Full text of DOI:10.1007/BF03344016

J. Endocrinol. Invest. 25: 345-350, 2002
Blood coagulation and fibrinolysis in patients with
hyperthyroidism
C. Erem*, H.Ö. Ersoz*, S.S. Kartı**, K. Ukinç***, A. Hacıhasanoglu***, O. Deg˘ er****,
and M. Telatar*
*Division of Endocrinology and Metabolism, **Division of Hematology, ***Department of Internal
Medicine, ****Department of Biochemistry, Faculty of Medicine, Karadeniz Technical University,
Trabzon, Turkey
ABSTRACT. Several papers concerning abnor-
malities of blood coagulation and fibrinolysis dur-
ing hyperthyroidism, have been published. In-
creased von Willebrand Factor (vWF) activity and
high fibrinogen levels have been reported. How-
ever, there is controversy concerning the pres-
ence of a hypercoagulable state in hyperthy-
roidism. We investigated various hemostatic pa-
rameters in 41 hyperthyroid patients and com-
pared them to 20 euthyroid controls. Pro-
thrombin time (PT), activated partial thrombo-
plastin time (aPTT), fibrinogen, factors V, VII, VIII,
IX and X activities, vWF, antithrombin III (AT III),
protein C, protein S, tissue plasminogen activa-
tor (t-PA) and tissue plasminogen activator in-
hibitor-1 (PAI-1), as well as common lipid vari-
ables, were measured. The relationships be-
tween serum thyroid hormones and these hemo-
static parameters were examined. Compared
with control subjects, fibrinogen, factor IX, vWF,
AT III and PAI-1 were significantly increased in
patients (p<0.05, p<0.0001, p<0.05, p<0.01
and p<0.0001; respectively), whereas factor X
and t-PA were decreased (p<0.05). We showed
that free T4 (FT3) levels were correlated with fac-
tor VIII activity (r=0.35, p<0.05). FT4, FT3 and
TSH did not correlate with fibrinogen, vWF, AT
III, t-PA, or PAI-1. AT III was inversely correlated
with factor VII activity (r=-0.48, p<0.01). Protein
C and S were correlated with vWF levels (r=0.58,
p<0.0001; r=0.55, p<0.0001, respectively). Protein
C was inversely correlated with t-PA (r=-0.39,
p<0.01). There was a negative correlation be-
tween triglycerides, LDL-C and F X (r=-0.45,
p<0.05; r=-64, p<0.01, respectively). Mean pla-
telet volume (MPV) was correlated with anti-thy-
roid peroxidase (TPO) antibodies (in Graves’dis-
ease) and F IX activity (r=0.57, p<0.05 and r=0.39,
p<0.05; respectively). We found important dif-
ferences in the coagulatory /fibrinolytic param-
eters between the hyperthyroid patients and
healthy controls. Hyperthyroid patients may ex-
perience vascular endothelial dysfunction and de-
creased fibrinolytic activity in blood. This en-
dothelial activation may represent a situation
with a higher thromboembolic potential.
(J. Endocrinol. Invest. 25: 345-350, 2002)
©2002, Editrice Kurtis
INTRODUCTION
be independently associated with thrombosis, it has
been suggested that hyperthyroidism per se is as-
sociated with an increased risk compared to nor-
mal subjects (1).
Hyperthyroidism is associated with an incidence of
8-40% arterial embolism, especially cerebral throm-
boembolism with possible risk factors being age,
atrial fibrillation, cardiac failure, an enlarged left atri-
um and (pre-existing) mitral valve dysfunction (1-2).
Even though a number of these risk factors could
It has been suggested that there is an association be-
tween thyroid dysfunction and hemostatic abnor-
malities (3). Hyperthyroidism increases the turnover
of coagulation factors II, VII, and IX and augments the
effects of oral anticoagulants (4, 5). Elevated levels of
coagulant factor VIII and fibrinogen have been con-
sistently reported to occur in hyperthyroid patients
or after administration of thyroid hormone, and have
been explained as expression of an acute phase re-
action (6-8). Disturbances in thyroid function may al-
ter cholesterol metabolism, which can influence fibri-
Key-words: Coagulation, fibrinolysis, endothelial dysfunction, hyperthy-
roidism.
Correspondence: Dr. Cihangir Erem, K.T.Ü. Tıp Fakültesi, Iç Hastalıkları
Anabilim Dalı, 61080, Trabzon, Turkey.
E-mail: cihangirerem@hotmail.com
Accepted November 9, 2001.
345

Hemostasis in hyperthyroidism
FT4, and 0.35-5.50 μU/ml for TSH. Thyroid autoantibodies were
measured by an enzyme-linked immunosorbent assay (ELISA)
(Synelisa, Pharmacia, Germany). Antibody levels were consid-
ered negative when they were below 100 IU/ml. Serum total
cholesterol (TC) was measured using a cholesterol oxidase en-
zymatic method; triglycerides, were measured by a glycerol ox-
idase enzymatic method; high density lipoprotein cholesterol
(HDL-C), by a cholesterol oxidase enzymatic method in super-
natant after precipitation with phosphotungstic acid-MgCl2.
These routine analyses were carried out by autoanalyzer
(Technicon AXON). Low density lipoprotein cholesterol (LDL-C)
was calculated by the Friedewald’s formule. For coagulation and
fibrinolysis, a venous blood sample (9 vol) was collected into
Vacutainer tubes (Becton Dickinson, Mountain View, U.S.A.) con-
taining 0.129 mol/l trisodium citrate (1 vol). Platelet-poor plasma
was obtained by centrifugation 3500 ꢀ g at 10 C for 20 min.
Platelet count, mean platelet volume (MPV), prothrombin time
(PT), activated partial thromboplastin time (aPTT), fibrinogen,
antithrombin III (AT III), factors V, VII, VIII, IX and X measure-
ments were performed immediately. Aliquots of plasma were
transferred into plastic tubes without delay and frozen at -80 C
until assays for determination of vWF, protein C, protein S, t-
PA, and PAI-1. Platelet count and MPV was measured with au-
tomatic cell counter (Coulter Micro Diff II). PT and aPTT were
determined with coagulometer, using, commercial kits of
Diagnostica Stago. Fibrinogen was determined using a neph-
elometric assay by commercial kits for fibrinogen (Cat No.OSCA
09, Dade Behring Marburg GmbH, Germany). Factors V, VII, VI-
II, IX and X activities were measured with coagulometer
(Diagnostica Stago) using commercial kits of Diagnostica Stago.
AT III assay was performed with spectrophotometric method
(Behring turbitimer, Turbiquant, AT III, Dade Behring).Normal
ranges are 200-400 mg/dl for fibrinogen, 50-150% for Factors V,
FVII, FVIII, FIX and FX. Protein C and Protein S activity assays
were performed with ELISA method using commercial kits of
Biopool International. vWF activity was determined by ELISA
method using commercial kits of Imtec Immundiagnostica
Gmbh. t-PA and PAI-1 assays were performed with ELISA using
commercial kits of American Diagnostica. According to the man-
ufacturer, normal ranges are 22-39 mg/dl for AT III, 70-150% for
vWF, 72-160% for protein C activity, 60-150% for protein S ac-
tivity, 1-20 ng/ml for t-PA Ag, and 20-44 ng/ml for PAI-1 Ag.
Statistical analysis was performed by Student’s t test, Mann-
Whitney U test, and multiple regression analysis. Results are pre-
sented as mean SD. The calculations were performed using SPSS
for Windows (SPSS, Inc., Chicago, U.S.A.).
nolytic activity (9, 10). Finally, strong indications exist
that hyperthyroidism influences endothelial function.
Levels of soluble vascular adhesion molecules and
thrombomodulin are increased in hyperthyroidism,
regardless of of its etiology (11-13).
Furthermore, the administration of thyroid hormone
to healthy volunteers significantly increases plasma
levels of von Willebrand Factor (vWF), a change sim-
ilar to that found in hyperthyroid patients (7). In-
creased vWF activity has been reported in hyper-
thyroid patients (6, 11). In contrast, vWF in circulating
blood originates mainly from the endothelium, and
high plasma levels are widely accepted as an im-
portant indicator of endothelial dysfunction (14). Until
recently, changes in other endothelium-derived pro-
teins, such as tissue plasminogen activator (t-PA) and
plasminogen activator inhibitor 1 (PAI-1), in hyper-
thyroid patients had not been reported. However,
literature data on the influence of thyroid function
on coagulation/fibrinolysis are ambiguous and often
contradictory. This may be related to the use of old-
er methodology, to the inclusion of patients with a
different etiology of hyperthyroidism or to the fact
that a highly variable relation exists between thyroid
dysfunction and the coagulation process.
The main purpose of this study was to investigate
the markers of endogenous coagulation/fibrinoly-
sis and of vascular endothelial cell function, and to
evaluate the relationships between serum lipid pro-
file, thyroid hormones and hemostatic parameters
in hyperthyroid patients.
PATIENTS AND METHODS
The study was carried out at the Karadeniz Technical University
Medical Faculty, Department of Internal Medicine. Forty-one
untreated hyperthyroid patients [12 men (M), 29 women (W);
aged 44.5 15.2 yr] were included; 20 patients with Graves’ dis-
ease, and 21 patients with toxic nodular goiter (16 multinodular
and 5 with toxic adenoma). Each patient was clinically and bio-
chemically hyperthyroid, defined as having increased serum thy-
roid hormone levels, a suppressed TSH concentration (<0.1
μU/ml). The diagnosis of Graves’ disease was based on the ad-
ditional presence of a smooth goiter, thyroid autoantibodies
[anti-TG, anti-thyroid peroxidase (anti-TPO) and anti-TSH re-
ceptor], or specific eye signs. Patients were taking neither drugs
nor had diseases (e.g. diabetes mellitus, collagen disease, liver
cirrhosis, atrial fibrillation, or renal disease) known to affect blood
coagulation or fibrinolysis at the time of the study. Twenty heal-
thy age- and sex-matched subjects (6 M, 14 W; aged 46 14.9 yr)
were used as controls.
RESULTS
Table 1 summarizes the clinical characteristics and
clinical data in patients with hyperthyroidism and
control subjects. Compared with the control sub-
jects, AT III, fibrinogen, F IX, vWF and PAI-1 were
significantly increased in hyperthyroid patients
(p<0.01, p<0.05, p<0.0001, p<0.05 and p<0.0001;
respectively), whereas F X and t-PA were decreased
(p<0.05). For protein C, protein S and the other co-
agulation factors’ activities in hyperthyroid patients
were not different from the controls.
Blood was collected in the morning 08:00-09:00 h after an
overnight fast. Serum total (TT3) and FT3, total and free thyrox-
ine (TT4 and FT4), and TSH concentrations were measured by
an automated chemiluminescence system (Bayer Corporation,
Tarrytown, U.S.A.). Normal ranges are 0.6-1.81 ng/ml for TT3,
4.5-10.9 μg/dl for TT4, 2.3-4.2 pg/ml for FT3, 0.89-1.76 ng/dl for
346

C. Erem, H.Ö. Ersoz, S.S. Kartı, et al.
Table 1 - Clinical and biological parameters of controls and patients with hyperthyroidism.
Controls
20
Hyperthyroidism
p
-
No. of subjects
Age (yr)
41
44.5 15.2
247,725 40,182
7.5 0.7
46 14.9
NS
Platelet count (per μl)
MPV (fl)
237,450 27,412
7.7 0.5
NS
NS
TT3 (ng/ml)
TT4 (μg/dl)
1.6 1.1
4.0 2.7
<0.01*
<0.0001
<0.001*
<0.001*
<0.001*
NS
8.0 1.6
14.6 4.5
FT3 (pg/ml)
FT4 (ng/dl)
2.9 0.9
6.9 3.2
1.2 0.4
3.6 2.1
TSH (μU/ml)
TC (mg/dl)
1.1 0.6
0.08 0.5
158.4 40.1
100.2 50.4
126.4 22
42.1 4.5
11.0 0.4
30.7 2.7
251.2 5.6
71.3 19.1
84.8 11.5
119.2 19.8
83.6 16.9
92.4 15.6
22.9 2.3
106.4 22.8
112.8 28.9
98.7 16.8
21.4 5.8
11.7 2.9
159.5 42.7
109.1 55.9
106.7 25.2
46.8 13.6
11.7 1.1
Triglycerides (mg/dl)
LDL-C (mg/dl)
HDL-C (mg/dl)
PT (s)
NS*
<0.05
NS
NS
aPTT
33.2 7.4
NS
Fibrinogen (mg/dl)
F V (%)
292.3 79.4
76.2 15.9
90.2 33.5
129.4 35.3
109.6 27.9
79.2 19.8
28.6 4.8
<0.05
NS
F VII (%)
NS
F VIII (%)
NS
F IX (%)
<0.0001
<0.05
<0.01
NS
F X (%)
AT III Ag (mg/dl)
Protein C (%)
Protein S (%)
vWF activity (%)
t-PA Ag (ng/ml)
PAI-1 Ag (ng/ml)
112.5 29.8
101.4 26.3
110.1 24.2
16.5 9.2
NS
<0.05
<0.05*
<0.0001
43.7 13.1
aPTT: activated partial thromboplastin time; AT III: antithrombin III; FT3: free T3; FT4: free T4; HDL-C: high density lipoprotein cholesterol; LDL-C: low densi-
ty lipoprotein cholesterol; MPV: Mean platelet volume; PAI-1: plasminogen activator inhibitor 1; PT: prothrombin time; TC: total cholesterol; t-PA: tissue plas-
minogen activator; vWF: von Willebrand Factor. *indicates p value according to Mann-Whitney-U test, others according to Student-t test.
We showed that FT4 levels correlated with F VIII ac-
tivity (r=0.35; p<0.05) (Fig. 1). Protein C and S were
correlated with vWF levels (r=0.58, p<0.0001; r=0.55,
p<0.0001, respectively). Protein C and vWF were in-
versely correlated with t-PA (r=-0.39, p<0.01; r=-0.31,
p<0.05) (Fig. 2). AT III was inversely correlated with
FVII (r=-0.48. p<0.01).
There was a negative correlation between triglyc-
erides, LDL-C and F X (r=-0.45, p<0.05; r=-64,
p<0.01, respectively) (Fig. 3). MPV was correlated
with anti-TPO antibodies (in Graves’disease) and F
IX activity (r=0.57, p<0.05 and r=0.39, p<0.05; re-
spectively) Platelet count was inversely correlated
with vWF activity (r=0.31, p<0.05).
measured. Among the lipids, only TC levels were in-
versely correlated with TSH values (r=-0.44, p<0.01).
For lipid and hemostatic parameters, we did not
find a significant difference between Graves’ dis-
ease and toxic nodular goiter.
DISCUSSION
Thyroid function disorder is known to cause car-
diovascular and metabolic abnormalities and these
may contribute to the increased incidence of arte-
rial thromboembolism in hyperthyroidism with re-
spect to normal subjects (1). The classic coagula-
tion tests that assess the overall coagulation status,
such as the PT and aPTT, are not greatly altered in
hyperthyroidism (15). It thus appears that these pa-
We did not find any significant correlation between
TSH levels and the hemostatic parameters that we
347

Hemostasis in hyperthyroidism
250
200
150
100
50
lated to increases in parameters, particularly after
anticoagulant therapy. Indeed, as far as we know,
there are no cut-off values for these parameters that
can be used to assess the risk for thromboembolic
events. Therefore we explored a different approach
in this study to gain insight into the possible mech-
anisms underlying the increased risk for throm-
boembolic in thyrotoxicosis. In our study, PT and
aPTT in hyperthyroid patients were not different
from the control subjects.
0
Because thyroid hormones influence the secretion
and degradation of a multitude of proteins, includ-
ing many synthesized in the endothelium, this study
focused on endothelial-associated-proteins (EAPs)
and on other endogenous factors involved in co-
agulation and fibrinolysis (11). Because it has been
suggested that thyroid hormones selectively influ-
ence EAPs and do not influence hepatically syn-
thesized factors (16), proteins synthesized in the liv-
er (factors of V, VII, VIII, IX, X, fibrinogen, AT III, pro-
tein C and S) were also studied.
0
2
4
6
8
10
Free T4 (ng/dl)
Fig. 1 - Correlation between serum free T4 levels and factor VIII
activity in patients with hyperthyroidism (r=0.35; p<0.05).
50
40
30
20
10
0
Abnormal plasma levels of vWF have previously
been associated with thyroid dysfunction (3, 17, 18).
Increased plasma concentrations of vWF were re-
ported in hyperthyroid patients and were observed
to decrease to normal levels in the patients who
became euthyroid after anti-thyroid treatment (3,
18). In a recent study, Burggraaf et al. (11) reported
that plasma concentrations of vWF increased in hy-
perthyroid patients. Baumgartner-Parzer et al. (19)
showed that T3 can increase the production of vWF
in cultured endothelial cell. Our findings for vWF
are in accordance with the observations of Li et al.
(3), Morishita et al. (20) and Burggraaf et al. (11).
In our study, the release of t-PA Ag by vascular en-
dothelial cells was significantly lower than in nor-
mal subjects. As the t-PA Ag concentration in blood
is not affected by PAI-1 and fibrin (21), it should be
a more reliable marker than t-PA activity of im-
paired endothelial release of t-PA. In addition, the
profile of plasma PAI-1 was similar to that of vWF.
t-PA, PAI-1 and vWF are among the important en-
dothelium-derived proteins. Although a gold stan-
dard for endothelial dysfunction is not available,
high plasma vWF and/or PAI-1 have been widely
considered as markers of general endothelial dys-
function in serial diseases (3, 22). Accordingly, it is
reasonable to suggest that patients with hyperthy-
roidism experience endothelial cell dysfunction. On
the other hand, although our findings of decreased
t-PA levels in plasma in patients with endothelial
dysfunction are in accordance with those obtained
by some investigators (3, 23, 24), contradictory re-
sults have been reported in different diseases by
others (25, 26). The reasons for the contradiction
60
80
100
120
140
160
180
von-Willebrand factor (%)
Fig. 2 - Correlation between tissue plasminogen activator (t-PA)
Ag levels and von Willebrand factor (vWF) activity in patients
with hyperthyroidism (r=-0.31; p<0.05).
rameters provide no explanation for the observed
increase in thromboembolic risk. This is not sur-
prising since PT and aPTT are crude measures and
are only suitable to assess bleeding tendency re-
200
180
160
140
120
100
80
60
40
40
60
80
100
120
Factor X (%)
Fig. 3 - Correlation between serum low density lipoprotein
cholesterol (LDL-C) levels and factor X activity in patients with
hyperthyroidism (r=-0.64; p<0.01).
348

C. Erem, H.Ö. Ersoz, S.S. Kartı, et al.
are not clear. Furthermore, in previous studies, it
was found a negative and/or positive correlation
between T3 and t-PA in hyperthyroid patients (3,
16). Morishita et al. (20) reported that positive cor-
relation between the plasma free tissue factor path-
way inhibitor (TFPI) antigen, is a vascular endothe-
lial anticoagulant which inhibits the initial reaction of
the tissue factor-mediated coagulation pathway,
and serum FT3 levels in patients with Graves’ dis-
ease. In our study, there were no correlations be-
tween thyroid hormones and EAPs. However, FT4
levels were correlated with F VIII activity, but F VIII
activity in hyperthyroid patients was not different
from the controls.
ferent results may be due to the effect of thyroid hor-
mones on the liver. The observations from our study
are more compatible with in vitro data showing that
thyroid hormone influences the synthesis and secre-
tion of various proteins of hepatic origin (30). It also
corroborates clinical data on single proteins showing
hepatically synthesized proteins such as fibrinogen,
and AT III to be increased. In our study, factor X ac-
tivity was decreased in hyperthyroid patients com-
pared to controls. This condition may be related to
an inhibitor effect of AT III on factor X.
In conclusion, we found important differences in
the coagulatory/fibrinolytic parameters between
the hyperthyroid patients and healthy controls.
Hyperthyroid patients may experience vascular en-
dothelial dysfunction and reduced fibrinolytic ac-
tivity in blood. This endothelial activation may rep-
resent a situation with a higher thromboembolic
potential. This may provide an additional explana-
tion for the association between hyperthyroidism
and (cerebral) thromboembolic events especially in
the case when further risk factors such as advanced
age or hemodynamic abnormalities as atrial fibril-
lation are present.
It is controversial as to whether blood fibrinolytic
activity is decreased or increased in hyperthyroid
patients. In the previous studies (15, 27), prolonged
euglobulin lysis time, reduced fibrinolytic activity
and plasminogen levels in blood were noted in hy-
perthyroidism, whereas elevated plasma levels of
Bꢀ15-42, a specific fragment of fibrinogen degra-
dation mediated by plasmin, were reported in hy-
perthyroidism by other investigators (8, 28). Our
findings of decreased plasma levels of t-PA and in-
creased PAI-1 in hyperthyroidism are fairly new. On
the basis of intensive investigations, the t-PA/PAI-1
system has been viewed as a potential control point
of fibrinolysis. Our data indicate that the balance
between t-PA and PAI-1 is disturbed in favour of
PAI-1 in hyperthyroid patients, which therefore re-
sults in a reduced fibrinolytic capacity and can ac-
count for the results by Rennie et al. (15) and Farid
et al. (27), in which prolonged euglobulin lysis time
and reduced fibrinolytic activity were found. This
appears to be in contrast with the recently report-
ed findings of an unchanged fibrinolytic activity in
hyperthyroidism (11). Moreover, high plasma lev-
els of fibrinogen and fibrinopeptide A, a sensitive
specific product of thrombin action on the fibrino-
gen molecule were also reported (8, 28), which,
concomitant with elevated plasma vWF and F VIII
activity (6), suggest a hypercoagulable state in hy-
perthyroidism. In our study, we found high vWF ac-
tivity and fibrinogen levels in hyperthyroid patients.
In literature, a positive correlation between TFPI ac-
tivity and LDL-C has been reported in both normal
subjects and hypercholesterolemic patients (29).
Morishita et al. (20) did not find a relationship be-
tween serum lipids and hemostatic parameters. In
our study, we found a negative correlation between
LDL-C, and TG and F X (Fig. 3).
REFERENCES
1. Presti C.F., Hart R.G. Thyrotoxicosis, atrial fibrillation and
embolism, revisited. Am. Heart J. 1989, 117: 976-977.
2. Bar-Sela S., Ehrenfeld M., Eliakim M. Arterial embolism in
thyrotoxicosis with atrial fibrillation. Arch. Intern. Med.
1981, 141: 1191-1192.
3. Li Y., Chen H., Tan J., Wang X., Liang H., Sun X. Impaired
release of tissue plasminogen activator from the endothe-
lium in Graves’ disease - indicator of endothelial dysfunc-
tion and reduced fibrinolytic capacity. Eur. J. Clin. Invest.
1998, 28: 1050-1054.
4. Loeliger E.A., Esch vd B. The biological disappearance rate
of prothrombin, factors VII, IX and X from plasma in hy-
pothyroidism, hyperthyroidism, and during fever. Thromb.
Diathes. Haemorrh. 1963, 10: 267-277.
5. Kellett H.A., Sawers J.S.A., Boulton F.E., Cholerton S., Park
B.K., Toft A.D. Problems of anticoagulation with warfarin in
hyperthyroidism. Q. J. M. 1986, 58: 43-51.
6. Rojers J.S., Shane S.R., Jencks F.S. Factor VIII activity and
thyroid function. Ann. Intern. Med. 1982, 97: 713-716.
7. Rojers J.S., Shane S.R. Factor VIII activity in normal volun-
teers receiving oral thyroid hormone. J. Lab. Clin. Med.
1983, 102: 444-449.
8. Marongiu F., Conti M., Mameli G., et al. Fibrinogen and fib-
rinolytic activity in hyperthyroidism before and after antithy-
roid treatment. J. Endocrinol. Invest. 1988, 11: 723-725.
In our study, we found increased fibrinogen, AT III,
factor IX and decreased F X levels in hyperthyroid pa-
tients. Protein C and S activities in hyperthyroid pa-
tients were not different from the controls. These dif-
9. Erem C., Deg˘ er O., Bostan M., et al. Plasma lipoprotein(a)
concentrations in hypothyroid, euthyroid and hyperthyroid
subjects. Acta Cardiol. 1999, 54: 77-81.
349

Hemostasis in hyperthyroidism
10. Padro T., Hoogen vd C.M., Emeis J.J. Experimental hy-
pothyroidism increases plasminogen activator inhibitor ac-
tivity in rat plasma. Blood Coagul. Fibrinolysis 1993, 4: 797-
800.
21. Pedersen K.R., Skouby S.O., Sidelmann J., Jespersen J.
Assessment of endothelial function during oral contra-
ception in women with insulin-dependent diabetes melli-
tus. Metabolism 1994, 43: 1379-1383.
11. Burggraaf J., Lalezari S., Emeis J.J., et al. Endothelial func-
tion in patients with hyperthyroidism before and after treat-
ment with propranolol and thimazol. Thyroid 2001, 11:
153-160.
22. Erem C., Savaskan H., Cagılcı F., et al. Plasma endothelin-
1 levels in patients with type II diabetes mellitus. Diabetes
Res. 1996, 31: 105-111.
23. Jensen T., Knudsen J.B., Rasmussen B.F., Deckert T.
Features of endothelial dysfunction in early diabetic
nephropathy. Lancet 1989, 1: 461-463.
12. Wenisch C., Myskiw D., Gessl A., Graninger W. Circulating
selectins, intercellular adhesion molecule-1, and vascular
cell adhesion molecule-1 in hyperthyroidism. J. Clin.
Endocrinol. Metab. 1995, 80: 2122-2126.
24. Hamsten A., Wiman B., de Faire U., Blomback M. In-
creased plasma levels of a rapid inhibitor of tissue plasmi-
nogen activator in young survivors of myocardial infarc-
tion. N. Engl. J. Med. 1985, 313: 1557-1563.
13. Soma M., Maeda Y., Matsuura R., et al. Study of serum
thrombomodulin (TM) levels in patients with hyper- or hy-
pothyroidism. Rinsho Byori 1997, 45: 77-81.
25. Van Den Berg M., Boers G.H., Franken D.G., et al. Hyper-
homocysteinamia and endothelial dysfunction in young
patients with peripheral arterial occlusive disease. Eur. J.
Clin. Invest. 1995, 25: 176-181.
14. Yamamoto C., Kaji T., Sakamoto M., Kazuka H., Kaizumi
F. Calcium regulation of tissue plasminogen activator in-
hibitor-1 release from cultured human vascular endothe-
lial cells. Thromb. Res. 1994, 74: 163-168.
26. Kario K., Matsuo T., Kobayashi H., Matsuo M., Sakata T.,
Miyata T. Activation of tissue factor-induced coagulation
and endothelial cell dysfunction in non-insulin-dependent
diabetic patients with microalumuniria. Arterioscler.
Thromb. Vasc. Biol. 1995, 15: 1114-1120.
15. Rennie J.A.N., Bewsher P.D., Murchison L.E., Ogston D.
Coagulation and fibrinolysis in thyroid disease. Acta
Haematol. 1978, 59: 171-177.
16. Graninger W., Prich K.R., Spesier W. Effect of thyroid hor-
mones on plasma protein concentrations in man. J. Clin.
Endocrinol. Metab. 1986, 63: 407-411.
27. Farid N.R., Griffiths R.L., Collins J.R., Marshall W.H., Ingram
D.W. Blood coagulation and fibrinolysis in thyroid disease.
Thromb. Haemost. 1976, 35: 415-422.
17. Takahashi H., Yamada M., Shibata A. Acquired von Wille-
brand’s disease in hyperthyroidism. Thromb. Haemost. 1987,
58: 1095.
28. Marongiu F., Conti M., Murtas M.L., Mameli G., Sorano G.G.,
Martino E. Activation of blood coagulation and fibrinolysis
in Graves’ disease. Horm. Metab. Res. 1991, 23: 609-611.
18. Liu L., Wang X., Lin Z., Wu H. Elevated plasma levels of
vWF: Ag in hyperthyroidism are mediated through beta-
adrenergic receptors. Endocr. Res. 1993, 19: 123-133.
29. Hansen J.B., Huseby N.E., Sandset P.M., Svensson B.,
Lyngmo V., Nordoy A. Tissue factor pathway inhibitor and
lipoproteins: evidence for association with and regulation
by LDL in human plasma. Arterioscler. Thromb. 1994, 14:
223-229.
19. Baumgartner-Parzer S.M., Wagner L., Reining C., et al.
Increase by tri-iodothyronine of endothelin-1, fibronectin
and von Willebrand factor in cultured endothelial cells. J.
Endocrinol. 1997, 154: 231-239.
30. Niessen R.W.L., Pfaffendorf B.A., Sturk A., Lamping R.J.
The influence of insulin, B-oestradiol, dexamethasone and
thyroid hormone on the secretion of coagulant and anti-
coagulant proteins by HepG2 cells. Thromb. Haemost.
1995, 74: 686-692.
20. Morishita E., Hashimoto T., Asakura H., et al. Increased
plasma levels of free tissue factor pathway inhibitor in pa-
tients with Graves’ disease. Thromb. Haemost. 1998, 79:
919-923.
350