Haemophilia (2016), 22, 739751

DOI: 10.1111/hae.12955

ORIGINAL ARTICLE Von Willebrand disease

Practical aspects of factor concentrate use in patients with

von Willebrand disease undergoing invasive procedures: a
European survey

D E Z and

E Z F E R N AN
J . W I N D Y G A , * G . D O L A N , C . A L T I S E N T , O . K A T S A R O U , M . - F . L OP

B . Z UL F I K A R * * O N B E H A L F O F T H E E H T S B
*Department of Disorders of Hemostasis and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw,
Poland; Haemophilia Unit, St Thomas Hospital, London, UK; Servicio de Hematologia Unidad de Hemofilia, Hospital
Vall DHebron, Barcelona, Spain; Thrombosis and Haemostasis Unit, Laikon General Hospital, Athens, Greece; Servicio
Hematologia Complexo, Hospitalario A Coru~
na, INIBIC, La Coru~
na, Spain; and **Department of Pediatric Hematology,
Cerrahpasa Faculty of Medicine, Istanbul University, Cerrahpasa, Istanbul, Turkey

Introduction: The bleeding propensity in von Willebrand disease (VWD) is usually moderate or mild and patients
with VWD do not need continuous treatment, but do require extra increased haemostatic cover when undergoing
dental or surgical procedures. Desmopressin can be effective in certain patient groups and this has been
considered in a previous publication. Aim: This paper now seeks to evaluate current knowledge and practice in
the use of factor concentrate in the management of VWD patients undergoing invasive procedures. Methods: A
literature search was performed on the use of factor concentrates to cover invasive procedures and a survey of
current practice in a number of specialist haematology centres across Europe represented by the European
Haemophilia Strategy Board was conducted. Results: Our review of the literature and the results of the survey
showed considerable heterogeneity in treatment regimens, and a lack of consistency in reporting of the variables
that determine factor concentrate dosing and monitoring. Conclusion: By analysing the literature, examining
guidelines and using consensus deliberation, this survey allowed the group to develop recommendations for
management of VWD patients undergoing invasive procedures.
Keywords: factor concentrate, haemostatic cover, invasive procedures, survey, von Willebrand disease

Introduction
von Willebrand disease (VWD) is characterized by a
quantitative or qualitative lack of von Willebrand factor (VWF). VWF functions to facilitate normal platelet
adhesion in primary haemostasis, and acts as carrier
and stabilizer of FVIII in secondary haemostasis. Lack
of VWF results, therefore, in decreased functioning
levels of FVIII. Secondary FVIII deficiency is usually
severe in VWD type 3, as well as in some homozygous
or doubly heterozygous type 2N VWD mutations,
whereas in other types of VWD, FVIII plasma levels
Correspondence: Professor Jerzy Windyga, Department of Disorders of Hemostasis and Internal Medicine, Institute of Hematology and Transfusion Medicine, 14, Gandhi Str., Warsaw,
Poland.
Tel.: +48 22 34 96 158; fax: +48 22 34 96 159; e-mail: jwindy
ga@ihit.waw.pl
Accepted after revision 25 March 2016
2016 John Wiley & Sons Ltd

may be only moderately or mildly decreased, or even

within the normal range.
For all types of VWD, the bleeding propensity is
usually moderate or mild, and unlike patients with
haemophilia, the majority do not need constant treatment to maintain clotting factor levels. However, the
deficiency of VWF and FVIII contributes to clinical
manifestations of excessive and prolonged postsurgical
bleeding and mucosal haemorrhages, such as nose
bleeds and menorrhagia [1].
Therefore, for any invasive procedures, additional
haemostatic interventions are often necessary to normalize functional levels of VWF and FVIII, using
either desamino D-arginine vasopressin (DDAVP),
which induces secretion of VWF from endothelial cells
via cAMP-mediated signalling [2] and/or administering
VWF concentrates with or without FVIII.
These two treatment options are well established,
but sometimes there is lack of consensus on which
treatment is most appropriate for a given individual,
739

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J. WINDYGA et al.

since treatment will depend on the subtype of VWD,

and the nature of the procedure. DDAVP is not an
option in type 3 VWD, where the body is incapable of
producing VWF; but for other subtypes, where the
lack of VWF is incomplete or the factor produced is
not fully functional, the choices are not so clear-cut.
Additionally, concentrates contain varying ratios of
FVIII and VWF activities, and the pharmacokinetic
(PK) response in VWD patients to infused VWF concentrates containing FVIII is not parallel for both factors. This makes the choice between different products
more complex in comparison with the situation in
haemophilia A or B, in which replacement therapy is
based on use of concentrates containing only one deficient protein.
There is also a paucity of information concerning
the laboratory parameters that should be monitored to
inform treatment. In most clinical situations, ristocetin
cofactor activity (VWF:RCo) is used to evaluate the
functional activity of VWF. However, from reviewing
the literature, and clinical experience, we cannot see a
clear correlation between VWF:RCo plasma activity
and bleeding.
We therefore conducted a literature survey on the
management of VWD during surgical interventions
and undertook a survey of specialist haematologists
across Europe to assess current clinical practice with a
view to identifying minimally effective doses for dental, minor and major surgery. We have previously
reported on the use of DDAVP to cover invasive procedures [3] and report here on our findings for the use
of factor concentrate.

Methods
The European Haemophilia Therapy Strategy Board
(EHTSB) is an independent collaborative group of 20
Haemophilia Centre Directors and researchers from
14 European countries. A subgroup of six Board
members (the authors) was responsible for overseeing
this project.
A literature survey was performed using PubMed
and Medline databases with keywords of VWD, desamino arginine vasopressin, surgical procedures, minimally invasive/or biopsy/or invasive procedure,
treatment or therapeutics and restricted to 2000
June 2015. The Cochrane database was searched and
additionally, a search was run for Guidelines on
treating VWD on Google, PubMed and Medline.
Members of the EHTSB provided national guidelines.
Eliminated papers were: review articles, those not giving specific details covering surgery in VWD or
surveys of physicians practice.
The resultant papers were evaluated by the subgroup, who also designed a questionnaire that was
sent to all members of the EHTSB as described previously [3].
Haemophilia (2016), 22, 739--751

Results
Literature survey
Our original literature search retrieved a list of 21
papers and nine guidelines. Studies using DDAVP to
cover surgical procedures in VWD have been considered previously [3]. In June 2015, the literature search
considering the use of factor concentrate was updated.

Studies using factor concentrates

Eighteen studies used concentrate to control bleeding
[421], but one was excluded [22] due to lack of
detail. The 17 remaining studies covered 614 patients
undergoing 914 surgical procedures (where reported
178 interventions were classified as major and 257 as
minor surgery) (see Table S1).

Concentrate dosages
Identifying commonly used doses was simply not possible, due to the huge range of values: 2474 IU kg 1
for dental (oral), 3070 IU kg 1 for minor and 29
101 IU kg 1 major surgery. Aligning doses between
studies was further confounded by the heterogeneity
of study design: studies reported dose by VWD subtype, by surgical procedure and by basal VWF level.
Many studies did not define major and minor surgery
or included lists of surgical procedures under each
heading that were not consistent across studies (see
Table S1). Some studies considered invasive procedures and dental surgery as distinct entities, whereas
others encompassed both under minor surgery.
Furthermore, the different concentrates used have
differing ratios of VWF:RCo/FVIII:C, so values in
IU kg 1 are not simply interchangeable between the
different preparations or comparable across studies.
Overall, efficacy was excellent to good for all concentrates: Haemate/Humate: 9199%; Biostate: 90100%;
Fandhi: 93100%; other concentrates: 92100%. The
concentrates were well tolerated with only few reports
of adverse events (six papers reported no AEs). It was
notable that there were only two reports of thromboembolism [18,19]. Five patients showed parvovirus seroconversion [14,15,19,20] but the relationship to study
medication was not always clear. The adverse events
that were noted were those that might be expected in
surgical patients and comprised nausea and/or vomiting
[4,9], urticaria [14], minor elevation of liver function
tests moderate dyspnoea [11], pruritus [13,20], chills
[20] and thrombophlebitis [4,11,13,18,19].

Target levels of haemostatic factors

A common approach to haemostasis during invasive
procedures in patients with inherited clotting factor
2016 John Wiley & Sons Ltd

USING FACTOR CONCENTRATE IN VWD PATI ENTS UNDERGOING INVASIVE PROCEDURES

deficiency is to set target levels of the deficient factor

and titrate concentrate doses against these targets.
Our intention was to compare the preoperative (postloading) and postoperative target vs. actual levels of
FVIII:C and VWF:RCo, however, we were not able to
do that for most of the studies due to lack of comprehensive data. Table 1, therefore, comprises the seven
studies that reported these parameters.
Four of the studies [4,6,13,20] defined target levels
for both FVIII:C and VWF:RCo; three only considered
target levels for FVIII:C [11,14,17]. Two studies
[4,20] defined targets for the time of surgery and the
postsurgical period, while four [6,13,14,17] gave
the postsurgical targets and one [11] did not separate
the pre- and postoperative periods.
The reporting of postoperative levels of FVIII:C and
VWF:RCo also varied. Four studies [4,11,14,20] presented the data graphically, which gives a good
impression of the pattern of factor levels over time,
but makes it difficult to ascertain plasma levels accurately. The other three studies [6,13,17] reported
plasma levels, but Khair [17] reported baseline levels
but not postoperative levels of VWF:RCo.
There was lack of clear-cut information on whether
the applied dosing was related to the predefined target
levels and aimed to maintain these targets, since in
every study postoperative plasma levels exceeded the
predefined minimal target values, and sometimes the
maximal target values occasionally by a notably
large margin. Three studies performed PK studies
prior to surgery [4,6,20].
This makes it difficult to gain insight into the minimally effective levels of FVIII:C or VWF:RCo required
for effective haemostasis and while the efficacy of the
replacement therapy was assessed very high in all
studies, efficacy was mostly assessed in terms of clinical parameters, such as bleeding, rather than plasma
factor levels.

Additional therapy
For eight of the studies, there was no mention of additional antifibrinolytic treatment; three studies mentioned that tranexamic acid or epsilon-aminocaproic
acid (EACA) were allowed, but did not report on their
use; in the remaining six papers, tranexamic acid use
ranged from 1/58 procedures [10] to 57% in major surgery [12] or routinely except in urological or spinal surgery [17]. Thromboprophylaxis was used for 10
patients (mainly orthopaedic surgery) in one study [20].

Guidelines or recommendations
It is worth mentioning that the majority of guidelines
are largely based on expert opinion, only three [23
25], used levels of evidence in the published literature
to support their conclusions.
2016 John Wiley & Sons Ltd

74 1

As with the investigative studies, drawing conclusions regarding the use of factor concentrate for surgical procedures was complicated by the different units
used and the wide spread of doses (Table 2).
So, for major surgery, a preoperative infusion of
50 IU kg 1 FVIII is recommended [26,27], while most
other guidelines express doses in units of VWF:RCo.
Doses of VWF:RCo range from 40 to 70 IU kg 1,
with higher doses (60100) for type 1 (recessive in
one guideline), type 2B, 2N and type 3 VWD
[23,24,28].
Recommended preoperative doses for minor surgery
range from 30 IU kg 1 FVIII:C [26] to 60 IU kg 1
VWF:RCo in pronounced type 2, recessive type 1 and
type 3 patients [23]. Other doses are within this range.
Michiels et al. [23] suggest 4060 IU kg 1 VWF:RCo
for types 2A, 2B, 2C recessive type 1 and severe type
2N; other guidelines suggest 3060 IU kg 1 VWF:
RCo/FVIII:C [27] or 3060 IU kg 1 VWF:RCo
[28,29]. Subsequent doses are 2040 IU kg 1 VWF:
RCo, with a higher dose up to 60 IU kg 1 VWF:RCo
recommended for pronounced type 2, recessive type 1
and type 3 patients [23].
Dental surgery is usually covered by a single dose of
concentrate at levels ranging from 20 40 IU kg 1
FVIII:C [26] to 4060 IU dL 1 VWF:RCo [23].
It should be stressed that a recommended dose of
one factor strictly defines the dose of the second factor
in a given concentrate; however, the dose of the second factor can be completely different when another
concentrate is used, due to the different ratios of
FVIII:C and VWF:RCo in different preparations. For
instance, infusion of 40 IU kg 1 of FVIII:C entails
infusion of about 100 IU kg 1 of VWF:RCo in case of
Haemate P, while for Fandhi infusion of 40 IU kg 1
of FVIII:C would entail infusion of about 60 IU kg 1
of VWF:RCo. This example demonstrates that dosage
recommendations should be based on product characteristics.
The desirable trough target levels for FVIII:C and
VWF:RCo given in the guidelines are summarized in
Table 2. Target trough levels are not comprehensively
defined; on the day of surgery for FVIII:C, they range
from >50 to 100 IU kg 1 for both major and minor
surgery and 30 to >50 IU dL 1 for dental surgery.

Additional therapy
Most guidelines would use tranexamic acid (or EACA)
in cases of dental/oral surgery, some recommend that
antifibrinolytics alone may be sufficient haemostatic
cover [2325,27,29], while others recommend concomitant use of DDAVP or concentrate [26,28,30].
The need to avoid thrombotic complications by not
allowing FVIII to become vastly elevated is discussed,
but the threshold level is not established [24,30]. No
recommendations discuss the use of antithrombotic
Haemophilia (2016), 22, 739--751

VWF:RCoF
(IU dL 1)

Dose of concentrate
(IU kg 1)

Wilfactin (VWF:RCo/FVIII:C ratio 10:1) (taken from Borel-Derlon et al., 2007)

Actual doses (VWF:RCo):
French Study:
Borel-Derlon At least 60 at time
Dental: median dose 53.2
target levels
et al. [20]
of surgery
(range 24.762.4)
of at least 60
French Study:
All other surgery median
until healing.
target levels of
41.3 (range 35.459.4) for
Monitored
at least 40 until
gynaecological surgery to
once a day.
healing.
median 46.8
European
Monitored
(range 33.269.3
Study: target
once a day.
for general surgery
levels of at
European study:
least 50 until
target levels of at
suture removal.
least 50 until
Monitoring
suture removal.
once a day.
Monitoring
once a day.
Haemate/HumateP (VVF:RCo/FVIII 2.4:1)*
Lethagen
Loading >80
VWF:RCo Minor: median
Loading >100
et al. [4]
Major surgery
loading dose:
Maintenance
80100 for 714 days
62.2 (48.986.6)
>50 for 6 days
02 days 46.8 (35.959.6)
Investigator
Minor surgery
36 days 38.9 (30.647.4)
targets:
T1 >50 for 4 days
Major: median loading
median 100
T2 and 3 >50
dose; 66.5 (51.692.1)
(IQR 100115)
for 7 days
02 days 46.1 (39.378.2)
Investigator targets:
36 days 43.9 (37.174.4)
median 98
>6 days 42.3 (37.151.0)
(IQR 82100)

References

FVIII:C
(IU dL 1)

Defined target levels IU dL

VWF:RCoF

Mean values
(figures read
from graph)
all patients
Day 0 (D0):
140
D1: 110
D2:120
D3: 100
D4: 90
D5: 70
D6: 65

(Figures read
from graph)
160 at 15 min
post first,
second and
third infusions
Mean levels
166170 after
the first three
therapeutic/
maintenance
infusions

Baseline values
T1: 17.0
(9.032.0)
T2A: 34.2
(20.459.0)
T2M: 19.0
(19.019.0)
T3: 3.0 (1.06.4)
All: 18.0
(6.732.0)
Mean value
(all patients)
6273
Loading dose
given 12 h
before surgery.
Level 150% at
15 min postloading
dose (figure read
form graph)
(Figures read
from graph)
150 at 15 min
post first infusion
160 at 15 min
post second infusion
175 at 15 min
post third infusion
Mean 158180 after
the first three
therapeutic/
maintenance
infusions

Baseline values
T1: 33.0 (14.051.0)
T2A: 40.5 (35.748.0)
T2M: 37.0 (37.037.0)
T3: 3.7 (1.630.0)
All: 36.0 (14.046.0)
Mean value
(all patients) 114136
Loading dose
given 12 h before
surgery
Level 100 at 15 min
postloading dose
(figure read form graph)

Postoperative
trough levels

Median levels
134 (range
60266)
from 47/108
procedures

Preoperative
levels

Mean values
(figures read from
graph) all patients
Day 0 (D0): 80
D1: 130
D2: 145
D3: 170
D4: 160
D5: 150
D6: 145

Postoperative
trough levels

Median preoperative
FVIII level was 79
(range 26210) from
33 available cases in
scheduled cases not given
FVIII but given an extra
dose of VWF
In remaining 48 cases
baseline FVIII was
considered high enough
to ensure haemostasis:
median 59 (range 31155)
from 13 available
measurements

Preoperative levels

FVIII:C

Measured Factor
levels IU dL 1

Table 1. Preoperative and postoperative target and actual of FVIII:C and VWF:RCo levels in studies using factor concentrate to cover surgical interventions in patients with VWD.

Haemophilia (2016), 22, 739--751

(continued)

Selection of target
levels was at the
discretion of the
investigators.
Median deviation
of FVIII:C levels
from investigatorspecified target
plasma levels
(3.3 IU dL 1;
IQR 16.7 to 19.3)
was smaller than
that for VWF:RCo
(21.5 IU dL 1;
IQR 10.835.9
IU dL 1)

Postoperative values
were never outside
the target range for
the two
measurements

Comment

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J. WINDYGA et al.

2016 John Wiley & Sons Ltd

 2016 John Wiley & Sons Ltd

FVIII
Mean preoperative dose
Minor surgery: 34.8
(range 22.672.3)
Major surgery: 73.0
(median 43,
range 27.3118.2)
Mean daily dose:
Minor surgery: 33.5
(range 19.772.3)
Major surgery: 41.3
(range 12.674.9)

Dental: loading
dose 42.6 (38.6121.1)
Maintenance
dose 24.7 (21.340.5)
Minor: loading
dose 49.9 (23.7135.3)
Maintenance
dose 36.3 (27.893.8)
Major: loading
dose 61.2 (17.4113.9)
MD 39.8 (21.7100.0)

Dose of concentrate
(IU kg 1)

Fanhdi (VWF:RCo/FVIII:C ratio 1.6:1) (ratio taken from Federici et al., 2002)
Bello
>80100
>80100
Minor: preoperative
et al. [13]
median dose 47
(41.778.4) FVIII:C
and 65.7
(53.5102.4) VWF:RCo
Major: preoperative
median dose 101
(88.9128.6) IU kg 1
FVIII and 142.7
(112.9193.4)
IU kg 1 VWF:RCo
Wilate (VWF:;RCo/FVIII:C ratio 1:1)*

Range not defined.

Nadir value in
maintenance
phase >50

5060 minor surgery

80100 major
surgery
Major
maintenance dose >50
After day 3,
>30 for major

>40 minor surgery

80100 major surgery
Major maintenance
dose >50
After day 3, >30
For minor and major

Biostate (VWF:RCo/FVIII:C ratio 2:1)*

Dunkley
50200
et al. [11]

Gill
et al. [6]

References

VWF:RCoF
(IU dL 1)

Defined target levels IU dL

FVIII:C
(IU dL 1)

Table 1. (continued)

Baseline:T2A: 22103
T2B:27 and 24
Median 42 preinfusion
Average of 141 at 30
min after infusion

D0: 25 (Figure read

from graph)

Preinfusion levels not

available. Dose adjustment
was made for the following
dose. Therapeutic phase:
median levels at 15 min
postsurgical loading dose 91
(8 h clearance group) 105
(12 h clearance group)

Preoperative levels

FVIII:C

All patients
mean 87
during surgery.
Mean 113
postsurgery

Major surgery
(Figures
read from graph)
D1: 90
D2:110
D3:115
D4: 130
D5: 130
D6: 90
D7: 85
D8: 90
D9: 75
D10:75

Maintenance phase
was the first 3 days
following surgery.
Premaintenance
dose 80153
IU dL 1 (8 h
clearance group)
and 98136 (12 h
clearance group)
Maintenance
phase At 15 min
Median levels
102143 (8 h
clearance group)
and 103171 (12 h
clearance group)

Postoperative
trough levels

Range of nine
preinfusion to an
average
114 at 30 min
after infusion

D0: 15
(Figures read
from graph)

Postoperative
trough levels

All patients
mean 62
during surgery
and mean 112
postsurgery

Major surgery
(Figures read
from graph)
D1: 80
D2:90
D3:85
D4:75
D5: 65
D6: 42
D7: 40
D8: 45
D9: 40
D10:45

Premaintenance
dose 84182
(8 h clearance
group)
96168 (12 h
clearance group)
Maintenance
phase at 15 min
120219 (8 h
clearance group)
136213 (12 h
clearance group)

VWF:RCoF
Preoperative
levels
Preinfusion levels not
available. Dose
adjustment was
made for
the following
dose. Therapeutic
phase: median levels
At 15 min 164 both
8 h and 12 h
clearance groups)

Measured Factor
levels IU dL 1

(continued)

Activity of FVIII:
C and VWF:RCoF
reached >50
postinfusion
ensuring good
correction of
haemostasis

During surgical
treatment
phase 62.8% of
subjects to have at
least one VWF:
RCoF or FVIII level
in excess of
200 IU dL 1
(98 instances of
VWF:RCoF and
52 instances of
FVIII)

Comment

USING FACTOR CONCENTRATE IN VWD PATI ENTS UNDERGOING INVASIVE PROCEDURES

74 3

Haemophilia (2016), 22, 739--751

Haemophilia (2016), 22, 739--751

Dose calculated on
baseline levels
Mean doses for dental were
70.7 (range 45.0125.0)
single dose for minor
surgery 44.4 (range
21.661.9) single dose.
Major surgery 43.4
(range 18.084.4) with
similar follow-up doses

Trough FVIII:C of >50

for minor surgery
and >100 for major
surgery for 35 days.

Khair
et al. [17]

*VWF:RCo/FVIII:C ratios are taken from product SMPCs.

Data not available for one patient.

T1 = type 1, T2 = type 2 and T3 = type 3 VWD.

FVIII:C Mean dose

Minor: loading 43  15
(median 39, range 1565)
MD: 25  10 (median 22,
range 938)
Major: loading 48  15
(median 49, range 779)

Major >50
Minor >30
Dental 30

Dose of concentrate
(IU kg 1)

Windyga
et al. [14]

References

VWF:RCoF
(IU dL 1)

Defined target levels IU dL

FVIII:C
(IU dL 1)

Table 1. (continued)

(Figures from two

individual patients,
undergoing
major surgery
read from graph)
D2:70160
D3: 80135
D4: 90150
D5: 70
D6: 85
D7: 60120
D8: 50
D9: 45110
Mean
maximum trough
level: 134.4 (91197).

Mean: 36.5  28.4.

Median: 40.0
(0.095.0).

Postoperative
trough levels

Baseline: Mean
values (range)
T1: 51.5 (6125)
T2: 50 (10105)
T3: 7 (239)
Total: 10 (225)
Postloading dose:
110 and 135
(Figures from two
individual patients,
undergoing
major surgery read
from graph)

Preoperative levels

FVIII:C

Mean: 16.2  16.6.

Median: 11.1
(0.047.0).

Postoperative
trough levels
(Figures from
two individual
patients
underground
major surgery,
read from graph)
D2: 70140
D3: 40140
D4: 60130
D5: 60
D6: 60
D7: 6090
D8: 40
D9: 4075
Not shown.

VWF:RCoF
Preoperative
levels
Mean values (range)
T1: 57.5 (1559)
T2: 31 (1086)
T3: 5 (0140)
Total: 10 (2125)
Postloading dose D1:
9095 (Figures
from two
individual patients
underground major
surgery, read
from graph)

Measured Factor
levels IU dL 1

Comment

744
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USING FACTOR CONCENTRATE IN VWD PATI ENTS UNDERGOING INVASIVE PROCEDURES

agents in detail and it is even stated that there is no

clear consensus on antithrombotic prophylaxis in surgery and further randomized studies are needed [30].

EHTSB survey of current practice

Responses were obtained from 13/20 (65%) of the
physicians who were caring for 2420 adults and children with VWD. Details of the subtypes of patients
seen have been published previously [3]. Given the
heterogeneity of dosing in both published studies and
guidelines, the issues concerning how doses are
expressed, and the lack of attention paid to the variations in the different factor concentrates, the survey
focused on concentrate characteristics and target levels
as a rationale for determining management.

Ratio of FVIII/RCo in factor concentrates

Physicians were asked their preference in ratio of
VWF:RCo/FVIII:C (<1, 1, >1) for different types of
VWD and different interventions. There was no consistency in preferred ratio, nor any apparent trends
across intervention type or VWD type. For major surgery, 5/13 physicians would use PK dosing for type 3
patients undergoing major surgery, but PK studies are
scarcely used in other types of VWD or before minor
surgery. Concentrate is very rarely given by continuous infusion.

Laboratory parameters and target levels

VWF:RCo, FVIII:C and platelet counts were the factors used to monitor treatment by all physicians; most,
also monitoring VWF:Ag. Preoperative target levels of
FVIII:C are 80100 IU dL 1, VWF:Ag 80
<150 IU dL 1 and for VWF:RCo >60100 IU dL 1.
The target postoperative trough levels are shown in
Table 3; Fig. 1 shows the minimum and maximum
levels for FVIII:C.
Postoperative monitoring is most intense in days 1
3 and there is a pattern dividing the monitoring period
into days 13, days 47, days 811 and days 1214,
during which the target levels fall progressively
(Fig. 1).

Additional haemostatic cover and

thromboprophylaxis
For mucosal surgery, antifibrinolytics are employed by
2/3 of physicians.
Thromboprophylaxis is used by approximately 2/3
of the physicians, mostly in at-risk adults, that is,
those who have accepted risk factors for venous
thromboembolism or high FVIII levels during replacement therapy (>100 to >300 IU dL 1). Thromboprophylaxis would only be used by two physicians (15%)
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in under 18 year olds. The most common treatment is

low molecular weight heparin, used by 61% and 77%
of physicians in 1840 year olds and in >40 year olds,
respectively, and/or elasticated stockings (used by
54% of physicians in adult patients).

Discussion
We have previously surveyed the use of DDAVP in
treating patients with VWD undergoing invasive procedures [3]. The survey showed that in broad terms,
in both the literature and the survey, there was agreement on appropriate doses and the subtypes of
patients for whom DDAVP is suitable. The use of concentrates containing VWF and FVIII, however, shows
far more variation across published studies, guidelines/
recommendations and also in our current survey.
Two guidelines [26,27] give recommended dose of
concentrate to cover major surgery in terms of dose of
FVIII:C. However, a crucial consideration is that different preparations of factor concentrate have different ratios of FVIII:C to VWF:RCo. The manufacturers
quote values from 2.4:1 (Haemate) to 0.75:1 (Immunate) in their SMPCs (Table 1), but not all countries
label VWF/FVIII concentrates with their VWF:RCo
content, so in these cases, FVIII content must be used
to guide replacement therapy [5] and this may lead to
less than optimal dosing of VWF:RCo.
Rodeghiero et al. [26] state that the concentrate
used should have a ratio of VWF:RCo/FVIII:C 1.
Mannucci et al. [27] state the dosages apply to Haemate-P, Alphanate and Fandhi. Yet, while all these
concentrate preparations do have a ratio of VWF:
RCo/FVIII:C >1, they vary from 2.4:1 (Haemate) to
1.2:1 (Alphanate), so concentrations of VWF:RCo
could vary by as much as 100%. All other guidelines
give dose recommendations in terms of VWF:RCo
which will result in very different levels of FVIII:C,
depending on the product used.
The problems associated with over- or under-treatment in terms of VWF:RCo when basing dosing on
FVIII:C and the converse situation, when using different formulations has been discussed in detail by
Michiels et al. [31]. An important conclusion from
this study is that doses of concentrate expressed in
IU dL 1 are not interchangeable between different
preparations of factor concentrate, and it might be
appropriate for dosing guidelines or recommendations
to be made for each individual concentrate, or at least
concentrates with the same ratio of FVIII:C to VWF:
RCo.
There are also considerations of whether dosing
should be based on the subtype of VWD. Only two
guidelines [27,28] give different dosages based on subtype: Michiels et al. [27] group type 2A, 2B, recessive
type 1 and severe type 2N as requiring lower doses,
while Klaassen & Halton [28] recommend lower
Haemophilia (2016), 22, 739--751

Haemophilia (2016), 22, 739--751

Klasssen & Halton

[28]
Type 2B and 3

Klaassen & Halton

[28]
Type 1, 2A

Mannucci [27]

Michiels et al.
[23]
Pronounced
Type 2 Recessive
Type 1 and Type 3

No target
levels given

No target
levels given

FVIII:C>50
IU dL 1

VWF:RCo
>60 IU dL

Loading: 6080
IU kg 1
VWF:RCo
Subsequent:
40 IU kg 1 q 12 h
for a few days and
30 IU kg 1 day 1
for another 24 days
Loading: 80100
IU kg 1
VWF:RCo
Subsequent:
3040 IU kg 1 q
12h for 24 days and
3040 IU kg 1 d 1
for another 36 days
Loading: 50 IU kg 1
FVIII
Subsequent:
50 IU kg 1 daily
until healing complete
(usually 510
days)Mentions that
recommendations
apply to Haemate,
Alphanate and Fandhi
Loading: 5070
IU kg 1
VWF:RCo
Subsequent:
4060 IU kg 1
q 812 h for 3 days
then 4060 IU
kg 1 d 1 up to 7 days
Loading: 6080
IU kg 1 VWF:RCo
up to 7 days
Subsequent:
4060 IU kg 1 q 8-12 h
for 3 days then 4060
IU d 1

Michiels et al.
[23]
Type 2A, 2B
recessive type 1
Severe 2N
1

FVIII:C 80100

Loading: 50 IU
dL 1 FVIII:C od
or qadSubsequent: n/a

Day of surgery

FVIII:C>50 IU
dL 1 for 5 days

Loading:4060 IU
kg 1
Subsequent:
40 IU kg 1 once
on d1, add
tranexamic acid

VWF:RCo >60
IU dL 1 47 days

4050 IU
kg 1 12 doses

3060 IU kg

Loading: 60 IU
kg 1
Subsequent:
4060 IU kg 1
for 3 days

30 od or qad

Concentrate dose

FVIII:C 80100
IU dL 1 for 2 days

Subsequent days

No target levels
given

FVIII:C>30
IU dL 1

VWF:RCo >50
IU dL 1 for 12 h

FVIII:C>50
IU dL 1

Day of surgery

FVIII:C>30 IU
dL 1 24 days

30 IU kg

Loading: 60 IU
kg 1
Subsequent:
40 IU kg 1 on d1

Loading: 2040
single
dose
Subsequent:
on clinical need
Loading: 4060
IU kg 1
Subsequent:
no factor, add
tranexamic acid

FVIII:C >30
IU dL 1
57 days

VWF:RCo >50
IU dL 1 for 2
days

Concentrate dose

Subsequent days

Target trough levels of FVIII:C and VWF:

RCo

Rodeghiero
et al. [26]

Concentrate dose

Minor surgery
Target trough levels of FVIII:C and VWF:
RCo

Major surgery

Table 2. Summary of recommendations for concentrate use and target trough levels of FVIII:C and VWF:RCo during surgery in patients with VWD.

(continued)

No target levels given

No target levels given

for 12 h

FVIII:C 3025 IU dL
for 12 h

FVIII:C>50 IU dL

Adequate VWF:Rco >12 h

FVIII:C 3050 IU dL

Day of surgery

Target trough levels of FVIII:C

and VWF:RCo

Dental surgery

746
J. WINDYGA et al.

2016 John Wiley & Sons Ltd

 2016 John Wiley & Sons Ltd

Concentrate dose

No dose given.
Treatment given
for 714 days
Loading: 4060
IU kg 1
VWF:RCo
Subsequent:
2040 U kg IU dL 1
q 824
h714 days
Loading: VWF
concentrate to reach
VWF:RCo of 80100
IU dL 1
Subsequent:
Maintain levels >50
IU dL 1
Doses given in
relation to baseline
levels not surgery
type: 5060 IU kg 1
VWF:RCo for pts
with v low basal
VWF:RCo.
VWF:RCo >50
IU dL 1 in major
surgery
Doses given in
relation to baseline
levels not surgery
type: 5060 IU kg 1
VWF:RCo for pts
with v low basal
VWF:RCo. Then,
2540 IU kg 1 q
12-24 h. After
2448 h od or qad.
Suggest normal
levels of FVIII:C
and VWF:RCo
but do not define
them

FVIII:C and
VWF:RCo 100
IU dL 1

VWF:RCo 80100
IU dL 1
FVIII:C
100 IU dL 1

VWF:RCo and
FVIII:C >50 IU dL

No target
levels given

FVIII:C and
VWF:RCo >50
IU dL 1

VWF:RCo >50 IU
dL 1
FVIII:C >50
IU dL 1 711 days

VWF:RCo and
FVIII:C >50 IU
dL 1 714 days

Subsequent days
Concentrate dose

Suggest normal
levels of FVIII:C
and VWF:RCo but
do not define them

Doses given in
relation to baseline
levels not surgery
type: 5060 IU
kg 1 VWF:RCo
for pts with v low
basal VWF:RCo.
Then 2540 IU
kg 1 q 1224 h.
After 2448 h
od or qad.

FVIII:C 100 IU dL

VWF:RCo 80100
IU dL 1
FVIII:C
100 IU dL 1

VWF:RCo and
FVIII:C >50 IU dL

FVIII:C should be
100 IU dL 1 to
cover most minor
surgery and
postoperatively
kept at >50 IU dL 1.

VWF concentrate
to reach
VWF:RCo of
80100 IU dL 1

3060 IU kg

No target levels
given

Day of surgery

Concentrate dose

Day of surgery

No target levels given

No target levels given

States
that FVIII:C should be
monitored

FVIII:C >50
IU dL 1

No target levels given

No target levels given

No target levels given

Single dose

Target trough levels of FVIII:C

and VWF:RCo

Dental surgery

VWF:RCo >50
IU dL 1
FVIII:C
>50 IU dL 1
35 days

VWF:RCo and
FVIII:C >50
IU dL 1 35
days

Subsequent days

Target trough levels of FVIII:C and VWF:

RCo

Target trough levels of FVIII:C and VWF:

RCo
Day of surgery

Minor surgery

Major surgery

d = day; od = once a day; q = every; qad = every other day.

Guidelines of the
Nordic Hemophilia
Council, 2008 [40]

Laffan et al. [25]

Batlle et al. [30]

Nichols et al. [24]

Yawn et al. [29]

Table 2. (continued)

USING FACTOR CONCENTRATE IN VWD PATI ENTS UNDERGOING INVASIVE PROCEDURES

74 7

Haemophilia (2016), 22, 739--751

>10>30
>10>30
>1050
>1050
>1060
1

Haemophilia (2016), 22, 739--751

D0 = day of surgery; D1 (2 etc.) = day 1 (2 etc.) after surgery.

D14

>1050

3040

D13
D12

3050

D11

3060

D10

3060
40150
>1050

D9

3060
4060

D8
D7

2580
25150
2580
2580
25150
2580

D6
D5

50100
50150
30100
50100
50150
>30100

D4

Fig. 1. Target levels of FVIII:C during the postoperative period in patients

with VWD. This figure shows the minimum levels and maximum levels recommended by the physicians in the survey for each day and the trend
derived from these values.

50100
50150
>30100

D3
D2

50100
50150
>30100

D1

>50100
80150
30100

<D0

>80100
80150
>50100

Table 3. Target trough levels in the postoperative period: overall ranges.

3040

J. WINDYGA et al.

FVIII:C IU dL 1
VWF:Ag IU dL 1
VWF:RCo IU dL

748

doses for type 1 and 2A VWD. The lack of consensus

on dosages, and the considerable heterogeneity in the
phenotypical expression for both type 1 and type 2
VWD suggest that rather than dosages being based on
the subtype of VWD, it might be better to base dosage
on baseline factor levels and titrate to predefined target trough levels, taking into account the nature and
severity of the surgical intervention.
Indeed, defining the desirable peri- and preoperative
target trough levels of the crucial haemostatic factors,
especially VWF:RCo and FVIII:C, is a practical and
useful approach to haemostatic management in VWD.
The required doses of concentrate may then be calculated since the expected rise in plasma levels obtained
in response to infusion of a defined dose is known for
individual formulations.
Maintenance of target FVIII:C plasma levels has traditionally been considered the main determinant for
surgical haemostasis [1], although VWF:RCo is considered by some to be more relevant measure of VWF
functional activity [24,25].
One of our aims in reviewing the literature was to
try and look at predefined target levels and see how
these were integrated into clinical practice and
whether we could identify safe factor levels during
surgery. However, this was not possible since only
seven studies actually took the approach of defining
targets and reporting postsurgical factor levels and
studies varied in the methodology used, the way
results were reported, and importantly the spread of
values was very wide. For the majority of studies,
actual levels always exceeded target levels making it
difficult to conclude what are the minimally effective
levels FVIII and VWF during and postsurgery.
It was also notable that few data were available that
correlated bleeding with levels of either FVIII:C or
VWF:RCo. The study of Gill et al. [6] considered
three haemorrhagic incidents in major surgery cases.
2016 John Wiley & Sons Ltd

USING FACTOR CONCENTRATE IN VWD PATI ENTS UNDERGOING INVASIVE PROCEDURES

74 9

Table 4. Recommendations.
1. Patients with von Willebrand disease undergoing surgery who do not respond to DDAVP, or in whom DDAVP is contraindicated, should be
given concentrate containing von Willebrand factor.
2. Since the ratio of VWF:RCo/FVIII:C in the concentrates varies significantly, doses of concentrate expressed in IU/dL are not interchangeable
between various preparations*.
3. Because various types of VWD are characterized by great variability in VWF:RCo and FVIII:C, patients should have baseline values of VWF:RCo
and FVIII:C measured before undergoing major surgery to plan treatment.
4. For major and minor surgery, preoperatively, we would suggest that peak levels of FVIII:C are 80100 IU dL 1 and of VWF:RCo are 50
IU dL 1.
5. For major surgery in the postoperative period, target trough levels of FVIII:C should be 80100 IU dL 1 on the day of surgery, decreasing to
5080 IU dL 1 on days 17 and 3040 IU dL 1 by day 14 or until wound healing has been completed. For VWF:RCo, these levels are >50 IU
dL 1 on day of surgery, >30 IU dL 1 until day 14 or until wound healing is complete.
6. For minor surgery in the postoperative period, target trough levels of FVIII:C and VWF:RCo should be >50 and 30 IU dL 1, respectively, on the
day of surgery and for 35 days or until wound healing is complete. Simple dental extractions may be performed with one infusion of concentrate
given immediately before the procedure, usually combined with tranexamic acid given orally for 710 days; the recommended peak target levels of
both FVIII:C and VWF:RCo for this indication is >50 IU dL 1.
7. Choosing too high target levels of VWF:RCo in patients receiving regular and frequent infusions of concentrate (e.g. perioperative prophylaxis in
cases of major surgery) may result in significant increase in FVIII:C plasma levels, particularly if concentrates with low VWF:RCo/FVIII:C ratio
are used. Even though there is no commonly accepted consensus with respect to which plasma levels of FVIII:C are dangerously high in this clinical
setting, we suggest avoiding levels above 250 IU dL 1.
8. If FVIII:C is significantly increased and VWF:RCo levels are below target and the patient is not bleeding (excessively), it is up to the clinician to
decide whether switch to a concentrate with higher VWF:RCo/FVIII ratio or to continue with current treatment. In this respect, in our opinion, the
clinical course of treatment is more relevant for decision-making than plasma level of VWF:RCo.
9. There are insufficient data to recommend measurement of other parameters, for example, PFA-100 or VWF collagen binding for monitoring
haemostatic efficacy of the infused concentrates in the perioperative period.
10. Tranexamic acid is a valuable adjunctive agent that may be used concomitantly with concentrates containing VWF in patients with VWD
undergoing surgery. This recommendation particularly applies to invasive procedures that involve mucous membranes.
11. We suggest that pharmacological thromboprophylaxis is not given routinely to patients with VWD undergoing surgery. Nevertheless, such
prophylaxis should be considered in patients with high risk of venous thromboembolism, particularly if high levels of FVIII:C are unavoidable.

1A
1A
1B
2B
2B

2B

2C

1B

2C
1B
2B

*It might be appropriate for dosing guidelines or recommendations to be made for each individual concentrate.

They showed that for one subject FVIII:C may be

below target values, but VWF:RCo were not. For the
second, quite possibly both factors were lower than
target values at some point, while for the third, both
factors were at least twice the target values. Additionally, in some studies, despite low levels of FVIII and/
or VWF the patients did not bleed further confounding attempts to define minimally effective levels.
Moreover, it is very difficult to maintain the target
levels of both factors (VIII and VWF) because their
course is not parallel.
Our survey has defined the ranges of FVIII:C, VWF:
RCo and also VWF:Ag that treatment centres currently consider appropriate in the period following
major surgery. While these are in good agreement
with those in the published guidelines, it still remains
that the spread of acceptable values is quite wide and
it might be more useful to refine these recommendations.
It is also important to define minimum levels, since
once minimum values of these haemostatic factors are
achieved, haemostatic control is not augmented by
increasing the levels above the minimum, and sustained high plasma concentrations of FVIII:C bring
the potential problem of deep vein thrombosis and/or
pulmonary embolism [19,32,33]. One recent analysis
has suggested that supranormal levels of FVIII and/or
VWF seen in surgical patients treated with concentrate
does not usually result in thromboembolic complications [34], but a potentially dangerous level of FVIII
has yet to be defined. One study has proposed a
2016 John Wiley & Sons Ltd

threshold of >270 IU dL 1 for individuals with no

additional risk factors [35], and the National Heart,
Lung, and Blood Institute guidelines [24] have suggested (>250300 IU dL 1), although others have suggested lower levels (150175 IU dL 1) [36,37].
Intra- and postoperative levels of VWF have been
examined in detail in normal individuals undergoing
surgery [38] and it has been shown that VWF parameters decreased intraopertively and increased postoperatively, with mean values remaining >100 IU dL 1 at
all times in the perioperative period. Therefore, the
target values for people with VWD may be lower than
those seen during the physiological response to surgery. However, individuals with VWD have complex
perturbations of haemostasis and there is the need to
balance managing a significant risk of bleeding against
the possible thromboembolic complications, taking
into account that infusions of FVIII:VWF will raise
FVIII:C levels due to the administered FVIII and also
due to stabilization of endogenous FVIII by the
administered VWF.

Conclusions
We undertook this investigation with the aim of identifying the most commonly used protocols for treating
patients with VWD who were undergoing surgical
procedures and to try and correlate circulating factor
levels with bleeding episodes to give more insight into
potentially crucial threshold levels of factor. However,
as the literature currently stands, this proved difficult
Haemophilia (2016), 22, 739--751

750

J. WINDYGA et al.

due to the considerable heterogeneity in treatment regimens and a lack of consistency in reporting, notably,
dosages of concentrate are difficult to establish; consequently, we focused on considering target levels of
haemostatic factors.
There is clearly a need for more alignment in how
we manage patients with VWD and to this end, publications need to include as much detail as possible on
subtype of VWD patients and factor levels both
actual levels and target levels. Comprehensive laboratory data may not be accessible in some centres, but
where facilities allow it, detailed reporting will provide valuable data for all physicians treating people
with VWD.
Our findings were presented to all Board members
and consensus discussions undertaken to assemble a
set of general recommendations for the management
of patients with VWD undergoing invasive procedures. Analysis of the literature, focusing on guidelines
and the consensus deliberation, yielded the following
recommendations (Table 4) rated according to the
GRADE system [39] in parentheses. Since we have
focused on target levels of haemostatic factors, rather
than prescribing recommended dosages of concentrate
to cover surgical interventions, these recommendations
compliment previous publications, which tend to focus
on concentrate dosages. In addition, the fact that varying ratios of FVIII:C and VWF:RCo in different concentrate preparations may impact significantly on their
physiological effects and the importance of the
patients clinical course have been highlighted.

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Disclosures
Jerzy Windyga has received grant/support from Biogen Idec, Baxter
Healthcare, Baxalta, Bayer, CSL Behring, LFB, Novo Nordisk, Octapharma, Pfizer, Sanofi. Gerry Dolan has no conflicts and was a member
of the EHTSB at the time of the study. Carmen Altisent is in receipt of
honoraria or consultation fees: Baxter, Bayer, CSL Behring, Grifols, Novo
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Acknowledgements and Author contributions

The European Therapy Strategy Board is supported by an unrestricted
educational grant from Baxalta with organizational support from Ashley
Communications. Assistance with questionnaire analysis and medical
writing was provided by Jan Hawthorn who was paid from the Baxalta
grant.
All authors developed the questionnaire, assessed the literature and
contributed critically to the writing of the manuscript. They approved the
final version before submission.
The majority of members of the EHTSB provided survey data; all
members of the group have commented critically on the manuscript and
approved the final version.
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Supporting Information
Additional Supporting Information may be
found in the online version of this article:
Table S1. Summary of studies using factor
concentrate to cover surgical interventions in
patients with VWD.

Haemophilia (2016), 22, 739--751