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Original Studies |
Service d’Endocrinologie-Métabolisme, Hôpital Pitié Salpétrière, 75013 Paris, France
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{at}psl.ap-hop-paris.fr
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Abstract |
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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.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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, 12, 13), 2) qualitative and quantitative modifications of lipoproteins (14), 3) effect on plasma homocysteine concentration (15), and 4) modification of circulating coagulation proteins and impaired fibrinolytic activity (8, 10, 16, 17, 18, 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, 18, 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.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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 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 pack-year. 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 µU/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 x 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.
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.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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
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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 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 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).
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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.
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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.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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2-antiplasmin activities, and higher t-PA and
PAI-1 Ag levels, whereas those who had severe hypothyroidism exhibited
higher DDI levels, lower 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, 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, 34, 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.
Received June 5, 2000.
Revised August 24, 2000.
Revised October 17, 2000.
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