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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-2644
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 8 3006-3012
Copyright © 2007 by The Endocrine Society

Altered Platelet Plug Formation in Hyperthyroidism and Hypothyroidism

Monika Homoncik, Alois Gessl, Arnulf Ferlitsch, Bernd Jilma and Heinrich Vierhapper

Department of Internal Medicine IV (M.H., A.F.), Division of Gastroenterology and Hepatology; Department of Internal Medicine III (M.H., A.G., H.V.), Division of Endocrinology and Metabolism; and Department of Clinical Pharmacology (B.J.), Medical University of Vienna, A-1090 Vienna, Austria

Address all correspondence and requests for reprints to: Bernd Jilma, M.D., Department of Clinical Pharmacology-TARGET, The Adhesion Research Group Elaborating Therapeutics, Medical University of Vienna, A-1090 Wien, Währinger Gürtel 18-20, Austria. E-mail: Bernd.Jilma{at}meduniwien.ac.at.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Objective: Patients with thyroid diseases have abnormalities of blood coagulation including an alteration of von Willebrand factor (vWF) levels. Because vWF plays an important role in primary hemostasis, we hypothesized that heightened and decreased vWF levels in hyper- and hypothyroidism enhance and decrease platelet plug formation, respectively.

Methods: We followed a cohort of 120 patients with overt hyperthyroidism, patients with subclinical and overt hypothyroidism, and euthyroid controls. vWF and in vitro platelet plug formation as collagen-epinephrine-induced closure time (CEPI-CT) were measured at baseline and during therapy with thiamazole or T4.

Results: Baseline vWF levels were higher in patients with hyperthyroidism and lower in patients with overt hypothyroidism than in controls (P < 0.01). High vWF antigen levels were associated with increased baseline platelet plug formation in patients with hyperthyroidism as compared with controls [114 sec (95% confidence interval, 105–122 sec) vs. 130 sec (120–140 sec), P = 0.01]. After 8 wk of therapy with thiamazole, serum concentrations of T4 and vWF levels decreased to normal values (P < 0.01 vs. baseline), and CEPI-CT was prolonged as compared with baseline (P < 0.01). During therapy with T4, vWF levels increased (P < 0.05 vs. baseline) and CEPI-CT was shortened as compared with baseline (P < 0.01).

Conclusion: Hyperthyroidism-induced vWF elevation is associated with enhanced platelet function and therefore shortened CEPI-CT values. These changes may contribute to the higher risk for cardiovascular disease in patients with hyperthyroidism. Platelet plug formation decreases during therapy with thiamazole. Furthermore, CEPI-CT appears to be sensitive to detect acquired von Willebrand disease associated with overt hypothyroidism.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
VARIOUS ACQUIRED ABNORMALITIES of coagulation have been reported in patients with thyroid dysfunction (1, 2, 3, 4, 5). Although patients with overt hypothyroidism are at particular risk of hemorrhage (6), patients with hyperthyroidism display a tendency to develop thromboembolic complications, with major embolism accounting for up to 18% of deaths in patients dying from thyrotoxicosis (7, 8). Long-term follow-up studies have revealed increased mortality from cardiovascular and cerebrovascular disease in patients with hyperthyroidism (9, 10, 11, 12).

Thyroid hormones exert effects on different levels of the hemostatic system, including a modulation of coagulation proteins (1, 2, 3, 4, 5). In this context, alterations of von Willebrand factor (vWF) may play a key role. Hyperthyroidism is associated with an increase of vWF activity levels (13). vWF is also a well-characterized marker of cardiovascular risk (14); plasma levels of vWF are increased in patients with coronary artery disease and predict subsequent acute coronary syndrome. vWF is also an independent risk factor for recurrent myocardial infarction and death (15, 16, 17). At high shear rates, vWF acts as an important adhesive protein for both platelet adhesion and aggregation (18). Because platelets play a dominant pathogenetic role in the development and outcome of cardiovascular diseases (19), and platelet function is strongly dependent on vWF, elevated vWF levels due to hyperthyroidism may lead to increased platelet plug formation and consecutively to an increased cardiovascular risk. Platelet function in patients with hyperthyroidism has hitherto not been investigated. Hence, we investigated whether elevated vWF levels due to hyperthyroidism may lead to increased platelet plug formation.

In contrast, hypothyroidism is associated with prolonged in vivo bleeding time as a consequence of acquired von Willebrand disease (vWD) type I, due to a decreased synthesis of factor VIII and vWF (2, 3, 4, 20). Substitution with levothyroxine reverses vWD (21). Until now, all studies concerning platelet function in patients with hypothyroidism were performed using in vivo bleeding time. However, bleeding time tests are crude, imprecise, insensitive, and cumbersome for the patient. They are not ideally suitable for serial investigations (22, 23). The platelet function analyzer, PFA-100 (Dade-Behring, Miami, FL), was developed as an in vitro substitute of bleeding time and is U.S. Food and Drug Administration (FDA)-approved to detect platelet dysfunction, vWD, and aspirin-induced platelet inhibition (24, 25, 26, 27). The PFA-100 test is a well reproducible and robust method for measurement of platelet function (24, 26). The PFA-100 measures platelet plug formation under high shear stress and is strongly dependent on vWF levels in plasma (18, 26). Recent reports showed that PFA-100 can replace the bleeding time as a platelet function screening test in clinical practice (28). No data are as yet available about PFA-100 platelet plug formation in patients with hypo- or hyperthyroidism. Because vWF plays an important role in primary hemostasis, and vWF alterations have been observed in patients with thyroid diseases, we hypothesized that the hyperthyroidism-induced vWF elevation might lead to an enhanced platelet plug formation and that the hypothyroidism-induced vWF decrease might lead to a decreased platelet plug formation.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients and study design

This study was performed in 120 patients. We included 30 consecutive patients with overt hyperthyroidism, 30 with overt hypothyroidism, and 30 with subclinical hypothyroidism. Thirty euthyroid individuals served as controls. Controls were patients with normal TSH levels who were admitted to our outpatient facility because of swallowing problems, obesity, or infertility. Overt hyperthyroidism was defined by suppressed serum TSH concentrations (<0.1 µU/ml) and concomitantly elevated concentrations of total T4 and free T4 (fT4). Overt hypothyroidism was defined by markedly (>10 µU/ml) elevated concentrations of TSH together with low concentrations of T4. Subclinical hypothyroidism was defined by elevated concentrations of TSH levels in the presence of normal serum T4, fT4, T4, and T3. Euthyroidism was defined by normal serum TSH levels. The normal TSH range was 0.1–4 µU/ml.

The underlying causes of hyperthyroidism were Graves’ disease (n = 27), toxic solitary adenoma (n = 1), and toxic multinodular goitre (n = 2). Hypothyroidism was caused by autoimmune lymphocytic thyroiditis (Hashimoto’s thyroiditis) (n = 28) or by postoperative hypothyroidism (n = 2). Subclinical hypothyroidism was due to Hashimoto’s thyroiditis in each case.

Patients with additional serious diseases such as diabetes mellitus or coronary heart disease and patients taking antiplatelet drugs (e.g. clopidogrel), acetylsalicylic acid, or other nonsteroidal antiinflammatory drugs were excluded. The study protocol was approved by the local ethics committee, and written informed consent was obtained from all subjects.

Treatments

In patients with overt hypothyroidism, T4 treatment was started at a dose of 0.05 mg/d in the first week. Thereafter, the dose was increased to 0.1 mg daily. In patients with overt hyperthyroidism, thiamazole therapy was begun with 60 mg/d during the first week and was tapered to 40 mg/d and to 20 mg/d in the second and the third week, respectively. Thereafter, the dose was adjusted depending on T4, T3, and TSH concentrations. Measurements to assess changes in bleeding time during and after normalization of thyroid function were performed before the beginning of therapy with T4 or thiamazole and during control visits after initiation of the respective therapy. No patients were lost during follow-up.

Thyroid function

Blood was collected in the morning between 0800–1000 h after an overnight fast to avoid the differences of diurnal variation, especially for hemostatic parameters. At first visit, thyroid tests included serum TSH and fT4. If TSH was abnormal, total T4, total T3, and T4-binding globulin were also measured by conventional RIA (29).

Platelet function analyzer (PFA-100) testing

The PFA-100 uses high shear rates (5000–6000 sec–1), corresponding to flow conditions present in stenotic arteries. Citrated blood is aspirated from a reservoir under vacuum through an aperture of a membrane. The membrane is coated with combinations of platelet agonists, either with collagen/epinephrine (CEPI) or with collagen/ADP (CADP). Platelets adhere to the membrane surrounding the aperture. Progressively, a platelet plug is formed that finally occludes the aperture. The time required for the complete occlusion is recorded as closure time (CT) and is indicative of platelet function and primary hemostasis capacity (24, 25, 26, 27). The maximal measurable CEPI-CT or CADP-CT is 300 sec. In a previous study, intra- and intersubject variability of CEPI-CT averaged 9 and 22%, respectively (26). Previous studies have shown that the PFA-100 system has a sensitivity of 95% for detecting aspirin effects (24). Other studies have found a mean coefficient of variance for duplicate samples of 5% using this system, indicating a high degree of consistency and reliability (30). In our study, we measured CEPI-CT. If it was abnormal, CADP-CT was measured. In patients taking nonsteroidal antiinflammatory drugs, CEPI-CT is increased and CADP-CT is normal. In patients with vWF disease, both values are increased (25, 26, 31).

vWF antigen (vWF-Ag) levels, vWF ristocetin-cofactor activity (vWF:RiCo), and factor VIII activity

Plasma levels of vWF-Ag were measured with a fully automated STA analyzer by use of the vWF-Liatest (Diagnostica Stago, Paris, France). vWF:RiCo was assayed by turbidometry using a commercial kit from Behring (Marburg, Germany) that consists of lyophilized platelets and ristocetin. Factor VIII was measured by a one-step clotting assay with use of factor VIII-deficient plasma obtained from Immuno Baxter (Baxter Healthcare, Vienna, Austria) and a fully automated coagulation analyzer (CA 6000; Sysmex, Kobe, Japan).

Statistical methods

All statistical analyses were performed using Statistica for Windows, version 6.0. All data are expressed as mean and 95% confidence intervals. Follow-up data are expressed as their percentage changes from baseline values. All statistical comparisons were performed using the Wilcoxon matched pairs test for post hoc comparisons. Differences between groups were assessed by the Mann-Whitney U test. Additional Spearman correlation and multiple regression analyses were performed. Applying the Bonferroni correction for multiple groups and time points, a P value between 0.0125 and 0.01 can be considered significant for individual post hoc tests.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Baseline characteristics of patients are shown in Table 1Go.


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  		TABLE 1. Baseline characteristics of patients

 
Platelet function in patients with hyperthyroidism

Baseline vWF-Ag, vWF:RiCo, and factor VIII levels were higher in patients with hyperthyroidism than in controls (P < 0.001). The high vWF-Ag levels were associated with shorter baseline CEPI-CT (P = 0.01) (Fig. 1Go and Table 1Go). vWF-Ag was increased in 27 of 30 patients with hyperthyroidism, CEPI-CT was not prolonged in any patient with hyperthyroidism. Normalization of thyroid function by thiamazole decreased vWF levels, vWF:RiCo, and concentrations of factor VIII to normal values (P < 0.01 vs. baseline) and prolonged closure times compared with baseline values (P < 0.01) (Fig. 2Go). Moreover, closure times become higher than normal due to therapy with thiamazole.


Figure 1
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  		FIG. 1. Baseline values of vWF-Ag (top) and CEPI-CT (bottom) measured by PFA-100 (CEPI-CT) in patients with overt hyperthyroidism (Hypert, circles), euthyroidism (Euth, triangles), subclinical hypothyroidism (sub Hypoth, squares), and overt hypothyroidism (Hypot, diamonds). Black lines show means.

 

Figure 2
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  		FIG. 2. Effects of thiamazole on T4 concentration, CEPI-CT, and vWF-Ag levels in patients with hyperthyroidism (n = 30). Data are presented as mean and 95% confidence intervals. The horizontal lines show the upper normal levels.

 
vWF-Ag and platelet function in patients with hypothyroidism

Baseline vWF-Ag, vWF:RiCo, and factor VIII levels were lower in patients with overt hypothyroidism than in controls (P = 0.01) leading to prolonged baseline CEPI-CT (P < 0.001; Fig. 1Go). CADP-CT was measured in patients with prolonged CEPI-CT and was also prolonged above the normal range (159 ± 29 sec).

CEPI-CT was prolonged in 17 of 30 (56%) patients with overt hypothyroidism, and CADP was prolonged in 15 of 30 (50%) patients with overt hypothyroidism. Patients with CEPI-CT of more than 300 sec invariably had prolonged CADP-CT (mean, 197 sec; range, 131–300 sec), and 75% of those patients had vWF:RiCo deficiency.

Therapy with T4 increased vWF-Ag levels and vWF:RiCo (P < 0.05 vs. baseline) and tended to increase factor VIII (P = 0.06 vs. baseline). CEPI-CT was shortened compared with baseline (P < 0.01) (Fig. 3Go). Six of 30 patients with overt hypothyroidism had vWF deficiency, i.e. vWF-Ag or vWF:RiCo less than 60%. Mean CEPI-CT was 234 sec (range, 167–300 sec) in patients with vWF deficiency and 202 sec (range, 174–232 sec) in those without vWF deficiency (P = 0.34). Five of six patients with vWF-Ag deficiency had prolonged CEPI-CT and CADP-CT.


Figure 3
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  		FIG. 3. Effects of T4 on TSH concentration, CEPI-CT, and vWF-Ag levels in patients with overt hypothyroidism. Data are presented as mean and 95% confidence intervals.

 
In patients with subclinical hypothyroidism, baseline vWF-Ag and vWF:RiCo were not different from controls (P > 0.05). Factor VIII levels were slightly lower than in controls (P = 0.06). CEPI-CT was prolonged in comparison with controls (P = 0.01) (Fig. 1Go) indicating impaired platelet function in patients with hypothyroidism independent of vWF.

Correlations and multivariate analysis

CEPI-CT, vWF-Ag, vWF:RiCo, and factor VIII levels correlated well with T4, T3, TSH, and fT4 concentrations (P < 0.0001) (part of data shown in Fig. 4Go). CEPI-CT correlated negatively with vWF (r = –0.45; P < 0.0001) and ristocetin-cofactor (r = –0.68; P < 0.0001) and positively with CADP-CT (r = 0.61; P < 0.001). vWF correlated with factor VIII (r = 0.9; P < 0.0001) and T4 (r = 0.71; P < 0.0001).


Figure 4
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  		FIG. 4. Thyroid function (T4 levels) correlates with platelet function, vWF-Ag, and vWF:RiCo.

 
We performed a multiple regression analysis for those parameters that correlated best with CEPI-CT, i.e. vWF:RiCo (r = –0.68; P < 0.001) and T4 (r = –0.60; P < 0.001). The regression model suggested that both vWF:RiCo (ß = –0.19; SE = 0.09) and T4 (ß = –0.38; SE = 0.09) were independently associated with CEPI-CT (P < 0.05).

Blood counts and coagulation markers

There were no differences in baseline hematocrit, platelet counts, leukocyte counts, and prothrombin time between patient groups with different thyroid function (Table 1Go). Patients with overt hypothyroidism had longer activated partial thromboplastin time (aPTT) (P = 0.01; Table 1Go), which correlated with vWF levels or factor VIII (r = –0.48 and –0.55; P < 0.01, respectively).

In patients with hyperthyroidism hematocrit, platelet counts and leukocyte counts increased slightly during therapy with thiamazole (P < 0.05), whereas prothrombin time and aPTT remained unchanged. In patients with overt hypothyroidism hematocrit, platelet counts, leukocyte counts, prothrombin time, and aPTT did not change during therapy with T4 (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
This study shows for the first time that the hyperthyroidism-induced vWF elevation is associated with enhanced platelet function as measured by CEPI-CT. Although an untreated state of hyperthyroidism is a relatively short event because of the availability of effective treatments, recent evidence suggests that there may, in fact, be adverse outcomes. Long-term follow-up studies have revealed increased mortality from cardiovascular and cerebrovascular disease in those with a past history of overt hyperthyroidism (10) as well as in those with subclinical hyperthyroidism indicated by a low serum TSH concentration (11). An elevated serum fT3 concentration was associated with a 2.6-fold greater likelihood of the presence of a coronary event (12). Several studies have recently indicated that measurement of platelet function by PFA-100 may be predictive for clinical outcome. Shortened CEPI-CT was predictive for additional cardiovascular events in patients with previous acute coronary syndrome during an observation period of 2 yr (32). The platelet function assessed with PFA-100 correlated with corrected thrombolysis in myocardial infarction frame count, ST-segment resolution, and myocardial necrosis in patients with ST elevation myocardial infarction. At 1 yr, patients with shortened CEPI-CT showed an adjusted 5- to 11-fold increase in the risk of death, reinfarction, and target vessel revascularization (33). Therefore, our data showing enhanced platelet plug formation in patients with hyperthyroidism may provide an additional explanation for the increased cardiovascular risk and mortality (10) in hyperthyroidism.

Furthermore, acute cerebral ischemia has been described in hyperthyroidism independent of thyrotoxic atrial fibrillation and cardioembolic stroke (34). It is conceivable that the hyperthyroidism-induced platelet activation might also play a role in the development of acute cerebral ischemia. Correction of hyperthyroidism by thiamazole decreases platelet plug formation and leads to prolonged platelet plug formation time despite normal T4 levels (Fig. 2Go). In previous studies, increased fibrinogen, factors VIII and IX, vWF, antithrombin III, and plasminogen activator inhibitor-1 have been described in patients with hyperthyroidism (13, 35). In contrast, factor X and tissue plasminogen activator were decreased, indicating vascular endothelial dysfunction and decreased fibrinolytic activity in blood. In another study, treatment with thiamazole and propranolol also decreased vWF levels (36). However, changes in platelet function during therapy with thiamazole have not been investigated until now.

This is the first study investigating platelet function measured by PFA-100 in patients with thyroid dysfunction. Patients with overt hypothyroidism have low levels of vWF and prolonged CEPI-CT and CADP-CT. Consistent with previous reports (21), a substantial proportion of our patients with overt hypothyroidism (20%) had acquired vWD. The CEPI-CT prolongation was reversed during therapy with T4. Furthermore, T4 concentrations correlated well with PFA-100 results. The multiple regression analysis showed that both vWF:RiCo and T4 were independently associated with CEPI-CT. This indicates not only that the correlation between T4 and CEPI-CT is due to the vWF increase but also that T4 has a direct impact on intrinsic platelet function. This could explain why 56% of our patients with overt hypothyroidism had prolonged CEPI-CT despite the fact that only 20% had vWF deficiency. Therefore, the PFA-100 could help to detect disorders in primary hemostasis induced by thyroid dysfunctions. In our study, we measured the platelet function during therapy of hypothyroidism after 3 months. Because the patients had a mean TSH that was still slightly elevated, longer treatment could possibly have additional effects on platelet function and could possibly lead to normalization of CEPI-CT in hypothyroid patients. In patients with hyperthyroidism, platelet function was measured over a period of 30 wk; in this period, T4 levels returned to normal values. Only one study investigated platelet function measured by PFA-100 in patients with thyroid diseases. However, this study was performed only in euthyroid patients; 2.8% of patients had prolonged CEPI-CT, in most cases due to vWD (37).

The reason that we chose the FDA-approved PFA-100 for our study is that the PFA-100 test has several advantages for the assessment of platelet function; it is well reproducible, robust, and rapid and has a low per-test cost. There is no gold-standard laboratory test for assessing platelet function, and each platelet function test may have certain advantages. The PFA-100 is FDA approved to detect platelet dysfunction, vWD, and aspirin-induced platelet inhibition. PFA-100 measures platelet function under high shear stress in whole blood, which mirrors the physiological conditions in the arteries. Recently, a number of publications have consistently shown the predictive value of PFA-100 measurements for outcome in cardiovascular diseases (19, 32, 33).

Our study has some clinical implications. Patients with subclinical hypothyroidism have longer platelet plug formation times than controls with euthyroidism. Aggregation of platelets at the site of plaque rupture has been implicated in the pathogenesis of atherosclerosis. The prolongation of CEPI-CT that is associated with subclinical hypothyroidism could possibly protect against atherosclerosis. This could explain why very old individuals with elevated levels of TSH have a better survival than patients with normal TSH levels (38). This hypothesis needs to be substantiated in additional studies. Furthermore, hypothyroidism was shown as a protective factor in acute stroke patients (39). On the contrary, subclinical hypothyroidism was shown as an independent risk factor for atherosclerosis, myocardial infarction, and coronary heart disease (40, 41). In another study, elevated TSH was associated with ischemic heart disease and increased mortality in men but not in women (42).

The decrease of vWF in hypothyroidism is generally explained by a decrease in protein synthesis (6). The reversal of vWD after thyroid hormone replacement could be the result of two effects: an increased release of vWF from endothelial cells due to increased sensitivity to epinephrine after thyroid hormone therapy and/or a nonspecific stimulation of hepatic protein synthesis by thyroid hormone. The pathogenic mechanisms of hyperthyroidism-induced vWF elevation are unknown. Administration of propranolol, a specific blocker of ß-adrenergic receptors, to hyperthyroid patients returned plasma vWF levels to the normal range, indicating that the elevation of plasma vWF by thyroid hormone could, at least in part, be mediated through ß-adrenergic receptors (36).

In our study, the number of patients with autoimmune disease far exceeds the number of patients with non-autoimmune thyroid dysfunction. Nonetheless, it is rather unlikely that autoimmunity affected platelet function in our study, because platelet function changed after therapy of thyroid dysfunction, although this therapy does not affect the autoimmune process. In addition, autoimmunity did not lead to abnormal platelet counts, which excluded relevant antiplatelet antibodies.

It is noteworthy that the PFA-100 has initially been developed to detect vWF deficiency. This explains why it is very sensitive to low vWF levels. Hence, a 50% reduction in vWF levels from normal 100% to 50% may increase closure time values from 100 to 300 sec (27). In contrast, an increase in vWF levels by 200–300% either in patients with myocardial infarction or after stimulation with desmopressin or endotoxin may reduce CEPI-CT by only 20–40% (19, 43, 44). This explains the fairly prolonged CEPI-CT associated with the moderately decreased vWF levels in patients with hypothyroidism and the minor shortening of CEPI-CT associated with the major increase in VWF levels in patients with hyperthyroidism.

In conclusion, PFA-100 can detect patients who are suffering from acquired vWD due to hypothyroidism. The hyperthyroidism-induced vWF elevation is associated with enhanced platelet function and therefore shortened CEPI-CT values. These changes may contribute to the higher risk for cardiovascular disease in patients with hyperthyroidism. Platelet plug formation, a predictor of cardiovascular risk, decreases during normalization of thyroid function induced by therapy with thiamazole.


   Footnotes
 
Disclosure Statement: The authors have nothing to disclose.

First Published Online May 8, 2007

Abbreviations: aPTT, Activated partial thromboplastin time; CADP, collagen/ADP; CEPI, collagen/epinephrine; CT, closure time; fT4, free T4; vWD, von Willebrand disease; vWF, von Willebrand factor; vWF-Ag, vWF antigen; vWF:RiCo, vWF ristocetin-cofactor activity.

Received November 30, 2006.

Accepted May 1, 2007.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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