0021-972X/01/$03.00/0
The Journal of Clinical Endocrinology & Metabolism
Copyright © 2001 by The Endocrine Society
Vol. 86, No. 2
Printed in U.S.A.
Components of the Fibrinolytic System Are Differently
Altered in Moderate and Severe Hypothyroidism
RITA CHADAREVIAN, ERIC BRUCKERT, LAURENCE LEENHARDT,
PHILIPPE GIRAL, ANNICK ANKRI, AND GÉRARD TURPIN
Service d’Endocrinologie-Métabolisme, Hôpital Pitié Salpétrière, 75013 Paris, France
ABSTRACT
T4 levels are determinant of several components of the fibrinolytic
system. However, relationships between hypothyroidism and alteration of fibrinolytic capacity are not well established, and published
data remain conflicting. As the impact of hypothyroidism on both
degradation and synthesis of proteins may vary according to the
severity of the disease, we measured fibrinolytic activity across varying states of hypothyroidism. We measured fibrinogen, D-dimers
(DDI), ␣2-antiplasmin activity, tissue plasminogen activator antigen
(t-PA Ag), plasminogen, plasminogen activator inhibitor antigen
(PAI-1 Ag), and factor XII (FXII) of the coagulation. We prospectively
included 76 middle-aged female subjects: 25 controls, 24 patients
displaying moderate hypothyroidism (TSH, 10 –50 mU/L), and 27
patients with severe hypothyroidism (TSH, ⬎50 mU/L). Blood pressure, body mass index, smoking habits, total cholesterol as well as
high and low density lipoprotein subfractions, triglyceride, fasting
glycemia, and insulinemia were recorded.
We found a different pattern of fibrinolytic abnormalities according
to the severity of hypothyroidism. Compared with controls, patients
with moderate hypothyroidism displayed a decreased fibrinolytic activity, as reflected by lower DDI levels, higher ␣2-antiplasmin activities, and higher levels of t-PA and PAI-1 Ag. In sharp contrast,
patients with severe hypothyroidism exhibited higher DDI levels,
lower ␣2-antiplasmin activities, and lower t-PA and PAI-1 Ag levels.
These results were not accounted for by confounding factors such as
age, smoking, and components of the insulin resistance syndrome.
Free T4 was significantly associated with fibrinogen, ␣2-antiplasmin,
PAI-1 Ag, total cholesterol, and triglyceride and was negatively associated with DDI. The main hypotheses underlying the mechanisms
by which thyroid status may affect the fibrinolytic system remain to
be established.
In conclusion, patients with moderate hypothyroidism, who were
consistently shown to be at high risk for cardiovascular disease, have
decreased fibrinolytic activity. Subjects with severe hypothyroidism
have a tendency toward increased fibrinolytic activity, and these
modifications may participate to the bleeding tendency observed in
such patients. (J Clin Endocrinol Metab 86: 732–737, 2001)
T
culating coagulation proteins and impaired fibrinolytic activity (8, 10, 16 –19). We and others have found that plasma
levels of fibrinogen (20, 21), d-dimers (DDI) (22), and plasminogen activator inhibitor type 1 (PAI-1) (17–19, 22) were
either correlated to plasma levels of T4 or altered in patients
displaying normal to low FT4 levels or hypothyroidism.
However, surprisingly, few studies have analyzed alteration
of fibrinolytic activity in patients with hypothyroidism. Furthermore, published data remain controversial, and the different results observed may be explained by the inclusion of
patients regardless of the severity of hypothyroidism. Indeed, T4 has an impact on synthesis and catabolism of proteins, and final modification of serum levels of these proteins
may depend on the severity of the disease. Therefore, we
undertook the present study to investigate 1) whether hypothyroidism would affect fibrinolytic activity, 2) whether
similar abnormalities were observed across varying states of
hypothyroidism, and 3) whether a confounding factor(s)
may explain alterations in fibrinolytic activity in hypothyroidism.
HYROID DYSFUNCTION, particularly hypothyroidism, is a common disorder in the general population
and occurs more frequently in women. Patients displaying
overt hypothyroidism are at high risk for cardiovascular
disease (1– 4). Subsequently, patients with subclinical hypothyroidism [i.e. high TSH levels and normal free T4 (FT4)
levels] were also shown to be at high risk for atherosclerosis
and cardiovascular disease (5, 6). A retrospective study corroborates the strong relationship between low plasma thyroid hormone levels and progression of cardiovascular disease (7). In contrast to the association of cardiovascular
disease with moderate hypothyroidism, a bleeding tendency
is described in patients with profound hypothyroidism
(8 –10).
The mechanisms by which low levels of thyroid hormones
may lead to atherosclerosis and its complications or, alternatively, to a bleeding tendency remain controversial. Indeed, these hormones have pleiotropic effects on the cardiovascular system. These effects include 1) direct action on
myocardium and arteries (3, 11–13), 2) qualitative and quantitative modifications of lipoproteins (14), 3) effect on plasma
homocysteine concentration (15), and 4) modification of cir-
Subjects and Methods
Patients
Received June 5, 2000. Revision received August 24, 2000. Rerevision
received October 17, 2000.
Address all correspondence and requests for reprints to: Dr. Rita
Chadarevian, Service d’Endocrinologie-Métabolisme, Hôpital Pitié Salpétrière, 83 boulevard de l’Hôpital, 75013 Paris, France. E-mail:
eric.bruckert@psl.ap-hop-paris.fr.
We prospectively included 51 consecutive female patients with hypothyroidism and 24 controls recruited among patients attending our
out-patient clinic for nontoxic goiter or asymptomatic benign nodule. All
patients were willing to participate to the study and gave written informed consent. Controls were defined by serum FT4 and TSH levels
within the normal range. Clinical examination included height and
732
HYPOTHYROIDISM AND FIBRINOLYSIS
weight measurements, and body mass index (BMI) was calculated as
weight (kilograms) divided by height (meters) squared. Blood pressure
was taken after 10 min in a resting position. A complete medical history,
including history of bleeding, was recorded. Patients who presented
before the study myocardial infarction or any serious medical disease
were excluded. For smoking habits, patients were classified as current
smoker or nonsmoker, and cumulative smoking was calculated as packyear. Treatment, including estrogen replacement therapy, received by
patients and controls were recorded. None of our patients was taking
aspirin on a current basis.
Methods
Blood was collected in the morning between 0800 – 0900 h after an
overnight fast. Serum levels of FT4 were measured by immunoluminometric assay (ILMA) by Lumitest FT4 (Brahms, Germany; normal range,
10 –25 pmol/L) and TSH by ILMA by Lumitest TSH (Brahms; normal
range, 0.1– 4 mU/L). Thyroid autoantibodies (antibodies to thyroid peroxidase and thyroglobulin) were measured by an enzyme-linked immunosorbent assay (Synelisa, Pharmacia, Germany). Antibody levels
were considered negative when they were below 100 IU/mL. Total
cholesterol and triglyceride levels were determined on a Kone analyzer
by an enzymatic method (BioMérieux, Marcy-l’Etoile, France). High
density lipoprotein (HDL) cholesterol was determined by a phosphotungstic acid/MgCl2 reagent (Roche Molecular Biochemicals, Mannheim, Germany) to precipitate the apolipoprotein B-containing lipoproteins and cholesterol was measured as indicated above. Low density
lipoprotein (LDL) cholesterol levels were calculated according to Friedewald’s formula. Blood glucose was determined by routine clinical chemistry. A double antibody RIA measured serum insulin levels (AxSYM)
with a sensitivity of 1 ␮U/mL with respective intra- and interassay
variations of 2.6 – 4.9% and 2–2.9%. Insulin resistance was evaluated by
the fasting glucose/fasting insulin ratio. For coagulation and fibrinolysis, a venous blood sample (9 vol) was collected into Vacutainer tubes
(Becton Dickinson, Mountain View, CA) containing 0.129 mol/L trisodium citrate (1 vol). Platelet-poor plasma was obtained by centrifugation
at 3500 ⫻ g at 10 C for 20 min. Fibrinogen and FXII measurements were
performed immediately. Aliquots of plasma were transferred into plastic tubes without delay and frozen at ⫺80 C until assays for determination of tissue plasminogen activator antigen (t-PA Ag), plasminogen
activator inhibitor 1 antigen (PAI-1 Ag), DDI, and ␣2-antiplasmin. Clottable fibrinogen was assayed by the Clauss method with the commercial
reagent Fibromat (BioMérieux). FXII was evaluated using a one-stage
clotting assay with aPTT reagent (Organon Teknika Corp., Durham, NC)
and specific factor-deficient plasma (STA-Deficient XII, Diagnostica
Stago, Asnière sur Seine, France). All of these tests were performed on
the automated coagulometer STA (Diagnostica Stago). Normal ranges
are 1.8 –3.5 g/L for fibrinogen and 60 –150% for FXII. Measurements of
t-PA Ag and PAI-1 Ag used an enzyme-linked immunosorbent assay
(Asserachrom tPA and Asserachrom PAI-1 from Diagnostica Stago).
According to the manufacturer, normal ranges are 1–12 ng/mL for t-PA
Ag and 4 – 43 ng/mL for PAI-1 Ag. Determination of functional activity
of ␣2-antiplasmin in plasma was made using an amidolytic assay
(Berichrom ␣2-antiplasmin, Dade Behring, Marburg, Germany). This
assay was performed on a BCT analyzer (Dade Behring). Normal ranges,
as determined by the manufacturer, are 80 –100%. DDI measurement
was performed by a standard enzyme-linked immunosorbent assay
(Asserachrom D-Di ELISA, Diagnostica Stago). Normal values are less
than 400 ng/mL.
Statistical analysis
Results are presented as the mean ⫾ sd. We divided patients into two
subgroups, which were determined before the study: moderate and
profound hypothyroidism defined by serum TSH levels below 50 mU/L
and above 50 mU/L, respectively. Results were evaluated by ANOVA
and Scheffe’s F test for comparison between groups. Relationships between FT4 and the other biological parameters were assessed by a simple
regression analysis. Log transformation of the data was performed when
appropriate, as was the case for PAI-1 Ag, t-PA Ag, triglycerides, and
DDI. P ⬍ 0.05 was considered significant. FT4 levels were divided into
quintiles to analyze the relationship between PAI-1 Ag and FT4. Comparison between quintiles of FT4 was assessed by ANOVA.
733
Statistical analysis was carried out on an Apple Macintosh computer
(Les Ulis, France), with the use of StatView (Abacus Concepts, Inc.,
Berkeley, CA), JMP (SAS Institute, Inc., Cary, NC), and Excel (Microsoft
Corp., Redmond, WA) software.
Results
Controls and patients: clinical description
Our population included 76 middle-aged female subjects.
Twenty-five control subjects had normal TSH and FT4 levels,
24 presented moderate hypothyroidism (TSH, 10 –50 mU/L),
and 27 had severe hypothyroidism (TSH, ⬎50 mU/L).
Among patients with moderate hypothyroidism, 11 presented subclinical hypothyroidism (normal FT4 levels).
Among hypothyroid patients, 38 had chronic Hashimoto
thyroiditis, 6 had atrophic thyroiditis, 3 had hypothyroidism
secondary to interferon treatment for hepatitis, 2 had hypothyroidism secondary to lithium treatment, one had hypothyroidism secondary to subacute thyroiditis, and one had
postpartum thyroiditis. There were no significant differences
between groups for mean age, BMI, and estrogen replacement therapy. Smoking habits, cumulative smoking, and
mean blood pressure were not different among the 3 subgroups. Clinical parameters are presented according to thyroid status in Table 1.
Hemostatic and lipid parameters in controls and patients
divided into two groups
A nonsignificant decrease in mean fibrinogen levels was
observed in patients as the degree of hypothyroidism worsened. Compared with control subjects, patients with moderate hypothyroidism had lower DDI levels, higher ␣2-antiplasmin activities, and higher t-PA and PAI-1 Ag levels,
whereas a distinct feature was encountered in those who had
severe hypothyroidism (Table 2). Indeed, in patients with
severe hypothyroidism, DDI levels were higher than those in
both controls and patients with moderate hypothyroidism; in
TABLE 1. Clinical characteristics of controls and patients with
moderate and severe hypothyroidism
Controls
(subgroup 1)
N
Age (year)
TSH (mU/L)
BMI (kg/m2)
No. of current
smokers
Cumulative
smoking
No. of estrogen
users
Systolic blood
pressure
Diastolic blood
pressure
Moderate
hypothyroidism
(subgroup 2)
Severe
hypothyroidism
(subgroup 3)
25
45.5 ⫾ 9
1.67
25.5 ⫾ 6.4
8
24
51.3 ⫾ 14
21
27.5 ⫾ 6.2
6
27
49.4 ⫾ 12
⬎50a
26.1 ⫾ 6
4
14.8 ⫾ 26.6
12.4 ⫾ 19.9
9.4 ⫾ 19.1
3
5
4
120 ⫾ 14
126 ⫾ 16
124 ⫾ 21
74.3 ⫾ 8.8
72.4 ⫾ 10.8
71.2 ⫾ 14.6
N, Number of patients; BMI, body mass index; cumulative smoking, pack-year; blood pressure expressed in millimeters of Hg. There
were no statistical differences for these parameters, except for TSH,
which was significantly higher in moderate hypothyroidism than in
controls and significantly higher in severe hypothyroidism than in
moderate hypothyroidism.
a
P ⬍ 0.0001.
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JCE & M • 2001
Vol. 86 • No. 2
CHADAREVIAN ET AL.
TABLE 2. Clinical and biological parameters according to thyroid class determined by TSH level
N
TSH (mU/L)
FT4 (pmol/L)
Fibrinogen (g/L)
DDI (ng/mL)
A2 antiplasmin activity (%)
t-PA Ag (ng/mL)
Plasminogen activity (%)
PAI-1 Ag (ng/mL)
FXII (%)
Platelets
Total cholesterol (g/L)
Triglycerides (g/L)
HDL cholesterol (g/L)
LDL cholesterol (g/L)
Fasting glucose (mmol/L)
Fasting insulin (␮IU/mL)
Glucose/insulin ratio
Controls
(subgroup 1)
Moderate
hypothyroidism
(subgroup 2)
Severe
hypothyroidism
(subgroup 3)
P
25
1.67
14.7 ⫾ 3.3
2.89 ⫾ 0.6
311.05 ⫾ 184
103.36 ⫾ 11
5.36 ⫾ 2.9
113.36 ⫾ 22
25.55 ⫾ 11.8
95.1 ⫾ 23
267 626
2.15 ⫾ 0.3
0.95 ⫾ 0.5
0.59 ⫾ 0.2
1.37 ⫾ 0.3
4.8 ⫾ 0.8
8.9 ⫾ 7.5
0.83 ⫾ 0.47
24
21
10.6 ⫾ 2.7
2.70 ⫾ 0.5
248.5 ⫾ 96
107.2 ⫾ 22
7.57 ⫾ 3.3
108.48 ⫾ 14
50.8 ⫾ 40.1
90.2 ⫾ 25
247 523
2.27 ⫾ 0.5
1.23 ⫾ 0.7
0.62 ⫾ 0.2
1.85 ⫾ 1.9
5.13 ⫾ 1.1
9.1 ⫾ 7.1
0.74 ⫾ 0.33
27
⬎50
5.6 ⫾ 2.9
2.65 ⫾ 0.6
476.81 ⫾ 429
92.35 ⫾ 11
5 ⫾ 3.3
113.85 ⫾ 19
20.4 ⫾ 12.7
98.3 ⫾ 20
249 476
3.1 ⫾ 0.6
1.46 ⫾ 0.9
0.65 ⫾ 0.2
2.15 ⫾ 0.5
4.72 ⫾ 0.6
9.0 ⫾ 4.8
0.70 ⫾ 0.37
0.0001a
0.0001a
NS
0.023a
0.0086a
0.018a
NS
0.0002a
NS
NS
0.0001a
NS
NS
0.07
NS
NS
NS
Results are presented as the mean ⫾ SD. Comparison between subgroups was made using the ANOVA test. The P value is given when it
is below 0.10. N, Number of patients; BMI, body mass index; DDI, D-dimers; t-PA Ag, tissue plasminogen activator antigen; PAI-1 Ag,
plasminogen activator inhibitor type 1 antigen; FXII, factor XII of the coagulation; HDL cholesterol, high density lipoprotein cholesterol; LDL
cholesterol, low density lipoprotein cholesterol. Comparisons are for subgroup 2 vs. 3 (by Scheffe’s F test): a Significant.
TABLE 3. Clinical and biological parameters according to thyroid class determined by TSH level
Nonsmokers
Controls
Moderate
hypothyroidism
Severe
hypothyroidism
N
Fibrinogen (g/L)
DDI (ng/mL)
A2 antiplasmin activity (%)
t-PA Ag (ng/mL)
Plasminogen activity (%)
PAI-1 Ag (ng/mL)
17
2.77 ⫾ 0.7
328 ⫾ 176
105 ⫾ 12
4.9 ⫾ 2.8
113 ⫾ 26
23.5 ⫾ 12
18
2.71 ⫾ 0.5
239 ⫾ 97
109 ⫾ 24
7.8 ⫾ 3
107 ⫾ 14
57 ⫾ 42
23
2.68 ⫾ 0.6
512 ⫾ 486
93 ⫾ 11
5.5 ⫾ 3.4
115 ⫾ 20
22 ⫾ 13
P
NS
0.036
0.026
0.025
NS
0.0003
Subgroup analysis in nonsmokers. Results are presented as the mean ⫾ SD. Comparison among the three groups was made using ANOVA
test. DDI, D-dimers; t-PA Ag, tissue plasminogen activator antigen; PAI-1 Ag, plasminogen activator inhibitor type 1 antigen.
TABLE 4. Clinical and biological parameters according to thyroid class determined by TSH level
N
Fibrinogen (g/L)
DDI (ng/mL)
A2 antiplasmin activity (%)
t-PA Ag (ng/mL)
Plasminogen activity (%)
PAI-1 Ag (ng/mL)
Controls
Moderate
hypothyroidism
Severe
hypothyroidism
22
2.95 ⫾ 0.6
322 ⫾ 195
103 ⫾ 11
5.3 ⫾ 2.7
110 ⫾ 14
26.1 ⫾ 12
19
2.74 ⫾ 0.4
265 ⫾ 96
107 ⫾ 25
7.4 ⫾ 3
109 ⫾ 13
43.7 ⫾ 33
23
2.65 ⫾ 0.6
510 ⫾ 455
90 ⫾ 10
5.1 ⫾ 3.5
113 ⫾ 20
20.4 ⫾ 13
P
NS
0.042
0.0142
NSa
NS
0.004
Results after exclusion of women taking estrogen replacement therapy are presented as the mean ⫾ SD. Comparison among the three groups
was made using ANOVA. DDI, D-Dimers; t-PA Ag, tissue plasminogen activator antigen; PAI-1 Ag, plasminogen activator inhibitor type 1
antigen.
a
After log transformation, P ⫽ 0.043.
contrast, ␣2-antiplasmin activities and PAI-1 and t-PA Ag
levels were lower than those in both controls and patients
with moderate hypothyroidism. Exclusion of smokers did
not change the results (Table 3). Similarly, exclusion of
women treated with estrogen replacement therapy did not
change the differences found among the 3 groups (differences for t-PA Ag were significant only after log transformation; Table 4). For DDI, 1 patient in the subgroup of
patients with severe hypothyroidism was an outliner with a
plasma DDI level of 2001 ng/mL. When this patient was
removed from the analysis, differences between groups remained significant (311 ⫾ 187, 284.5 ⫾ 95.9, and 400.6 ⫾ 256
in the control group and in patients with moderate and
severe hypothyroidism, respectively; P ⫽ 0.038) as did differences between patients with moderate or severe hypothyroidism (P ⬍ 0.05, by Scheffe’s F test). Platelet count was
HYPOTHYROIDISM AND FIBRINOLYSIS
not different among the 3 subgroups. Only total cholesterol
differed among the groups and LDL cholesterol levels were
higher, but the difference failed to reach statistical significance. The results were not different when we included in the
analysis the presence or absence of autoimmunity assessed
by the measurement of antibodies to thyroid peroxidase and
thyroglobulin (data available for 38 patients with hypothyroidism).
PAI-1 levels according to FT4 quintiles
We divided the overall population according to FT4 quintiles (mean FT4 levels were 3.7, 7, 9.8, 12.6, and 16.8 pmol/L
in quintiles 1–5, respectively). We observed an increase in
plasma levels of PAI-1 in patients in the second, third, and
fourth quintiles, whereas patients in the first quintile exhibited significantly lower levels of PAI-1 (Fig. 1). These patients
displayed severe hypothyroidism as indicated by very low
mean FT4 levels.
Correlation coefficients (Table 5)
In the overall study group, a significant positive correlation was found between FT4 and fibrinogen (r ⫽ 0.33), FT4
and log PAI-1 Ag (r ⫽ 0.27), and FT4 and ␣2-antiplasmin (r ⫽
0.32). A negative correlation was found between FT4 and log
DDI (r ⫽ ⫺0.24). For DDI, when the outliner patient was
removed from the analysis, correlation coefficient failed to
reach significance. FT4 was also significantly associated with
total and LDL cholesterol and triglycerides. No associations
were found between FT4 and the following characteristics:
age, BMI, log t-PA Ag, plasminogen, FXII, HDL cholesterol,
fasting glucose, fasting insulin, glucose/insulin ratio, and
systolic and diastolic blood pressures.
Discussion
The main finding of our study is that hypothyroid patients
display a distinct pattern of alteration of the fibrinolytic
system depending on the severity of the disease. Compared
with controls, patients with moderate hypothyroidism had
lower DDI levels, higher ␣2-antiplasmin activities, and
higher t-PA and PAI-1 Ag levels, whereas those who had
severe hypothyroidism exhibited higher DDI levels, lower
FIG. 1. Plasma PAI-1 levels according to FT4 quintiles in the overall
population (n ⫽ 76). Mean FT4 levels were 3.7, 7, 9.8, 12.6, and 16.8
pmol/L in quintiles 1–5, respectively. There were 14, 16, 15, 14, and
17 patients in quintiles 1–5, respectively.
735
TABLE 5. Simple regression analysis: correlation coefficients (r)
between FT4 and clinical, biological, and hemostatic factors in the
overall population (n ⫽ 76)
FT4/age
FT4/BMI
FT4/fibrinogen
FT4/log DDI
FT4/␣2-antiplasmin
FT4/log t-PA Ag
FT4/plasminogen
FT4/log PAI-1 Ag
FT4/FXII
FT4/platelets
FT4/total cholesterol
FT4/log triglycerides
FT4/LDL-cholesterol
FT4/HDL-cholesterol
FT4/fasting glucose
FT4/fasting insulin
FT4/ratio glucose/insulin
Simple regression
coefficient (r)
P value
0.09
0.05
0.33
⫺0.24
0.32
0.22
0.05
0.27
0.1
0.03
0.54
0.28
0.26
0.15
0.12
0.02
0.18
0.4
0.6
0.0044
0.056
0.009
0.07
0.67
0.022
0.4
0.8
0.0001
0.016
0.026
0.2
0.3
0.8
0.2
BMI, body mass index; DDI, D-dimers; t-PA Ag, tissue plasminogen activator antigen; PAI-1 Ag, plasminogen activator inhibitor type
1 antigen; FXII, factor XII of the coagulation; HDL cholesterol, high
density lipoprotein cholesterol; LDL cholesterol, low density lipoprotein cholesterol.
␣2-antiplasmin activities, and lower t-PA and PAI-1 Ag
levels.
This biphasic effect of thyroid hormone deficiency might
explain the contradictory results previously found in the
literature. Some studies of hypothyroidism found low levels
of t-PA and PAI-1 activities (17) and increased fibrinolytic
activity (19), whereas others found the opposite results, i.e.
plasma PAI-1 activity increased (16, 18). However, these
studies included a small number of patients and did not
compare the effects of severe and moderate hypothyroidism.
We included a carefully selected group of subjects. Male
and female subjects may have different patterns of fibrinolytic parameters. Therefore, as hypothyroidism is far more
frequent in women, we only included female patients. As we
included patients without a prior history of myocardial infarction, we cannot explain our results by a referral bias (i.e.
those patients with hypothyroidism and acute cardiovascular event would have been more likely referred to a specialized center).
We analyzed whether differences in fibrinolytic activity
could be explained by any of the components of the so-called
plurimetabolic syndrome. Indeed, triglyceride and blood
glucose levels as well as fasting insulin and BMI were significantly correlated to PAI levels (23, 24). However, none of
these characteristics differed significantly between patients
with either moderate or severe hypothyroidism and controls.
Our results are in line with the finding that there was no link
between thyroid hormones and the insulin resistance syndrome (25). Smoking is associated with increased prevalence
of hypothyroidism (26) and impaired endogenous fibrinolysis (27). However, we found the same results in nonsmokers. Finally, as aging might affect both thyroid status (28) and
fibrinolysis (29), it is noticeable that our study population
involved middle-aged subjects, and mean age did not differ
significantly between patients and controls. Taken together,
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Vol. 86 • No. 2
CHADAREVIAN ET AL.
our results strongly suggest that the alteration of the fibrinolytic system found in our patients were only explained by
thyroid status.
The finding that patients with severe hypothyroidism display both higher DDI levels and slightly lower fibrinogen
levels than controls suggests that these patients present an
increased capacity of degradation of normal amount of fibrin. This increased capacity might be explained by decreased levels of PAI-1 Ag and reduced levels of ␣2-antiplasmin. Such modifications may contribute to the bleeding
tendency described in these patients. High DDI levels were
shown to be a risk factor for cardiovascular disease (30, 31).
Whether this remains true for our population is therefore
debatable. It is noticeable that no major increase risk of
thrombotic events was described in patients with severe
hypothyroidism.
In sharp contrast, the finding of lower DDI levels without
significant modification of fibrinogen levels in patients with
moderate hypothyroidism suggests a decreased capacity of
degradation of normal amount of fibrin. This hypofibrinolytic state might be explained by increased levels of both
PAI-1 Ag and ␣2-antiplasmin. In this respect, it is interesting
to note that myocardial infarction occurrence in hypothyroid
patients was described during the rapid initiation of levothyroxine treatment, a state during which patients have moderate hypothyroidism (2, 32). This is particularly true for
elderly subjects or patients with preexisting ischemic heart
disease in whom high t-PA and PAI-1 levels precede acute
myocardial infarction (33–35). Two recent epidemiological
studies support the concept that subclinical hypothyroidism
is an independent cardiovascular risk factor (4, 6). Therefore,
accumulating evidence suggests that moderate hypothyroidism should not be regarded as benign.
Binding of plasmin to ␣2-antiplasmin forms inactive complexes. The finding of relatively higher levels of ␣2-antiplasmin in moderate hypothyroidism suggests higher inactivation of plasmin. To our knowledge, there is only one small
study of patients with hypothyroidism in which FXII was
determined (19). Our results indicate that FXII levels were
not different between patients with and without hypothyroidism. Thus, differences found in DDI or fibrinogen levels
cannot be explained by differences in plasma levels of this
factor, which has fibrinolytic properties (36, 37).
The mechanisms by which thyroid hormone status is associated with fibrinolysis alteration remain to be established.
The main hypotheses are the following: 1) reduction of catecholamine receptor density in hypothyroidism, leading to
an increase in PAI-1 level (38); 2) consequences of atherosclerosis and endothelial dysfunction, a condition associated
with reduced release of hemostatic factors (39); 3) direct
effect of thyroid hormones on either synthesis or catabolism
of proteins; and, finally, 4) indirect effect through autoimmunity. However, although our population is too small to
draw any firm conclusion, our results do not suggest that
autoimmunity as detected by positive antibodies to thyroglobulin or that thyroid peroxidase is associated with greater
abnormalities of fibrinolytic components.
In conclusion, we found a hypofibrinolytic state in patients
with moderate hypothyroidism. Our results suggest that the
risk of developing thrombosis and ultimately myocardial
infarction via high PAI-1 levels may be increased in patients
with moderate hypothyroidism, a result in line with recent
epidemiological data (4, 6). These results are of importance
because in a large cross-sectional study in which prevalence
of hypothyroidism was high (9.5%), 40% of patients were
incompletely controlled by T4 substitution (40). In contrast,
patients with severe hypothyroidism not only have low levels of von Willebrand factor (8, 9), but also exhibit a reversal
toward an activation of the fibrinolytic system. The clinical
relevance of higher DDI levels in patients with severe hypothyroidism is debatable. Whether these differences may
lead to a somewhat lower risk of myocardial infarction in
patients with severe hypothyroidism compared with patients with moderate hypothyroidism remains to be
established.
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