Letters to the Editor

1804–1818); iii) failure to regulate the FVIII activation/inacti- Maria Patrizia Bicocchi1, Mirella Pasino1, Tiziana Lanza1, Federico
vation in the overlapping region of action (residues 2009–2022) Bottini1, Angelo Claudio Molinari1, Camillo Rosano2, Maura Acquila1
by the reciprocal competitors APC and vWF. However, since 1Department of Haematology and Oncology, Thrombosis and Hae-

there is no reason to believe that a stable RNA is not produced, mostasis Unit, Giannina Gaslini Institute, Genova, Italy
we can not rule out that a misfolded protein may not be secreted, 2X-Ray Structural Biology Unit (B2), Advanced Biotechnology Centre

or may be readily degraded in the circulation. (CBA), Genova, Italy

References
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gene rearrangements in 18 hemophilia A patients: five
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splice junctions of human genes: causes and con-
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Analysis of thyroid hormone status in 131 consecutive individuals with low

von Willebrand factor levels
Dear Sir, that is, whether some individuals with low VWF levels found
It is well known that various coagulation abnormalities occur in during coagulation screening tests have a concomitant thyroid
patients with thyroid diseases, these abnormalities ranging from hormone deficiency. This was the aim of our study, in which we
subclinical laboratory findings to hemorrhage or thromboem- screened 131 consecutive subjects with low VWF levels for thy-
bolism (1, 2).The coagulation abnormalities in patients with thy- roid hormone levels.
roid deficiency are varied, but frequently consist of a defect of
primary haemostasis, which results in a bleeding tendency that is Table 1: Characteristic of the 131 individuals with low von
Willebrand factor levels included in the study.
usually mild (e.g. nose or gingival bleeding, menorrhagia, easy
bruising), but that can, rarely, be severe (e.g. hemorrhages fol-
Characteristics Results* Normal values
lowing trauma or surgery) (3). The most frequent haemostatic
defect described in patients with hypothyroidism is an acquired Median age 37 (17–71)
von Willebrand syndrome (AVWS), usually of type 1, which re- Males 62
sults from decreased synthesis of factor VIII and von Willebrand Females 69
factor (VWF), responds to desmopressin with normal half-life
Ratio M/F 0.9
times for factor VIII and VWF parameters, and disappears after
treatment with l-thyroxine (4, 5). In spite of this information, no APTT (ratio) 1.22 +0.2 0.85–1.17
studies have so far evaluated whether the opposite is also true: Closure time (PFA-100)
CADP (seconds) 133.2 +17.7 <110 seconds
Correspondence to:
CEPI (seconds) 157.3+26.1 <140 seconds
Massimo Franchini, MD VWF:Ag (%) 41.1+7.3 50–150%
Servizio Trasfusionale – Azienda Ospedaliera di Verona
Policlinico “G.B. Rossi“ VWF:RCo (%) 44.3+6.5 50–150%
P.le L.A. Scuro 10
37134 Verona, Italy FVIII:C (%) 47.8+9.2 50–150%
E-mail: massimo.franchini@mail.azosp.vr.it
APTT = activated partial thromboplastin time; VWF:Ag = von Willebrand factor antigen; VWF:Rco =
Received September 14, 2004 von Willebrand factor ristocetin cofactor; FVIII:C = coagulant factor VIII; PFA = platelet function ana-
Accepted after resubmission November 25, 2004 lyzer; CADP = collagen ADP; CEPI = collagen epinephrine.
*Plus-minus values are means ± SD.
Thromb Haemost 2005; 93: 392-3

392
 Letters to the Editor

Table 2: Characteristics of the 8 patients with low von Wille- clinical characteristics of these individuals. Eight out of the 131
brand factor levels and subclinical hypothyroidism. individuals (6.1%) with low VWF levels had a concomitant sub-
clinical hypothyroidism as documented by normal thyroid hor-
Characteristics Results* Normal values mone levels and raised TSH concentration (6). Table 2 shows the
Median age 42 (26–67) main characteristics of these 8 patients. Three of them (37.5%)
Males 2 had bleeding symptoms (2 had menorrhagia and 1 had bleeding
after dental extraction). These 8 patients started thyroid hormone
Females 6
replacement therapy with l-thyroxine given orally at a dosage of
Ratio M/F 0.3 50 mg/day. A laboratory check performed 3 months after the be-
Blood group 7 A, 1 O ginning of thyroid hormone replacement therapy showed that ab-
APTT (ratio) 1.24 ±0.2 0.85–1.17 normal laboratory results, including serum TSH levels and he-
Closure time (PFA-100)
mostatic parameters, had returned to normal in all patients. Re-
placement treatment was also accompanied by improvement of
CADP (seconds) 143.0 ±11.7 <110 seconds
bleeding symptoms in the symptomatic patients.
CEPI (seconds) 155.8±22.6 <140 seconds Thus, our study documents for the first time that some indi-
VWF:Ag (%) 43.3±7.0 50–150% viduals with low VWF levels may have concomitant subclinical
VWF:RCo (%) 43.6±6.1 50–150% hypothyroidism. A possible explanation for this phenomenon is
that the metabolic changes observed in patients with subclinical
FVIII:C (%) 47.1±9.0 50–150%
hypothyroidism could also include a reduction in VWF syn-
TSH (mU/L) 10.3±2.1 0.35–4.30 mU/L

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T3 (pmol/L) 4.4±0.3 3.5–5.7 pmol/L
T4 (pmol/L) 13.1±1.4 10–23 pmol/L
APTT = activated partial thromboplastin time; VWF:Ag = von Willebrand factor antigen; VWF:Rco =
von Willebrand factor ristocetin cofactor; FVIII:C = coagulant factor VIII; PFA = platelet function
analyzer; CADP = collagen ADP; CEPI = collagen epinephrine; TSH = thyroid stimulating hormone;
T3 = triiodothyronine; T4 = thyroxine.
*Plus-minus values are means ±SD.
Between January 2001 and June 2004, 131 consecutive indi-
viduals with low von Willebrand factor levels found during co-
agulation screening tests performed in the Laboratory of our
hospital, were tested for serum levels of thyroid hormones, triio-
dothyronine (T3) and thyroxine (T4), and of thyroid stimulating
hormone (TSH). Of these 131 individuals, 47 underwent coagu-
lation tests because they were relatives of patients with hered-
itary bleeding disorders and 41 because they had bleeding symp-
toms. In the remaining 43 cases, the haemostatic defect was
found during routine or preoperative laboratory tests. All abnor-
mal coagulation parameters were confirmed by repeat testing on
a new blood sample. Table 1 reports the main demographic and
thesis. A direct influence of blood group on VWF levels (blood
group O is associated with VWF levels below the normal range)
was excluded since all but one of our eight patients had blood
group A. The reversal of the haemostatic defect after l-thyroxine
therapy was interesting, although this finding does not confirm a
causal relationship between subclinical hypothyroidism and
VWF since this could be due to a general effect of thyroid hor-
mones on VWF levels regardless of thyroid status. Furthermore,
controlled studies on larger populations of patients are needed in
order to verify our data. However, if our results are confirmed,
clinical and laboratory (serum T3, T4 and TSH levels) assess-
ment of thyroid function could be helpful when a defect of pri-
mary hemostasis is detected, in order to differentiate true von
Willebrand disease from an acquired von Willebrand syndrome.
Massimo Franchini,1 Dino Veneri,2 Giuseppe Lippi3
1
Servizio di Immunoematologia e Trasfusione – Centro Emofilia,
Azienda Ospedaliera di Verona, Verona; 2Dipartimento di Medicina
Clinica e Sperimentale, Sezione di Ematologia, Università di Verona,
Verona; and 3Istituto di Chimica e Microscopia Clinica, Dipartimen-
to di Scienze Biomediche e Morfologiche, Università di Verona, Ve-
rona, Italy

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