Abstract

The management of von Willebrand disease (VWD) is based upon the dual correction of the primary hemostasis defect, due to the inherited deficiency of von Willebrand factor (VWF), and of the secondary defect of factor VIII coagulant activity (FVIII:C), due to the loss of binding and stabilization by VWF of this intrinsic coagulation factor in flowing blood. The traditional therapeutic weapons (the synthetic derivative of the antidiuretic hormone desmopressin and plasma-derived VWF/FVIII concentrates) are able to transiently correct both the defects. With the goal of tackling the primary deficiency in the disease, that is, VWF, but at the same time exploiting the normal capacity of patients to produce FVIII, the novel approach of replacing only VWF was implemented in the last 10 years. Following the manufacturing of a concentrate fractionated from human plasma and of one obtained by recombinant DNA technology, clinical studies have shown that VWF-only products correct not only the primary VWF deficiency but also the secondary FVIII:C deficiency. The demonstrated efficacy of these products in various clinical situations and, ultimately, in such a hemostasis-challenging context as surgery testifies to the effectiveness and safety of this approach. It remains to be seen whether VWF-only products are efficacious and safe in still-unexplored situations, such as use in children; the long-term use for prophylaxis; and in recurrent gastrointestinal (GI) bleeding due to angiodysplasia, a major therapeutic problem in VWD.

References

References
1.
Sohal
M
,
Laffan
M
.
Von Willebrand disease and angiodysplasia responding to atorvastatin
.
Br J Haematol
.
2008
;
142
(
2
):
308
-
309
.
2.
Alikhan
R
,
Keeling
D
.
Von Willebrand disease, angiodysplasia and atorvastatin
.
Br J Haematol
.
2010
;
149
(
1
):
159
-
160
.
3.
Mannucci
PM
.
Treatment of von Willebrand’s disease
.
N Engl J Med
.
2004
;
351
(
7
):
683
-
694
.
4.
Leebeek
FW
,
Eikenboom
JC
.
Von Willebrand’s disease
.
N Engl J Med
.
2016
;
375
(
21
):
2067
-
2080
.
5.
Springer
TA
.
von Willebrand factor, Jedi knight of the bloodstream
.
Blood
.
2014
;
124
(
9
):
1412
-
1425
.
6.
Mannucci
PM
,
Franchini
M
.
Laboratory monitoring of replacement therapy for major surgery in von Willebrand disease
.
Haemophilia
.
2017
;
23
(
2
):
182
-
187
.
7.
Leissinger
C
,
Carcao
M
,
Gill
JC
,
Journeycake
J
,
Singleton
T
,
Valentino
L
.
Desmopressin (DDAVP) in the management of patients with congenital bleeding disorders
.
Haemophilia
.
2014
;
20
(
2
):
158
-
167
.
8.
James
PD
,
Lillicrap
D
,
Mannucci
PM
.
Alloantibodies in von Willebrand disease
.
Blood
.
2013
;
122
(
5
):
636
-
640
.
9.
Revel-Vilk
S
,
Schmugge
M
,
Carcao
MD
,
Blanchette
P
,
Rand
ML
,
Blanchette
VS
.
Desmopressin (DDAVP) responsiveness in children with von Willebrand disease
.
J Pediatr Hematol Oncol
.
2003
;
25
(
11
):
874
-
879
.
10.
Castaman
G
,
Lethagen
S
,
Federici
AB
, et al
.
Response to desmopressin is influenced by the genotype and phenotype in type 1 von Willebrand disease (VWD): results from the European Study MCMDM-1VWD
.
Blood
.
2008
;
111
(
7
):
3531
-
3539
.
11.
Stoof
SC
,
Cnossen
MH
,
de Maat
MP
,
Leebeek
FW
,
Kruip
MJ
.
Side effects of desmopressin in patients with bleeding disorders
.
Haemophilia
.
2016
;
22
(
1
):
39
-
45
.
12.
Windyga
J
,
Dolan
G
,
Altisent
C
,
Katsarou
O
,
López Fernández
MF
,
Zülfikar
B
;
EHTSB
.
Practical aspects of DDAVP use in patients with von Willebrand disease undergoing invasive procedures: a European survey
.
Haemophilia
.
2016
;
22
(
1
):
110
-
120
.
13.
Ragni
MV
,
Novelli
EM
,
Murshed
A
,
Merricks
EP
,
Kloos
MT
,
Nichols
TC
.
Phase II prospective open-label trial of recombinant interleukin-11 in desmopressin-unresponsive von Willebrand disease and mild or moderate haemophilia A
.
Thromb Haemost
.
2013
;
109
(
2
):
248
-
254
.
14.
Castaman
G
,
Goodeve
A
,
Eikenboom
J
;
European Group on von Willebrand Disease
.
Principles of care for the diagnosis and treatment of von Willebrand disease
.
Haematologica
.
2013
;
98
(
5
):
667
-
674
.
15.
Nichols
WL
,
Hultin
MB
,
James
AH
, et al
.
von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA)
.
Haemophilia
.
2008
;
14
(
2
):
171
-
232
.
16.
Laffan
MA
,
Lester
W
,
O’Donnell
JS
, et al
.
The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology
.
Br J Haematol
.
2014
;
167
(
4
):
453
-
465
.
17.
Mannucci
PM
,
Tenconi
PM
,
Castaman
G
,
Rodeghiero
F
.
Comparison of four virus-inactivated plasma concentrates for treatment of severe von Willebrand disease: a cross-over randomized trial
.
Blood
.
1992
;
79
(
12
):
3130
-
3137
.
18.
Mannuccio
PM
,
Lattuada
A
,
Ruggeri
ZM
.
Proteolysis of von Willebrand factor in therapeutic plasma concentrates
.
Blood
.
1994
;
83
(
10
):
3018
-
3027
.
19.
Coppola
A
,
Franchini
M
,
Makris
M
,
Santagostino
E
,
Di Minno
G
,
Mannucci
PM
.
Thrombotic adverse events to coagulation factor concentrates for treatment of patients with haemophilia and von Willebrand disease: a systematic review of prospective studies
.
Haemophilia
.
2012
;
18
(
3
):
e173
-
e187
.
20.
Goudemand
J
,
Scharrer
I
,
Berntorp
E
, et al
.
Pharmacokinetic studies on Wilfactin, a von Willebrand factor concentrate with a low factor VIII content treated with three virus-inactivation/removal methods
.
J Thromb Haemost
.
2005
;
3
(
10
):
2219
-
2227
.
21.
Borel-Derlon
A
,
Federici
AB
,
Roussel-Robert
V
, et al
.
Treatment of severe von Willebrand disease with a high-purity von Willebrand factor concentrate (Wilfactin): a prospective study of 50 patients
.
J Thromb Haemost
.
2007
;
5
(
6
):
1115
-
1124
.
22.
Turecek
PL
,
Mitterer
A
,
Matthiessen
HPH
, et al
.
Development of a plasma- and albumin-free recombinant von Willebrand factor
.
Hamostaseologie
.
2009
;
29
(
suppl 1
):
S32
-
S38
.
23.
Reininger
AJ
.
The function of ultra-large von Willebrand factor multimers in high shear flow controlled by ADAMTS13
.
Hamostaseologie
.
2015
;
35
(
3
):
225
-
233
.
24.
Budde
U
,
Metzner
HJ
,
Müller
HG
.
Comparative analysis and classification of von Willebrand factor/factor VIII concentrates: impact on treatment of patients with von Willebrand disease
.
Semin Thromb Hemost
.
2006
;
32
(
6
):
626
-
635
.
25.
Mannucci
PM
,
Kempton
C
,
Millar
C
, et al
;
rVWF Ad Hoc Study Group
.
Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a prospective clinical trial
.
Blood
.
2013
;
122
(
5
):
648
-
657
.
26.
Gill
JC
,
Castaman
G
,
Windyga
J
, et al
.
Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease
.
Blood
.
2015
;
126
(
17
):
2038
-
2046
.
27.
Leebeek
F
,
Chapman
M
,
Ploder
B
,
Sytkowski
A
,
Novack
A
,
Ewenstein
B
.
Treatment of gastrointestinal bleeding episodes with recombinant von Willebrand factor (rVWF) in patients with severe von Willebrand disease (VWD): sub-analysis from pivotal phase III on-demand study [abstract]
.
Res Pract Thromb Haemost.
2017
;
1
(
suppl 1
):
880
.
28.
Peyvandi
F
,
Mamaev
A
,
Wang
JD
, et al
.
Phase 3 study of recombinant von Willebrand factor in patients with severe von Willebrand disease who are undergoing elective surgery
.
J Thromb Haemost
.
2019
;
17
(
1
):
52
-
62
.
29.
Franchini
M
,
Mannucci
PM
.
Gastrointestinal angiodysplasia and bleeding in von Willebrand disease
.
Thromb Haemost
.
2014
;
112
(
3
):
427
-
431
.
30.
Quick
AJ
.
Telangiectasia: its relationship to the Minot-von Willebrand syndrome
.
Am J Med Sci
.
1967
;
254
(
5
):
585
-
601
.
31.
Fressinaud
E
,
Meyer
D
.
International survey of patients with von Willebrand disease and angiodysplasia
.
Thromb Haemost
.
1993
;
70
(
3
):
546
.
32.
Holm
E
,
Abshire
TC
,
Bowen
J
, et al
.
Changes in bleeding patterns in von Willebrand disease after institution of long-term replacement therapy: results from the von Willebrand Disease Prophylaxis Network
.
Blood Coagul Fibrinolysis
.
2015
;
26
(
4
):
383
-
388
.
33.
Berntorp
E
,
Windyga
J
;
European Wilate Study Group
.
Treatment and prevention of acute bleedings in von Willebrand disease--efficacy and safety of Wilate, a new generation von Willebrand factor/factor VIII concentrate
.
Haemophilia
.
2009
;
15
(
1
):
122
-
130
.
34.
Abshire
TC
,
Federici
AB
,
Alvárez
MT
, et al
;
VWD PN
.
Prophylaxis in severe forms of von Willebrand’s disease: results from the von Willebrand Disease Prophylaxis Network (VWD PN)
.
Haemophilia
.
2013
;
19
(
1
):
76
-
81
.
35.
Castaman
G
,
Federici
AB
,
Tosetto
A
, et al
.
Different bleeding risk in type 2A and 2M von Willebrand disease: a 2-year prospective study in 107 patients
.
J Thromb Haemost
.
2012
;
10
(
4
):
632
-
638
.
36.
Vincentelli
A
,
Susen
S
,
Le Tourneau
T
, et al
.
Acquired von Willebrand syndrome in aortic stenosis
.
N Engl J Med
.
2003
;
349
(
4
):
343
-
349
.
37.
Federici
AB
,
Stabile
F
,
Castaman
G
,
Canciani
MT
,
Mannucci
PM
.
Treatment of acquired von Willebrand syndrome in patients with monoclonal gammopathy of uncertain significance: comparison of three different therapeutic approaches
.
Blood
.
1998
;
92
(
8
):
2707
-
2711
.
38.
Nomikou
E
,
Tsevrenis
V
,
Gafou
A
,
Bellia
M
,
Theodossiades
G
.
Type IIb von Willebrand disease with angiodysplasias and refractory gastrointestinal bleeding successfully treated with thalidomide
.
Haemophilia
.
2009
;
15
(
6
):
1340
-
1342
.
39.
Khatri
NV
,
Patel
B
,
Kohli
DR
,
Solomon
SS
,
Bull-Henry
K
,
Kessler
CM
.
Lenalidomide as a novel therapy for gastrointestinal angiodysplasia in von Willebrand disease
.
Haemophilia
.
2018
;
24
(
2
):
278
-
282
.
40.
Stockschlaeder
M
,
Schneppenheim
R
,
Budde
U
.
Update on von Willebrand factor multimers: focus on high-molecular-weight multimers and their role in hemostasis
.
Blood Coagul Fibrinolysis
.
2014
;
25
(
3
):
206
-
216
.
41.
Randi
AM
,
Laffan
MA
.
Von Willebrand factor and angiogenesis: basic and applied issues
.
J Thromb Haemost
.
2017
;
15
(
1
):
13
-
20
.
42.
Gao
J
,
Ewenstein
B
,
Ploder
B
, et al
.
Infusion requirements in on demand treatment of bleeding events in von Willebrand disease (VWD): an indirect treatment comparison between recombinant von Willebrand factor (VWF) and plasma derived VWF concentrates [abstract]
.
Res Pract Thromb Haemost
.
2019
;
3
(
suppl 1
):
391
.
Abstract PB0803
.
43.
Hazendonk
HCAM
,
Heijdra
JM
,
de Jager
NCB
, et al
;
“OPTI-CLOT” and “WIN” study group
.
Analysis of current perioperative management with Haemate® P/Humate P® in von Willebrand disease: identifying the need for personalized treatment
.
Haemophilia
.
2018
;
24
(
3
):
460
-
470
.
44.
Wang
L
,
Rosenberg
JB
,
De
BP
, et al
.
In vivo gene transfer strategies to achieve partial correction of von Willebrand disease
.
Hum Gene Ther
.
2012
;
23
(
6
):
576
-
588
.
45.
Portier
I
,
Vanhoorelbeke
K
,
Verhenne
S
, et al
.
High and long-term von Willebrand factor expression after Sleeping Beauty transposon-mediated gene therapy in a mouse model of severe von Willebrand disease
.
J Thromb Haemost
.
2018
;
16
(
3
):
592
-
604
.
You do not currently have access to this content.

Comments

0 Comments