acquired von willebrand syndromw type 1 in hypothyroidism: reversal after treatment with thyroxine
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7/29/2019 Acquired von Willebrand Syndromw Type 1 in Hypothyroidism: Reversal After Treatment With Thyroxine
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ppl Thmmhnsis/Hctnnsiusis. 7(2): M3-I \5, 200!& Wilkins. tnc, Philadelphia
Original Report
von Willebrand Syndrome Type 1 in Hypothyroidism
Reversal After Treatment With Thyroxine
*tJan Jacques Michiels, M.D., ^-Wilfried Schroyens, M.D., *Zwi Berneman, M.D., and
ifMarc van der Planken , M.D .
andThrombosis, Department ofHem atology. University Hospital Antwerp, Ant^verp. Belgium: fGoodhean
Institute. Center for Hemostasis Thrombosis atid Vascular Pathology. Rotterdam, TheNetherlands: and ^Laboratoty of
Hemostasis and Hematology, Department ofClinical Biology, University Hospital Antwerp, Ant^'erp. Belgium
In 16 cases, acquired von Willebrand syndrome
and hypothyroidism have been described that occur
15 women and one man, at a mean age of 32
13 to 82 years of age. Activated partial thrombo-
wasnormal in six patients, and live pa-
had factor VIII concentration (factor VIIIc) levels in
of6 0 %. The bleeding time was prolonged in nine of 13
was
in seven patients, and five of these had factor VIIIc18 and 45% , with two patients having levels in
of 6 0 %. A deficiency of other coagulation factors, in-
VII, V, IX, and X. caused by a generalized
in protein synthesis in hypotbyroidism, mayhave
to the prolongation of the APTT. The Av WS was
1 in all cases because of a normal von Will-
(vWF Ag/RCF) ratio.
von Willebrand syndrome wasdocumented via cross
in three patients and via multimeric
analysis of vW F in six patients. Adefinite diagnosis of Av WS
type Ihas to be confirmed bya normal response to I-desamino-
8-D -arginine vasopressin (D D AVP). Treatment of hypothy-
roidism with thyroxine was associated with the disappearance
of the Av WS and the bleeding diathesis. D ecreased 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 ofbleeding, 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 type I shouldbe considered whenever hypothyroidism isdiagnosed and thy-
roid biopsy or surgery iscontemplated. The complete relief of
Av WS via treatment of hypothyroidism with thyroxine is the
final proof of this association and causal relationship. Key
Words : Acqui red von Willebrand Syndrome—Hypothyroid-
ism—Thyroxine—l-desamino-8-arginine vasopressin.
von Willebrand syndromes (AvWS)
the subtypes of congenital von Wil-
(I). In type I vWD, factor VIIIc,
and vWF ris-
are decreased
a normal vWF multimeric pattern occurs both in
and platelets and in a normal ristocetin-induced
(1). Mild type FT with normal
ased RIPA, and type IIB with increased increased
an absence of the highest vWF mul-
In type HA with decreased or absent RIPA, the
and intermediate vWF multimers are absent (1).
s correspondence and reprint requests to Jan Jacques Mich-
The key to a diagnosis of AvWS is its late-onset ac-
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 ofthe 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.
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114 J. J. MICH IELS ET AL
cases—13 women and one man—at a mean age of 32
year s with a range of 13 to S2 years of age (Table I)
( 6 - 1 3 ) . Six ot these patients had no symptoms, and eight
presented with mild bleeding symptoms, ineluding easy
bruising, mild lo 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 Vlll c levels between 18 and 45% , with three pa-tients having levels in excess of 50% (Tables 1,2). Ac-
quired von W illebrand sy ndrom e 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 multimeric 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 acct)nipanied with the complete relief of
bleeding in all patients except one. In the case of thispatient , congenita l vWD is probable . The decreased
mean values of factor VIIIC, vWF Ag, and vWF RCF
(5 0 ^ , 3 3% , and 36% , respectively) before treatment
with thyroxine increased to normal values {97%. 93 % ,
and 107%, respectively) after treatment (Table 2). A
typical D D AV P respons e with an eightfold increa
faetor VI Ilc/v W F param eters w as observed in on
tient tested, which is consistent with a mild AvWS
I (Table 2) .
D IS C U S S IO N
In Levesque's prospective study (11). four of el
patients with hypothyroidism had asymptomatic A
type I with mild deficiencies of vWF parameters betw
26 and 49 % . In occasional repo rts. 12 patients wh
sym ptom s for AvW S and hypothyroidism presented
mild bleeding symptoms and had the lowest value
both vWF.Ag and vWF.RCF in the range betwee
and 46% of normal (6-10,12.13). The absence of b
ing, or mild bleeding symptoms, in relation to those
com monly recognized with hypothyro idism, has l
the comp lication of acquired vW F deficiency beinderdiagnosed. The routine coagulation screening
Including bleeding time and APTT, were usually no
in patients without symptoms, and prolonged in pat
who had symptoms of hypothyroidism. A deficienc
other coag ulation factors, includ ing factor V II, V
and X, caused by a generalized diminution in pr
synthesis in hyp othyroidism , m ay have contributed
prolongation of the APTT (7,13,14). Acquired von
lebrand sy ndro me typ e I should be considered whe
hypo thyro idism is diagno sed and thyroid biopsy o
gery is contemplated. A definite diagnosis of AvWSI caused by decreased synthesis of factor VIIIc and
should be supported by a good response to DD AV
the demonstration of the absence of an inhibitor ag
factor VIIIc when using the Bethesda assay; by abs
of inhibition of the vWF.RCF or vWF collagen-bin
TA BLE 1 . Clinical manifestations and abnormal coagulation param eters on routine testing in 14 reported cases of acqui
von Willebrand syndrome associated with hypothyroidi.sm
Study
Dal ton (6)
Takahsahi . (7)
Sm ith (8)
M a c C a l l u m ( 9 )
C o c c i a ( 1 0 )
L e v e s q u e ( 1 1 )
Braggers (twin s isters) (12)
C a s e
12
3
4
5
6
7
89
10
11
12
13
14
A e e , VM/F
I7 F53 F
29 F
34 F
29 F
13 F
34 F
15F32 F
43 M
82 F
40 F
13 F
13 F
F
Clinical bleedingmanifestations
Gum bleeding, bruising, bleeding after dental extraction
Easy bruising
Bruising, menorrhagia, bleeding after dental extraction
Gum bleeding
Mild menorrhagia
Asymptomatic
Bruising, menorrhagia
Menorrhagia
Asymptomatic
Asymptomatic
Asymptomatic
Asymplomatic
Menorrhagia
AsymplomatiL-
Menorrhagia, bleeding posttonsillectomy
BT
+
+
+
++++nnn+n+
Routine coagulation
Platelets
n
n
n
nnnnnnnnnnn
PT
n
n
n• +
nn+
n
n
nn
n
paramet
A P T T
++
+
++
n+
+
nnn
+
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ACQUIRED VON WILLEBRAND SYNDROM E TYPE I IN HYPOTHYRO IDISM 11 5
TABLE 2. Acquired von Willebrand syndrome tvpe I in hypothyroidi.sm in 14 reported cases: reversal after treatment
with thxro.xine
Study Case
i
2
3
4
5
6
7
8
9
10
11
12
13
14*
15
16
pe 1 AvWS documented
Age, y
M/F
I 7 F
33 F
29 F
34 F
29 F
I 3 F
34 F
13 F
32 F
43 M
S 2 F
40 F
13 F
13 F
22 F
34 F
15 F
l M
by vWF
FV III c. •%
67
18
43
31
36
62
38
70
62
80
82
40
41
33
58
36
50
Before thyroxine
1 vWF-Ag. %
45
17
34
17
3027
23
32
41
46
49
26
39
37
42
24
33
cross immunoelectrophoresis
FVIIIc
33
24 0
vWF-Ag
37
32 0
-RCF,
27
17
5519
-
30
44
48
46
44
30
30
36
55
27
36
(6) or
% AvWS cure. MM*
Type \* Ye s
Type \* Ye s
Type [* Yes
Type I Yes
Type I Yes
Type I Yes
Type 1 Yes
Type I Yes
Type 1* Yes
Type P Yes
Type I* Yes
Type I^ No
Type I Yes
Type I Yes
Type 1* Yes
Type 1* Yes
Cure 15
v W D l
multimeric analysis (11,13)
vWF-RCF
36
278
After thyroxine
FVIIIc. %
122
83
126
103
100
169
39
79
115
9397
70
71
90
97
vWF-Ag. %
144
74
93
69
86147
80
105
I t 2
80
85
35
51
9 3
-RCF. %
120
68
13 9
6 0-
>50
144
86
140
102
3S
160
110
107
1 vWD. in which there is
The eightfold increase of factor VTII/vWF levels
R E F E R E N C E S
3. Tefferi A. Nichols WL. Acquired von Willebrand disease: concisereview of occurrence, diagnosis, pathogenesis and treatment. Am J
M ed 1997;103:336.
4. Mohri H. Motomura S. Matsuzaki M. et al. Clinical significance ofinhibitors in acquired von Willebrand Syndrome. Blood I998;91;
3623.
3. van Genderen PJJ, Michiels JJ. Acquired von Willebrand disease.Baillieres din Haematol 1998; I 1:319.
6. Dalton RG . Sa\ idge GF . Matthew KB . et al. Hypothyro idism as a
cause of acquired von Willebrand Disease. Lancet 1987;1:1OO7.
7. Takahashi H. Yamada M. Shibata A. Acquired \on Willebrand's
disease in hypothyroidism.Thnmib Haemost
I987:3S:1O93.8. Smith SR, Auger MJ. Hypothyroidism and von Willebrand's dis-
ease. Lancet I987;I:13I4.
9. MacCallum PK, Rodgers M. Tabcrner DA. Acquired von Wille-
brand's disease and hypothyroidism. Lancet 1987;I:1314.
10. Coccia MR. Barnes HV, Hypotliyroidism and acquired von Wille-
brand disease. J Adolesc Health \^9\:\2:\52.
11. Levesque H. Borg JY. Vasse M, et al . Acquired von Willebrand's
syndrome associated with decrease of plasminigen activator and its
inhibitors during hypothyroidism. Eiir J Med 199.1;2:284.
12. Bruggers CS. McElligott K. Rallison ML. Acquired von Wille-
brand disease in twins with auioimmunc hypothyroidism: response
to dcsmopressin and 1-thyroxine therapy. ,/ Pediatr I994;123:9 ! 1.
13. Nitu-Whalley C. Lee CA. Acquired \on Willebrand syndrome;report of 10 cases and review of the literature. Haemophilia 1999-5:318,
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