Abstract

von Willebrand disease (VWD) is the most common autosomal inherited bleeding disorder, with an estimated prevalence of 1 in 1000 individuals. VWD is classified into quantitative and qualitative forms. Diagnosis of VWD is complex and requires (1) a personal history of bleeding symptoms, (2) family history of bleeding or VWD, and (3) confirmatory laboratory testing. There are certain bleeding assessment tools to objectively measure bleeding symptoms in patients that have been shown to correlate with the diagnosis as well as the severity of VWD. Laboratory diagnosis requires at least initially a measurement of von Willebrand factor (VWF) antigen levels, VWF platelet binding activity (VWF:RCo, VWF:GPIbM, and VWF:GPIbR), and factor VIII (FVIII) activity. Additional testing to confirm the specific subtype may include VWF collagen binding activity, low-dose ristocetin VWF-platelet binding, FVIII-VWF binding, VWF multimer analysis, and VWF propeptide antigen. Recent advances have been made regarding some of these assays. Molecular testing in VWD is not found to be useful in “low VWF” or most type 1 VWD cases but may be informative in patients with severe type 1 VWD, type 1C VWD, type 2 VWD, or type 3 VWD for accurate diagnosis, genetic counseling, and appropriate treatment. The diagnostic algorithm for VWD is complex, but advances continue to be made in improving VWF functional assays and diagnostic pathways.

References

References
1.
Sadler
JE
,
Budde
U
,
Eikenboom
JC
, et al
;
Working Party on von Willebrand Disease Classification
.
Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor
.
J Thromb Haemost
.
2006
;
4
(
10
):
2103
-
2114
.
2.
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
.
3.
Nichols
WL
,
Rick
ME
,
Ortel
TL
, et al
.
Clinical and laboratory diagnosis of von Willebrand disease: a synopsis of the 2008 NHLBI/NIH guidelines
.
Am J Hematol
.
2009
;
84
(
6
):
366
-
370
.
4.
Elbatarny
M
,
Mollah
S
,
Grabell
J
, et al
;
Zimmerman Program Investigators
.
Normal range of bleeding scores for the ISTH-BAT: adult and pediatric data from the merging project
.
Haemophilia
.
2014
;
20
(
6
):
831
-
835
.
5.
Sanders
YV
,
Fijnvandraat
K
,
Boender
J
, et al
;
WiN Study Group
.
Bleeding spectrum in children with moderate or severe von Willebrand disease: relevance of pediatric-specific bleeding
.
Am J Hematol
.
2015
;
90
(
12
):
1142
-
1148
.
6.
Bowman
M
,
Riddel
J
,
Rand
ML
,
Tosetto
A
,
Silva
M
,
James
PD
.
Evaluation of the diagnostic utility for von Willebrand disease of a pediatric bleeding questionnaire
.
J Thromb Haemost
.
2009
;
7
(
8
):
1418
-
1421
.
7.
Tosetto
A
,
Castaman
G
,
Plug
I
,
Rodeghiero
F
,
Eikenboom
J
.
Prospective evaluation of the clinical utility of quantitative bleeding severity assessment in patients referred for hemostatic evaluation
.
J Thromb Haemost
.
2011
;
9
(
6
):
1143
-
1148
.
8.
Deforest
M
,
Grabell
J
,
Albert
S
, et al
.
Generation and optimization of the self-administered bleeding assessment tool and its validation as a screening test for von Willebrand disease
.
Haemophilia
.
2015
;
21
(
5
):
e384
-
e388
.
9.
Casey
LJ
,
Tuttle
A
,
Grabell
J
, et al
.
Generation and optimization of the self-administered pediatric bleeding questionnaire and its validation as a screening tool for von Willebrand disease
.
Pediatr Blood Cancer
.
2017
;
64
(
10
):
e26588
.
10.
Rott
H
,
Kappert
G
,
Siebert
M
.
Establishment of a reference range for the Pbac-score
.
Blood
.
2013
;
122
(
21
):
4772
.
11.
Sadler
JE
.
Slippery criteria for von Willebrand disease type 1
.
J Thromb Haemost
.
2004
;
2
(
10
):
1720
-
1723
.
12.
Lavin
M
,
Aguila
S
,
Schneppenheim
S
, et al
.
Novel insights into the clinical phenotype and pathophysiology underlying low VWF levels
.
Blood
.
2017
;
130
(
21
):
2344
-
2353
.
13.
Lavin
M
,
Aguila
S
,
Dalton
N
, et al
.
Significant gynecological bleeding in women with low von Willebrand factor levels
.
Blood Adv
.
2018
;
2
(
14
):
1784
-
1791
.
14.
Federici
AB
,
Mannucci
PM
,
Castaman
G
, et al
.
Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease type 2B: a cohort study of 67 patients
.
Blood
.
2009
;
113
(
3
):
526
-
534
.
15.
Bodó
I
,
Eikenboom
J
,
Montgomery
R
,
Patzke
J
,
Schneppenheim
R
,
Di Paola
J
;
von Willebrand factor Subcommittee of the Standardization and Scientific Committee of the International Society for Thrombosis and Haemostasis
.
Platelet-dependent von Willebrand factor activity. Nomenclature and methodology: communication from the SSC of the ISTH
.
J Thromb Haemost
.
2015
;
13
(
7
):
1345
-
1350
.
16.
Flood
VH
,
Gill
JC
,
Morateck
PA
, et al
.
Common VWF exon 28 polymorphisms in African Americans affecting the VWF activity assay by ristocetin cofactor
.
Blood
.
2010
;
116
(
2
):
280
-
286
.
17.
Vanhoorelbeke
K
,
Cauwenberghs
N
,
Vauterin
S
,
Schlammadinger
A
,
Mazurier
C
,
Deckmyn
H
.
A reliable and reproducible ELISA method to measure ristocetin cofactor activity of von Willebrand factor
.
Thromb Haemost
.
2000
;
83
(
1
):
107
-
113
.
18.
Boender
J
,
Eikenboom
J
,
van der Bom
JG
, et al
;
WiN Study Group
.
Clinically relevant differences between assays for von Willebrand factor activity
.
J Thromb Haemost
.
2018
;
16
(
12
):
2413
-
2424
.
19.
Patzke
J
,
Budde
U
,
Huber
A
, et al
.
Performance evaluation and multicentre study of a von Willebrand factor activity assay based on GPIb binding in the absence of ristocetin
.
Blood Coagul Fibrinolysis
.
2014
;
25
(
8
):
860
-
870
.
20.
Flood
VH
,
Gill
JC
,
Morateck
PA
, et al
.
Gain-of-function GPIb ELISA assay for VWF activity in the Zimmerman Program for the Molecular and Clinical Biology of VWD
.
Blood
.
2011
;
117
(
6
):
e67
-
e74
.
21.
Szederjesi
A
,
Baronciani
L
,
Budde
U
, et al
.
An international collaborative study to compare different von Willebrand factor glycoprotein Ib binding activity assays: the COMPASS-VWF study [published online ahead of print 13 June 2018]
.
J Thromb Haemost
.
doi:10.1111/jth.14206
.
22.
Haberichter
SL
,
Balistreri
M
,
Christopherson
P
, et al
.
Assay of the von Willebrand factor (VWF) propeptide to identify patients with type 1 von Willebrand disease with decreased VWF survival
.
Blood
.
2006
;
108
(
10
):
3344
-
3351
.
23.
Sanders
YV
,
Groeneveld
D
,
Meijer
K
, et al
;
WiN study group
.
von Willebrand factor propeptide and the phenotypic classification of von Willebrand disease
.
Blood
.
2015
;
125
(
19
):
3006
-
3013
.
24.
Eikenboom
J
,
Federici
AB
,
Dirven
RJ
, et al
;
MCMDM-1VWD Study Group
.
VWF propeptide and ratios between VWF, VWF propeptide, and FVIII in the characterization of type 1 von Willebrand disease
.
Blood
.
2013
;
121
(
12
):
2336
-
2339
.
25.
Schooten
CJ
,
Tjernberg
P
,
Westein
E
, et al
.
Cysteine-mutations in von Willebrand factor associated with increased clearance
.
J Thromb Haemost
.
2005
;
3
(
10
):
2228
-
2237
.
26.
Haberichter
SL
,
Castaman
G
,
Budde
U
, et al
.
Identification of type 1 von Willebrand disease patients with reduced von Willebrand factor survival by assay of the VWF propeptide in the European study: molecular and clinical markers for the diagnosis and management of type 1 VWD (MCMDM-1VWD)
.
Blood
.
2008
;
111
(
10
):
4979
-
4985
.
27.
Eikenboom
JC
,
Tjernberg
P
,
Van Marion
V
,
Heering
KJ
.
Acquired von Willebrand syndrome: diagnostic problems and therapeutic options
.
Am J Hematol
.
2007
;
82
(
1
):
55
-
58
.
28.
Castaman
G
,
Tosetto
A
,
Federici
AB
,
Rodeghiero
F
.
Bleeding tendency and efficacy of anti-haemorrhagic treatments in patients with type 1 von Willebrand disease and increased von Willebrand factor clearance
.
Thromb Haemost
.
2011
;
105
(
4
):
647
-
654
.
29.
Favaloro
EJ
.
Collagen binding assay for von Willebrand factor (VWF:CBA): detection of von Willebrands Disease (VWD), and discrimination of VWD subtypes, depends on collagen source
.
Thromb Haemost
.
2000
;
83
(
1
):
127
-
135
.
30.
Favaloro
EJ
,
Bonar
R
,
Chapman
K
,
Meiring
M
,
Funk Adcock
D
.
Differential sensitivity of von Willebrand factor (VWF) ‘activity’ assays to large and small VWF molecular weight forms: a cross-laboratory study comparing ristocetin cofactor, collagen-binding and mAb-based assays
.
J Thromb Haemost
.
2012
;
10
(
6
):
1043
-
1054
.
31.
Flood
VH
,
Gill
JC
,
Friedman
KD
, et al
;
Zimmerman Program Investigators
.
Collagen binding provides a sensitive screen for variant von Willebrand disease
.
Clin Chem
.
2013
;
59
(
4
):
684
-
691
.
32.
Baronciani
L
,
Federici
AB
,
Cozzi
G
,
Canciani
MT
,
Mannucci
PM
.
von Willebrand factor collagen binding assay in von Willebrand disease type 2A, 2B, and 2M
.
J Thromb Haemost
.
2006
;
4
(
9
):
2088
-
2090
.
33.
Federici
AB
,
Canciani
MT
,
Forza
I
,
Cozzi
G
.
Ristocetin cofactor and collagen binding activities normalized to antigen levels for a rapid diagnosis of type 2 von Willebrand disease--single center comparison of four different assays
.
Thromb Haemost
.
2000
;
84
(
6
):
1127
-
1128
.
34.
Flood
VH
,
Lederman
CA
,
Wren
JS
, et al
.
Absent collagen binding in a VWF A3 domain mutant: utility of the VWF:CB in diagnosis of VWD
.
J Thromb Haemost
.
2010
;
8
(
6
):
1431
-
1433
.
35.
Flood
VH
,
Gill
JC
,
Christopherson
PA
, et al
.
Critical von Willebrand factor A1 domain residues influence type VI collagen binding
.
J Thromb Haemost
.
2012
;
10
(
7
):
1417
-
1424
.
36.
Flood
VH
,
Schlauderaff
AC
,
Haberichter
SL
, et al
;
Zimmerman Program Investigators
.
Crucial role for the VWF A1 domain in binding to type IV collagen
.
Blood
.
2015
;
125
(
14
):
2297
-
2304
.
37.
Sharma
R
,
Flood
VH
.
Advances in the diagnosis and treatment of Von Willebrand disease
.
Hematology Am Soc Hematol Educ Program
.
2017
;
2017
(
1
):
379
-
384
.
38.
Christopherson
PA
,
Perry
CL
,
Bellissimo
DB
, et al
.
Genotype-phenotype relationship and the role of alloantibodies in type 3 VWD in the Zimmerman Program
.
Blood
.
2017
;
130
(
suppl 1
):
19
.
39.
Bellissimo
DB
,
Christopherson
PA
,
Flood
VH
, et al
.
VWF mutations and new sequence variations identified in healthy controls are more frequent in the African-American population
.
Blood
.
2012
;
119
(
9
):
2135
-
2140
.
40.
Corrales
I
,
Catarino
S
,
Ayats
J
, et al
.
High-throughput molecular diagnosis of von Willebrand disease by next generation sequencing methods
.
Haematologica
.
2012
;
97
(
7
):
1003
-
1007
.
41.
Liang
Q
,
Qin
H
,
Ding
Q
, et al
.
Molecular and clinical profile of VWD in a large cohort of Chinese population: application of next generation sequencing and CNVplex® technique
.
Thromb Haemost
.
2017
;
117
(
8
):
1534
-
1548
.
42.
Christopherson
PA
,
Udani
RA
,
Perry
C
, et al
.
Identification of copy number variants in type 1 and type 3 VWD by aCGH in the Zimmerman Program
.
Blood
.
2016
;
128
(
22
):
872
.
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