Review Article

Advances in the diagnosis and treatment of Von Willebrand disease

Ruchika Sharma1,2 and Veronica H. Flood1-3
1
Pediatric Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI; 2Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI; and
3
Children’s Research Institute, Children’s Hospital of Wisconsin, Milwaukee, WI

Von Willebrand disease (VWD) is the most assessment of von Willebrand factor not helpful in type 1 VWD. Finally, treat-
common inherited bleeding disorder, yet (VWF) activity include a new platelet- ment options for VWD are reviewed, in-
diagnosis and management remain chal- binding assay, the VWF:GPIbM, which is cluding the use of recombinant VWF.
lenging. Development and use of bleeding subject to less variability than the ristoce- Despite these advances, still more work
assessment tools allows for improved tin cofactor activity assay, and collagen- is required to improve diagnosis, treat-
stratification of which patients may re- binding assays that provide insight into a ment, and quality of life for affected

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quire further assessment and which pa- different function of VWF. Genetic testing patients. (Blood. 2017;130(22):2386-2391)
tients are most likely to require treatment may be helpful in some cases where a type
of their VWD. New options for laboratory 2 VWD variant is suspected but is usually

Introduction
Von Willebrand disease (VWD) is the most common inherited bleeding connective tissue disorders must be considered in the differential
disorder, with a reported prevalence of approximately 1 in 1000 diagnosis.
persons.1 Quantitative defects include type 1 VWD, with partial
deficiency of von Willebrand factor (VWF), and type 3 VWD, with
virtually complete deficiency of VWF. Qualitative variants include
defects in multimerization (type 2A), spontaneous platelet binding Bleeding assessment tools
(type 2B), defects in ligand binding with intact multimers (type 2M),
and defects in factor VIII (FVIII) binding (type 2N). Type 1 VWD is the Bleeding history is critically important for the diagnosis of VWD. To
most common, accounting for up to 85% of VWD.2 Type 3 is the least that end, attempts have been made to quantify reported bleeding
common, affecting about 1 in 1 million individuals.3 Type 2 qualitative symptoms using bleeding assessment tools. The International Society
variants account for the remainder of VWD patients. The possibility on Thrombosis and Haemostasis (ISTH) has developed and performed
and reasonably high frequency of qualitative defects prevent diagnosis initial validation of a bleeding assessment tool for use in screening
of VWD with a single simple assessment of total VWF protein. The patients for VWD.5 Normal ranges have been established for children,
frequency of mild bleeding symptoms in the general population also adult males, and adult females.6 A pediatric bleeding questionnaire
makes choosing which patient to test for VWD a difficult task. (PBQ) has also been shown to have utility as a screening tool for VWD
Diagnosis of VWD rests on a history of bleeding symptoms, often in the pediatric population.7 The PBQ had a high negative predictive
with a family history of bleeding symptoms or diagnosed VWD, and value, meaning it was useful to assess which patients did not require
confirmatory laboratory testing.3 Typical bleeding includes mucosal further testing. The PBQ had a low positive predictive value. One
bleeding symptoms such as easy bruising, epistaxis, gingival bleed- explanation is the fact that VWD and platelet defects, among other
ing, surgical bleeding, and heavy menstrual bleeding. Gastrointestinal conditions (eg, connective tissue disorders), can present with similar
bleeding is a particular problem for patients with type 2A VWD.4 Type 3 mucosal bleeding symptoms. There is also potential overlap with the
and type 2N VWD patients may have joint bleeds due to low FVIII. wide range of normal bleeding symptoms seen in healthy individuals.8
There is overlap in the spectrum of normal bleeding with bleeding Bleeding scores in general correlate with severity of VWD. Type 3
attributable to defects in VWF, and the diagnosis is not always patients have the highest bleeding scores, type 2 patients are inter-
straightforward. In addition, children and young adults with VWD who mediate, and type 1 patients have the lowest bleeding scores.9 In
have not experienced significant hemostatic challenges may lack a addition, lower VWF:Ag and FVIII have been associated with
bleeding history. However, recent advances in quantifying bleeding, as increased bleeding scores.10 However, obtaining a bleeding score on
well as advances in diagnostic testing, should serve to improve our a patient who has previously been diagnosed and received treatment
ability to diagnose patients properly. Treatment of VWD continues to may be difficult, as treatment in and of itself will raise the bleeding
involve use of desmopressin or VWF concentrates, but a recently score. It is possible that history of bleeding is relevant for treatment,
available recombinant VWF has now been added to our treatment panel. as a recent study in adults showed that a bleeding score .10 was
VWD is of course not the only cause of mucosal bleeding. Ac- highly predictive of need for future treatment.11 This suggests that
quired VWD, platelet-type VWD, platelet function defects, vascular there is clinical utility in determining bleeding scores both for
malformations such as hereditary hemorrhagic telangiectasias, and diagnostic purposes and for treatment purposes.

Submitted 28 April 2017; accepted 30 July 2017. Prepublished online as Blood and Hematology 2017. It is reprinted in Hematology Am Soc Hematol Educ
First Edition paper, 29 November 2017; DOI 10.1182/blood-2017-05-782029. Program. 2017;2017:379-384.
This article was selected by the Blood and Hematology 2017 American Society © 2017 by The American Society of Hematology
of Hematology Education Program editors for concurrent submission to Blood

2386 BLOOD, 30 NOVEMBER 2017 x VOLUME 130, NUMBER 22

BLOOD, 30 NOVEMBER 2017 x VOLUME 130, NUMBER 22 DIAGNOSIS AND TREATMENT OF VWD 2387

There are some limitations to bleeding scores that should be Table 1. Comparison of VWF:RCo and VWF:GPIbM
considered. Time and lack of hemostatic challenges with which to VWF:RCo VWF:GPIbM
measure bleeding are of particular issue in the pediatric population. Lower limit of detection 10%-20% ,2.2%
Inclusion of pediatric-specific questions may be helpful but does Coefficient of variation 20% 2%-7%
not always provide complete reassurance that a given patient will Affected by “benign” sequence variations Yes No
not develop bleeding in the future.9 In addition, some studies are Widely available Yes Not yet
complicated by the fact that bleeding scores rely on the worst historical
episode to generate points; a patient who receives a diagnosis of VWD
assays described above under VWF and GPIba. Most VWD diagnostic
and is subsequently treated for surgery can generate an increased
panels do not include any assessment of collagen binding. To further
bleeding score independent of their recent symptoms because of that
complicate the collagen picture, there are different vascular collagens
treatment. Because VWF levels increase with age,12 it is possible that a
that interact with VWF and require specific testing. Types I and III
patient might “outgrow” their diagnosis. However, it is also possible
collagen bind to the VWF A3 domain.18 Types IV and VI collagen also
that higher VWF levels are required as patients age, so patients with
bind VWF but via the VWF A1 domain.19
increased VWF levels should be evaluated cautiously and in context of

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All collagen binding is dependent on the presence of high–
their present and past bleeding history.
molecular-weight multimers, but types I and III collagen in particular
have been shown to serve as a surrogate for the presence of
high–molecular-weight VWF multimers.20 There may be a dual role
for collagen-binding assays in VWD diagnosis, in order to evaluate
Advances in diagnostic testing multimer status and in order to screen for a possible collagen-binding
VWF and GPIba defect. Currently, many laboratories can perform type I or III collagen-
binding assays, although this is not typically done as part of a first line
Classic laboratory testing for VWD involves measurement of total evaluation. Commercial testing of types IV and VI collagen binding is
VWF protein levels via VWF antigen (VWF:Ag) and measurement of not currently available, although a kit for type VI collagen is marketed
VWF activity via ristocetin cofactor (VWF:RCo). This provides an for purchase.
assessment of VWF function in terms of platelet binding, as VWF binds Assays of either type I, type III, or a combination of the two will
to platelet glycoprotein Iba through a binding site in the VWF A1 suffice to detect specific A3 domain collagen-binding variants, of
domain. The VWF:RCo assay, however, has several issues limiting its which a handful have been reported to date.21-23 Specific A1 binding
usefulness. One problem is the high coefficient of variation, with the defects are more common, although binding to types IV and VI
potential for either falsely high or falsely low results.13 Another issue is collagen is rarely assessed in clinical practice.24 Research from the
the lower limit of detection, usually 10-20 IU/dL. This makes accurate Zimmerman Program, a large multicenter United States study on
assessment of possible type 2 variants difficult in patients with low patients with all types of VWD, has shown a relatively high incidence of
VWF:Ag, because the VWF:RCo/VWF:Ag ratio may be difficult to type IV and VI collagen-binding defects in patients with both type 1
determine. Because the VWF:RCo uses the nonphysiologic agonist (5%) and type 2M VWD (27%).24 In both cohorts, presence of a
ristocetin to bridge VWF and GPIba, there is the potential for false collagen-binding variant was associated with an increased bleeding
results due to defects in VWF’s ability to bind ristocetin. The most score compared with similar subjects without a collagen-binding
common of these is the p.D1472H variant, which affects ristocetin defect.
binding but not VWF function.14 Patients with increased bleeding scores and unexplained bleeding
Fortunately, a new assay is available that avoids the use of ristocetin. symptoms may benefit from collagen-binding testing to explore the
The VWF:GPIbM assay, using the terminology recommended by the possibility of an undiagnosed collagen-binding defect in VWF. As noted
International Society on Thrombosis and Haemostasis, introduces in the Introduction, however, there are a number of other diagnoses that
gain-of-function mutations into GPIba, allowing it to bind VWF should be considered, as not all bleeding is due to a defect in VWF.
spontaneously in vitro without the requirement for ristocetin.15 The
VWF:GPIbM allows greater precision, with a reported lower limit of VWF genetics
detection of 2 IU/dL and a reported-within-laboratory coefficient
The increased availability and lower cost of genetic testing enable
of variation of 5.6%.16 There is reasonable correlation between
increased use in diagnosis of VWD. Genetic testing is certainly simpler
VWF:RCo and VWF:GPIbM results.15 One study did show increased
than laboratory testing, where a number of different tests on plasma
qualitative VWF defects using the VWF:GPIbM.16 This may be due to
samples are required to make the diagnosis. In addition, plasma VWF
use of ristocetin as the “gold standard,” when in reality ristocetin is not
levels vary due to other underlying illnesses or stress, whereas VWF
the most accurate assay. At the time of writing, commercial availability
genetics should remain stable. However, there are a number of issues
of VWF:GPIbM assays is limited, but in some countries these have
with genetic analysis of VWF. First, there is a great deal of variability in
replaced the VWF:RCo entirely. In Europe and Canada, an automated
the VWF gene in healthy individuals.25 Many variants that were
VWF:GPIbM is available,15,16 whereas in the US, an ELISA version
previously called pathogenic have been found in healthy people, some
is available through the BloodCenter of Wisconsin.17 Both use a
at relatively high frequency, particularly in the African American
combination of 2 gain-of-function GPIba variants to elicit binding in
population and presumably other minority populations. For example,
the absence of ristocetin. It should be noted, however, that neither the
p.M740I was found in 18% of the African American controls, which
VWF:RCo nor the VWF:GPIbM is physiologic, as neither use shear to
suggests this is not likely to be the sole cause of VWD in an affected
induce VWF-platelet interactions (Table 1).
individual.25 Novel variants should be considered with caution, as
VWF and collagen changes in DNA do not necessarily imply changes to the VWF protein.
Another impediment to routine use of genetic analysis for VWD is
VWF has another function in binding exposed collagen at sites of the poor correlation between VWF sequence variants and disease for
injury, which requires specific testing apart from the platelet-binding type 1, the most common VWD type. A large study of VWD subjects
2388 SHARMA and FLOOD BLOOD, 30 NOVEMBER 2017 x VOLUME 130, NUMBER 22

Figure 1. Genetic variants in VWF in type 1 VWD.

100 Frequency of genetic variants in VWF for 5 large
population studies of type 1 VWD including the United
% of type 1 subjects with sequence variations

90 Kingdom,27 European Union,29 Canada,28 Germany,30

81% and United States.26 Overall 65% had a variant in VWF
80 found, but 35% did not.

70 68%
63% 62%
60
53%
50

40

30

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20

10

0
UK EU Canada Germany US

in the United States showed a relatively low rate of probably causative VWF.”3 As noted in VWF genetics, this group is less likely to have
VWF variants in those subjects with VWF:Ag .30 IU/dL.26 Figure 1 genetic variants, but may still have significant bleeding. This brings up
compares the overall rate of sequence variants in subjects diagnosed as the possibility of low VWF as a risk factor for bleeding, as originally
type 1 VWD, with an average rate of approximately 65% across 5 different proposed by Sadler.35
studies from the United Kingdom,27 Canada,28 Europe,29 and Germany.30
Therefore, at least a third of patients with type 1 VWD will not have a
specific genetic variant in VWF. In the Zimmerman program, sequence
variants were found in 84% of subjects with VWF levels ,30 and 44% in
those with levels of 30-50, whereas in the MCMDM-1VWD study from Advances in treatment
the European Union, sequence variants were found in 83% of subjects Current treatment of VWD is summarized in Table 2. Desmopressin is
with VWF:Ag ,30 and 69% of subjects with VWF:Ag 31-45.26,29 effective in treatment of VWD because it causes release of stored
Variants outside the VWF locus may also be responsible for VWF endothelial cell VWF. Testing of VWF is recommended at baseline,
levels. Blood group has been known for years to affect VWF levels.12 then 1 and 4 h following administration to ensure patients have a good
More recently, CLEC4M has been shown to affect VWF clearance.31 response (defined as threefold increase and to hemostatic levels).36
Other genes implicated in modifying VWF levels include scavenger Patients with VWD clearance defects will have an initial response but
molecule SCARA5,32 syntaxin binding protein 5 (STXBP5),32 and fall rapidly to a low level, limiting desmopressin’s utility in severe
ubiquitin fold modifier 1 (UFM1).33 Although these have not yet been
bleeds. Intranasal and IV administration are the most common, but
implicated in VWD, they and other unidentified genes may account for subcutaneous administration has also been used. Typical dosing is
some low VWF levels in patients without a clear genetic diagnosis. 1 spray for patients ,50 kg and 2 sprays for patients .50 kg. Side effects
Genetic analysis is most useful in type 2 VWD. Many type 2 include flushing, headache, and tachyphylaxis following repeated
variants, particularly type 2B, have been well characterized, and con- dosing due to exhaustion of stores. In addition, there is the potential for
firmation of a known genetic variant in VWF will confirm the diagnosis. hyponatremic seizures. It is recommended that patients have their total
In addition, many confirmatory plasma tests are not readily available fluid intake restricted for 24 hour following each dose, and high-risk
at many centers, whereas genetic testing may be easier to perform. patients may require monitoring of sodium levels. Approximately 80%
However, caution must again be applied to novel variants, as they may or of type 1 patients will have a good response, but some type 1 patients
may not represent true causes of disease. Analysis of type 3 VWD will not respond, particularly those with levels ,30 IU/dL.36,37
patients may also be helpful for prenatal diagnosis of potentially affected Plasma-derived VWF has been available for decades and is both
siblings.34 Genetic analysis either specifically for the p.D1472H variant safe and effective in treating bleeds in VWD. Most currently available
or of VWF exon 28 is helpful when the VWF:RCo/VWF:Ag ratio is concentrates contain both VWF and FVIII, although the ratio varies by
decreased in the setting of a normal multimer distribution. Sequencing
product. Humate-P has a VWF:FVIII ratio of approximately 2.4:1,
can either verify that the low ratio is caused by p.D1472H or, in patients whereas Wilate has a ratio of approximately 1:1. Alphanate also
with suspected type 2M VWD, reveal a causative variant. contains both FVIII and VWF but with a VWF:FVIII ratio of 0.5 to 1.38
Wilfactin, which is currently available in Europe, has plasma-derived
VWF with very low FVIII. Humate-P has been available since the
1980s and, as detailed in a recent review, has been effective with
The low VWF conundrum minimal adverse events.39 One recent surgery study of Humate-P
showed that .90% of subjects had good (minor oozing) or excellent
Recent guidelines have cited a cutoff value of 30 IU/dL for a diagnosis (normal hemostasis) results.40 A surgery study using Wilate had .95%
of VWD, leaving patients with levels below the lower limit of the of procedures with excellent (no further bleeding) or good (minor
reference range, but higher than 30 IU/dL in the gray zone of “low bleeding, no additional product needed) responses.41 Wilfactin has also
BLOOD, 30 NOVEMBER 2017 x VOLUME 130, NUMBER 22 DIAGNOSIS AND TREATMENT OF VWD 2389

Table 2. Comparison of VWD treatment options

Route of
administration Advantages Disadvantages Typical dosing
Desmopressin Intranasal, IV, SQ Easily given at home Fluid restriction required 0.3 mcg/kg IV or 2 sprays IN (.50 kg)/1
Not effective for all VWD types spray IN (,50 kg)
Plasma-derived VWF IV Most products contains both VWF Plasma product 50-60 ristocetin cofactor activity units/kg
concentrates and FVIII Most products contain both VWF and for major surgery, depending on
FVIII baseline VWF level and desired goal
level
Recombinant VWF IV Recombinant, allows titration of May require addition of recombinant 50-80 ristocetin cofactor activity units/kg
concentrate FVIII level FVIII for emergency treatment for major surgery, depending on
baseline VWF level and desired goal
level; for emergency treatment may
require addition of recombinant FVIII
depending on patient’s endogenous

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FVIII level
Antifibrinolytics PO, IV Easily given at home May not work for nonmucosal bleeds Aminocaproic acid: loading dose of
100 mg/kg then 50 mg/kg every 6 h
Tranexemic acid: 1500 mg 3 times
daily 3 5 d for menorrhagia

IN, intranasal; IV, intravenous; PO, oral

been shown to be safe and effective, although for emergency surgi- Despite this, the recommendation to infuse FVIII along with the initial
cal procedures a dose of FVIII was given along with the VWF dose of VWF remains prudent in most patients with low baseline FVIII
concentrate.42 levels, but the separation of VWF and FVIII allows for individualized
The currently available plasma-derived products appear to have therapy.
similar efficacy, with the vast majority of VWD patients having an Other treatment options include antifibrinolytics as well as hormone
adequate response. Typical treatment doses of plasma-derived VWF therapy for women with heavy menstrual bleeding. Antifibrinolytics
depend in part on the patient’s endogenous VWF level but are generally such as tranexamic acid or aminocaproic acid have been used with
50 to 60 ristocetin cofactor activity units/kg for major surgery. Repeat success to treat heavy menstrual bleeding and surgery involving
dosing is often required given the typical half-life of around 12 hours.40 mucosal surfaces (typically tonsillectomy or dental surgery).3 For
Risk of viral transmission is always a concern with plasma-derived women with heavy menstrual bleeding, hormone therapy given either
products but has not been an issue for several decades. Risk of as combined estrogen/progesterone pills or via IUD has been shown
thrombosis may be of increased concern, especially in adult patients, to be effective at reducing blood loss and maintaining a normal
but has not been reported as a significant issue in any of the above hemoglobin.45 Treatment of heavy menstrual bleeding is of particular
studies. Of more concern is the risk of inhibitor formation, particularly importance due to the low quality of life reported by patients.46
in patients with type 3 VWD. Patients with large deletions are most GI bleeding represents a specific challenge in the management of
likely to experience inhibitor formation.43 VWD. Type 2A VWD patients in particular are subject to an increased
Although prophylactic factor dosing is typically associated with frequency of GI bleeding, attributed to increased angiodysplasia in the
hemophilia, there is a role for prophylaxis in VWD. Some patients with GI tract.47 Treatment includes blood transfusion acutely and VWF
type 3 VWD will have significant bleeding such that prophylaxis is replacement for a prolonged period of time. In cases of refractory
useful to prevent recurrence. In addition, secondary prophylaxis is used bleeding, additional options include octreotide, estrogen, thalidomide,
in certain circumstances (eg, menorrhagia, recurrent gastrointestinal and atorvastatin.48
[GI] bleeds). Data from the von Willebrand Disease Prophylaxis
Network demonstrate that prophylaxis in severe VWD can reduce both
mucosal and joint bleeds.43 Joint bleeds were reduced from an average
of 15.6 to an average of 1.3 per year, whereas epistaxis was reduced Who to treat
from 24 to 6.43 Another area where secondary prophylaxis may be
required is GI bleeding, which is particularly prevalent in type 2A Although treatment options for VWD remain largely unchanged, save
VWD.4 for the new availability of recombinant VWF, there have been
Recombinant VWF has recently been approved in the United States improvements in the ability to predict which patients will require
and has been shown to be effective in treatment of surgery and major treatment. Federici and colleagues recently published an algorithm
bleeds.44 One caveat with its use is that the recombinant VWF using bleeding score and VWF level to predict which patients would
preparation does not contain FVIII. Therefore, most patients with low require treatment of their bleeding symptoms.11 Patients with a
FVIII levels will require concomitant administration of recombinant bleeding score .10 had the highest incidence of bleeding, regardless
FVIII along with the initial dose of recombinant VWF. Current dosing of VWD subtype. This study was limited to adults but does provide
recommendations for major surgery include 50 to 80 ristocetin cofactor evidence that bleeding begets more bleeding. This suggests that history
activity units of recombinant VWF (along with recombinant FVIII of bleeding should be taken into account when planning individualized
if immediate hemostasis is required). Subsequent dosing can use treatment.
exclusively recombinant VWF, as endogenous FVIII production will Adequate treatment is key to allowing patients to have the highest
maintain normal FVIII levels once VWF is present. Interestingly, in the possible quality of life. Joint bleeds are associated with decreased
initial publication on recombinant VWF, 10 initial bleeding treatment health-related quality of life, as is menorrhagia.49,50 Pediatric patients
doses were given without recombinant FVIII with good results.44 with a diagnosis of VWD also experience a lower quality of life.51 It is
2390 SHARMA and FLOOD BLOOD, 30 NOVEMBER 2017 x VOLUME 130, NUMBER 22

to be hoped that improvements in diagnosis and treatment will translate

to improvements in quality of life for affected patients. However, more Acknowledgments
work is needed to identify those patients who will benefit most from
treatment without overdiagnosis of VWD. V.H.F. would like to acknowledge research funding from the
National Institutes of Health (HL126810) and the MACC Fund
Center for Cancer and Blood Disorders.

Summary
VWD is a common and challenging bleeding disorder, given the
difficulties in diagnosis and treatment. New options for diagnosis, Authorship
including use of bleeding assessment tools and new assays for VWF
activity, may help alleviate some of these challenges. Because VWD Contribution: R.S. and V.H.F. composed and edited the manuscript.
has a major impact on patient quality of life, improved treatment options Conflict-of-interest disclosure: R.S. declares no competing financial

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are always helpful. The addition of recombinant VWF to available interest. V.H.F. has consulted for CSL Behring and Shire. Off-label
therapeutic options will allow clinicians to continue to tailor treatment drug use: None disclosed.
to optimize outcomes for individual patients. Despite these advances, Correspondence: Veronica H. Flood, Comprehensive Center for
more work is required to streamline diagnosis and improve treatment of Bleeding Disorders, 8739 Watertown Plank Rd, PO Box 2178,
affected patients. Milwaukee, WI, 53201-2178; e-mail: vflood@mcw.edu.

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