review

New developments in von Willebrand disease

Helen Fogarty,1,2 Dearbhla Doherty1 and James S. O’Donnell1,2,3

1
Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, 2National
Coagulation Centre, St James’s Hospital, and 3National Children’s Research Centre, Our Lady’s Children’s Hospital Crumlin, Dublin,
Ireland

approximately one in 1000 individuals.5,6 This prevalence of

Summary
VWD is relatively consistent across different races and eth-
Von Willebrand disease (VWD) constitutes the most com- nicities. Patients with VWD typically present with mucocuta-
mon inherited human bleeding disorder. It is associated with neous bleeding including epistaxis, easy bruising, gum
a mucocutaneous bleeding phenotype that can significantly bleeding and menorrhagia.7,8 Significant bleeding can also
impact upon quality of life. Despite its prevalence and associ- occur after trauma, delivery or following surgical proce-
ated morbidity, the diagnosis and subclassification of VWD dures.2 Spontaneous joint bleeding is also a feature in
continue to pose significant clinical challenges. This is in part patients with Type 3 VWD.9 Although most types of VWD
attributable to the fact that plasma von Willebrand factor are inherited in an autosomal manner, symptomatic bleeding
(VWF) levels vary over a wide range in the normal popula- is more common in females, due to the fact that they experi-
tion, together with the multiple different physiological func- ence more frequent haemostatic challenges, notably menstru-
tions played by VWF in vivo. Over recent years, substantial ation and delivery.10
progress has been achieved in elucidating the biological roles In clinical practice, diagnosis of VWD is based upon
of VWF. Significant advances have also been made into bleeding phenotype combined with abnormal VWF labora-
defining the pathophysiological mechanisms underpinning tory testing.11,12 In some cases, the VWD diagnosis may be
both quantitative and qualitative VWD. In particular, several supported by a documented family history. Nevertheless,
new laboratory assays have been developed that enable more diagnosis and subclassification of VWD remain complicated
precise assessment of specific aspects of VWF activity. In the and continue to pose significant challenges.13,14 In the pre-
present review, we discuss these recent developments in the sent review, we consider recent developments in the field of
field of VWD diagnosis, and consider how these advances VWD diagnosis, and briefly discuss recent advances with
can impact upon clinical diagnostic algorithms for use in respect to treatment options. We hope that this brief synop-
routine clinical practice. In addition, we review some impor- sis of the state-of-the-art regarding VWD will be useful for
tant recent advances pertaining to the various treatment trainees and general haematologists involved in providing
options available for managing patients with VWD. care for patients with VWD.

Keywords: Low VWF, von Willebrand disease, von Wille- VWD classification
brand factor.
Correct VWD classification is of direct clinical significance,
Von Willebrand disease (VWD) represents the most com- as patients with specific types of VWD display different
mon inherited bleeding disorder.1 It is caused by quantitative inheritance patterns, and may require different therapies.15,16
or qualitative reductions in plasma von Willebrand factor VWD classification has been addressed in a number of expert
(VWF).2 Studies suggest that reduced plasma VWF levels consensus guidelines. The International Society for Throm-
have a population prevalence of 1%.3,4 Significant bleeding bosis and Haemostasis (ISTH) guidelines published in 2006
symptoms due to reduced VWF levels have been reported in recommended that patients with VWD should be classified
into three major categories.17 Type 1 VWD is characterised
by a partial quantitative deficiency in plasma VWF and
accounts for the majority (~75%) of cases. Type 2 VWD
Correspondence: Prof. James O’Donnell, Irish Centre for Vascular includes all patients with qualitative defects that impair one
Biology, Royal College of Surgeons in Ireland, Ardilaun House, 111 or more aspects of VWF function (~25% cases). Type 2
St Stephens Green, Dublin 2, Ireland. VWD is further classified into four subtypes (Type 2A, 2B,
E-mail jamesodonnell@rcsi.ie 2M and 2N, respectively) based upon the nature of the
H.F. and D.D. contributed equally to this review. underlying VWF qualitative defect (Table I). Finally, rare

ª 2020 British Society for Haematology and John Wiley & Sons Ltd doi: 10.1111/bjh.16681
Review

Type 3 VWD (one per million individuals) is characterised condensed Molecular and Clinical Markers for the Diagnosis
by a quantitative VWF deficiency, with near complete and Management of Type 1 (MCMDM-1) VWD score and
absence of plasma VWF. an ISTH-endorsed BAT. For adult patients the normal scores
using the ISTH BAT range from zero to 3 in male subjects
and 0–5 in female subjects.27 Thus, laboratory testing for
ADVANCES IN VWD DIAGNOSIS
VWD (and/or additional bleeding disorders) should be con-
Several different clinical algorithms have been proposed to sidered in male referrals scoring ≥ 4, females scoring ≥ 6 or
optimise diagnostic accuracy in VWD.11,12,18 These guidelines children scoring ≥ 3, respectively. More recently, modified
share several common features. In particular, they consis- BATs have been developed to enable (i) self-administration
tently recommend that clinical VWD diagnosis should be by adult patients (https://letstalkperiod.ca/self-bat/)20 and (ii)
based upon assessment of bleeding symptoms coupled with specific use in paediatric populations.28 In this context, it is
specialised VWF laboratory testing. Over recent years there perhaps unsurprising that more recent consensus guidelines
have been important advances pertaining to specific aspects recommend that clinical investigation for VWD should begin
of VWD diagnosis: with the use of one of these validated BATs to objectively
quantify bleeding history. However, there is limitations to
the use of BAT testing.19 In particular, children or adults
Advances in assessment of bleeding phenotype in VWD
who have not undergone previous haemostatic challenges
diagnosis
may have a negative BAT score even in the presence of
Investigation of patients referred with possible VWD assess- underlying VWD. Also, recent studies suggest that important
ment begins with an assessment of bleeding history. Over the differences may exist between individual BAT scores in terms
past decade, a number of standardised bleeding assessment of their sensitivity in detecting heavy menstrual bleeding
tools (BATs) have been developed to enable objective assess- (HMB) in VWD.29 Finally, it remains unclear whether BAT
ment of bleeding symptoms.19 These comprehensive BAT scores have any role to play in predicting future bleeding risk
questionnaires provide a numeric score based on cumulative in newly diagnosed patients with different types of VWD.30
bleeding severity and frequency across a number of different
domains (including menorrhagia, cutaneous bleeding, dental
Advances in laboratory testing for quantitative VWD
bleeding and postoperative bleeding). Several different BATs
have been specifically validated for use in screening patients Quantitative VWD (which includes Type 1 and Type 3
referred with possible VWD (Table II [20–24]).19,25,26 The two VWD) accounts for the majority of clinical cases. For many
questionnaires most widely studied in VWD are the years, the concentration of circulating plasma VWF antigen

Table I. Overview of VWD subtypes.

VWD Subtype Inheritance Pathobiology and laboratory testing Comments

Type 1 Autosomal dominant but Partial quantitative VWF deficiency. Most common subtype ~75% of VWD
incomplete penetrance Concordant reductions in VWF:Ag and VWF cases.
functional assays. Includes VWF mutations causing rapid
clearance (e.g. VWF Vicenza).
Type 2A Mostly autosomal Decreased VWF-dependent platelet adhesion. 10–20% of VWD cases.
dominant Discordant reduction in VWF functional assays Hallmark is reduction in high-molecular
compared to VWF:Ag levels (ratio <0
6). weight multimers (HMWMs).
Type 2B Autosomal dominant Increased VWF affinity for platelet Gp1b. 5% of VWD cases.
Discordant reduction in VWF functional assays May be associated with loss of
compared to VWF:Ag levels (ratio <0
6). HMWMs  thrombocytopenia.
Must be distinguished from platelet-type
VWD.
Type 2M Autosomal dominant Decreased VWF-dependent platelet adhesion. 5% of VWD cases.
Discordant reduction in VWF functional assays Normal multimers.
compared to VWF:Ag levels (ratio <0
6). Diagnosis by exclusion.
Type 2N Autosomal recessive Decreased VWF binding affinity for FVIII. Must be distinguished from mild FVIII
Reduced FVIII:C levels with plasma VWF:Ag deficiency.
often normal or slightly reduced
Type 3 Autosomal recessive Severe quantitative VWF deficiency. Rare <1% of VWD.
Plasma VWF:Ag < 3 iu/dl. Joint bleeding in addition to
mucocutaneous bleeds.

2 ª 2020 British Society for Haematology and John Wiley & Sons Ltd
 Review

Table II. Bleeding assessment tools (BATs) in the diagnosis of VWD.

Time to
BAT Study population Sensitivity, % Specificity, % administer, min Comments

ISTH-BAT Prospective investigation for VWD 65
2 94
6 20

(n = 56) [90]
Condensed MCDM-1 VWD Prospective investigation for VWD 100 87 5–10 May
Score (n = 217) [91] underestimate
HMB in VWD
Self-BAT Prospective investigation for VWD 78 23 10 May be useful
(n = 64) [23] screening tool
Paediatric Bleeding Prospective investigation for VWD 83 79 20 Lack of
Questionnaire (n = 151) [92] haemostatic
challenges in
children may
reduce
sensitivity
Vicenza Bleeding Type 1 VWD carriers (n = 42) [93] 69
1 98
6 40
questionnaire

(VWF:Ag) has been determined by enzyme-linked VWF interaction with platelet Gp1b
immunosorbent assay (ELISA) methodology. This assay is
The VWF ristocetin cofactor activity assay (VWF:RCo) has
accurate and allows detection of even very low VWF:Ag
traditionally represented the ‘gold standard’ test for measur-
levels.31 However, the VWF:Ag ELISA is time-consuming to
ing VWF function.31 In the absence of any shear stress, this
perform. Consequently, automated latex immuno-assays for
assay uses ristocetin as a surrogate to induce VWF interac-
VWF:Ag have recently been developed. Data suggest that
tion with platelet Gp1b and thereby induce platelet aggluti-
these assays not only have shorter turn-around times, but
nation. Despite its widespread use, it is well recognised that
also produce results comparable to those derived by standard
the VWF:RCo assay has significant limitations. For example,
ELISA.32,33 Of note however, falsely elevated VWF:Ag levels
the assay demonstrates high inter- and intra-laboratory coef-
have been observed using the new latex assays in the pres-
ficients of variation (CVs).40,41 In addition, the lower limit of
ence of rheumatoid factor.34
detection in the VWF:RCo assay is approximately 10 iu/dl,
Recent large cohort studies have contributed significantly
so that accurate identification of qualitative VWD becomes
to our understanding of the pathobiology underpinning
difficult if plasma VWF:Ag levels are low.42 Recent studies
quantitative VWD. From a clinical perspective, an important
have shown that polymorphisms in the VWF A1 domain (in
finding from these studies is that enhanced VWF clearance
particular D1472H) can significantly attenuate VWF binding
commonly plays a key role in the pathogenesis of quantita-
to ristocetin.43 As a result, the D1472H substitution results
tive VWD.35 Accumulating evidence suggests that patients
in significantly reduced VWF:RCo levels in vitro, but is not
with enhanced VWF clearance can be identified by measuring
associated with any decrease in VWF functional activity
plasma VWF propeptide (VWFpp) levels by ELISA and then
in vivo. Consequently, individuals with D1472H were previ-
defining the VWFpp:VWFAg ratio.36,37 Although the VWFpp
ously mis-diagnosed with qualitative VWD based on their
ELISA is not yet widely available, truncated VWF responses
reduced VWF:RCo results.43 These findings are clinically
following 1-deamino-8-D-arginine vasopressin (DDAVP)
important because D1472H is common in the general popu-
administration have been reported in some patients with
lation. For example, in the USA Zimmerman cohort, VWF
VWD with enhanced clearance.37–39
D1472H was identified in 63% of African-American and
17% of Caucasian controls.43
Advances in laboratory testing for qualitative VWD In view of the limitations of the VWF:RCo assay, several
new commercial assays have recently been developed in an
In view of the fact that VWD can be quantitative or qualitative
effort to better assess platelet-dependent VWF functional activ-
in nature, laboratory testing must also include assays that
ity.44–47 These assays include the VWF:GP1bR and the VWF:
assess the different functional activities of VWF [notably its
GP1bM assays (Fig 1) 44,48. The VWF:GP1bR assay still
interactions with platelet glycoprotein Ib (GpIb), collagen and
requires the presence of added ristocetin, but uses a recombi-
factor VIII (FVIII) respectively].12 It is important to note that
nant GpIb fragment rather than platelets. As this assay involves
pre-analytical variables (including collection methodology,
ristocetin, it is subject to the same issues as the VWF:RCo assay
temperature during transport and freeze thaw) have the poten-
with respect to ristocetin-binding polymorphisms. In contrast,
tial to significantly impact upon VWF functional assessment.

ª 2020 British Society for Haematology and John Wiley & Sons Ltd 3
Review

the VWF:GpIbM assay uses a recombinant GpIba molecule utility. In addition, the pathological significance for many of
that contains a number of gain-of-function mutations, which these VWF variants has not been defined. Interpretation of
were previously associated with platelet-type VWD.49–51 Con- the pathological relevance of these sequence changes is fur-
sequently, this Gp1b variant binds to the A1 domain of VWF ther complicated by the fact that the VWF gene is highly
even in the absence of ristocetin. In addition to not being polymorphic in healthy individuals.61 There is also a VWF
affected by the common VWF P1467S and D1472H polymor- pseudogene located on chromosome 22 that demonstrates
phisms, accumulating data suggests that the new VWF activity approximately 97% sequence homology with VWF exons 23–
assays have reduced CVs and lower limits of detection com- 24.62 Several examples of gene conversion have also been
pared to the original VWF:RCo assays.50,51 However, it is described. Notwithstanding these caveats, recent cohort stud-
important to emphasise that none of the available static VWF ies have reported putative VWF mutations in ~65% of
functional assays directly assess the physiological function of patients with Type 1 VWD.38,59,60 Importantly, VWF coding
VWF in vivo (i.e. the ability of VWF to interact with platelet mutations were more common in patients with plasma
Gp1b under shear stress conditions). VWF:Ag levels < 30 iu/dl. In contrast, VWF mutations were
less common in patients with plasma VWF:Ag levels in the
30–50 iu/dl range.38,63] Also, familial linkage studies suggest
VWF interaction with collagen
that the reduced plasma VWF levels in this latter cohort are
In order for VWF to effectively mediate platelet recruitment often independent of the VWF gene. Although the role of
during primary haemostasis, it must bind to exposed suben- genetic testing in the diagnosis of Type 1 VWD remains
dothelial collagen at sites of vascular injury.1 Studies have unclear, it is clinically useful in confirming the diagnosis of
shown that discrete VWF domains interact with a number of Type 2 VWD (e.g. in Type 2B and 2N) and in particular dis-
different types of collagen. In particular, the A3 domain of criminating from mild haemophilia A and platelet-type
VWF binds to types I and III collagen, whereas the VWF A1 VWD.1,64 Furthermore, molecular analysis may also be useful
domain instead interacts with types IV and VI collagen, respec- for counselling and prenatal diagnosis in families with Type
tively (Fig 2).52,53 Several different commercial assays have 3 VWD.
been developed to assess VWF collagen binding (VWF:CB).
These assays typically contain types I and/or III collagen and
Factors complicating the diagnosis of VWD in clinical
are sensitive to reduced levels of VWF high-molecular-weight
practice
multimers (HMWMs).54 In general, VWF:CB assays have
improved CVs and lowered limits of detection compared to Several expert consensus guidelines have addressed how the
traditional VWF:RCo assays. Interestingly, a number of speci- diagnostic tests outlined above should be integrated in the
fic point mutations in the VWF A3 domain (including diagnosis and subclassification of VWD. For example, the
p.Ser1731Thr, pTrp1745Cys and pSer1783Ala) have been UK Haemophilia Centre Doctors Organisation (UKHCDO)
reported in patients with VWD.55,56 These patients had bleed- guidelines were updated in 2014 (Fig 3).11 Nevertheless, a
ing phenotypes but normal levels of VWF:Ag, HMWMs and number of important confounding factors continue to make
VWF activity as assessed by VWF:RCo assay. In contrast, sig- VWD diagnosis challenging in clinical practice.13,14
nificantly reduced levels of activity were observed when VWF:
CB testing was performed, leading to a diagnosis of Type 2M
Diagnostic thresholds
VWD. To date, testing for VWF binding to collagen types IV
and VI has been mainly limited to research laboratories. Normal plasma VWF levels vary over a wide range in the
Nonetheless, emerging data suggest that some VWF A1 normal population (~50–200 iu/dl). The UKHCDO guideli-
domain polymorphisms can specifically attenuate binding to nes recommend that quantitative VWD should be diagnosed
these types of collagen (e.g. pArg1399His, which is present in on the basis of the VWF:Ag levels.11 Undetectable plasma
up to 2% of Caucasians).57 Further studies will be required to VWF:Ag levels (typically <3 iu/dl) are consistent with a diag-
define the clinical importance of these findings. nosis of Type 3 VWD. For patients with significant bleeding
phenotypes and partial quantitative VWF deficiencies, most
guidelines recommend that two distinct subsets should be
Advances in genetic testing in VWD
considered.11,12 Patients with plasma VWF:Ag levels <30 iu/dl
The human VWF gene was cloned in 1985. It consists of 52 should be labelled with ‘Type 1 VWD’. These individuals are
exons and spans 178 kb on chromosome 12. Despite recent likely to have VWF gene mutations and exhibit autosomal
advances in next-generation sequencing, the utility of genetic dominance and high penetrance. In contrast, patients with
testing in the diagnosis of VWD remains unclear.58 In VWF:Ag levels in the 30–50 iu/dl range should be considered
patients with Type 1 VWD, a variety of different point muta- in a distinct category labelled ‘Low VWF levels.’ Although
tions have been described spanning the VWF gene (https://da these individuals may present with significant bleeding, they
tabases.lovd.nl/shared/genes/VWF).38,59,60 This heterogeneity are less likely to have underlying VWF gene mutations and
represents a significant obstacle to clinical genetic testing thus the inheritance pattern is less clear.38,63 The

4 ª 2020 British Society for Haematology and John Wiley & Sons Ltd
 Review

Fig 1. Biology underlying novel VWF-Gp1b functional activity assays. (i) In the traditional VWF:RCo assay, VWF binding to Gp1b is induced by
the addition of ristocetin to trigger platelet agglutination and increased optical density; (ii) In the VWF:Gp1bR assay, recombinant Gp1b is
expressed on latex particles rather than platelets. VWF binding is again induced by addition of ristocetin. (iii) In the VWF:Gp1bM assay, the
recombinant Gp1b molecule contains a number of again of function mutations that enable VWF interaction without the need for addition of ris-
tocetin. Adapted from Vangenechten et al.47

Fig 2. VWF ligand interaction sites including different collagen binding sites.

subclassification of quantitative VWD is complicated by the European Group on VWD did not include a Low VWF cate-
fact that recent consensus guidelines have differed regarding gory and recommended that patients with plasma VWF:Ag
specific diagnostic thresholds for Low VWF versus Type 1 levels <40 iu/dl who had relatives with equivalent levels
VWD. For example, the UKHCDO and National Heart, Lung should be considered for the diagnosis of mild VWD.18
and Blood Institute (NHLBI) guidelines both recommend a Current guidelines agree that Type 2 VWD should be
diagnosis of Low VWF for patients with plasma VWF:Ag diagnosed when there is a significant discrepancy between
levels in the 30–50 iu/dl range.11,12 In contrast however, the VWF functional assays (e.g. VWF:RCo, VWF:CB, VWF:

ª 2020 British Society for Haematology and John Wiley & Sons Ltd 5
Review

Fig 3. Suggested VWD diagnostic algorithm with defined threshold cut-offs. Adapted from UKHCDO guidelines.11

Gp1bR, Gp1bM or FVIII:C) compared to plasma VWF:Ag commonly results in VWF:Ag levels increasing to >50 iu/
levels. In the UKHCDO and European Union guidelines, dl.63 Interestingly however, it is not clear that this increase
Type 2 VWD is diagnosed if the VWF function:Ag ratio is in VWF levels is necessarily associated with complete cor-
<0
6.11,18 In contrast, the NHLBI guidelines recommend that rection of bleeding phenotype.63,70
the threshold for an abnormal ratio should be <0
5–0
7.12
Clearly, regardless of the arbitrary threshold limit used, we
ADVANCES IN THE TREATMENT OF VWD
must remain cogniscent that different VWF activity assays
display different sensitivities to specific VWF functional As well as recent advances in VWD diagnosis, there have also
defects and/or common VWF polymorphisms. been important developments with respect to the treatment
of patients with VWD. Established treatment options include
tranexamic acid (TA), DDAVP and several plasma-derived
Factors that can affect plasma VWF levels
VWF concentrates. In addition, there are a number of clini-
For many years it has been established that a number of cally useful adjunctive therapies that are commonly used in
different variables can influence plasma VWF:Ag levels. patients with VWD (including the oral contraceptive pill and
ABO blood group has a major effect, with significantly levonorgestrel intrauterine devices for HMB).71 These differ-
lower VWF levels in group O compared to non-O individu- ent therapies have been comprehensively reviewed in previ-
als.65 Plasma VWF:Ag levels are also significantly elevated ous publications.15,72–75 Consequently, here we will
by: (i) combined oral contraceptive pill use, (ii) pregnancy, specifically focus upon more recent advances pertaining to
(iii) acute phase responses, and (iv) circadian rhythm.66,67 VWD treatment.
As VWF levels vary so widely, it is recommended that
plasma VWF:Ag levels be repeated on several occasions
Tranexamic acid
before formal VWD diagnosis and classification, especially
in mild deficiencies. From a diagnostic perspective, it is also TA had been widely used in the treatment of VWD.11,71 It
important to emphasise that plasma VWF levels in normal can be administered orally [typical dose 15–25 mg/kg, thrice
individuals increase significantly with age.68 Recent studies daily (TID)], or intravenonsly [IV; typical dose 15 mg/kg,
have shown that plasma VWF:Ag levels also increase in TID). It inhibits fibrinolysis by binding to the lysine binding
many patients with VWD.69,70 Indeed, for many patients sites of plasminogen. Accumulating recent evidence has
with levels in the Low VWF range, this age-effect emphasised that use of TA, even in high-risk populations

6 ª 2020 British Society for Haematology and John Wiley & Sons Ltd
 Review

(e.g. trauma, postpartum haemorrhage, major orthopaedic findings have led to the suggestion that this cohort of
surgery) does not appear to be associated with significant patients do not require a formal DDAVP trial at diagnosis,
thrombotic risk.76–78 Nevertheless, it is usually avoided in but rather that VWF responses could simply be confirmed
patients with VWD with significant haematuria, as it has following the first clinical use of DDAVP therapy. Finally,
been associated with clot colic and urinary obstruction.15 although DDAVP can be of therapeutic use in some patients
with Types 2A and 2M VWD, it is generally avoided in
patients with Type 2B VWD, where it can cause significant
DDAVP
thrombocytopenia.
DDAVP can be administered subcutaneously (typical dose
0
3 lg/kg), IV (typical dose 0
3 lg/kg in 100 ml of normal
Plasma-derived VWF concentrates
saline infused over 20 min) or as a nasal spray (typical adult
dose 300 lg; typical paediatric dose 150 lg). DDAVP trig- A number of different commercial plasma-derived (pd-)VWF
gers secretion of VWF stores from endothelial cells and containing concentrates have been developed and licensed
thereby can be used to transiently elevate plasma VWF for use in patients with VWD (Table III). Important differ-
levels.79,80 However, not all patients with VWD experience ences between these concentrates include: (i) source of
significant increases in VWF levels following DDAVP ther- plasma, (ii) purification methodologies, (iii) viral inactivation
apy. Furthermore, as previously discussed, pathological processing, (iv) VWF multimer composition, and (v) FVIII
enhanced VWF clearance has been observed in >40% of content.15,74 Recent review articles have discussed the use of
patients with Type 1 VWD.35 Increased clearance has also VWF concentrates, and in particular specific VWF target
been demonstrated in some patients with Low VWF, as well levels in patients who have bleeding complications or who
as in Types 2 and 3 VWD.39,81 Consequently, in order to require surgical procedures.15,72,75 Repeated dosing with
fully define individual VWF pharmacokinetic responses after FVIII-containing VWF concentrates has been associated with
DDAVP therapy, a DDAVP trial is usually recommended. In significantly elevated plasma FVIII:C levels, and cases of
addition to measuring peak VWF and FVIII responses at objectively confirmed thrombosis have been observed in
30 min post-DDAVP, guidelines now also recommend some patients with VWD following treatment.82 However,
repeating these assays after 4 h to ensure that VWF although elevated FVIII:C levels have been shown to be a
responses are maintained.11 Evidence from the Low VWF dose-dependent risk factor for venous thromboembolism in
Ireland Cohort (LoVIC) study has shown that most patients the general population,83 the importance of elevated FVIII
registered with Low VWF (range 30–50 iu/dl) have excellent levels in the aetiology of thrombosis in patients with VWD
and sustained VWF responses following DDAVP.63 These following concentrate therapy remains unclear.

Table III. Plasma-derived VWF containing concentrates used in the treatment of VWD.

VWF:RCo/FVIII
Product Manufacturer Plasma source Viral inactivation ratio

Fandhi Grifols, Spain USA, Spain, Czech Republic, SD and dry heat 1
04
Slovakia (80 °C for 72 h)
Haemate P CSL Behring, Germany USA Pasteurisation 2
4
(60 °C for 10 h)
Wilate Octapharma, Austria USA, Sweden, Austria, SD and dry heat 0
9
Germany (100 °C for 2 h)
Wilfactin LFB, France Germany, France, SD and dry heat 50
Switzerland (80 °C for 72 h)
Nanofiltration (35 nM)
Immunate Takeda, Austria USA, Austria, Germany, SD and vapour heat 1
1
Sweden, Czech Republic (60 °C for 10 h at 190 mbar)
Factor 8Y BioProducts Laboratory, England USA Dry heat 0
81
(80 °C for 72 h)
Voncento CSL Behring, Germany USA, Australia, New SD and dry heat 2
4
Zealand, Malaysia, (80 °C for 72 h)
Singapore, Hong Kong
Veyvondi/ Vonvendi Takeda, Japan Recombinant VWF NA rVWF – negligible
concentrate FVIII

SD, solvent/detergent; NA, not available.

ª 2020 British Society for Haematology and John Wiley & Sons Ltd 7
Review

Recombinant VWF described. These differences are likely due in a large part to
the fact that platelet-VWF undergoes different post-transla-
The first recombinant human VWF concentrate (Vonicog
tional modification (including glycosylation) before its secre-
alfa, brand name Veyvondi in Europe and Vonvendi in USA;
tion.91,92 These insights into the structure and function of
Takeda Pharmaceutical Co. Ltd, Nihonbashi, Tokyo, Japan)
platelet-VWF have translational relevance. It is well recog-
has recently been developed and licenced for the treatment
nised that some patients with VWD may have ongoing
of VWD in adult patients in many countries. This rVWF is
bleeding even after plasma VWF levels have been normalised
expressed in Chinese Hamster Ovary (CHO) cells and con-
following VWF-concentrate infusion. Anecdotal reports have
tains only trace amounts of FVIII. Compared to pd-VWF
suggested that platelet transfusion can be useful in attenuat-
containing concentrates, the rVWF product is also enriched
ing this resistant bleeding phenotype.89,90 Further studies will
in HMWMs because it does not encounter ADAMTS13 (A
be required to fully define the biological importance of plate-
disintegrin and metalloproteinase with thrombospondin type
let-VWF, and specifically its role in contributing to the vari-
1 motifs, member 13) during its production.84 Recent clinical
able bleeding phenotype associated with VWD.
trials have reported that the rVWF therapy is associated with
good levels of haemostatic efficacy.85–87 In a pivotal phase 3
trial, rVWF was used to treat 192 bleeding episodes in 22 CONCLUSION
patients with VWD (including 17 with Type 3 VWD).85 A
In conclusion, recent years have seen significant advances in
single dose of rVWF was sufficient to manage bleeding in
our understanding of the biological mechanisms involved in
approximately 82% of these episodes. Overall haemostatic
the pathogenesis underlying VWD. These novel insights have
efficacy was rated as excellent in 97% and good in 3% of the
led to important progress in relation to diagnostic algorithms
treated cases. Subsequently, another phase 3 trial recently
and therapeutic options for VWD. Nevertheless, the diagno-
reported that rVWF is also efficacious in the prevention of
sis and subclassification of VWD undoubtedly continue to
bleeding for elective surgical procedures.87 Importantly, the
pose significant challenges for physicians in the clinic. In an
rVWF product has been well tolerated, with no evidence of
effort to address some of the important outstanding issues,
thrombotic or microangiopathic complications despite its
updated evidence-based guidelines are currently being devel-
HMWMs enrichment. In defining clinical treatment plans for
oped by a collaborative group representing the American
patients with VWD, it is important to remember that the
Society of Hematology (ASH), the ISTH, the National
rVWF does not contain significant amounts of FVIII. Conse-
Hemophilia Foundation (NHF) and the World Federation of
quently, for patients with VWD with reduced plasma FVIII:C
Hemophilia (WFH). Importantly, a recent international sur-
levels, co-administration of rFVIII should be considered
vey of >600 stakeholders (including patients, caregivers and
along with the first dose of rVWF in order to ensure that
healthcare providers) has highlighted some of the key topics
haemostatic FVIII levels are immediately achieved in patients
that need to be prioritised in the new guidelines.93 Perhaps
with VWD with significant bleeding. Without this concurrent
unsurprisingly, these include the need to clearly define evi-
rFVIII infusion, it may take approximately 6 h after rVWF
dence-based diagnostic criteria and to standardise VWD
treatment before plasma FVIII:C levels rise >40 iu/dl in
classification.
patients with Type 3 VWD.85 Finally, data from both the
phase 1 and 3 clinical trials suggest that the plasma half-life
of rVWF is significantly longer than that of pd-VWF (VWF: Acknowledgements
Ag 25
5 vs. 17
9 h, respectively). The molecular mechanisms
This work was performed within the Irish Clinical Academic
responsible for this half-life prolongation have not been
Training (ICAT) Programme, supported by the Wellcome
defined, but may relate to hypersialylation of the rVWF
Trust and the Health Research Board (Grant Number
product.88
203930/B/16/Z), the Health Service Executive, National Doc-
tors Training and Planning and the Health and Social Care,
Platelet-derived VWF Research and Development Division, Northern Ireland. In
addition, James S. O’Donnell was supported by a Science
In normal platelet-rich plasma, an estimated 15–20% of the
Foundation Ireland Principal Investigator Award (11/PI/
total VWF is stored within platelet a-granules.89 This plate-
1066); a Health Research Board Investigator Lead Project
let-VWF is secreted in high local concentrations following
Award (ILP-POR-2017-008) and a National Children’s
platelet activation at sites of vascular injury. In vitro and
Research Centre Project Award (C/18/1).
in vivo data support the hypothesis that platelet-VWF plays
an important role in regulating normal haemostasis.90
Importantly, recent studies have shown that platelet-VWF is Author contributions
not only enriched in HMWMs, but is also partially resistant
All authors drafted the first version of different sections of the
to ADAMTS13 proteolysis.91 Other functional discrepancies
manuscript and all critically reviewed the final manuscript.
between platelet-VWF and plasma-VWF have also been

8 ª 2020 British Society for Haematology and John Wiley & Sons Ltd
 Review

disease: a report of the Subcommittee on von Willebrand Factor. J Thromb

Conflict of interest Haemost. 2006;4:2103–14.
18. Castaman G, Goodeve A, Eikenboom J, European Group on von Wille-
James S. O’Donnell has served on the speaker’s bureau for Bax- brand disease. Principles of care for the diagnosis and treatment of von
ter, Bayer, Novo Nordisk, Boehringer Ingelheim, Leo Pharma, Willebrand disease. Haematologica. 2013;98:667–74.
Takeda and Octapharma. He has also served on the advisory 19. Rydz N, James PD. The evolution and value of bleeding assessment tools.
boards of Baxter, Bayer, Octapharma CSL Behring, Daiichi San- J Thromb Haemost. 2012;10:2223–9.
20. Deforest M, Grabell J, Albert S, Young J, Tuttle A, Hopman WM, et al.
kyo, Boehringer Ingelheim, Takeda and Pfizer. James S. O’Don-
Generation and optimization of the self-administered bleeding assessment
nell has also received research grant funding awards from tool and its validation as a screening test for von Willebrand disease. Hae-
Baxter, Bayer, Pfizer, Shire, Takeda and Novo Nordisk. mophilia. 2015;21:e384–388.
21. Bidlingmaier C, Grote V, Budde U, Olivieri M, Kurnik K. Prospective
evaluation of a pediatric bleeding questionnaire and the ISTH bleeding
REFERENCES assessment tool in children and parents in routine clinical practice. J
Thromb Haemost. 2012;10:1335–41.
1. Lillicrap D. von Willebrand disease: advances in pathogenetic understand-
22. Bowman M, Mundell G, Grabell J, Hopman WM, Rapson D, Lillicrap D,
ing, diagnosis, and therapy. Hematology Am Soc Hematol Educ Program.
et al. Generation and validation of the Condensed MCMDM-1VWD
2013;2013:254–60.
Bleeding Questionnaire for von Willebrand disease. J Thromb Haemost.
2. Leebeek FW, Eikenboom JC. Von Willebrand’s Disease. N Engl J Med.
2008;6:2062–6.
2016;375:2067–80.
23. Bowman M, Riddel J, Rand ML, Tosetto A, Silva M, James PD. Evaluation
3. Bowman M, Hopman WM, Rapson D, Lillicrap D, James P. The preva-
of the diagnostic utility for von Willebrand disease of a pediatric bleeding
lence of symptomatic von Willebrand disease in primary care practice. J
questionnaire. J Thromb Haemost. 2009;7:1418–21.
Thromb Haemost. 2010;8:213–6.
24. Rodeghiero F, Castaman G, Tosetto A, Batlle J, Baudo F, Cappelletti A,
4. Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the
et al. The discriminant power of bleeding history for the diagnosis of type
prevalence of von Willebrand’s disease. Blood. 1987;69:454–9.
1 von Willebrand disease: an international, multicenter study. J Thromb
5. Nosek-Cenkowska B, Cheang MS, Pizzi NJ, Israels ED, Gerrard JM. Bleed-
Haemost. 2005;3:2619–26.
ing/bruising symptomatology in children with and without bleeding disor-
25. Rodeghiero F, Tosetto A, Abshire T, Arnold DM, Coller B, James P, et al.
ders. Thromb Haemost. 1991;65:237–41.
ISTH/SSC bleeding assessment tool: a standardized questionnaire and a
6. Sadler JE, Mannucci PM, Berntorp E, Bochkov N, Boulyjenkov V, Gins-
proposal for a new bleeding score for inherited bleeding disorders. J
burg D, et al. Impact, diagnosis and treatment of von Willebrand disease.
Thromb Haemost. 2010;8:2063–5.
Thromb Haemost. 2000;84:160–74.
26. Tosetto A, Rodeghiero F, Castaman G, Goodeve A, Federici AB, Batlle J,
7. de Wee EM, Sanders YV, Mauser-Bunschoten EP, van der Bom JG, Dege-
et al. A quantitative analysis of bleeding symptoms in type 1 von Wille-
naar-Dujardin ME, Eikenboom J, et al. Determinants of bleeding pheno-
brand disease: results from a multicenter European study (MCMDM-1
type in adult patients with moderate or severe von Willebrand disease.
VWD). J Thromb Haemost. 2006;4:766–73.
Thromb Haemost. 2012;108:683–92.
27. Elbatarny M, Mollah S, Grabell J, Bae S, Deforest M, Tuttle A, et al. Nor-
8. Sanders YV, Fijnvandraat K, Boender J, Mauser-Bunschoten EP, van der
mal range of bleeding scores for the ISTH-BAT: adult and pediatric data
Bom JG, de Meris J, et al. Bleeding spectrum in children with moderate
from the merging project. Haemophilia. 2014;20:831–5.
or severe von Willebrand disease: relevance of pediatric-specific bleeding.
28. Biss TT, Blanchette VS, Clark DS, Bowman M, Wakefield CD, Silva M,
Am J Hematol. 2015a;90:1142–8.
et al. Quantitation of bleeding symptoms in children with von Willebrand
9. van Galen KP, Mauser-Bunschoten EP, Leebeek FW. Hemophilic
disease: use of a standardized pediatric bleeding questionnaire. J Thromb
arthropathy in patients with von Willebrand disease. Blood Rev.
Haemost. 2010;8:950–6.
2012;26:261–6.
29. Lavin M, Aguila S, Dalton N, Nolan M, Byrne M, Ryan K, et al. Signifi-
10. De Wee EM, Knol HM, Mauser-Bunschoten EP, van der Bom JG, Eikenboom
cant gynecological bleeding in women with low von Willebrand factor
JC, Fijnvandraat K, et al. Gynaecological and obstetric bleeding in moderate
levels. Blood Adv. 2018;2:1784–91.
and severe von Willebrand disease. Thromb Haemost. 2011;106:885–92.
30. Federici AB, Bucciarelli P, Castaman G, Mazzucconi MG, Morfini M, Rocino
11. Laffan MA, Lester W, O’Donnell JS, Will A, Tait RC, Goodeve A, et al.
A, et al. The bleeding score predicts clinical outcomes and replacement therapy
The diagnosis and management of von Willebrand disease: a United King-
in adults with von Willebrand disease. Blood. 2014;123:4037–44.
dom Haemophilia Centre Doctors Organization guideline approved by the
31. Rao ES, Ng CJ. Current approaches to diagnostic testing in von Wille-
British Committee for Standards in Haematology. Br J Haematol.
brand Disease. Transfus Apher Sci. 2018;57:463–5.
2014;167:453–65.
32. Sukhu K, Martin PG, Cross L, Keeling DM, Giangrande PL. Evaluation of
12. Nichols WL, Hultin MB, James AH, Manco-Johnson MJ, Montgomery RR,
the von Willebrand factor antigen (vWF-Ag) assay using an immuno-tur-
Ortel TL, et al. von Willebrand disease (VWD): evidence-based diagnosis
bidimetric method (STA Liatest vWF) automated on the MDA 180 coagu-
and management guidelines, the National Heart, Lung, and Blood Institute
lometer. Clin Lab Haematol. 2000;22:29–32.
(NHLBI) Expert Panel report (USA). Haemophilia. 2008;14:171–232.
33. Villa P, Iborra J, Serra J, Gilsanz A, Casana P, Aznar JA, et al. Evaluation
13. Leebeek FW, Susen S. Von Willebrand disease: Clinical conundrums. Hae-
of an automated method for the quantification of von Willebrand factor
mophilia. 2018;24(Suppl. 6):37–43.
antigen. Its application in the study of vascular dysfunction. Haematolog-
14. Quiroga T, Goycoolea M, Belmont S, Panes O, Aranda E, Zuniga P,
ica. 2001;86:1180–5.
et al. Quantitative impact of using different criteria for the laboratory
34. Favaloro EJ, Aboud M, Arthur C. Possibility of potential VWD misdiagno-
diagnosis of type 1 von Willebrand disease. J Thromb Haemost.
sis or misclassification using LIA technology and due to presence of
2014;12:1238–43.
rheumatoid factor. Am J Hematol. 2001;66:53–6.
15. Lavin M, O’Donnell JS. New treatment approaches to von Willebrand dis-
35. O’Sullivan JM, Ward S, Lavin M, O’Donnell JS. von Willebrand factor
ease. Hematology Am Soc Hematol Educ Program. 2016;2016:683–9.
clearance - biological mechanisms and clinical significance. Br J Haematol.
16. Sharma R, Flood VH. Advances in the diagnosis and treatment of Von
2018;183:185–95.
Willebrand disease. Blood. 2017;130:2386–91.
36. Haberichter SL. von Willebrand factor propeptide: biology and clinical
17. Sadler JE, Budde U, Eikenboom JC, Favaloro EJ, Hill FG, Holmberg L,
utility. Blood. 2015;126:1753–61.
et al. Update on the pathophysiology and classification of von Willebrand

ª 2020 British Society for Haematology and John Wiley & Sons Ltd 9
Review

37. Haberichter SL, Castaman G, Budde U, Peake I, Goodeve A, Rodeghiero F, 55. Flood VH, Lederman CA, Wren JS, Christopherson PA, Friedman KD,
et al. Identification of type 1 von Willebrand disease patients with reduced Hoffmann RG, et al. Absent collagen binding in a VWF A3 domain
von Willebrand factor survival by assay of the VWF propeptide in the Euro- mutant: utility of the VWF:CB in diagnosis of VWD. J Thromb Haemost.
pean study: molecular and clinical markers for the diagnosis and manage- 2010;8:1431–3.
ment of type 1 VWD (MCMDM-1VWD). Blood. 2008;111:4979–85. 56. Riddell AF, Gomez K, Millar CM, Mellars G, Gill S, Brown SA, et al.
38. Flood VH, Christopherson PA, Gill JC, Friedman KD, Haberichter SL, Bel- Characterization of W1745C and S1783A: 2 novel mutations causing
lissimo DB, et al. Clinical and laboratory variability in a cohort of patients defective collagen binding in the A3 domain of von Willebrand factor.
diagnosed with type 1 VWD in the United States. Blood. 2016;127:2481–8. Blood. 2009;114:3489–96.
39. Sanders YV, Groeneveld D, Meijer K, Fijnvandraat K, Cnossen MH, van 57. Flood VH, Schlauderaff AC, Haberichter SL, Slobodianuk TL, Jacobi PM,
der Bom JG, et al. von Willebrand factor propeptide and the phenotypic Bellissimo DB, et al. Crucial role for the VWF A1 domain in binding to
classification of von Willebrand disease. Blood. 2015b;125:3006–13. type IV collagen. Blood. 2015;125:2297–304.
40. Chandler WL, Peerschke EI, Castellone DD, Meijer P, Committee NP. 58. de Jong A, Eikenboom J. Von Willebrand disease mutation spectrum and
Von Willebrand factor assay proficiency testing. The North American Spe- associated mutation mechanisms. Thromb Res. 2017;159:65–75.
cialized Coagulation Laboratory Association experience. Am J Clin Pathol. 59. Goodeve A, Eikenboom J, Castaman G, Rodeghiero F, Federici AB, Batlle
2011;135:862–9. J, et al. Phenotype and genotype of a cohort of families historically diag-
41. Kitchen S, Jennings I, Woods TA, Kitchen DP, Walker ID, Preston FE. nosed with type 1 von Willebrand disease in the European study, Molecu-
Laboratory tests for measurement of von Willebrand factor show poor lar and Clinical Markers for the Diagnosis and Management of Type 1
agreement among different centers: results from the United Kingdom von Willebrand Disease (MCMDM-1VWD). Blood. 2007;109:112–21.
National External Quality Assessment Scheme for Blood Coagulation. 60. James PD, Notley C, Hegadorn C, Leggo J, Tuttle A, Tinlin S, et al. The
Semin Thromb Hemost. 2006;32:492–8. mutational spectrum of type 1 von Willebrand disease: Results from a
42. Favaloro EJ, Bonar R, Marsden K. Lower limit of assay sensitivity: an Canadian cohort study. Blood. 2007;109:145–54.
under-recognised and significant problem in von Willebrand disease iden- 61. Bellissimo DB, Christopherson PA, Flood VH, Gill JC, Friedman KD,
tification and classification. Clin Lab Sci. 2008;21:178–83. Haberichter SL, et al. VWF mutations and new sequence variations identi-
43. Flood VH, Gill JC, Morateck PA, Christopherson PA, Friedman KD, fied in healthy controls are more frequent in the African-American popu-
Haberichter SL, et al. Common VWF exon 28 polymorphisms in African lation. Blood. 2012;119:2135–40.
Americans affecting the VWF activity assay by ristocetin cofactor. Blood. 62. Mancuso DJ, Tuley EA, Westfield LA, Lester-Mancuso TL, Le Beau MM,
2010;116:280–6. Sorace JM, et al. Human von Willebrand factor gene and pseudogene:
44. Bod o I, Eikenboom J, Montgomery R, Patzke J, Schneppenheim R, Di structural analysis and differentiation by polymerase chain reaction. Bio-
Paola J, et al. Platelet-dependent von Willebrand factor activity. Nomen- chemistry. 1991;30:253–69.
clature and methodology: communication from the SSC of the ISTH. J 63. Lavin M, Aguila S, Schneppenheim S, Dalton N, Jones KL, O’Sullivan JM,
Thromb Haemost. 2015;13:1345–50. et al. Novel insights into the clinical phenotype and pathophysiology
45. Flood VH, Gill JC, Morateck PA, Christopherson PA, Friedman KD, underlying low VWF levels. Blood. 2017;130:2344–53.
Haberichter SL, et al. Gain-of-function GPIb ELISA assay for VWF activity 64. Bowman ML, James PD. Controversies in the diagnosis of Type 1 von
in the zimmerman program for the molecular and clinical biology of Willebrand disease. Int J Lab Hematol. 2017;39(Suppl. 1):61–8.
VWD. Blood. 2011;117:e67–74. 65. Jenkins PV, O’Donnell JS. ABO blood group determines plasma von
46. Stufano F, Lawrie AS, La Marca S, Berbenni C, Baronciani L, Peyvandi F. Willebrand factor levels: a biologic function after all? Transfusion.
A two-centre comparative evaluation of new automated assays for von 2006;46:1836–44.
Willebrand factor ristocetin cofactor activity and antigen. Haemophilia. 66. Miller CH, Dilley AB, Drews C, Richardson L, Evatt B. Changes in von
2014;20:147–53. Willebrand factor and factor VIII levels during the menstrual cycle.
47. Vangenechten I, Mayger K, Smejkal P, Zapletal O, Michiels JJ, Moore Thromb Haemost. 2002;87:1082–3.
GW, et al. A comparative analysis of different automated von Willebrand 67. Timm A, Fahrenkrug J, Jorgensen HL, Sennels HP, Goetze JP. Diurnal
factor glycoprotein Ib-binding activity assays in well typed von Willebrand variation of von Willebrand factor in plasma: the Bispebjerg study of diur-
disease patients. J Thromb Haemost. 2018;16:1268–77. nal variations. Eur J Haematol. 2014;93:48–53.
48. Higgins RA, Goodwin AJ. Automated assays for von Willebrand factor 68. Albanez S, Ogiwara K, Michels A, Hopman W, Grabell J, James P, et al.
activity. Am J Hematol. 2019;94:496–503. Aging and ABO blood type influence von Willebrand factor and factor
49. Graf L, Moffat KA, Carlino SA, Chan AK, Iorio A, Giulivi A, et al. Evalua- VIII levels through interrelated mechanisms. J Thromb Haemost.
tion of an automated method for measuring von Willebrand factor activity 2016;14:953–63.
in clinical samples without ristocetin. Int J Lab Hematol. 2014;36:341–51. 69. Rydz N, Grabell J, Lillicrap D, James PD. Changes in von Willebrand fac-
50. Lawrie AS, Stufano F, Canciani MT, Mackie IJ, Machin SJ, Peyvandi F. A tor level and von Willebrand activity with age in type 1 von Willebrand
comparative evaluation of a new automated assay for von Willebrand fac- disease. Haemophilia. 2015;21:636–41.
tor activity. Haemophilia. 2013;19:338–42. 70. Sanders YV, Giezenaar MA, Laros-van Gorkom BA, Meijer K, van der
51. Patzke J, Budde U, Huber A, Mendez A, Muth H, Obser T, et al. Perfor- Bom JG, Cnossen MH, et al. von Willebrand disease and aging: an evolv-
mance evaluation and multicentre study of a von Willebrand factor activ- ing phenotype. J Thromb Haemost. 2014;12:1066–75.
ity assay based on GPIb binding in the absence of ristocetin. Blood Coagul 71. Pasi KJ, Collins PW, Keeling DM, Brown SA, Cumming AM, Dolan GC,
Fibrinolysis. 2014;25:860–70. et al. Management of von Willebrand disease: a guideline from the UK
52. Pareti FI, Niiya K, McPherson JM, Ruggeri ZM. Isolation and characteri- Haemophilia Centre Doctors’ Organization. Haemophilia. 2004;10:218–31.
zation of two domains of human von Willebrand factor that interact with 72. Lavin M, O’Donnell JS. How I treat low von Willebrand factor levels.
fibrillar collagen types I and III. J Biol Chem. 1987;262:13835–41. Blood. 2019;133:795–804.
53. Saelman EU, Nieuwenhuis HK, Hese KM, de Groot PG, Heijnen HF, Sage 73. Leebeek FW, Atiq F. How I manage severe von Willebrand disease. Br J
EH, et al. Platelet adhesion to collagen types I through VIII under condi- Haematol. 2019;187:418–30.
tions of stasis and flow is mediated by GPIa/IIa (alpha 2 beta 1-integrin). 74. Mannucci PM. New therapies for von Willebrand disease. Blood Adv.
Blood. 1994;83:1244–50. 2019;3:3481–7.
54. Favaloro EJ. An update on the von Willebrand factor collagen binding 75. O’Donnell JS, Lavin M. Perioperative management of patients with von
assay: 21 years of age and beyond adolescence but not yet a mature adult. Willebrand disease. Hematology Am Soc Hematol Educ Program.
Semin Thromb Hemost. 2007;33:727–44. 2019;2019:604–9.

10 ª 2020 British Society for Haematology and John Wiley & Sons Ltd
 Review

76. WOMAN Trial Collaborators. Effect of early tranexamic acid administra- 85. Gill JC, Castaman G, Windyga J, Kouides P, Ragni M, Leebeek FW, et al.
tion on mortality, hysterectomy, and other morbidities in women with Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von
post-partum haemorrhage (WOMAN): an international, randomised, dou- Willebrand factor in severe von Willebrand disease. Blood. 2015;126:2038–46.
ble-blind, placebo-controlled trial. Lancet. 2017;389:2105–16. 86. Mannucci PM, Kempton C, Millar C, Romond E, Shapiro A, Birschmann
77. Poeran J, Rasul R, Suzuki S, Danninger T, Mazumdar M, Opperer M, I, et al. Pharmacokinetics and safety of a novel recombinant human von
et al. Tranexamic acid use and postoperative outcomes in patients under- Willebrand factor manufactured with a plasma-free method: a prospective
going total hip or knee arthroplasty in the United States: retrospective clinical trial. Blood. 2013;122:648–57.
analysis of effectiveness and safety. BMJ. 2014;349:g4829. 87. Peyvandi F, Mamaev A, Wang JD, Stasyshyn O, Timofeeva M, Curry N,
78. Roberts I, Shakur H, Coats T, Hunt B, Balogun E, Barnetson L, et al. The et al. Phase 3 study of recombinant von Willebrand factor in patients with
CRASH-2 trial: a randomised controlled trial and economic evaluation of severe von Willebrand disease who are undergoing elective surgery. J
the effects of tranexamic acid on death, vascular occlusive events and Thromb Haemost. 2019;17:52–62.
transfusion requirement in bleeding trauma patients. Health Technol 88. Ward S, O’Sullivan JM, O’Donnell JS. von Willebrand factor sialylation-A
Assess. 2013;17:1–79. critical regulator of biological function. J Thromb Haemost. 2019;17:1018–29.
79. Federici AB. The use of desmopressin in von Willebrand disease: the experi- 89. McGrath RT, McRae E, Smith OP, O’Donnell JS. Platelet von Willebrand
ence of the first 30 years (1977–2007). Haemophilia. 2008;14(Suppl. 1):5–14. factor–structure, function and biological importance. Br J Haematol.
80. Leissinger C, Carcao M, Gill JC, Journeycake J, Singleton T, Valentino L. 2010;148:834–43.
Desmopressin (DDAVP) in the management of patients with congenital 90. Mannucci PM. Platelet von Willebrand factor in inherited and acquired
bleeding disorders. Haemophilia. 2014;20:158–67. bleeding disorders. Proc Natl Acad Sci USA. 1995;92:2428–32.
81. Aguila S, Lavin M, Dalton N, Patmore S, Chion A, Trahan GD, et al. 91. McGrath RT, van den Biggelaar M, Byrne B, O’Sullivan JM, Rawley O,
Increased galactose expression and enhanced clearance in patients with O’Kennedy R, et al. Altered glycosylation of platelet-derived von Wille-
low von Willebrand factor. Blood. 2019;133:1585–96. brand factor confers resistance to ADAMTS13 proteolysis. Blood.
82. Makris M, Colvin B, Gupta V, Shields ML, Smith MP. Venous thrombosis 2013;122:4107–10.
following the use of intermediate purity FVIII concentrate to treat patients 92. Preston RJ, Rawley O, Gleeson EM, O’Donnell JS. Elucidating the role of
with von Willebrand’s disease. Thromb Haemost. 2002;88:387–8. carbohydrate determinants in regulating hemostasis: insights and opportu-
83. Jenkins PV, Rawley O, Smith OP, O’Donnell JS. Elevated factor VIII levels nities. Blood. 2013;121:3801–10.
and risk of venous thrombosis. Br J Haematol. 2012;157:653–63. 93. Kalot MA, Al-Khatib M, Connell NT, Flood V, Brignardello-Petersen R,
84. Peyvandi F, Kouides P, Turecek PL, Dow E, Berntorp E. Evolution of James P, et al. An international survey to inform priorities for new guide-
replacement therapy for von Willebrand disease: From plasma fraction to lines on von Willebrand disease. Haemophilia. 2020;26:106–16.
recombinant von Willebrand factor. Blood Rev. 2019;38:100572.

ª 2020 British Society for Haematology and John Wiley & Sons Ltd 11