thrombosis and

Hemostasis Fellowship in the Division of Hematology/Oncology at the Hospital for Sick
Children. DL holds a Canada Research Chair in Molecular Hemostasis and is a Career
Investigator of the Heart and Stroke Foundation of Ontario.
* Corresponding author.
E-mail address: jamesp@queensu.ca (P.D. James).

0031-3955/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.pcl.2008.01.008 pediatric.theclinics.com
378 ROBERTSON et al

von Willebrand factor

Cloning and characterization of the VWF gene, by four groups simulta-
neously in 1985 [2–5], has facilitated understanding of the molecular biology
of VWD. Located on the short arm of chromosome 12 at p13.3, the VWF
gene spans 178 kilobases (kb) and comprises 52 exons that range in size
from 1.3 kb (exon 28) to 40 base pairs (bp) (exon 50) [6]. The encoded
VWF mRNA is 9 kb in length and the translated pre-pro-VWF molecule
contains 2813 amino acids (AA), comprising a 22 AA signal peptide,
a 741 AA propolypeptide, and a 2050 AA-secreted mature subunit that
possesses all the adhesive sites required for VWF’s hemostatic function
[7]. There is a partial, unprocessed pseudogene located on chromosome
22, which duplicates the VWF gene sequence for exons 23–34 with 97% se-
quence homology [8]. Also, the VWF gene is highly polymorphic, and to
date, 140 polymorphisms are reported, including promoter polymorphisms,
a highly variable tetranucleotide repeat in intron 40, two insertion/deletion
polymorphisms, and 132 distinct single nucleotide polymorphisms involving
exon and intron sequences [9].
VWF is synthesized in endothelial cells [10] and megakaryocytes [11] as
a protein subunit that undergoes a complex series of post-translational mod-
ifications, including dimerization, glycosylation, sulfation, and ultimately
multimerization. The fully processed protein then is released into the circu-
lation or stored in specialized organelles: the Weibel-Palade bodies of
endothelial cells or the a-granules of platelets. VWF is secreted into the
plasma, where it circulates as a very large protein that has a molecular
weight ranging from 500 to 20,000 kd depending on the extent of subunit
multimerization [12]. After secretion, under the influence of shear flow,
high-molecular-weight (HMW) VWF, multimers undergo partial proteoly-
sis mediated by the ADAMTS-13 plasma protease (A Disintegrin And
Metalloprotease with ThrombSopondin type 1 motif, member 13), with
cleavage occurring between AA residues tyrosine 1605 and methionine
1606 in the A2 domain of the VWF protein [13].
VWF is a multifunctional adhesive protein that plays major hemostatic
roles, including:
A critical role in the initial cellular stages of the hemostatic process. VWF
binds to the platelet glycoprotein (GP)Ib/IX receptor complex to initi-
ate platelet adhesion to the subendothelium [14]. After adhesion, plate-
let activation results in the exposure of the GPIIb/IIIa integrin receptor
through which VWF and fibrinogen mediate platelet aggregation
(Fig. 1) [15].
As a carrier protein for the procoagulant cofactor FVIII. VWF binds to
and stabilizes FVIII; therefore, low levels of VWF or defective binding
of VWF to FVIII results in correspondingly low levels of FVIII be-
cause of its accelerated proteolytic degradation by activated protein
C [16].
 VON WILLEBRAND DISEASE 379

Fig. 1. Role of VWF in mediating the initial events in the hemostatic process. Platelets, rolling
along the endothelial cell surface, are tethered to the site of endothelial cell injury through the
binding of subendothelial VWF to the GpIb protein of the Ib/IX receptor. The platelets subse-
quently are activated and the GpIIb/IIIa complex is exposed on the platelet surface. Interaction
of fibrinogen and VWF with GpIIb/IIIa then consolidates the platelet adhesive event and
initiates platelet aggregation.

Clinical features of von Willebrand disease

VWD is stated as the most common inherited bleeding disorder known in
humans. This is based on two large epidemiologic studies that reported the
prevalence of VWD in healthy school-aged children to be approximately 1%
[17,18]. More recent studies, however, suggest that the prevalence of individ-
uals who have VWD who present to primary care physicians with symptom-
atic bleeding or bruising is closer to 1 in 1000 [19]. The number of
individuals referred to a tertiary care center for management of VWD is
much lower, at approximately 1 in 10,000 [20].
VWD is characterized by three key features: a personal history of exces-
sive mucocutaneous bleeding, abnormal VWF laboratory studies, and
evidence of a family history of the condition. A diagnostic algorithm for
possible VWD cases is presented in Fig. 2.

Bleeding histories
The clinical hallmark of VWD is the presence of excessive and prolonged
mucocutaneous bleeding. Most often, this involves bruising, epistaxis,
bleeding from the gums and trivial wounds, and menorrhagia and postpar-
tum hemorrhage in women. Prolonged and excessive bleeding also occurs
380 ROBERTSON et al

Fig. 2. A proposed diagnostic algorithm for possible VWD cases.

after surgical and dental procedures. Children who have VWD also may
experience bruising after routine immunizations and gum bleeding after
the loss of primary teeth. Typically, only patients who have type 3 VWD
(characterized by an absence of VWF, accompanied by low FVIII levels,
less than 0.10 IU/mL [10%]) experience spontaneous musculoskeletal bleed-
ing, such as that seen in patients who have severe hemophilia. An accurate
assessment of hemorrhagic symptoms is a key component in diagnosing
VWD but often presents a significant challenge, particularly in the pediatric
population.
Although bruising and epistaxis are common among children who have
VWD, these symptoms also are reported in normal children. An additional
consideration is that bleeding symptoms manifest in children in distinctly
different ways compared with adults. Some of the classical symptoms of
VWD in adults (eg, menorrhagia and postsurgical bleeding) are not preva-
lent in the pediatric population. Children who have a bleeding disorder may
not have had surgery or (in the case of girls) reached the age of menarche;
however, they may have symptoms that cause difficulty and merit treatment.
To address these issues, there has been significant recent interest in develop-
ing new clinical tools for quantifying bleeding, and although much of this
work has focused on adult populations, tools have been developed that
are specific to pediatrics [21]. The Epistaxis Scoring System is a semiquanti-
tative system, in which children with recurrent epistaxis are either catego-
rized as ‘‘mild’’ or ‘‘severe,’’ and represents one such tool [22].
 VON WILLEBRAND DISEASE 381

Abnormal von Willebrand factor laboratory studies

The laboratory evaluation for VWD involves qualitative and quantitative
measurements of VWF and FVIII. The results from affected individuals are
highly variable, ranging from the near complete absence of VWF in type
3 VWD to modest quantitative reductions in VWF and FVIII levels as
seen in type 1 VWD. The type 2 variants are characterized by qualitative ab-
normalities in VWF and include four subtypes, 2A, 2B, 2M, and 2N (see
classification later). It is critical that the laboratory investigations for
VWD be interpreted by physicians who have experience in this area, given
the heterogeneity of possible results.
Although it is important to perform screening tests in the diagnostic work-
up of patients who have possible VWD, it also is important to recognize the
limitations of these tests. The complete blood count can be completely nor-
mal in individuals who have VWD but may show evidence of an iron defi-
ciency anemia resulting from chronic blood loss; type 2B VWD often is
associated with mild thrombocytopenia. If the VWF level is reduced to levels
less than approximately 0.35 IU/mL (35%), the commensurate low level of
FVIII may result in the prolongation of the activated partial thromboplastin
time (aPTT); however a normal aPTT does not rule out VWD, particularly in
milder cases. The bleeding time may be prolonged [23]; however, this test
lacks sensitivity and specificity and patients who have known VWD may
have normal bleeding times. Parenthetically, the bleeding time is poorly re-
producible and invasive and no longer should be a routine component of
the investigation of children who have possible VWD. Recently, a newer an-
alyzer, known as the PFA-100, has been evaluated in the diagnostic work-up
of VWD. Its reported sensitivity for VWD is high (ranging from 71%–97%);
however, given that it is a test of global hemostasis, the specificity is lower. As
a result, the PFA-100 may have a role as a screening test; however, its precise
clinical usefulness remains unresolved [21,24,25].
Laboratory tests specific for VWD include a measurement of the amount
of circulating plasma VWF antigen, a measurement of the VWF function
(a ristocetin-based platelet aggregation test, known as the VWF ristocetin
cofactor assay [VWF:RCo] [26], or the VWF collagen-binding assay) [27]
and a measurement of FVIII coagulant activity. One other VWF test also
uses ristocetin, the ristocetin-induced platelet agglutination (RIPA) assay.
In contrast to the VWF:RCo (which evaluates the interaction between
patients’ VWF and formalin-fixed platelets), the RIPA assay evaluates the
sensitivity of patients’ platelets to low-dose ristocetin and is useful particu-
larly in identifying individuals who have type 2B VWD. In these cases, the
platelet membrane is ‘‘overloaded’’ with high-affinity mutant VWF, result-
ing in platelet agglutination at low ristocetin concentrations, less than
0.6 mg/mL [27]. The final laboratory test performed to characterize VWD
involves the assessment of the molecular-weight profile of circulating plasma
VWF [28]. As discussed previously, VWF circulates in the plasma as
382 ROBERTSON et al

a heterogenous mixture of multimers. HMW multimers are the most hemos-

tatically active, as they contain the most active binding sites for platelets,
and characteristically are absent in some type 2 forms of VWD. The molec-
ular-weight profile of VWF is evaluated most often using sodium dodecyl
sulfate polyacrylamide gel electrophoresis (SDS-PAGE), which is techni-
cally challenging and available only in a few laboratories (Fig. 3). Recent
efforts have been made to simplify and enhance the objectivity of this assay
by combining nonradioactive, chemiluminescent detection methods with
densitometric analysis of the multimer bands.
Normal plasma levels of VWF are approximately 1 U/mL (100%, corre-
lating to approximately10 mg/mL) with a wide population range of 0.50 to
2.0 U/mL (50%–200%). These variations are influenced by several genetic
and environmental factors. ABO blood group is the genetic influence char-
acterized best; VWF and FVIII levels in individuals who have blood group
O are approximately 25% lower than individuals who have blood group A,
B, or AB [29]. This difference is believed a result of the lack of glycosylation
(and therefore stabilization) of VWF in individuals who are in blood group
O. Two major environmental factors affecting VWF levels are stress and
hormones. The plasma levels of VWF and FVIII increase approximately
twofold to fivefold during physiologic stress, such as fainting [30] or exercise
[31]. VWF and FVIII levels also fluctuate over the course of a menstrual
cycle and under the influence of oral contraceptive pills and pregnancy
[32]. Additionally, VWF levels vary with age, with neonatal levels higher
than adult levels [33,34], although many laboratories do not report age-
specific normal ranges. These factors all must be considered when interpret-
ing VWF laboratory results and, as a result, most clinicians support at least
two sets of tests to confirm or refute a diagnosis of VWD.

Fig. 3. VMF multimer analysis. Multimer analysis in two patients who have type 2 VWD.
Lanes 1 and 4 represent normal plasma multimer patterns. Lane 2 shows the plasma VWF
multimers for a patient who had type 2A and lane 3 the plasma multimers for a patient who
has type 2B VWD. LMW, low molecular weight.
 VON WILLEBRAND DISEASE 383

Family history
Most cases of VWD are inherited, and often there is evidence of a family
history of excessive bleeding. This issue is complicated, however, by some
forms of the disease showing incomplete penetrance of bleeding symptoms.
As a result, many clinicians do not consider the lack of a positive family
history (especially in type 1 VWD) an exclusion criterion. The disease is
inherited as a dominant trait in type 1 and in the qualitative variants types
2A, 2B, and 2M. In contrast, the rare type 2N and severe type 3 forms of the
disease show a recessive pattern of inheritance.

Classification of von Willebrand disease

The current International Society on Thrombosis and Haemostasis estab-
lished classification of VWD comprises three types: type 1 VWD, a partial
quantitative deficiency of qualitatively normal VWF; type 2 VWD, a quali-
tative deficiency caused by functionally abnormal VWF; and type 3 VWD,
which represents a virtual absence of the VWF protein (Table 1) [35].

Type 1 von Willebrand disease

Type 1 VWD, which represents approximately 80% of VWD cases unfor-
tunately is the most difficult subtype of VWD to diagnose. As discussed pre-
viously, circulating VWF levels are influenced by several factors, and there is
overlap between normal individuals who have VWF levels at the lower end of
the normal range and those who have mild type 1 VWD. Additionally, muco-
cutaneous bleeding symptoms in individuals who have type 1 VWD can be
mild and potentially overlooked by patients and physicians. Convincing fam-
ily histories may be absent, given the incomplete penetrance of this subtype.
Consideration of all of these factors has led to much recent debate about the
proper definition of this disorder [36]. The suggestion has been made that a di-
agnosis of type 1 VWD be reserved for individuals who have significant
reductions in VWF to less than 0.15 IU/mL (15%); although this may not
have become a widely accepted clinical definition, it highlights the importance

Table 1
Characteristic laboratory findings in von Willebrand disease by subtype
von Willebrand RCo:Ag Multimer
disease subtype VWF:Ag VWF:RCo FVIII:C ratio pattern RIPA
1 Y Y Y or 4 O0.60 Normal d
2A Y YY Y or 4 !0.60 Abnormal Y
2B Y YY Y or 4 !0.60 Abnormal [
2M Y YY Y or 4 !0.60 Normal d
2N Y or 4 Y or 4 0.10–0.40 O0.60 Normal d
3 YYY YYY !0.10 d d d
Abbreviations: FVIII:C, Factor VIII coagulant activity; RCo:Ag Ratio, VWF, ristocetin co-
factor/VWF antigen ratio.
384 ROBERTSON et al

of considering a diagnosis carefully. Assigning an incorrect diagnostic label of

VWD to patients can be difficult to revise subsequently and may lead to con-
fusion and inappropriate management. In addition, the wider implications of
this diagnosis, including the potential social stigma and health insurance im-
plications, should be considered carefully before making a diagnosis. In con-
trast, underdiagnosis of type 1 VWD can be a concern in young children who
may not have been subjected to a sufficient hemostatic challenge to manifest
a bleeding tendency that would lead to consideration of a diagnosis of VWD.
Taking all of these factors into consideration, a suggested definition of type 1
VWD in children could include both definite (for children with excessive mu-
cocutaneous bleeding and low VWF levels) and possible (for children with
low VWF levels but no history of excessive mucocutaneous bleeding poten-
tially because of the lack of opportunity).
The genetic basis of type 1 VWD has been the focus of much recent in-
vestigation, and two large multicenter trials have reported consistent results
[37,38]. Mutations throughout the VWF gene were identified in approxi-
mately 65% of index cases and the majority of these were missense muta-
tions. Mutations were identified more frequently in cases of lower VWF
levels and more highly penetrant in those cases. The genetic variation
reported most frequently identified in both studies was a missense mutation
resulting in an AA substitution of tyrosine to cysteine at codon 1584
(Y1584C), identified in 10% to 20% of patients who had type 1 VWD
[39]. In both studies, however, some patients who had type 1 VWD had
no obvious VWF mutation identified, and in these (often milder) cases,
the genetic determinants likely are more complex and could involve other
genetic loci. At this time, genetic testing for type 1 VWD generally is neither
available nor required for establishing the diagnosis.

Type 2 von Willebrand disease

Type 2 VWD is characterized by a qualitative deficiency of VWF activity
and is classified further into the qualitative variants that affect VWF-platelet
interactions (2A, 2B, and 2M) and the rare type 2N characterized by defec-
tive VWF binding to FVIII. The clinical presentation of type 2 VWD is
similar to type 1 VWD in that patients present with excessive mucocutane-
ous bleeding; however, in contrast to the variably positive family histories in
type 1 VWD, patients who have type 2 VWD usually present with a clearly
positive family history.

Type 2A
Type 2A VWD accounts for approximately 10% of all VWD cases and is
characterized by the loss of HMW and intermediate-molecular-weight multi-
mers. This is the result of a defect in the synthesis of the higher-molecular-
weight multimers (group 1 mutations) or the synthesis of multimers that are
more susceptible to cleavage by ADAMTS-13 (group 2 mutations) [40].
Type 2A can be suspected because of disproportionately low functional
 VON WILLEBRAND DISEASE 385

activity compared with von Willebrand factor antigen level (VWF:Ag) (ie,
VWF:RCo to VWF:Ag ratio of !0.60). The FVIII level may be low or nor-
mal. RIPA is reduced and the multimer profile shows a loss of HMW and
sometimes intermediate-molecular-weight multimers. The molecular genetic
basis of type 2A VWD is well characterized, with missense mutations in the
VWF A2 domain predominating. Other type 2A cases are caused by muta-
tions that disrupt dimerization or multimerization; these mutations are lo-
cated outside of the A2 domain (Fig. 4).

Type 2B
Type 2B VWD is the result of gain-of-function mutations within the
GpIb-binding site on VWF. This leads to an increase in VWF-platelet inter-
actions that result in the selective depletion of HMW multimers [27,41]. The
increased binding of mutant VWF to platelets also results in the formation
of circulating platelet aggregates and subsequent thrombocytopenia. As in
type 2A VWD, the laboratory profile shows a decrease in VWF:RCo to
VWF:Ag ratio; however, in contrast to 2A, there is increased sensitivity
to low doses of ristocetin in the RIPA. HMW multimers are absent in the
plasma. Type 2B mutations are well characterized and represent a variety
of different missense mutations in the region of the VWF gene encoding
the GpIb-binding site in the A1 protein domain. A disorder known as plate-
let-type VWD (PT-VWD) exhibits identical clinical and laboratory features
to those of type 2B VWD [42]. This condition is caused by mutations within
the platelet GPIB gene that affect the region of the GPIb/IX receptor that
binds to VWF [43]. It can be distinguished from type 2B VWD using platelet
aggregation tests that identify enhanced ristocetin-induced binding of VWF,
by mixing combinations of patient and normal plasma with patient and nor-
mal washed platelets. In rare cases, genetic analysis of the A1 domain of the
VWF gene and the GPIB gene can be performed. It is assumed that PT-
VWD is less prevalent than type 2B VWD although the level of misdiagnosis
is not known. The distinction is important, however, because the treatment
is plasma based in type 2B VWD and platelet based in PT-VWD.

Fig. 4. Type 2 VWD mutations. Repeating multidomain structure of the VWF protein. The
regions of the protein comprising the prepropolypeptide and mature VWF subunits are indi-
cated at the bottom of the diagram. Regions of the protein in which the causative mutations
for types 2A, 2B, 2M, and 2N VWD are shown above the protein diagram.
386 ROBERTSON et al

Type 2M
Type 2M VWD (the ‘‘M’’ refers to multimer) is characterized by de-
creased VWF-platelet interactions. The laboratory work-up shows a reduced
ratio of VWF:RCo to VWF:Ag but a normal multimer pattern. RIPA also
is reduced. Causative mutations are localized to the platelet GPIB-binding
site in the A1 domain of VWF [44].
Type 2N
Type 2N VWD (the ‘‘N’’ refers to Normandy, where the first cases were
reported) is described as an autosomal form of hemophilia A [45] and is an
important differential in the investigation of all individuals (male and fe-
male) presenting with a low FVIII level. The characteristic laboratory fea-
ture is a significant reduction in FVIII level when compared with VWF
level (which may be low or normal). The VWF multimer pattern in 2N is
normal. The definitive diagnosis requires the demonstration of reduced
FVIII binding in a microtiter plate-based assay or the identification of caus-
ative mutations in the FVIII-binding region of the VWF gene [46].
Type 3 von Willebrand disease
Patients who have type 3 VWD typically manifest a severe bleeding phe-
notype from early childhood, although clinical heterogeneity exists. In addi-
tion to more significant presentations of the cardinal mucocutaneous
bleeding symptoms seen in the other subtypes, individuals who have type
3 VWD experience joint and soft tissue bleeds frequently, similar to patients
who have hemophilia A, because of the commensurate reduction in plasma
FVIII levels. In the laboratory, this condition is characterized by prolonga-
tion of the aPTT and bleeding time, undetectable levels of VWF:Ag, and
VWF:Rco, and FVIII levels less than 0.10 IU/mL (10%). The inheritance
of type 3 VWD is autosomal recessive and although parents of affected
individuals often are unaffected, there is a growing realization that some
obligate carriers of type 3 VWD mutations manifest an increase in mucocu-
taneous bleeding symptoms compared with normal individuals [47]. Molec-
ular genetic studies of individuals who have type 3 VWD reveal that the
phenotype is the result of a variety of genetic defects, including large gene
deletions and frameshift and nonsense mutations within the VWF gene,
all of which result in a premature stop codon [48]. As a result of the lack
of circulating VWF, these mutations in some cases are associated with the
development of alloantibodies to VWF, which represent a serious complica-
tion of treatment [49,50].

Clinical management of von Willebrand disease

In general, the management of VWD can be divided into three main
categories: (1) localized measures to stop or minimize bleeding; (2)
 VON WILLEBRAND DISEASE 387

pharmacologic agents that provide indirect hemostatic benefit; and (3) treat-
ments that increase plasma VWF and FVIII levels directly.

Localized measures
The importance of localized measures to control bleeding in VWD, such
as the application of direct pressure to a site of bleeding or injury, should
not be understated. Biting down on a piece of gauze may halt bleeding
from a tooth socket, and application of a compression bandage and cold
pack to an injured limb may reduce subsequent hematoma formation. Man-
agement of nosebleeds can be problematic particularly for some affected
children, however, and patients may benefit from a stepwise action plan
that escalates from initial direct pressure to packing after a certain time
period and that includes guidelines regarding how long to wait before seek-
ing medical attention. In selected cases, nasal cautery may be required for
prolonged or excessive epistaxis.

Adjunctive therapies
Several adjunctive therapies can be used with significant benefit in VWD,
particularly at the time of minor surgical and dental procedures and to treat
menorrhagia. These interventions include the use of antifibrinolytic agents,
such as tranexamic acid and epsilon aminocaproic acid, and the application
of topical hemostatic preparations, such as fibrin glue, to exposed sites of bleed-
ing. In women who have menorrhagia, the administration of estrogens (that
work, at least in part, by elevating plasma VWF and FVIII levels) often results
in significant clinical benefit. Topical estrogen creams applied to the nasal
mucosa also are used in children to reduce epistaxis with variable efficacy.

Desmopressin
Desmopressin (1-deamino-8-D-arginine vasopressin) is a synthetic analog
of the antidiuretic hormone vasopressin [51]. Its administration increases
plasma VWF and FVIII levels by approximately twofold to eightfold within
1to 2 hours of administration [52]. The effect is presumed to be the result of
the release of stored VWF from endothelial cell Weibel-Palade bodies, with
the secondary stabilization of additional FVIII. Desmopressin can be
administered by the intravenous, subcutaneous, or intranasal route [53]. Its
peak effect is achieved within 30 and 90 minutes with the intravenous and in-
tranasal routes, respectively. The usual parenteral dose is 0.3 mg/kg (maxi-
mum dose 20 mg) infused in approximately 50 mL of normal saline over
approximately 30 minutes. The dose of the highly concentrated intranasal
preparation is 150 mg for children under 50 kg and 300 mg for larger children.
Highly concentrated products (eg, Stimate) deliver 150 mg per spray, a much
higher concentration than found in the nasal sprays used to treat enuresis.
388 ROBERTSON et al

Desmopressin is safe and generally well tolerated; however, its use in

pediatric patients must be undertaken cautiously. Common mild side effects
include facial flushing and headache. Tachycardia and mild reductions in
blood pressure can occur and, given that patients sometimes feel lightheaded
during the infusion, it is best to administer it with patients lying down. The
most serious side effects that can develop are severe hyponatremia and sei-
zures [54,55] because of the antidiuretic effect of the medication. Reduction
of fluid intake for 24 hours after administration to maintenance levels is an
important precaution to prevent water intoxication. Children under 3 years
of age are especially prone to this complication and extra attention must be
paid in these cases. With repeated desmopressin administrations, serial mon-
itoring of serum sodium levels should be performed.
An important limitation in the use of desmopressin is the development of
tachyphylaxis with repeated administration. The magnitude of the VWF
and FVIII increments often falls to approximately 70% of that documented
with the initial dose when given at repeated intervals of less than 24 hours
[56]. Presumably, a greater period of time is required for the Weibel-Palade
body VWF stores to be replenished. For practical purposes, a single dose of
desmopressin before dental procedures or at the onset of menses usually is
sufficient. Doses can be repeated at 12 or 24 hours; however, the potential
decrease in efficacy (described previously) must be considered. Additionally,
in situations where repeat dosing is considered, the duration of fluid restric-
tion must be increased. Generally, more than three doses of desmopressin
(preprocedure, at 12 hours, and at 24 hours) are not recommended.
Most patients who have type 1 VWD respond to desmopressin; however,
patients who have severe type 1 and many who have type 2 VWD do not
respond adequately [57]. Therefore, it is critical to perform a therapeutic
trial of the agent before any clinical use. VWF and FVIII levels should
be checked before desmopressin administration and at several time points
after (eg, at 1, 2, and 4 hours). Although the repeated phlebotomies can
present a significant challenge, particularly for young patients, documenta-
tion of an adequate response is recommended strongly. An increment of
VWF and FVIII to threefold over baseline and to at least 0.30 IU/mL
(30%) usually is considered adequate for situations, such as dental proce-
dures, minor surgery, or the treatment of epistaxis or menorrhagia; how-
ever, major surgery and significant bleeding episodes should be treated
with factor replacement therapy. Desmopressin responsiveness may be sub-
optimal in young children (!3 years), and repeat assessment at an older age
may be warranted. In addition, certain VWF mutants that show increased
clearance are described, limiting the clinical usefullness of desmopressin in
this setting [58].
Most patients who have type 1 VWD respond adequately to desmopres-
sin and, for these patients, the concomitant use of desmopressin and an
antifibrinolytic agent is sufficient for most clinical situations. Patients who
have type 3 VWD typically do not respond to desmopressin, however, given
 VON WILLEBRAND DISEASE 389

the lack of stored VWF in this condition. Patients who have type 2 VWD
respond variably to desmopressin. Patients who have type 2A often exhibit
adequate responses and, therefore, may benefit from a therapeutic trial.
Patients who have type 2M typically do not respond well to desmopressin.
Desmopressin long has been considered contraindicated in type 2B VWD
because of the transient thrombocytopenia that follows the release of the
mutant VWF; however, its hemostatic efficacy is documented, allowing its
use on an individualized basis [59,60]. Finally, desmopressin has been
used in patients who have type 2N, with a twofold to ninefold increase in
the VWF and FVIII levels [61]; however, the duration of the FVIII incre-
ment usually is only approximately 3 hours. This suggests that for patients
who have type 2N, desmopressin should be considered only in clinical situ-
ations where a brief, transient rise in FVIII is required.

Blood component therapy

Situations, such as major surgery, trauma, and life-threatening bleeding,
require intravenous treatment with plasma-derived concentrates of VWF
and FVIII. Cryoprecipitate was used commonly in these settings in the
1970s and 1980s, but it no longer is the treatment of choice because of
the lack of an effective viral inactivation process for this product. The blood
components currently used are plasma-derived, intermediate purity concen-
trates that have undergone several viral inactivation steps to prevent viral
transmission [62–64] (eg, Humate-P and Alphanate). Dosing recommenda-
tions currently are made in VWF:RCo units and are weight based; repeat
infusions can be given every 12 to 24 hours depending on the clinical situa-
tion. It is recommended to measure VWF:RCo and FVIII levels in patients
receiving repeat infusions not only to ensure adequate hemostasis but also to
monitor for supraphysiologic levels of FVIII. High FVIII levels associated
with treatment with these concentrates can contribute to venous thrombosis
[65]. In the rare event that infusion of an intermediate purity concentrate is
ineffective at stopping bleeding, transfusion of a platelet concentrate is ben-
eficial [66], presumably because it facilitates the delivery of a small amount
of VWF (contained in normal platelets) to the site of vascular injury. The
role of prophylactic factor infusions in patients who are affected severely
currently is the subject of an international randomized trial.

Summary
VWD is a common inherited bleeding disorder and many cases are diag-
nosed in childhood. VWD has a negative impact on the quality of life of af-
fected individuals; therefore, it is important that the condition be recognized
and diagnosed. This article reviews the pathophysiology of the condition,
the current classification scheme, and the available treatments, highlighting
issues specific to the pediatric population.
390 ROBERTSON et al

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