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.



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

+



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

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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.

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Acquired von Willebrand Syndromw Type 1 in Hypothyroidism: Reversal After Treatment With Thyroxine

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