Original Report
Acquired von Willebrand Syndrome Type 1 in Hypothyroidism:
Reversal After Treatment With Thyroxine
*†jan Jacques Michiels, M.D., *Wilfried
‡Marc van der Planken,
*Clinical Hemostasis and Thrombosis, Department of Hematology, University Hospital Antwerp, Antwerp, Belgium; †Goodheart
Institute, Center for Hemostasis Thrombosis and Vascular Pathology, Rotterdam, The Netherlands; and ‡Laboratory of
Hemostasis and Hematology, Department of Clinical Biology, University Hospital Antwerp, Antwerp, Belgium
Summary: In 16 cases, acquired von Willebrand syndrome
(AvWS) and hypothyroidism have been described that occur
with each other: 15 women and one man, at a mean age of 32
years, range, 13 to 82 years of age. Activated partial thrombo-
plastin time (APTT) was normal in six patients, and five pa-
tients had factor VIII concentration (factor VIIIc) levels in
excess of 60%. The bleeding time was prolonged in nine of 13
evaluable patients. Activated partial thromboplastin time was
prolonged in seven patients, and five of these had factor VIIIc
levels between 18 and 45%, with two patients having levels in
excess of 60%. A deficiency of other coagulation factors, in-
cluding factor VII, V. IX, and X, caused by a generalized
diminution in protein synthesis in hypothyroidism, may have
contributed to the prolongation of the APTT. The AvWS was
very likely type 1 in all cases because of a normal von Will-
ebrand factor antigen/ristocetin cofactor (vWF Ag/RCF) ratio.
Acquired von Willebrand syndrome was documented via cross
immunoelectrophoresis in three patients and via multimeric
The acquired von Willebrand syndromes {AvVVS~
most closely parallel the subtypes of congenital von Wil-
lebrand disease (vWD) (1). In type I vVYD, factor VlIlc,
von Willebrand factor antigen ~vt~’~.Ag), and vWF is-
tocetin cofactor activity (v~~.R~F~ are decreased
equally; a normal ~~’F multimeric pattern occurs both in
plasma and platelets and in a normal ristoc~tin-induced
platelet aggregation (RIPA) (I). Mild type II, with normal
or RIPA, and.type.IIB with increased increased
RIPA~ both involve an absence of the highest v mul-
timers. In type HA with decreased or absent RIPA, the
highest and intermediate vWF multimers are absent (1).
Address correspondence and reprint requests to Jan Jacques Mich-
iels, M.D., Clinical Hemostasis and Thrombosis, Department of He-
matology, University Hospital Antwerp, Antwerp, Belgium; and Good-
heart Institute, Center for Hemostasis Thrombosis and Vascular Pa-
thology, Erasmus Tower Veenmos 13, 3069 AT Rotterdam, The
Netherlands; e-mail : postbus@goodheartcenter.demon.nl.
Schroyens, M.D., *Zwi Bememan, M.D., and
M.D.
analysis of vWF in six patients. A definite diagnosis of AvWS
type I has to be confirmed bya normal response to 1-desamino-
8-D-arginine vasopressin (DDAVP). Treatment of hypothy-
roidism with thyroxine was associated with the disappearance
of the AvWS and the bleeding diathesis. Decreased factor
VIIIc, vWF Ag ,and vWF RCF levels (50%, 33%, and 36%
respectively) before thyroxine treatment increased to normal
values (97%, 93%, and 107% respectively) after treatment. The
absence of bleeding, or mild bleeding, symptoms, in relation to
those more commonly recognized with hypothyroidism, has led
to the complication of acquired vWF deficiency being under-
diagnosed. Acquired von Willebrand syndrome typeI should
be considered whenever hypothyroidism is diagnosed and thy-
roid biopsy or surgery is contemplated. The complete relief of
AvWS via treatment of hypothyroidism with thyroxine is the
final proof of this association and causal relationship. Key
Words: Acquired von Willebrand Syndrome-Hypothyroid-
ism—Thyroxine—1-dcsamino-8-arginine vasopressin.
The key to a of AvWS is its late-onset ac-
diagnosis
quired bleeding diathesis with a negative family history
and no earlier history of prolonged bleeding (2-5). Ac-
quired von Willebrand Syndrome has been described in
association with monoclonal gammopathies; lymphoid,
‘
myeloproliferative, autoimmune, and metabolic or hor-
monal disorders; tumors; infection; or the use of medical
drugs (2-5). The type, natural history, severity, and out-
come of treatment in patients with AvWS largely depend
on the mechanism of the vWF deficiency associated with
or caused by the nature of the underlying disorder. In this
study, we have critically analyzed the clinical manifes-
tations, laboratory features, and the outcome of thyrox-
ine treatment in reported cases of AvWS associated
with hypothyroidism.
RESULTS
Acquired von Willebrand syndrome and hypothyroid-
ism have been reported to occur with each other in 16
113
 7M
cases-] 3 women and one man-at a mean age of 32
years with a range of 13 to 82 years of age (Table 1)
(6-13). Six of these patients had no symptoms, and eight
presented with mild bleeding symptoms, including easy
bruising, mild to moderate menorrhagia, and nonsevere
bleeding after dental extraction. Routine bleeding time
was normal in four patients and prolonged in nine pa-
tients, with normal platelet counts in all. Ristocetin-
induced platelet aggregation was not tested in 12 patients
and was indicated to be decreased in one patient without
symptoms; however, the study cited did not showing data
as to whether this was a consistent finding (8).
Activated partial thromboplastin time was normal in
six patients, and five patients had factor VIIIc levels in
excess of 60%. Activated partial thromboplastin time
was prolonged in nine patients, of whom six patients had
factor VIIIC levels between 18 and 45%, with three pa-
tients having levels in excess of 50% (Tables 1,2). Ac-
quired von Willebrand syndrome type I was very likely
in all cases because of a normal vWF Ag/RCF ratio.
Acquired von Willebrand syndrome type I was docu-
mented by cross immunoelectrophoresis (6) in three pa-
tients and by multimeic analysis of vWF in plasma in
six patients (11,13). Treatment of hypothyroidism with
thyroxine was associated with the correction of bleeding
times, APTT, and factor Vlllc/vWF parameters to nor-
mal, which was accompanied with the complete relief of
bleeding in all patients except one. In the case of this
patient, congenital ~WT~ is probable. The decreased
mean values of factor VIIIC, vWF Ag, and vWF RCF
(50%, 33%, and 36%, respectively) before treatment
with thyroxine increased to normal values (97%, 93%,
and 107%, respectively) after treatment (Table 2). A
TABLE 1. Clinical manifestations and t~o~M~
von Willebrand syndrome associated with ~ypof~yro~M~!
+, increased; -’, decreased.
APTT, activated partial thromboplastin time; BT, bleeding time; F, female; M, male; n, normal; NT,
ristocetin-induced platelet aggregation.
typical DDAVP response with an eightfold increase of
factor Vlllc/vWF parameters was observed in one pa-
tient tested, which is consistent with a mild AvWS type
I (Table 2).
’
DISCUSSION
In Levesque’s prospective study (II), four of eleven
patients with hypothyroidism had asymptomatic AVWS
type I with mild deficiencies of vWF parameters between
26 and 49%. In occasional reports, 12 patients who had
symptoms for AVWS and hypothyroidism presented with
mild bleeding symptoms and had the lowest values for
both vWF.Ag and v’~VF.R!~F’ in the range between 17
and 46% of normal (6--10, 1 2, 1 3). The absence of bleed-
ing, or mild bleeding symptoms, in relation to those more
commonly recognized with hypothyroidism, has led to
the complication of acquired vWF deficiency being un-
derdiagnosed. The routine coagulation screening tests, .
including bleeding time and APTT, were usually normal
in patients without symptoms, and prolonged in patients,
who had symptoms of hypothyroidism. A deficiency of
other coagulation factors, including factor VII, V, IX,
‘
and X, caused by a generalized diminution in protein
synthesis in hypothyroidism, may have contributed to the f
prolongation of the APTT (’~*13*14~. Acquired von Wil-
lebrand syndrome type I should be considered whenever
hypothyroidism is diagnosed and thyroid biopsy or sur-
gery is contemplated. A definite diagnosis of AVWS type
I caused by decreased synthesis of factor VIIIc and vWF
should be supported by a good response to DDAVP; by 1
the demonstration of the absence of an inhibitor against !
factor Vlllc when using the Bethesda assay; by absence i,
of inhibition of the vWF.RCF or vWF collagen-binding
coagulation parameters on routine testing in 14 r~pe’~~ cases of acquired
I
I
not tested; PT, prothrombin time;.RiPA,I
’
 115

TABLE 2. Acquired von Willebrand ~~<?M~ type’ 7 in p in 14 reported cases: reverval after ~<?~?M’n~
. I&dquo; . with,thyroxine
’
’

.’ .~ &horbar;
/ ~~ ~ ~’

Ag..antigen: AvWS, acquired von Willebrand syndromes; DDAVP, I -desamino-8-D-arginine e v° a sc~ p re~~in~ F, female; PVUtc, factor Vlllc; M, mate;
MM, multimer; RCF, ristocetin cofactor: v vW I~. von Willebrand disease; vWF von Willebrand factor.

assay (vWF.CBA) in a mixture of patient and normal
plasma; and, when possible, by multimeric analysis of
the vWF in plasma. All patients with AvWS who have
hypothyroidism reveal a vWF multimeric pattern indis-
tinguishable from that of type I vWD, in which there is
uniform reduction of all multimers. This finding is con-
sistent with reduced protein synthesis in hypothyroidism
(14). The eightfold increase of factor VIII/vWF levels
after the use of DDAVP in only one patient tested is
r~n:~arkabl~’ ~rid
remarkable gt~t~ntialiy nc~rr~z~
r~f~~~cts a~ potentially
and reflects ~~ri~~~i~
normal synthesis
and release of vWF by endothelial cells at a reduced level
during the hypothyroid state. The most likely explanation
of reversibility of AvWS in is that the
observed changes in the factor VIIIc/vWF. complex, be-
fore and after treatment, reflect the nonspecific action of
thyroxine-on-protein synthesis through stimulation of
mRNA synthesis.by. tri-iodóthyroxine(15). The com-
plete relief of AvWS. in hypothyroidism via treatment
with thyroxine is the final proof of this association and
causal relationship.
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