European Journal of Haematology 87 (99–106)

REVIEW ARTICLE

Pathophysiology of acquired von Willebrand disease: a

concise review
Shrimati Shetty, Priyanka Kasatkar, Kanjaksha Ghosh
National Institute of Immunohaematology (ICMR), KEM Hospital, Parel, Mumbai, India

Abstract
Acquired von Willebrand disease (AVWD) is a rare, underdiagnosed hemorrhagic disorder, which is similar
to congenital VWD with regard to the clinical and laboratory parameters; however, it is found in individuals
with no positive family history and has no genetic basis. The etiology is varied, the commonest being
hematoproliferative disorders and cardiovascular disorders. Other disorders associated with AVWD are
autoimmune disorders such as systematic lupus erythematosus, hypothyroidism, and neoplasia, or it may
also be drug induced. In quite a few cases, the etiology is unknown. The pathogenic mechanisms are dif-
ferent in different underlying disorders or they may be overlapping among these disorders. Some of the
proposed mechanisms include the development of autoantibodies, selective absorption of high molecular
weight von Willebrand factor (VWF) multimers, non-selective absorption of VWF, mechanical destruction
of VWF under high shear stress, and increased proteolysis. This report presents a concise review of the
pathophysiological mechanisms of AVWD in these various underlying conditions.

Key words acquired von Willebrand disease; lymphoproliferative disorders; myeloproliferative disorders; hypothyroidism; systematic
lupus erythematosus; tumors

Correspondence Shrimati Shetty, National Institute of Immunohaematology (ICMR), 13th Floor, KEM Hospital, Parel, Mumbai 400
012, India. Tel: 9122 241 38518; Fax: 9122 241 38521; e-mail : shrimatishetty@yahoo.com

Accepted for publication 26 April 2011 doi:10.1111/j.1600-0609.2011.01636.x

von Willebrand factor (VWF) is a large multifunctional
glycoprotein that performs two critical functions in
hemostasis: it acts as a bridging molecule for platelet
adhesion and aggregation at sites of injury and acts as a
carrier for factor VIII in the circulation rendering stabil-
ity to the molecule (1). VWF is characterized by its mul-
timeric nature, the size being as large as 15–20 million
daltons, the subunits of which vary in size from 240 to
270 kd (2). The VWF multimers differ only in the num-
ber of VWF monomer units, the largest being the most
competent in maintaining hemostasis. The multimeric
size of VWF is regulated by the metalloproteinase AD-
AMTS13, which cleaves the VWF molecule at the A2
domain (3).
Hereditary von Willebrand disease (VWD) results as a
result of a variety of mutations occurring throughout the
VWF gene (4). This may result in qualitative (type 2) or
quantitative deficiency (type 1 and type 3) of VWF,
depending on the type of mutation in a specific family.
The inheritance pattern is both autosomal recessive and
dominant, i.e. type three is autosomal recessive, while
types 1 and 2 are generally autosomal dominant with a
few exceptions. VWF is predominantly synthesized by
endothelial cells and megakaryocytes which undergoes
initially dimerization within the endoplasmic reticulum
and the final multimerization and glycosylation within
the Golgi complex (5). The prevalence of all the subtypes
of congenital VWD has been reported to be up to 1%
(6).
Acquired von Willebrand disease (AVWD) is a rare
disorder as far as the reports published across the world
literature and also in the International Registry for
AVWD (7–9); however, there are concerns that whatever
has been reported may just be the tip of the iceberg (10).
This is primarily because of the milder forms of AVWD,
which generally may not manifest until a hemostatic
challenge is encountered by these patients. This may be
well observed by the contrasting prevalence rates of the

ª 2011 John Wiley & Sons A/S 99

Acquired von Willebrand disease Shetty et al.

different types of congenital VWD in western countries Lymphoproliferative disorders

where a systematic screening of VWD is being performed
and the same is not true for developing countries like
India (11–13).
Unlike acquired hemophilia A (14), which has mainly
an immune etiology, AVWD has a multifactorial etiol-
ogy (15–18). The mechanisms involved also are different
in different underlying disorders (19, 20). The heteroge-
neity in the etiology is probably due to multiple func-
tions attributed to the different functional domains of
VWF, the size, and the multimeric nature of the protein
itself. The present review summarizes the various patho-
physiological mechanisms proposed in different disorders
associated with AVWD.
Table 1 shows the various underlying disorders and
their prevalence in various reports published in litera-
ture.
Table 1 Acquired von Willebrand disease cases from published litera-
ture associated with different disorders (data retrieved from PUB-
MED)
Number of
Underlying disorder patients (%)
After cardiovascular disorders, the largest number of
patients with AVWD belongs to this group, as evident
from the reports in literature (7). Among the lymphopro-
liferative disorders, monoclonal gammopathy of undeter-
mined significance (MGUS) of type IgG, IgM, and
rarely IgA form the major group (7, 21) followed by
multiple myeloma (22). AVWD has also been reported in
association with Waldenstrom’s macroglobulinemia (23),
Wilms’ tumor (24), non-Hodgkin’s lymphoma (25),
chronic lymphocytic leukemia (26), and hairy cell leuke-
mia (27).
Development of autoantibodies against VWF is the
major pathophysiological mechanism working in the
development of AVWD in lymphoproliferative disorders.
These may bind to the functional epitopes of VWF and
neutralize its activity (27) or these antibodies may form
immune complexes with VWF, accelerating its clearance
from circulation (27). Abnormal expression of GP1b
receptors on the surface of malignant cells has also been
reported, which would facilitate the binding of VWF to
these cells, thus reducing their levels in the circulation
(28).

Lymphoproliferative disorders
Myeloproliferative disorders (MPD)
Monoclonal gammopathy of 45
undetermined significance Myeloproliferative disorders present a paradoxical situa-
Multiple myeloma 19 tion in medicine in that excess platelets result in a pro-
Non-Hodgkin’s lymphoma 1 thrombotic tendency and also a bleeding tendency. In
Waldenstrom’s macroglobulinemia 5
most of the cases, bleeding manifestations are because of
Hairy cell leukemia 1
Myeloproliferative disorders
the development of AVWD, which in MPDs generally
Essential thrombocythemia 20 follow a milder course in contrast to immune-associated
Polycythemia vera 10 AVWD.
Chronic myeloid leukemia 23 Among MPDs, essential thrombocythemia (ET) is
Tumors more commonly associated with AVWD (29, 30)than
Wilms’ tumor 13 polycythemia vera (PV) (31, 32) and chronic myeloid leu-
Ewing’s sarcoma 1
kemia (33, 34). Another report, however, states that
Autoimmune
Systematic lupus erythematosus 7
AVWD is seen in more than 50% of the patients with
Other autoimmune disorders 4 PV (35).A retrospective study (36) from a single Institu-
Cardiac disorders tion in Argentina has shown that among the 99 patients
Aortic stenosis and ⁄ or ventricular 202 with AVWD, 75 (75.7%) were associated with MPDs, of
assist devices which 20 (26.7%) were type 1 and 55 (73.3%) were type
Heart transplantation 1 2 VWD. Another study has shown that 17 of 147
Coronary artery bypass surgery 1
(11.6%) cases of MPD are associated with AVWD (37).
Hypothyroidism 48
Drug induced
There are different mechanisms proposed for the
Cefotaxime 1 occurrence of AVWD in case of MPDs. However, in all
Levofloxacin 1 cases, increased platelet count is the major pathophysio-
Ciprofloxacin 2 logic explanation offered for the association of MPD
Valproic acid 25 with AVWD (38, 39); a few studies, however, refute this
Hydroxy ethyl starch 11 observation (36, 39).
High-dose recombinant factor VIII 1
Type 2A is the major subtype observed in patients with
Miscellaneous
Gaucher’s disease 6
MPD, indicating that the high molecular weight multi-
Renal transplantation 1 mers (HMWM) are the key players in the pathogenesis of

100 ª 2011 John Wiley & Sons A/S

Shetty et al. Acquired von Willebrand disease

AVWD in these disorders. The objective measurement of
HMWM by SDS PAGE followed by densitometry scan-
ning has shown reduced levels of HMWM in PV and ET
but not in patients with myelofibrosis (MF) (40), and they
were negatively correlated with platelet count.
Another mechanism proposed in MPDs is increased
viscosity of blood in MPDs resulting in high shear stress
leading to an acceleration of proteolysis of VWF that is
bound to platelets. Interaction between platelet glycopro-
tein receptor GPIb and VWF has also been proposed by
a few authors (25, 26). Very rarely, an immune mecha-
nism has also been observed in MPDs (41, 42). In case
of carriers of the recently identified acquired somatic
mutation JAK2 V617F, increased kinase activity has
been found to further increase platelet activation aggra-
vating both bleeding and thrombotic tendency (43).
The various pathological mechanisms associated with
AVWD are shown in Table 2.
Cardiovascular disorders
Since the first description of loss of high molecular
weight multimers in congenital heart defects (44), several
cases of AVWD have been reported to be associated
with congenital and acquired cardiac defects, patients
with ventricular septum devices and other associated
conditions. In fact, they form the largest group of dis-
orders among the underlying pathogenic conditions asso-
ciated with AVWD. The two major groups under this
category are aortic stenosis associated with gastric angi-
odysplasia (Heyde’s syndrome) (45, 46) and patients with
ventricular assist device (VAD) (47, 48).
The association between gastric angiodysplasia and
aortic stenosis is still not characterized in detail. Angio-
dysplasia refers to submucosal vascular abnormalities
commonly found in the GI tract, the prevalence of which
increases with age. An International survey has shown
that Type 2A is the commonest subtype of VWD in
angiodysplasia, while type 3 is encountered in a few cases
(49). GI angiodysplasia has also been observed in other
cardiac disorders, other than arterial stenosis (50).
Ventricular assist devices (LVAD) are being used as a
permanent therapy for selected patients with end-stage
heart failure. The outcomes after the device implantation
have significantly improved during the last decade. Sev-
eral cases of AVWD have also been reported in patients
with ventricular assist device (VAD) (51, 52). This reduc-
tion has been hypothesized to be a result of accelerated
proteolysis caused by shear stress induced by the device,
similar to the mechanism for VWF abnormalities in
severe aortic stenosis (53). The condition gets reversed
after the explanation of the device.
The chief mechanism in case of cardiovascular disor-
ders put forward is the shear stress–induced reduction of
high molecular weight multimers leading to a hemor-
rhagic condition. Proteolysis of von Willebrand factor as
it passes through the stenotic valve is another hypothesis
proposed as a cause of the bleeding (54). In case of aor-
tic stenosis, a direct correlation between the in vivo
shears stress and the loss of multimers has been observed
(54). In case of VADs, it is the device-related increase in
the shear stress, which creates a condition similar to that
of aortic stenosis. A second mechanism that is possible is
that under high shear stress, platelets may get activated
resulting in the adsorption of HMWM (27). Proteolytic
degradation of VWF by fibrinolytic components like
plasmin is another mechanism that must be working in
AVWD associated with cardiac disorders (55).
Immune-mediated etiology
Acquired von Willebrand disease was first described in a
case of systematic lupus erythematosus (SLE) in 1968 (56).
It is mainly associated with the development of autoanti-
bodies against VWF. All the different subtypes of VWD
are represented in AVWD associated with autoantibodies

Table 2 shows the proposed mechanisms and the different subtypes of VWD reported in association with different underlying disorders

Predominant
Mechanism Underlying disorders VWD subtype

Specific or non-specific antibodies, immune complex Autoimmune disorders 1, 2A

formation, and early clearance Lymphoproliferative disorders
Myeloproliferative disorders
Adsorption of HMWM onto the malignant cells or Myeloproliferative disorders, tumors, lymphoproliferative disorders, 2A
activated platelets or drugs (HES) cardiovascular disorders
Drugs
Increased viscosity of blood, proteolytic degradation Drug induced myeloproliferative disorders, tumors, lymphoproliferative 2A
disorders, cardiovascular disorders
Shear stress–induced proteolytic degradation Cardiovascular disorders 2A
Defective synthesis ⁄ secretion Hypothyroidism 1

VWD, von Willebrand disease; HES, Hydroxy ethyl starch.

ª 2011 John Wiley & Sons A/S 101

Acquired von Willebrand disease
(43). AVWD is also reported in other autoimmune disor-
ders, like scleroderma (57), and mixed connective tissue
disease (58). Other diseases associated with antibodies are
monoclonal gammopathies (43), multiple myeloma (22),
Waldenstrom’s macroglobulinemia (59), chronic myeloid
leukemia (60), and angiodysplasia (61). The antibodies are
predominantly IgG, but Ig M and IgA antibodies have
also been reported (62). Antibodies against FVIII–VWF
complex have also been reported (63). A case of AVWD
has also been reported owing to graft-versus-host disease
(64).
The antibodies are found to be directed against both
functional and non-functional epitopes of VWF, thus
forming immune complexes facilitating a premature
clearance from circulation, which results in low levels of
factor VIII and vWF antigen and reduced vWF:RCo
activity (8). Antibodies directed against different epitopes
of VWF have been reported, i.e. against collagen binding
epitope (65) and GP1bIX and GP IIb ⁄ IIIa preventing
the binding of VWF to platelets (66).
Hypothyroidism
The relationship between coagulation system and endo-
crine disorders has long been established and reviewed
by several authors (67, 68). Approximately 7–8% of the
reported cases of AVWD have this underlying etiology.
The clinical manifestations are generally moderate to
mild with type 1 being the predominant VWD subtype
(69). Both asymptomatic and symptomatic cases have
been detected under this group.
This is the only subgroup where a defect in the synthe-
sis or release of VWF is the major pathophysiological
mechanism. In vitro studies have confirmed that decrease
in VWF levels is either attributed to decreased synthesis
or to decreased secretion and not to increased clearance
or proteolysis (70).
Acquired von Willebrand disease has also been
reported in cases with euthyroidism (71). A large study
involving 1342 cases scheduled for thyroid surgery
showed that 39 patients (2.9%) had AVWD and all these
were euthyroid patients.
Neoplasia
The first association of non-hematologic malignancies
with AVWD has been reported in a case of Wilms’
tumor (72). Since then, there are several reports of asso-
ciation between AVWD and Wilms’ tumor (73, 74).
AVWD has also been associated with carcinoma (75),
peripheral neurectodermal tumors (76), and Ewing’s
sarcoma (77).
Selective absorption of HMWM by the malignant cells
and aberrant expression of GP1b or GP IIb ⁄ IIIa recep-
102
Shetty et al.
tors by the tumor cells (78) are some of the pathophysio-
logical mechanisms proposed to explain the finding of
AVWD in these cases. In case of Wilms’ tumor, the
causative agent is thought to be hyaluronic acid secreted
by nephroblastoma cells of the Wilms’ tumor (79).
Drug-induced AVWD
The drugs reported to be associated with AVWD are
hydroxyethyl starch (HES) (80, 81), valproic acid (82),
griseofulvin (83), ciprofloxacin (84), high-dose infusion of
recombinant factor VIII (85), tetracycline (15), pesticides
(15), and thrombolytic agents (86).
Although the exact pathogenic mechanisms associated
with these drugs is not known, discontinuation of each
of these drugs has resulted in the normalcy of all the
hemostatic parameters suggesting the pathogenicity of
these drugs. It has been hypothesized that there is a
non-immunologic precipitation of VWF in the presence
of hydroxyethyl starch (64) or there is absorption of
large multimers onto the large molecules of HES (20).
Both medium and large molecular weight HES are
known to be causing type 1 AVWD (87). A study by
Annie Pierr Jon ville and Bera et al. has shown that of
all cases, six were type 1 AVWD and all the clinically
overt bleeding symptoms disappeared once the drug was
withdrawn (88).Some authors have shown that there is
an accelerated degradation of FVIII–VWF complex
bound to starch molecules (89). In case of ciprofloxacin-
induced AVWD, increased proteolysis of VWF has been
shown to be the main pathogenic mechanism (84).
Miscellaneous causes
Acquired von Willebrand disease has also been found to
be associated with Epstein–Barr virus (EBV) infection
(90), e beta thalassemia (91), and telangiectasia (92).
Whether they are coincidental cooccurrence or whether
AVWD is secondary to these disorders is not clear.
Besides, there are quite a few cases in literature without
any established underlying disorders (7, 15, 19).
Summary
Pathophysiological mechanisms leading to the develop-
ment of AVWD are highly heterogeneous. The mecha-
nisms are different in different underlying disorders.
They may act independently or in concurrence which in
turn might decide the severity of the disease. The diagno-
sis is complex and requires experienced laboratories.
Understanding the pathomechanisms of this rare disor-
der is important for an appropriate management of the
cases, as in most of the cases the coagulation parameters
are reversed after treating the underlying condition.
ª 2011 John Wiley & Sons A/S
Shetty et al.
Take home message
l AVWD is a rare, highly heterogeneous, hemorrhagic
disorders with multiple etiology
l In most of these cases, the symptoms are reversible
and return to normal hemostasis, once the underlying
condition is treated
l Diagnosis of AVWD requires an experienced labora-
tory. Physicians should be aware of the underlying con-
ditions and the pathophysiological mechanism associated
with AVWD, and any bleeding symptoms in these disor-
ders should be suspected for AVWD
l All the cases should be reported either to a National
Registry or to an International data base that would
facilitate better diagnostic and management of these rare
complex disorder
References
1. Ikeda Y, Handa M, Kawano K, et al. The role of von
Willebrand factor and fibrinogen in platelet aggregation
under varying shear stress. J Clin Invest 1991;87:1234–40.
2. Titani K, Kumar S, Takio K, Ericsson LH, Wade RD,
Ashida K, Walsh KA, Chopek MW, Sadler JE, Fujikawa
K. Amino acid sequence of human von Willebrand factor.
Biochemistry 1986;25:3171–84.
3. Dong JF, Moake JL, Bernardo A, Fujikawa K, Ball C,
Nolasco L, López JA, Cruz MA. ADAMTS-13 metallo-
protease interacts with the endothelial cell-derived
ultra-large von Willebrand factor. J Biol Chem
2003;278:29633–9.
4. ISTH-SSC VWF Online Database. Available at: http://
www.ragtimedesign.com/vwf/mutation, Accessed on
18 ⁄ 03 ⁄ 2011.
5. Wagner DD, Marder VJ. Biosynthesis of von Willebrand
protein by human endothelial cells: processing steps and
their intracellular localization. J Cell Biol 1984;99:2123–
30.
6. Rodeghiero F, Castaman G, Dini E. Epidemiological
investigation of the prevalence of von Willebrand’s
disease. Blood 1987;69:454–9.
7. Budde U, Bergmann F, Michiels JJ. Acquired von
Willebrand syndrome: experience from 2 years in a single
laboratory compared with data from the literature and an
international registry. Semin Thromb Hemost 2002;28:227–
38.
8. Franchini M, Lippi G. Acquired von Willebrand syn-
drome: an update. Am J Hematol 2007;82:368–75.
9. Federici AB, Rand JH, Bucciarelli P, Budde U, van
Genderen PJ, Mohri H, Meyer D, Rodeghiero F, Sadler
JE. Subcommittee on von Willebrand factor. Acquired
von Willebrand syndrome: data from an international
registry. Thromb Haemost 2000;84:345–9.
10. Federici AB. Acquired von Willebrand syndrome: is it an
extremely rare disorder or do we see only the tip of the
iceberg? J Thromb Haemost 2008;6:565–8.
ª 2011 John Wiley & Sons A/S
Acquired von Willebrand disease
11. Kumar S, Kishore R, Gupta V, Jain M, Shukla J.
Prevalence and spectrum of von Willebrand disease in
Eastern Uttar Pradesh. Indian J Pathol Microbiol
2010;53:486–9.
12. Srivastava A, Rodeghiero F. Epidemiology of von Wille-
brand disease in developing countries. Semin Thromb
Hemost 2005;31:569–76.
13. Trasi S, Shetty S, Ghosh K, Mohanty D. Prevalence and
spectrum of von Willebrand disease from western India.
Indian J Med Res 2005;121:653–8.
14. Shetty S, Bhave M, Ghosh K. Acquired hemophilia A:
diagnosis, etiology, clinical spectrum and treatment
options. Autoimmun Rev 2011;10:311–6.
15. Michiels JJ, Budde U, van der Planken M, van Vliet HH,
Schroyens W, Berneman Z. Acquired von Willebrand syn-
dromes: clinical features, etiology, pathophysiology, classi-
fication and management. Best Pract Res Clin Haematol
2001;14:401–36.
16. Federici AB. Acquired von Willebrand syndrome associ-
ated with hypothyroidism: a mild bleeding disorder to be
further investigated. Semin Thromb Hemost 2011;37:35–40.
17. Crow S, Chen D, Milano C, et al. Acquired von Wille-
brand syndrome in continuous-flow ventricular assist
device recipients. Ann Thorac Surg 2010;90:1263–9.
18. Federici AB. Acquired von Willebrand syndrome: an un-
derdiagnosed and misdiagnosed bleeding complication in
patients with lymphoproliferative and myeloproliferative
disorders. Semin Hematol 2006;43:S48–58.
19. Veyradier A, Jenkins CS, Fressinaud E, Meyer D.
Acquired von Willebrand syndrome: from pathophysiol-
ogy to management. Thromb Haemost 2000;84:175–82.
20. Mohri H. Acquired von Willebrand syndrome: its patho-
physiology, laboratory features and management. J
Thromb Thrombolysis 2003;15:141–9.
21. Lamboley V, Zabraniecki L, Sie P, Pourrat J, Fournié B.
Myeloma and monoclonal gammopathy of uncertain sig-
nificance associated with acquired von Willebrand’s syn-
drome. Seven new cases with a literature review. Joint
Bone Spine 2002;69:62–7.
22. Mohri H, Tanabe J, Ohtsuka M, Yoshida M, Motomura
S, Nishida S, Fujimura Y, Okubo T. Acquired von
Willebrand disease associated with multiple myeloma;
characterization of an inhibitor to von Willebrand factor.
Blood Coagul Fibrinolysis 1995;6:561–6.
23. Mazurier C, Parquet-Gernez A, Descamps J, Bauters F,
Goudemand M. Acquired von Willebrand’s syndrome in
the course of Waldenström’s disease. Thromb Haemost
1980;44:115–8.
24. Jonge Poerink-Stockschlader AB, Dekker I, Risseeuw-
Appel IM, Hählen K. Acquired Von Willebrand disease in
children with a Wilms’ tumor. Med Pediatr Oncol
1996;26:238–43.
25. van Genderen PJ, Michiels JJ, Bakker JJ, van‘t Veer MB.
Effectiveness of high-dose intravenous gamma globulin
therapy in acquired von Willebrand’s disease. Vox Sang
1994;67:14–7.
103
Acquired von Willebrand disease
26. Roussi JH, Houbouyan LL, Alterescu R, Franc B, Goguel
AF. Acquired Von Willebrand’s syndrome associated with
hairy cell leukaemia. Br J Haematol 1980;46:503–6.
27. Mohri H. Acquired von Willebrand syndrome: features
and management. Am J Hematol 2006;81:616–23.
28. Facon T, Caron C, Courtin P, Wurtz A, Deghaye M,
Bauters F, Mazurier C, Goudemand J. Acquired type II
von Willebrand’s disease associated with adrenal cortical
carcinoma. Br J Haematol 1992;80:488–94.
29. Rolf N, Suttorp M, Budde U, Siegert G, Knoefler R.
Essential thrombocythaemia in a teenage girl resulting in
acquired von Willebrand syndrome with joint haemor-
rhage and menorrhagia. Thromb Haemost 2010;103:1272–
4.
30. Giannini S, Solimando M, Fierro T, Baronciani L,
Federici AB, Gresele P. Acquired von Willebrand
syndrome type 2A in a JAK2-positive essential thrombo-
cythaemia-affected member of a large von Willebrand
disease family with a novel autosomal dominant A1716P
mutation. Thromb Haemost 2011;105:921–4.
31. Tefferi A, Smock KJ, Divgi AB. Polycythemia vera-asso-
ciated acquired von Willebrand syndrome despite near-
normal platelet count. Am J Hematol 2010;85:545.
32. Landolfi R, Cipriani MC, Novarese L. Thrombosis and
bleeding in polycythemia vera and essential thrombo-
cythemia. Best Pract Res Clin Haematol. 2006;19:617–33.
33. Uchiyama M, Ikeda T. Successful imatinib mesylate ther-
apy for acquired von Willebrand syndrome in chronic
myelogenous leukemia. Leuk Res 2009;33:1723–4.
34. Mohri H, Tanabe J, Yamazaki E, Yoshida M, Harano H,
Matsuzaki M, Motomura S, Okubo T. Acquired type 2A
von Willebrand disease in chronic myelocytic leukemia.
Hematopathol Mol Hematol 1996;10:123–33.
35. Mohri H. Acquired von Willebrand disease in patients
with polycythemia rubra vera. Am J Hematol 1987;
26:135–46.
36. Sánchez-Luceros A, Meschengieser SS, Woods AI, Blanco
AN, Kempfer AC, Casais P, et al. Acquired von Wille-
brand factor abnormalities in myeloproliferative disorders
and other hematologic diseases: a retrospective analysis by
a single institution. Haematologica 2002;87:264–70.
37. Mohri H, Motomura S, Kanamori H, Matsuzaki M,
Watanabe S, Maruta A, Kodama F, Okubo T. Clinical
significance of inhibitors in acquired von Willebrand
syndrome. Blood 1998;91:3623–9.
38. van Genderen PJ, Budde U, Michiels JJ, van Strik R, van
Vliet HH. The reduction of large von Willebrand factor
multimers in plasma in essential thrombocythemia is
related to the platelet count. Br J Haematol 1996;93:962–5.
39. Budde U, Scharf RE, Franke P, Hartmann-Budde K,
Dent J, Ruggeri ZM. Elevated platelet count as a cause of
abnormal von Willebrand factor multimer distribution in
plasma. Blood 1993;82:1749–57.
40. Tatewaki W, Takahashi H, Shibata A. Multimeric compo-
sition of plasma von Willebrand factor in chronic myelo-
proliferative disorders. Clin Lab Haematol 1988;10:417–25.
104
Shetty et al.
41. Lazarchick J, Pappas AA, Kizer J, Hall SA. Acquired von
Willebrand syndrome due to an inhibitor specific for von
Willebrand factor antigens. Am J Hematol 1986;21:305–14.
42. Mohri H, Ohkubo T. Acquired von Willebrand’s syn-
drome due to an inhibitor of IgG specific for von Wille-
brand’s factor in polycythemia rubra vera. Acta Haematol
1987;78:258–64.
43. Michiels JJ, Berneman Z, Schroyens W, Finazzi G, Budde
U, van Vliet HH. The paradox of platelet activation and
impaired function: platelet-von Willebrand factor inter-
actions, and the etiology of thrombotic and hemorrhagic
manifestations in essential thrombocythemia and poly-
cythemia vera. Semin Thromb Hemost 2006;32:589–604.
44. Gill JC, Wilson AD, Endres-Brooks J, Montgomery RR.
Loss of the largest von Willebrand factor multimers from
the plasma of patients with congenital cardiac defects.
Blood 1986;67:758–61.
45. Massyn MW, Khan SA. Heyde syndrome: a common
diagnosis in older patients with severe aortic stenosis. Age
Ageing 2009;38:267–70.
46. Warkentin TE, Moore JC, Anand SS, Lonn EM, Morgan
DG. Gastrointestinal bleeding, angiodysplasia, cardiovas-
cular disease, and acquired von Willebrand syndrome.
Transfus Med Rev 2003;17:272–86.
47. Heilmann C, Geisen U, Beyersdorf F, Nakamura L, Benk
C, Berchtold-Herz M, Trummer G, Schlensak C, Zieger
B. Acquired von Willebrand syndrome in patients with
ventricular assist device or total artificial heart. Thromb
Haemost 2010;103:962–7.
48. Geisen U, Heilmann C, Beyersdorf F, Benk C, Berchtold-
Herz M, Schlensak C, Budde U, Zieger B. Non-surgical
bleeding in patients with ventricular assist devices could
be explained by acquired von Willebrand disease. Eur J
Cardiothorac Surg 2008;33:679–84.
49. Fressinaud E, Meyer D. International survey of patients
with von Willebrand disease and angiodysplasia. Thromb
Haemost 1993;70:546.
50. Banerjee AK. Angiodysplasia associated with hypertrophic
obstructive cardiomyopathy (HOCM). Br J Clin Pract
1990;44:326–7.
51. Meyer AL, Malehsa D, Bara C, Budde U, Slaughter MS,
Haverich A, Strueber M. Acquired von Willebrand syn-
drome in patients with an axial flow left ventricular assist
device. Circ Heart Fail 2010;3:675–81.
52. Heilmann C, Geisen U, Beyersdorf F, Nakamura L, Benk
C, Berchtold-Herz M, Trummer G, Schlensak C, Zieger
B. Acquired von Willebrand syndrome in patients with
ventricular assist device or total artificial heart. Thromb
Haemost 2010;103:962–7.
53. Pereira NL, Chen D, Kushwaha SS, Park SJ. Discontinu-
ation of antithrombotic therapy for a year or more in
patients with continuous-flow left ventricular assist
devices. Interact Cardiovasc Thorac Surg 2010;11:503–5.
54. Vincentelli A, Susen S, Le Tourneau T, et al. Acquired
von Willebrand syndrome in aortic stenosis. N Engl J
Med 2003;349:343–9.
ª 2011 John Wiley & Sons A/S
Shetty et al.
55. Sadler JE. Aortic stenosis, von Willebrand factor, and
bleeding. N Engl J Med 2003;349:323–5.
56. Simone JV, Cornet JA, Abildgaard CF. Acquired von
Willebrand’s syndrome in systemic lupus erythematosus.
Blood 1968;31:806–12.
57. Sampson BM, Greaves M, Malia RG, Preston FE.
Acquired von Willebrand’s disease: demonstration of a
circulating inhibitor to the factor VIII complex in four
cases. Br J Haematol 1983;54:233–44.
58. Yoshida H, Arai K, Wakashin M. Development of
acquired von Willebrand’s disease after mixed connective
tissue disease. Am J Med 1988;85:445–6.
59. Mazurier C, Parquet-Gernez A, Descamps J, Bauters F,
Goudemand M. Acquired von Willebrand’s syndrome in
the course of Waldenström’s disease. Thromb Haemost
1980;44:115–8.
60. Mohri H, Tanabe J, Yamazaki E, Yoshida M, Harano H,
Matsuzaki M, Motomura S, Okubo T. Acquired type 2A
von Willebrand disease in chronic myelocytic leukemia.
Hematopathol Mol Hematol 1996;10:123–33.
61. Inbal A, Bank I, Zivelin A, Varon D, Dardik R, Shapiro
R, Rosenthal E, Shenkman B, Gitel S, Seligsohn U.
Acquired von Willebrand disease in a patient with angi-
odysplasia resulting from immune-mediated clearance of
von Willebrand factor. Br J Haematol 1997;96:179–82.
62. Kumar S, Pruthi RK, Nichols WL. Acquired von Wille-
brand disease. Mayo Clin Proc 2002;77:181–7.
63. Meyer D, Frommel D, Larrieu MJ, Zimmerman TS.
Selective absence of large forms of factor VIII ⁄ von Wille-
brand factor in acquired von Willebrand’s syndrome.
Response to transfusion. Blood 1979;54:600–6.
64. Lazarchick J, Green C. Acquired von Willebrand’s disease
following bone marrow transplantation. Ann Clin Lab Sci
1994;24:211–5.
65. van Genderen PJ, Vink T, Michiels JJ, van‘t Veer MB,
Sixma JJ, van Vliet HH. Acquired von Willebrand disease
caused by an autoantibody selectively inhibiting the bind-
ing of von Willebrand factor to collagen. Blood
1994;84:3378–84.
66. Goudemand J, Samor B, Caron C, Jude B, Gosset D,
Mazurier C. Acquired type II von Willebrand’s disease:
demonstration of a complexed inhibitor of the von Wille-
brand factor-platelet interaction and response to treat-
ment. Br J Haematol 1988;68:227–33.
67. Vescovi PP, Favaloro EJ, Lippi G, Garofano M,
Montagnana M, Manzato F, Franchini M. The spectrum
of coagulation abnormalities in thyroid disorders. Semin
Thromb Hemost 2011;37:7–10.
68. Targher G, Pichiri I, Zoppini G, Bonora E, Chonchol M.
Hemostatic and fibrinolytic abnormalities in endocrine
diseases: a narrative review. Semin Thromb Hemost
2009;35:605–12.
69. Manfredi E, van Zaane B, Gerdes VE, Brandjes DP,
Squizzato A. Hypothyroidism and acquired von Wille-
brand’s syndrome: a systematic review. Haemophilia
2008;14:423–33.
ª 2011 John Wiley & Sons A/S
Acquired von Willebrand disease
70. Baumgartner-Parzer SM, Wagner L, Reining G, Sexl V,
Nowotny P, Müller M. Increase by tri-iodothyronine of
endothelin-1, fibronectin and von Willebrand factor in
cultured endothelial cells. J Endocrinol 1997;154:231–9.
71. Franchini M, Zugni C, Veneri D, Gandini G, Lippi G,
Manzato F, Brazzarola P. High prevalence of acquired
von Willebrand’s syndrome in patients with thyroid
diseases undergoing thyroid surgery. Haematologica
2004;89:1341–6.
72. Noronha PA, Hruby MA, Maurer HS. Acquired von
Willebrand disease in a patient with Wilms tumor. J
Pediatr 1979;95:997–9.
73. Jonge Poerink-Stockschlader AB, Dekker I, Risseeuw-
Appel IM, Hählen K. Acquired Von Willebrand disease in
children with a Wilms’ tumor. Med Pediatr Oncol
1996;26:238–43.
74. Han P, Lou J, Wong HB. Wilms’ tumor with acquired
von Willebrand’s disease. Aust Paediatr J 1987;23:253–5.
75. Holland L, Adamson A, Ingram GI, Chalmers DG.
Acquired von Willebrand’s syndrome. Br J Haematol
1980;45:161–4.
76. Nowak-Göttl U, Kehrel B, Budde U, Hoffmann C, Win-
kelmann W, Jürgens H. Acquired von Willebrand disease
in malignant peripheral neuroectodermal tumor (PNET).
Med Pediatr Oncol 1995;25:117–8.
77. Elli M, Pinarli FG, Dagdemir A, Dabak N, Fisgin T,
Selcuk MB. Acquired von Willebrand syndrome in a
patient with Ewing sarcoma. Pediatr Hematol Oncol 2006;
23:111–4.
78. Scrobohaci ML, Daniel MT, Levy Y, Marolleau JP,
Brouet JC. Expression of GpIb on plasma cells in a
patient with monoclonal IgG and acquired von Wille-
brand disease. Br J Haematol 1993;84:471–5.
79. Michiels J, Schroyens W, Berneman Z, van der Planken
M. Atypical variant of acquired von Willebrand syndrome
in Wilms tumor: is hyaluronic acid secreted by nephro-
blastoma cells the cause?. Clin Appl Thromb Hemost
2001;7:102–5.
80. Dalrymple-Hay M, Aitchison R, Collins P, Sekhar M,
Colvin B. Hydroxyethyl starch induced acquired von
Willebrand’s disease. Clin Lab Haematol 1992;14:209–11.
81. Jonville-Béra AP, Autret-Leca E, Gruel Y. Acquired type
I von Willebrand’s disease associated with highly substi-
tuted hydroxyethyl starch. N Engl J Med 2001;345:622–3.
82. Serdaroglu G, Tütüncüoglu S, Kavakli K, Tekgül H.
Coagulation abnormalities and acquired von Willebrand’s
disease type 1 in children receiving valproic acid. J Child
Neurol 2002;17:41–3.
83. Conrad ME, Latour LF. Acquired von Willebrand’s dis-
ease, IgE polyclonal gammopathy and griseofulvin ther-
apy. Am J Hematol 1992;41:143.
84. Castaman G, Lattuada A, Mannucci PM, Rodeghiero F.
Characterization of two cases of acquired transitory von
Willebrand syndrome with ciprofloxacin: evidence for
heightened proteolysis of von Willebrand factor. Am J
Hematol 1995;49:83–6.
105
Acquired von Willebrand disease
85. Rock G, Adamkiewicz T, Blanchette V, Poon A, Sparling
C. Acquired von Willebrand factor deficiency during
high-dose infusion of recombinant factor VIII. Br J
Haematol 1996;93:684–7.
86. Federici AB, Berkowitz SD, Lattuada A, Mannucci PM.
Conditions in which there is heightened proteolysis Degra-
dation of von Willebrand factor in patients with acquired
clinical. Blood 1993;81:720–5.
87. van Den Brink WA, van Genderen P, Thijsse WJ,
Michiels JJ. Hetastarch coagulopathy. J Neurosurg
1996;85:367.
88. Jonville-Béra AP, Autret-Leca E, Gruel Y. Acquired
type I von Willebrand’s disease associated with highly
substituted hydroxyethyl starch. N Engl J Med
2001;345:622–3.
106
Shetty et al.
89. Stump DC, Strauss RG, Henriksen RA, Petersen RE,
Saunders R. Effects of hydroxyethyl starch on blood
coagulation, particularly factor VIII. Transfusion 1985;
25:349–54.
90. Kinoshita S, Yoshioka K, Kasahara M, Takamiya O.
Acquired von Willebrand disease after Epstein-Barr virus
infection. J Pediatr 1991;119:595–8.
91. Benson PJ, Peterson LC, Hasegawa DK, Smith CM II.
Abnormality of von Willebrand factor in patients with
hemoglobin E-beta (0) thalassemia. Am J Clin Pathol
1990;93:395–9.
92. McGrath KM, Johnson CA, Stuart JJ. Acquired von
Willebrand disease associated with an inhibitor to factor
VIII antigen and gastrointestinal telangiectasia. Am J Med
1979;67:693–6.
ª 2011 John Wiley & Sons A/S