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Clin Appl Thmmhnsis/Hctnnsiusis. 7(2): M3-I \5, 200! 2001 Lippincoii Williams & Wilkins.

tnc, Philadelphia

Original Report

Acquired 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.
^Clinical Hemostasis and Thrombosis, Department of Hematology. University Hospital Antwerp, Ant^verp. Belgium: fGoodhean Institute. Center for Hemostasis Thrombosis atid Vascular Pathology. Rotterdam, The Netherlands: and ^Laboratoty of Hemostasis and Hematology, Department of Clinical Biology, University Hospital Antwerp, Ant^'erp. 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 thromboplastin time (APTT) was normal in six patients, and live patients 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, including factor VII, V, IX, and X. caused by a generalized diminution in protein synthesis in hypotbyroidism, may have contributed to the prolongation of the APTT. The AvWS was very likely type 1 in all cases because of a normal von Willebrand factor antigen/ristocetin cofactor (vWF Ag/RCF) ratio. Acquired von Willebrand syndrome was documented via cross immunoelectrophoresis in three patients and via multimeric

analysis of vWF in six patients. A definite diagnosis of AvWS type I has to be confirmed by a normal response to I-desamino8-D-arginine vasopressin (DDAVP). Treatment of hypothyroidism 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 underdiagnosed. Acquired von Willebrand syndrome type I should be considered whenever hypothyroidism is diagnosed and thyroid 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 SyndromeHypothyroidismThyroxinel-desamino-8-arginine vasopressin.

The acquired von Willebrand syndromes (AvWS) most closely parallel the subtypes of congenital von Willebrand disease (vWD) (I). In type I vWD, factor VIIIc, von Willebrand factor antigen (vWF.Ag), and vWF ristocetin cofactor activity (vWF.RCF) are decreased equally; a normal vWF multimeric pattern occurs both in plasma and platelets and in a normal ristocetin-induced platelet aggregation (RIPA) (1). Mild type F T , with normal or decreased RIPA, and type IIB with increased increased RIPA, both involve an absence of the highest vWF multimers. 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 Michiels, M.D., Clinical Hemostasis and Thrombosis, Department of Hematology. University Hospital Antweq?, Antwerp, Belgium; and Goodheart Institute, Center for Hemostasis Thrombosis and Vascular Pathology, Erasmus Tower Veenmos 13, 3069 AT Rotterdam, The Netherlands; e-mail: postbus@goodbeartcenter.demon.nl.

The key to a diagnosis of AvWS is its late-onset acquired bleeding diathesis with a negative family history and no earlier history of prolonged bleeding (2-5). Acquired von Willebrand Syndrome has been described in association with monoclonal gammopathies; lymphoid, myeloproliferative, autoimmune, and metabolic or hormonal disorders; tumors; infection; or the use of medical drugs (2-5). The type, natural history, severity, and outcome 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 manifestations, laboratory features, and the outcome of thyroxine treatment in reported cases of AvWS associated with hypothyroidism. RESULTS Acquired von Willebrand sytidrome and hypothyroidism have been reported to occur with each other in 16 113

114

J. J. MICHIELS ET AL typical DDAVP response with an eightfold increase of faetor VIIlc/vWF parameters was observed in one patient tested, which is consistent with a mild AvWS type I (Table 2). DISCUSSION In Levesque's prospective study (11). 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 vWF.RCF in the range between 17 and 46% of normal (6-10,12.13). 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 underdiagnosed. 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 prolongation of the APTT (7,13,14). Acquired von Willebrand syndrome type I should be considered whenever hypothyroidism is diagnosed and thyroid biopsy or surgery 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 the demonstration of the absence of an inhibitor against factor VIIIc when using the Bethesda assay; by absence of inhibition of the vWF.RCF or vWF collagen-binding

cases13 women and one manat a mean age of 32 years with a range of 13 to S2 years of age (Table I) (6-13). 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 patients, with normal platelet counts in all. Ristocetininduced 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 Vlllc levels between 18 and 45%, with three patients having levels in excess of 50% (Tables 1,2). Acquired 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 documented by cross immunoelectrophoresis (6) in three patients 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 normal, which was acct)nipanied with the complete relief of bleeding in all patients except one. In the case of this patient, congenital vWD is probable. The decreased mean values of factor VIIIC, vWF Ag, and vWF RCF ( 5 0 ^ , 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 abnormal coagulation parameters on routine testing in 14 reported cases of acquired von Willebrand syndrome associated with hypothyroidi.sm
Aee, V Study Dalton (6) Case

M/F I7F
53 F 29 F 34 F 29 F 13 F 34 F

Clinical bleeding manifestations 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 AsymplomatiLMenorrhagia, bleeding posttonsillectomy Easy bruising, bleeding post-dental treatment

Routine coagulation parameters

BT
+ + +

Platelets n n

PT
n n

APTT

RIPA

Takahsahi. (7) Smith (8) MacCallum (9) Coccia (10) Levesque (11)

1 2 3 4 5 6 7

+
+ + + +

n
+

+ + + +

n
n n

n n
+ n n

NT NT NT NT n
_i

n
+ +

8 9
10 11 12 13 14 13 16

15F
32 F 43 M 82 F 40 F 13 F 13 F 22 F 34 F

n n
n +

n n
n n

n
n

n
+

n n
n n

n n
n

Braggers (twin sisters) (12) Nitu-Whalley (13j

NT NT NT NT NT NT NT NT

+ +

+, increased; - ' . decreased. APTT. activated partial thmmboplastin time; BT, bleeding time; F, female; M, male; n, normal: NT. not tested; PT. prothrombin time; RIPA, ristocetin-induced platclel aggregation.

Clin Appl Thmmbosi.t/Hemostasi.i. Vol. 7. No. 2. 2001

ACQUIRED VON WILLEBRAND SYNDROME TYPE I IN HYPOTHYROIDISM


TABLE 2. Acquired von Willebrand syndrome tvpe I in hypothyroidi.sm in 14 reported cases: reversal after treatment with thxro.xine
Age, y Study Dalton (6) Case i 2 3 4 5 6 7 8 9 10 11 12 13 14* 15 16 Before thyroxine FVIIIc. % 1 67 18 43 31 36 62 38 70 62 80 82 40 41 33 58 36 50 15 F lM vWF-Ag. % 45 17 34 17 30 27 23 32 41 46 49 26 39 37 42 24 33 -RCF, % 27 17 55 19 30 44 48 46 44 AvWS cure. MM* Type \* Yes Type \* Yes 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 After thyroxine FVIIIc. % 122 83 126 103 100 169 39 79 115 93 97 70 71 90 vWF-Ag. % 144 74 93 69 86 147 80 105 It2 80 85 35 51

115

M/F
I7F 33 F 29 F 34 F 29 F I3F 34 F 13 F 32 F 43 M S2F 40 F 13 F 13 F 22 F 34 F

-RCF. % 120

68
139 60 >50 144

Takahaslii (7) Smith (8) MacCallum (9) Coccia (10) Levesque (11)

86
140 102

30
30 36 55 27 36

3S
160 110

Bnjggers (twin sisters) (12) Nitu-Whalley (13) Mean Total

97 Cure 15 vWDl

93

107

* MM. type 1 AvWS documented by vWF cross immunoelectrophoresis (6) or multimeric analysis (11,13) DDAVP response in Case 14*, % Before After
FVIIIc

33 240

vWF-Ag 37 320

vWF-RCF 36 278

Ag, antigen; AvWS. acquired von Willebrand syndromes; DDAVP. l-desamino-8-D-argininc vasopressin; F, female; FVIIIc, factor VIIIc; M. male; MM. multimer; RCF, ristocetin cofactor; vWD, von Willebrand disease: vWF, von Willebrand factor.

assay (vWF.CBAj 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 indistinguishable from that of type 1 vWD. in which there is uniform reduction of all multimers. This fmding is consistent with reduced protein synthesis in hypothyroidism (14). The eightfold increase of factor VTII/vWF levels after the use of DDAVP in only one patient tested is remarkable and reflects a potentially normal synthesis and release of vWF by endotheliai cells at a reduced level during the hypothyroid state. The most likely explanation of reversibility of AvWS in hypothyroidism is that the observed changes in the factor VIIIc/vWF complex, before and after treatment, reflect the nonspecific action of thyroxine-on-protein synthesis through stimulation of mRNA synthesis by tri-iodothyroxine (15). The complete relief of AvWS in hypothyroidism via treatment with thyroxine is the fmal proof of this association and causal relationship. REFERENCES
1. Sadler JE. A revised classification of von Willebrand disease. Thromb Haemost 1994;71:320. 2. Jakway JF. Acquired von Willebrand's disease. Hematol Oncol Clin N Am I992;6:14O9.

3. Tefferi A. Nichols WL. Acquired von Willebrand disease: concise review of occurrence, diagnosis, pathogenesis and treatment. Am J Med 1997;103:336. 4. Mohri H. Motomura S. Matsuzaki M. et al. Clinical significance of inhibitors 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. Hypothyroidism 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 disease. Lancet I987;I:13I4. 9. MacCallum PK, Rodgers M. Tabcrner DA. Acquired von Willebrand's disease and hypothyroidism. Lancet 1987;I:1314. 10. Coccia MR. Barnes HV, Hypotliyroidism and acquired von Willebrand 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 Willebrand 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 19995:318, 14. Simone JV. Abildgaard CF. Schulman I. Blood coagulation in thyroid dysfunction. A' /j,i,' ./ Med 1963;273;1057. 13. Oppenheimer JH. Thyroid hormone action at the cellular level Science I979;2O3:971.

Ctin Appl Thromhosis/Hemostasis. Vol. 7. No. 2. 2001