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ORIGINAL ARTICLE
Year : 2023 | Volume
: 22
| Issue : 2 | Page : 183-188
Association between hyperthyroidism and thromboembolism: A retrospective observational study
Aseel Awad Alsaidan1, Fahad Alruwiali2
1 Department of Family and Community Medicine, College of Medicine, Jouf University, Sakaka 72388, Saudi Arabia
2 Department of Family Medicine, Ministry of Health, Aljawf, Saudi Arabia
Correspondence Address:
Aseel Awad Alsaidan
Department of Family and Community Medicine, Jouf University, Domat Aljandal, Al Jawf
Saudi Arabia
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/aam.aam_105_22
Abstract
Background: Thyroid gland diseases are a common health problem worldwide. Increase of thyroid gland hormones can cause numerous conditions that range from mild cases to life-threatening diseases. Hyperthyroidism is not a common risk factor for venous thrombosis (VT), many studies found a relation between hyperthyroidism and thromboembolism. Objectives: We sought to detect any changes in thyroid-stimulating hormone (TSH), and free T4 value associated with the occurrence of Deep vein thrombosis (DVT), pulmonary embolism (PE), and cerebral VT. Methodology: An observational retrospective review of outpatients' records in King Abdulaziz Medical City in Riyadh from January 2018 to March 2020 includes all patients with hyperthyroidism, patients who are bedridden, recent surgeries, and those on oral contraceptives pills or on anticoagulants were excluded from the study. All symptomatic VT cases are objectively confirmed. Results: Three hundred patients were recognized, of whom most were female (80%), whereas (20%) were male, mean age in identified patients was (42.3 ± 14.5 years; range, 18–80 years). Of all patients, 3 (1%) patients had DVTs, equally 3 (1%) patients had PE, and 2 (0.7%) patients had cerebral embolism. TSH level has a significant association with the overall risk of DVT, PE, and cerebral embolism. In the FT4 level, there was a significant association with the risk of DVT and PE but not with cerebral embolism. Conclusions: The literature indicates a significantly associated between the development of VT and hyperthyroidism. Furthermore, the data support that hyperthyroidism is considered an additional risk factor for VT.
Abstract in French Résumé
Contexte: Les maladies de la glande thyroïde sont un problème de santé courant dans le monde entier. L'augmentation des hormones de la glande thyroïde peut causer de nombreux des conditions allant des cas bénins aux maladies potentiellement mortelles. L'hyperthyroïdie n'est pas un facteur de risque courant de thrombose veineuse (TV), de nombreux des études ont trouvé une relation entre l'hyperthyroïdie et la thromboembolie. Objectifs: Nous avons cherché à détecter tout changement dans la stimulation de la thyroïde (TSH) et la valeur de T4 libre associée à la survenue d'une thrombose veineuse profonde (TVP), d'une embolie pulmonaire (EP) et d'une TV cérébrale. Méthodologie: Un examen rétrospectif observationnel des dossiers des patients ambulatoires dans la King Abdulaziz Medical City à Riyad de janvier 2018 à Mars 2020 inclut tous les patients atteints d'hyperthyroïdie, les patients alités, les interventions chirurgicales récentes et ceux qui prennent des pilules contraceptives orales ou. sous anticoagulants ont été exclus de l'étude. Tous les cas de TV symptomatiques sont objectivement confirmés. Résultats: Trois cents patients ont été reconnus, dont la plupart étaient des femmes (80 %), alors que (20 %) étaient des hommes, l'âge moyen des patients identifiés était de (42,3 ± 14,5 ans ; intervalle, 18-80 ans). De tous les patients, 3 (1%) patients avaient une TVP, également 3 (1%) patients avaient une EP et 2 (0,7%) patients avaient une embolie cérébrale. TSH a une association significative avec le risque global de TVP, d'EP et d'embolie cérébrale. Au niveau FT4, il y avait une association significative avec le risque de TVP et d'EP mais pas d'embolie cérébrale. Conclusions: La littérature indique une association significative entre la développement de la TV et de l'hyperthyroïdie. De plus, les données confirment que l'hyperthyroïdie est considérée comme un facteur de risque supplémentaire de TV.
Mots-clés: Hyperthyroïdie, embolie pulmonaire, thrombose veineuse
Keywords: Hyperthyroidism, pulmonary embolism, venous thrombosis
Introduction 
Thyroid gland diseases are a common health problem worldwide. Dysregulation of thyroid gland hormones can cause numerous conditions that range from mild cases to life-threatening diseases. Define hyperthyroidism as an increase in the synthesis and secretion of thyroid hormone from the thyroid gland, and Graves' disease is the leading cause of hyperthyroidism, followed by toxic nodular goiter.[1] The majority of thyroid diseases are affected by ethnicity and geographical location along with the age, sex, and iodine intake of the different populations.[2] Thyroid disease is markedly increasing in the general population. The prevalence of hyperthyroidism was 1.3% in the USA and 0.8% in Europe.[3] One of the important physiological roles of the thyroid is hematopoiesis, this process occurs in the bone marrow under the effect of the thyroid hormones. Hence, the effect of thyroid disturbance and abnormalities in hematological parameters is well known.[4] The term of venous thromboembolism (VTE) is used for pulmonary embolism (PE) and deep-vein thrombosis (DVT). It is the third-most common cardiovascular disease (CVD), and it is associated with complications and a potentially fatal outcome. A hypercoagulable state has been related to both hyperthyroidism and subclinical cases, as well as overt and moderate hypothyroidism. A relationship has also been reported between thyroid dysfunction and arterial CVDs.[5] The effect of thyroid function on DVT risk has not been extensively investigated. Many case-control and case reportss support a relationship between hyperthyroidism and VT. Reversible increase of von Willebrand factor (vWF) and factor VIII with Prothrombotic changes in the coagulation pathway in a thyrotoxic state give biological probability to the association and possibly causation for VT.[6],[7] Furthermore, a prospective cohort study was conducted on a patient who was taking thyroxine as a treatment and the study found a significant increase in the hypercoagulation factors such as fibrinogen, vWF, factor VIII, plasminogen activator inhibitor, and other factors will have a significant association with hypercoagulation, and this will increase the risk of deep vein thrombosis (DVT) even in the mild cases.[8] A prospective cohort study was performed and found a strong risk factor for VT was FT4 level at the upper end of the normal range. Furthermore, the risk increased with more increased levels of thyroxine and a shorter time between blood samples and thrombosis.[9] Usually, studies in Saudi Arabia concentrates on the incidence of thyroid dysfunction, especially in female but not on the effect of the thyroid dysfunction on the different organs. The important systems that will be affected are the hematological and reproductive systems. Furthermore, these systems if it affects the outcome of this abnormality and can we manage these complications or not, sometimes the affection may be fatal even in a mild case, especially if the patient has other risk factors for hematological disease. This study aimed to detect the relationship between hyperthyroidism and VT.
Objectives
We sought to detect any changes in thyroid-stimulating hormone (TSH), and free T4 value associated with the occurrence of DVT, PE, and cerebral VT.
Methodology Study design
An observational, retrospective chart review was conducted in King Abdulaziz medical city in Riyadh between January 2018 and March 2020. After the approval of this study which obtained from King Abdullah International Medical Research Center (KAIMRC), the confidentiality of data and ethical issues was considered and used only for research purposes. We review the medical records of all patients who are diagnosed with hyperthyroidism, the same patient diagnosed with hyperthyroidism we follow them through chest computed tomography (CT), brain CT, and limb ultrasound for 2 years. The study included all adult patients diagnosed with hyperthyroidism between January 2018 and March 2020. Bedridden patients, recent surgery, patient on oral contraceptives pill (OCP), and patients on anticoagulation were excluded from the study. The planned total sample size of 166 patients was based on a confidence interval of 95%, power of 80%, the ratio of controls to cases of 1% of controls exposed 1,[1] the odds ratio of 13.[5] we calculate the sample size using openEpi epidemiologic calculator. The calculator can be accessed freely online. Sampling methods: data collection sheet developed by researcher after literature review. And reviewed by the principal investigator. The data collection sheet was completed from the electronic medical records in the best care system.
Data collection tool and variables
Review all the hospital records of the patients and the data were obtained from the record included demographic data (age and sex), clinical characteristics (body mass index), history of chronic disease (diabetes mellitus [DM], hypertension, CVD, and cerebrovascular accidents), drug history (thyroxine, antithyroid drug, OCP, and anticoagulants), and past medical history (DVT, PE, cerebral VT). The last part was included the thyroid function test (TSH and FT4).
Statistical methods
Statistical Package for the Social Sciences (SPSS) version 20.0 (IBM, SPSS Inc, Armonk, New York, USA) software was used to enter and analyze all the data. Continuous variables were reported in terms of mean and standard deviation. Categorical variables were described using frequencies and percentages. Comparison of means was done using t-test. Compare the proportions of continuous with multiple items of continuous use paired Y (repeated measures) test. A P < 0.05 is statistically significant.
Results Among the 300 cases, there were 60 (20%) men and 240 (80%) women. The mean age was (42 and 3 years; range standard deviation, 18–80 years). Of all patients with DVT three cases (1%), PE 3 (1%) cases, and cerebral embolism one case (0.7%). Baseline characteristics for cases are summarized in [Table 1]. Mean of BMI of the patients was 29.62 (STD ±6.5). Minimum of TSH level was 0.01 and maximum 0.32 and mean was 0.034, and mean of T4 was 25.5 as show in [Table 2].
Table 1: Frequency and percentage of the sociodemographic data and medical history of the study sample
Table 2: Mean, standard deviation, maximum, and minimum of study sample age, body mass index, thyroid-stimulating hormone, free thyroxineThyroid-stimulating hormone, FT4 and risk of venous thrombosis
The mean TSH in all patients with DVT was (0.0100), PE was (0.0133), and cerebral embolism was (0.0100). The mean FT4 in all patients with DVT, PE, and cerebral embolism was 39, 23.66, and 32, respectively. TSH levels were significantly associated with the overall risk of DVT, PE, and cerebral embolism. FT4 levels were significantly associated with the risk of DVT, and PE but not associated with cerebral embolism [Table 3]. The risk of developed VT was almost 1 fold increased for cases with a mild-to-moderate elevation of TSH and FT4, whereas 2 fold increased for cases with severe elevation of TSH and FT4.
Table 3: Association between hypertension, diabetes, medication like thyroxine, and antithyroid drug as a risk for developing deep vein thrombosisComorbid disease, drugs, and the risk for the development of venous thromboembolism
Statistically no significant difference between hypertension, diabetes, and use of the thyroid dysfunction drugs with the risk for developing VTE events as shown in [Table 4], [Table 5], [Table 6].
Table 4: Association between hypertension, diabetes, medication like thyroxine, and antithyroid drug as a risk for developing pulmonary embolism
Table 5: Association between hypertension, diabetes, medication like thyroxine, and antithyroid drug as a risk for developing cerebral embolism
Table 6: The mean and P value of the thyroid-stimulating hormone and free thyroxine for the cases who have deep vein thrombosis, pulmonary embolism, and cerebral embolism Discussion Patients with overt hyperthyroidism have reported abnormality in the coagulation system, which causes a hypercoagulable state.[10],[11],[12],[13],[14],[15],[16] Many possible pathways have been suggested to describe this association, but no clear pathological mechanism shows an association between coagulation abnormality and hyperthyroidism. Raised thyroid hormones may increase the synthesis or secretion of coagulation factors[17] or may decrease fibrinolysis. Previous studies found an association between hypercoagulation disorders and hyperthyroidism, including a decreased level of protein S[18] or antithrombin III,[18],[19] and high levels of vWF,[6],[8] factor VIII,[6],[20] factor IX,[6] and plasminogen activator inhibitor-1 (PAI-1).[21],[22] During the last few years, a variant of genetic or acquired factors identified as a risk factor for VT. The estimated effects of each vary widely. To describe, thrombosis risk after hospital admission increases by 8–11 fold and the risk after surgery increases by 6–15 fold, in pregnancy the VT risk is 1–5 fold increased, whereas in puerperium 14–60 fold, also in women using OCPs the risk is increase by 1.4–5 fold, and risk increased in heterozygotes of factor V Leiden by 3–8 fold.[21],[22],[23] The current analysis is the first to study the effects of thyroid disorders on venous thromboembolism in Saudi Arabia. In this observational retrospective study of patients with hyperthyroidism, we found a significant association between increase level of thyroid hormone and the development of VT events. Our findings in constant with other research, in 2016, Lerstad et al. found that cases with high TSH had slightly more increased risk estimates for VTE than did cases with normal TSH.[24] In contrast, the experimental studies[25],[26],[27] documented that high TSH levels with normal FT4 have no effect on hemostatic parameters and that the influence on the coagulation system is mostly mediated by FT4. In the literature review, no evidence found an association between mean FT4 and cerebral embolism. In contrast to other research, hyperthyroidism has associated with cerebral venous thromboembolism in multiple case reports, and high levels of factor VIII and vWF have been proposed as the possible link in this association, but only a few rare research and case reports have shown an association of hypothyroidism with cerebral venous thromboembolism. Hypothyroidism increases the incidence of cerebral embolism through several pathways such as procoagulant by decreasing fibrinolysis.[28] Increased level of plasma thrombin-activatable fibrinolysis inhibitor was monitored with patients who have mild or overt hypothyroidism, and the level decreased after treatment used with levothyroxine,[29] also affects venous flow, which slows and leads to endothelial injury. A registry-based study[30] of 19,519,000 participants revealed no association between VTE and hyperthyroidism, although the risk of VTE was increased in patients with hypothyroid by 1.6 fold determined by diagnosis codes. Furthermore, the risk of developing lethal PE was reported in the case of hypothyroidism, not hyperthyroidism; in 2015, Hostiuc et al.[31] the reported death of two cases of young patients who have a low level of thyroid hormones and increased thromboembolism status with pulmonary thromboembolism and VT. In the current study, there was no statistically significant difference between diabetes, hypertension, and the use of thyroid dysfunction drugs with the risk of developing VTE events. Studies revealed that there is a different factor that can be significantly contributing to the development of VTE. Hypertension is one of these factors, and its association with the development of VTE is a controversial issue found in many researches. Some studies clarified that hypertension might increase the risk of VTE occurrence.[32],[33] On the other hand, there are other studies revealed that there was no statistically significant association between hypertension and the development of VTE.[34],[35] Our finding was no statically significant association between hypertension and increase risk of VTE. DM has been considered a risk factor for developing of venous thromboembolism (VTE). A meta-analysis study supports a very low or no association of DM with VTE risk in the general population. DM is not like to play a significant role in VTE development.[36] The current study revealed no significant association between DM and the development of VTE. Actually, the clear association between thyroid dysfunction and the development of VT was not clear. This study considers to be the first study that assesses the risk of developed VTE in a known patient of hyperthyroidism, and this is a strong point for us but we also need to assess the risk of VTE in hypothyroidism patients, and in the end, we can detect the patients who will be more risk to develop the thromboembolic disease.
Limitation
The study focuses only on the relation between hyperthyroid and VT; further studies on other vascular diseases and hypothyroid remain to be seen. Furthermore, this study was conducted only in one tertiary hospital, and expanded medical centers are recommended for more sample size.
Conclusion Results data suggest that increased levels of thyroid hormones consider a risk factor for the development of VTE. More studies are needed to widen our knowledge on this topic and to assess whether the implementation and monitoring of these risk factors in practice lead to improving our ability to prevent and manage VTE by reducing its risks. Further insights into the clinical relevance of our result data could be obtained by assessing the association between levels of thyroid hormone and VT in high-risk patients.
Recommendation
Increased awareness of thyroid disorder even the subclinical cases in clinical practice, may decrease mortality and disability, which may result from the thromboembolic disease. Furthermore, it would be interesting to investigate and detect at which level the risk of VTE will be increase.
Ethical approval
The approval of this study was obtained from KAIMRC. Data confidentiality and ethical issues were considered and used only for research purposes. We review the medical records of all patients diagnosed with hyperthyroidism; for the same patient diagnosed with hyperthyroidism, we follow them through chest CT, brain CT, and limbs ultrasound for 2 years.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References 
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