Abstract
Purpose
Aberrant thyroid function causes dysregulated metabolic homeostasis. Literature has demonstrated hypercoagulability in hypothyroidism, suggesting a risk for thromboembolic events (TEE). We hypothesize that individuals with hypothyroidism will experience more clinically-diagnosed TEE than euthyroid individuals.
Methods
De-identified patient data from the University of New Mexico Health Sciences Center were retrieved using thyrotropin (TSH; thyroid-stimulating hormone) for case-finding from 2005 to 2007 and ICD billing codes to identify TEE during the follow-up period of 10 to 12 years. Diagnoses affecting coagulation were excluded and 12 109 unique enrollees were categorized according to TSH concentration as Hyperthyroid (n = 510), Euthyroid (n = 9867), Subclinical Hypothyroid (n = 1405), or Overtly Hypothyroid (n = 327). Analysis with multiple logistic regression provided the odds of TEE while adjusting for covariates.
Results
There were 228 TEEs in the cohort over 5.1 ± 4.3 years of follow-up. Risk of TEE varied significantly across study groups while adjusting for sex, race/ethnicity, levothyroxine, oral contraceptive therapy, and visit status (outpatient vs non-outpatient), and this risk was modified by age. Overt Hypothyroidism conferred a significantly higher risk of TEE than Euthyroidism below age 35, and Hyperthyroidism conferred an increased risk for TEE at age 20. Analysis also demonstrated a higher age-controlled risk for a subsequent TEE in men compared with women (odds ratio [OR] = 1.36; 95% confidence interval [CI], 1.02–1.81). Subanalysis of smoking status (n = 5068, 86 TEE) demonstrated that smokers have 2.21-fold higher odds of TEE relative to nonsmokers (95% CI, 1.41–3.45).
Conclusions
In this retrospective cohort study, Overt Hypothyroidism conferred increased risk of TEE over the next decade for individuals younger than 35 years of age, as compared with Euthyroidism.
Keywords: Hypothyroidism, subclinical hypothyroidism, euthyroid, hyperthyroidism, thromboembolic events
Hypothyroidism is known to cause fatigue, myalgia, weight gain, cold intolerance, and in severe cases, myxedema with or without coma (1). As such, the condition is a significant cause of morbidity and rare mortality in the United States, with 0.3% of the population affected by overt hypothyroidism and 4.3% affected by subclinical hypothyroidism (1). Recently, the effect of thyroid function on blood clotting has become a subject of investigation due to the potential risk of bleeding or thromboembolic events (TEE). A 2017 meta-analysis by Ordookhani and Burman found that laboratory parameters of patients with hypothyroidism suggested variable effects on coagulation status based on the severity of disease. Severe hypothyroidism was associated with lower platelet counts, lower platelet activity, and lower coagulation factor concentrations, suggesting a possible hypocoagulable state (2). Conversely, moderate hypothyroidism was associated with markers of decreased fibrinolysis, including lower D-dimer and increased alpha-2-antiplasmin and plasminogen activator inhibitor-1 compared with the euthyroid state (2). Additional studies have also described a normalization of selected coagulation parameters with thyroid hormone replacement therapy (3). Nevertheless, despite evidence indicating the possibility of altered clotting function in patients with thyroid dysfunction, the clinical health risk of hypothyroidism relative to hemostasis has not been established. Investigation into a possible link between hypothyroidism and clinically significant TEE is necessary because it represents a potentially modifiable risk factor for vascular compromise. As such, we hypothesize that individuals with a history of hypothyroidism will experience more clinically diagnosed venous or arterial TEE over subsequent years than those who have normal thyroid function.
Methods
Study subjects
Adult study patients who had a serum thyrotropin (TSH; thyroid-stimulating hormone) concentration determined during the index period of 2005–2007 were identified from the University of New Mexico Health Sciences Center (UNM HSC) PowerInsight electronic medical records database. We used only a single TSH to define the study cohorts. For patients with more than one TSH measurement drawn in the index period, we used the earliest available result for classification purposes. The resulting dataset was queried for subsequent venous or arterial TEE over 10 to 12 years of follow-up using relevant ICD-9 and ICD-10 codes for the years 2005–2017. PowerInsight is the institutional database of de-identified Electronic Health Records for all patients served by the UNM Healthcare System, comprising unique visits from approximately half of the population of New Mexico. This retrospective, de-identified data study was deemed exempt from the necessity of obtaining informed consent by the UNM HSC Human Research Review Committee.
Study protocol
ICD-9 and ICD-10 billing codes were used to identify venous, arterial, and dural thromboembolic disease diagnosed in either inpatient or outpatient encounters. Exclusion criteria were employed using ICD-9 and ICD-10 billing codes to eliminate diagnoses known to affect the coagulation cascade, including inherited or acquired thrombophilia, inherited or acquired coagulopathy, septic emboli, and pituitary gland disease. The diagnostic codes employed in this study are provided in Reference (4).
Data collected for each patient included age, sex, race, ethnicity, weight, visit status (inpatient or outpatient), smoking status, medications used during the index period (including oral contraceptives, antiplatelet, anticoagulant, and levothyroxine therapy), and TSH and free thyroxine (FT4) concentrations. Data were collected during the index period from 2005–2007. All subsequent TSH and FT4 concentrations were also collected during the follow-up period.
Cohort definitions
The Overt Hypothyroidism cohort included all patients with a TSH ≥ 10.00 μIU/L during the index period. The Subclinical Hypothyroidism cohort included all patients with a TSH level of 3.80 to 9.90 μIU/L during the index period. The Euthyroid control cohort included all patients with a TSH of 0.36 to 3.70 μIU/L (inclusive) during the index period. The Hyperthyroidism cohort included all patients with a TSH < 0.36 μIU/L during the index period.
Statistical analysis
The Fisher-Exact Test was used to compare the frequency of diagnosed TEE in each of the 4 stratified thyroid function cohorts. Continuous variables were compared using the Kruskal–Wallis Test, when appropriate. Multiple logistic regression analysis was also performed, and the odds of TEE for Overt Hypothyroidism and Hyperthyroidism as compared with the Euthyroid cohort were reported while adjusting for baseline age, sex, race/ethnicity, levothyroxine, oral contraceptive therapy, and visit status. In subanalyses, we have also adjusted for smoking status, and weight. Results are reported as the odds ratio (OR) for occurrence of TEE with 95% confidence intervals (CI). In all models, area under the Receiver Operating Characteristic curves was approximately 0.80, indicating acceptable accuracy and robustness of the models. All analyses were performed using SAS Version 9.4 (SAS Institute, Cary, NC).
Results
The initial query of the index period identified 20 736 unique individuals with a TSH concentration recorded during 2005–2007. Application of the exclusion criteria disqualified 8627 patients due to a documented condition known to affect the coagulation cascade, so that 12 109 unique individuals who met study criteria were included in the final analysis over the follow-up period of 10 to 12 years, ending in 2017.
The Hyperthyroid cohort comprised 510 unique individuals, the Euthyroid cohort comprised 9867 unique individuals, the Subclinical Hypothyroidism cohort comprised 1405 unique individuals, and the Overt Hypothyroidism cohort comprised 327 unique individuals. Descriptive characteristics of the cohorts are depicted in Table 1. There were statistically significant differences with respect to age, weight, sex distribution, visit status, levothyroxine therapy, and race/ethnicity between the study groups at baseline.
Table 1.
Descriptive Characteristics of the Study Cohorts
| Hyperthyroid | Euthyroid | Subclinical Hypothyroid | Overt Hypothyroid | P valuec | |
|---|---|---|---|---|---|
| Individuals, n (%) a | 510 (4.2) | 9867 (81.5) | 1405 (11.6) | 327 (2.7) | <0.0001 |
| Outpatient status, n (%) b | 359 (70.4) | 7797 (79.0) | 1031 (73.4) | 235 (71.9) | <0.0001 |
| Age, years | 37.1 ± 8.8 | 35.8 ± 9.1 | 37.0 ± 8.9 | 37.6 ± 9.0 | <0.0001 |
| Weight, kg | 74.9 ± 19.2 | 80.4 ± 22.8 | 85.1 ± 25.5 | 82.3 ± 24.2 | <0.0001 |
| Female, n (%) b | 365 (71.6) | 6129 (62.1) | 919 (65.4) | 221 (67.6) | <0.0001 |
| Smoker, n (%) b | 49 (30.2) | 1193 (28.0) | 129 (24.4) | 32 (28.6) | 0.29 |
| Using OCP, n (%) b | 63 (12.4) | 1318 (13.4) | 168 (12.0) | 39 (11.9) | 0.44 |
| Patients receiving anticoagulants, n (%) b | 20 (3.9) | 281 (2.9) | 52 (3.7) | 12 (3.7) | 0.14 |
| Patients receiving antiplatelet agents, n (%) b | 21 (4.1) | 533 (5.4) | 84 (6.0) | 18 (5.5) | 0.46 |
| Patients receiving levothyroxine, n (%) b | 161 (31.6) | 823 (8.3) | 577 (41.1) | 274 (83.8) | <0.001 |
| Race/ethnicity, n (%) b | NHC 166 (32.6) | NHC 3692 (37.4) | NHC 581 (41.4) | NHC 107 (32.7) | <0.0001 |
| Hispanic 205 (40.2) | Hispanic 3873 (39.3) | Hispanic 520 (37.0) | Hispanic 152 (46.5) | ||
| Native 40 (7.8) | Native 356 (3.6) | Native 64 (4.6) | Native 15 (4.6) | ||
| Black 19 (3.7) | Black 383 (3.9) | Black 41 (2.9) | Black 2 (0.6) | ||
| Asian 12 (2.4) | Asian 274 (2.8) | Asian 25 (1.8) | Asian 7 (2.1) | ||
| Unknown 68 (13.3) | Unknown 1289 (13.1) | Unknown 174 (12.4) | Unknown 44 (13.5) | ||
| TEE events during follow-up, n (%) b (total n = 228) | 10 (2.0) | 175 (1.8) | 31 (2.2) | 12 (3.7) | 0.08 |
Abbreviations: NHC, non-Hispanic Caucasian; OCP, oral contraceptive pills; TEE, thromboembolic events.
a% = Row Percentage
b% = Column Percentage
cThe Kruskal–Wallis Test was used to determine the difference between the groups for continuous variables and the Fisher-Exact test was used to determine the association between categorical variables.
There were 228 individuals who experienced at least one TEE over an average of 5.1 ± 4.3 years of follow-up among the 12 109 unique individuals analyzed. The number of observed TEEs per individual who suffered a TEE in each study group during the follow-up period did not differ significantly (P = 0.13).
Mean thyroid function test results for each cohort are depicted in Table 2. Patients had from 1 to 41 TSH values drawn within a year of their TEE, with a mean of 3 ± 6 values determined for each patient. The principal finding of the analysis was that the risk of TEE in the Overt Hypothyroidism cohort is age-dependent and increased as compared with the Euthyroid cohort while adjusting for sex. As shown in Table 3, for adults aged 20 to 35 years, there was a statistically significant increase in the odds of having a TEE, and the risk was inversely associated with age. The highest risk was seen in patients aged 20 years (OR = 11.14; 95% CI, 1.63–76.34), and the lowest statistically significant OR was observed in patients aged 35 years (OR = 2.67; 95% CI, 1.10–6.48). At age 40, there was no difference in the risk of TEE between the Overt Hypothyroid and Euthyroid groups (OR = 1.66; 95% CI, 0.83–3.31). After age 50, Overt Hypothyroidism was associated with a statistically insignificant decrease in risk of TEE. Parenthetically, Hyperthyroidism was also found to be associated with subsequent TEE in individuals aged 20 years while adjusting for the same variables (OR = 7.55; 95% CI, 1.05–54.48).
Table 2.
Mean Thyroid Function Test Results for Each Cohort at Baseline and Surrounding the Occurrence of 228 Total TEEs
| Hyperthyroid | Euthyroid | Subclinical Hypothyroidism | Overt Hypothyroidism | ||||||
|---|---|---|---|---|---|---|---|---|---|
| TSHf (μIU/mL) | Free T4f (ng/dL) | TSHf (μIU/mL) | Free T4f (ng/dL) | TSHf (μIU/mL) | Free T4f (ng/dL) | TSHf (μIU/mL) | Free T4f (ng/dL) | P valuee | |
| Baseline Index Period 2005 - 2007 | |||||||||
| Group n (%) a | 510 (4.2) | 9867 (81.5) | 1405 (11.6) | 327 (2.7) | |||||
| Mean ± SD | 0.12 ± 0.12 | 1.68 ± 1.32 | 1.73 ± 0.81 | 1.28 ± 0.26 | 5.30 ± 1.52 | 1.27 ± 0.30 | 53.83 ± 85.67 | 1.01 ± 0.73 | <0.001 |
| Sample n (%) b | 510 (100) | 68 (13) | 9867 (100) | 443 (4) | 1405 (100) | 111 (8) | 327 (100) | 46 (14) | |
| In Temporal Proximity to 228 TEEs | |||||||||
| Group n (%) a | 10 (2.0) | 175 (1.8) | 31 (2.2) | 12 (3.7) | 0.08 | ||||
| Mean ± SD | 0.57 ± 0.71 | 1.46 ± 1.79 | 2.02 ± 3.27 | 1.17 ± 0.51 | 6.56 ± 14.61 | 1.05 ± 0.33 | 22.36 ± 32.52 | 1.14 ± 0.70 | <0.001 |
| Sample n (%) c | 10 (100) | 8 (80) | 175 (100) | 82 (47) | 31 (100) | 16 (52) | 12 (100) | 8 (67) | |
| Time interval between index and TEE, years | 3.8 ± 3.8 | 5.3 ± 4.3 | 5.2 ± 4.1 | 3.1 ± 4.4 | 0.22 | ||||
| Time interval between TEE and nearest TSH, days d | 79 ± 118 | 69 ± 94 | 32 ± 67 | 58 ± 102 | 0.02 | ||||
| Patients receiving levothyroxine at TEE, n (%) c | 2 (20) | 26 (15) | 14 (45) | 11 (92) | <0.001 |
Abbreviations: SD, standard deviation; T4, thyroxine; TEE, thromboembolic events; TSH, thyrotropin (thyroid stimulating hormone).
a% = Row Percentage
b% = Column Percentage
c% = Column Percentage with TEE as the denominator
d“Time Interval between TEE and Nearest TSH (days)” was restricted to results available within 365 days of TEE.
eThe Kruskal–Wallis Test was used to determine the difference between the groups for continuous variables and the Fisher-Exact test was used to determine the association between categorical variables.
fReference Ranges: TSH = 0.36–3.7 μIU/mL, Free T4 = 0.7–1.6 ng/dL
Table 3.
Odds Ratios for Risk for a Thromboembolic Event Among the Overt Hypothyroid Cohort as Compared With the Euthyroid Cohort by Age Group
| Age at Time of Classification | OR for TEE (95% CI) | P value |
|---|---|---|
| 20 years | 11.14 (1.63–76.34) | 0.014 |
| 25 years | 6.92 (1.47–32.58) | 0.014 |
| 30 years | 4.30 (1.30–14.20) | 0.017 |
| 35 years | 2.67 (1.10–6.48) | 0.030 |
| 40 years | 1.66 (0.83–3.31) | 0.151 |
| 45 years | 1.03 (0.51–2.09) | 0.934 |
| 50 years | 0.64 (0.25–1.61) | 0.344 |
| 55 years | 0.40 (0.12–1.38) | 0.145 |
| 60 years | 0.25 (0.05–1.22) | 0.087 |
Abbreviations: CI, confidence interval, OR, odds ratio.
Secondary findings of the analysis included a statistically significant increase in risk for TEE in males as compared with females that was independent of age (OR = 1.36; 95% CI, 1.02–1.81). Hispanic ethnicity was associated with an increased occurrence of TEE, compared with other ethnicities (OR = 1.47; 95% CI, 1.01–2.13), as was levothyroxine therapy (OR = 1.51; 95% CI, 1.04–2.18). Outpatient visit status was associated with a lower risk of TEE compared with inpatient visit status (OR = 0.42; 95% CI, 0.32–0.56). Additionally, a subanalysis of patients with available data for smoking status (n = 5068, 86 TEEs) demonstrated that individuals who smoke cigarettes had significantly higher odds of experiencing TEE as compared with nonsmokers (OR = 2.21; 95% CI, 1.41–3.45) while adjusting for the same variables. Similarly, a subanalysis of patients with available data for weight (n = 6567, 104 TEEs) demonstrated that individuals who weighed at least 90.7 kg (200 lbs) had significantly higher odds of experiencing TEE compared with those who weighed less than 90.72 kg (OR = 1.70; 95% CI, 1.32–2.55) while adjusting for the same variables.
As shown in Table 2, The interval between the index period and the occurrence of subsequent TEEs varied from 58 ± 102 to 505 ± 1108 days between the groups, but this difference was not statistically significant (P = 0.22). TSH concentrations recorded during the index period and used to assign individuals to the study groups were predictive of future thyroid function during the 10-year follow-up period. Thyroid function tests drawn in temporal proximity (± 365 days) to the occurrence of the TEEs were significantly different among the 4 study groups (P < 0.001), with TSH concentrations being lowest in the Hyperthyroid cohort and highest in the Overt Hyporthyroid cohort. The mean interval between the occurrence of a TEE and the nearest thyroid function tests was less than 80 days in all 4 study groups.
Discussion
This retrospective cohort study demonstrates that young adults with hypothyroidism have higher odds of experiencing a subsequently diagnosed TEE over the ensuing 10 to 12 years. These results suggest that individuals aged 35 years or younger with inadequately or untreated hypothyroidism should be considered to have a relative hypercoagulable state. Although not the primary focus of our investigation, Hyperthyroidism was also found to be associated with TEE in 20-year-old individuals.
The clinical features of the study subgroups differed significantly with respect to several of the descriptive characteristics ascertained. The Euthyroid cohort was significantly younger than the other 3 study groups, possibly owing to widespread screening for thyroid disease in young to middle-aged adults. Age is an independent risk factor for venous thrombosis and rates of deep venous thrombosis are relatively low during the first 40 years of life, at 1 per 10 000 annually (5). Rates rise precipitously starting at age 45 and reaching 6 per 1000 annually by age 80 (5). Comorbidities acquired throughout an individual’s lifespan as well as immobility in the later years contribute to this risk with aging. The fact that the average age difference between the groups in this study was less than 2 years, on average, makes these differences an unlikely confounder in the rates of TEE observed in this study. The Hyperthyroid cohort weighed significantly less than the other study groups, which is likely attributable to an increased metabolic rate stimulated by hyperthyroidism (6). Obesity is a risk factor for venous thrombosis and individuals with obesity are at a 2- to 3-fold risk of venous thrombosis (5). Unfortunately, ascertaining body mass index from the electronic health record is difficult due to inaccurate and incomplete documentation. However, the mean body mass of the Subclinical and Overt Hypothyroid groups was greater than 80 kg in this study, suggesting that some of the individuals in these groups may have been obese and, as such, were at an elevated baseline risk for TEE. All 4 study groups consisted of greater than 50% female individuals, reflecting the fact that the incidence of autoimmune thyroid disease is increased in women (7). The race/ethnicity differences reported among the cohorts may reflect the differential risk for thyroid disease, or it may simply be attributable to incompletely available race and ethnicity data in the electronic health record (8). Race/ethnicity is an important covariate because differences have been described among groups within the United States. African Americans have a 25% higher risk for venous thrombosis than any other racial/ethnic group, and the risk of recurrence is greater than incident risk (5). This may be reflective of poor adherence to chronic anticoagulation regimens, and genetic factors may contribute as well. African Americans were demonstrated to have higher levels of factor VII, von Willebrand factor, and D-dimer compared with Caucasians (5). Hospitalization and immobilization are well-known risk factors for TEE, and while there was a statistically significant difference between the groups with respect to baseline visit status in this study, the difference in hospitalization rates between the groups during the index period was modest (range, 21%–29%) (5).
A recent meta-analysis by Ordookhani and Burman from 2017 reviewed 213 papers related to thyroid dysfunction and its effects on hemostasis. Their analysis suggested that the effect was heterogeneous and likely related to disease severity (2). Specifically, they noted that the laboratory findings associated with severe hypothyroidism would most likely be associated with a hypocoagulable state due to acquired factor VIII deficiency and a resultant qualitative defect in platelet function, decreased availability of factors II, VII, IX, XI, and enhanced fibrinolysis, while more moderate hypothyroidism would most likely be associated with a prothrombotic state (2). Consistent with this supposition, 1 large retrospective study of patients discharged from short-stay hospitalizations in the United States from 1979 to 2005 found that the relative risk (RR) for pulmonary embolism (RR = 1.64) and deep venous thrombosis (RR = 1.62) were significantly increased in patients with hypothyroidism compared with patients without hypothyroidism, and that this risk was increased in patients younger than age 40 (RR = 3.99 and 2.25, respectively) (9). Contrary to the current study, this analysis found that hypothyroid women were at increased risk of pulmonary embolism and deep vein thrombosis compared with hypothyroid men (9). Their analysis also demonstrated increased risk of pulmonary embolism and deep vein thrombosis in white as compared with black patients with hypothyroidism, and there was no associated increase in the risk of thrombosis for patients with hyperthyroidism. The findings of this 27-year retrospective study, combined with the findings of the current study, strongly suggest an increase in the risk of venous thromboembolism in young patients with hypothyroidism.
The current study suggests that overt hypothyroidism is associated with an increased risk of TEE and a putative hypercoagulable state among younger individuals. Proposing a feasible mechanism for this finding is challenging given the limited body of extant literature regarding childhood thyroid homeostasis and hemostasis. Whether or not the increased risk of TEE associated with hypothyroidism is attributable to excess TSH, inadequate triiodothyronine or thyroxine concentrations, or another as yet unidentified mechanism, is an area of active investigation. One study has demonstrated that exogenous administration of TSH to supraphysiologic levels in the setting of normal thyroxine levels had no effect on coagulation parameters (10). Although speculative, one possible explanation involves the role of thrombin-activatable fibrinolysis inhibitor (TAFI), which is a bloodborne protein that inhibits fibrinolysis by reducing the binding of plasminogen to fibrin, thus reducing the fibrin-plasminogen interaction and promoting thrombosis (2). Elevated TAFI levels have been documented in hypothyroidism, and elevated TAFI concentrations have been confirmed in hypothyroid children (11). Perhaps more pertinent, the same authors have found that levels of a potent inhibitor of thrombogenesis, tissue factor pathway inhibitor (TFPI), was decreased to 5% of euthyroid controls during hypothyroidism, and that these levels returned to normal after restoration of the euthyroid state (11). Moreover, a different group have demonstrated that levels of free TFPI are significantly increased in the hyperthyroid state, thus favoring a hypocoagulable state (12). Interestingly, TFPI levels are significantly increased in healthy children as compared with adults, so the dramatic decreases in TFPI observed during hypothyroidism may have a disproportionate effect on childhood hemostasis and may thus partially explain the inversed age-related increase in risk of TEE observed in the current study (13). Although more research into the mechanism(s) of age-related, hypothyroidism-associated TEE is clearly needed, postulated mechanisms, such as the one articulated above, render the findings of the current study biologically plausible.
Peralta and Canhão have suggested that the pathogenesis of the hypothyroid state (autoimmune versus non-autoimmune) may be an important determinant of the predilection to thrombosis, since both of the cases of cerebral venous thrombosis that they report occurred in the setting of autoimmune thyroid disease (14). Others have reported alterations in the structure of fibrin clots in overt hypothyroidism that favor hypocoagulability, such as a study by Stuijver and colleagues that described less compact fibrin polymers and enhanced fibrinolysis in individuals in patients with overt hypothyroidism as compared with euthyroid controls (15). The findings of the current study suggest that such fibrin clot structure and lytic factors may be less important in clinically apparent disease than other potential, as yet unidentified factors, such as the rate and/or the location of clot formations. Additionally, because the odds of TEE were highest in young individuals in the current study, the observed increase in risk may be unrelated to the burden of atherosclerotic disease, despite the fact that hypothyroidism is a well-recognized cardiovascular disease risk factor (16).
Thyroid dysfunction is associated with cardiac dysrhythmia. Atrial fibrillation, a common risk factor for thromboembolism, often treated with anticoagulation therapy, is 5 to 10 times more prevalent in patients with overt hyperthyroidism compared with the general population (17). Surprisingly, among the 8962 study participants with atrial fibrillation in a recent report, 141 were found to have a history of hyperthyroidism and 540 had a history of hypothyroidism, and the prevalence of atrial fibrillation was 3 times greater in patients with a history of hypothyroidism compared with hyperthyroidism (17). This study found a statistically insignificant increase in risk of stroke or systemic embolism in patients with atrial fibrillation and a history of hypothyroidism compared with those who had atrial fibrillation and a history of hyperthyroidism or euthyroidism (17). The authors conclude that physiologic changes in the cardiac conduction system during a period of hypothyroidism may contribute to the higher incidence of TEE observed in the current study.
The strengths of this study include its contributions to understanding of the clinical impact of thyroid disease on hemostasis, the use of PowerInsight as a tool for pragmatic clinical investigation, and the fact that the multiple logistic regression was adjusted for several confounding factors known to impact the risk for thromboembolism, such as smoking status and oral contraceptive use (18). Further, the use of PowerInsight allowed interrogation of the diverse New Mexico population and yielded data on traditionally understudied populations, including Hispanics and Native Americans, while remaining generalizable to the larger United States population. An additional strength of the study was that thyroid function tests were analyzed around the time of an identified TEE to ensure that initial classification during the index period accurately described future thyroid function during the follow-up period. The study also employed robust exclusion criteria, thus decreasing the influence of confounding medical conditions on observed rates of TEE and better isolating the effects of thyroid function in the analysis. Conversely, more than 8000 individuals were excluded from study analysis, and some of these were almost certainly excluded for diagnoses with minimal or no effect on the coagulation cascade, such as benign neoplasms or familial neoplastic syndromes. We have made efforts to ensure that the most prevalent of these diagnoses deemed to have minimal effect on coagulation were included in the analysis.
Limitations of this study include the single-center design, the lack of prospective data collection, and the sometimes incomplete datasets. TSH is an imperfect marker for hypothyroidism, since patients with secondary hypothyroidism can have apparently normal TSH values and acutely ill patients may also have TSH values that do not accurately reflect thyroid homeostasis. Although there are conditions that may yield falsely normal TSH values, the prevalence of these conditions is low: secondary hypothyroidism 0.001%, heterophile antibodies 0.3%, thyroid hormone resistance 0.003%, and TSH secreting adenomas 0.0003% (19, 20). Radiocontrast dye and acute illness may also alter thyroid hormone concentrations, but we do not have data relevant to the number of patients who may have experienced these events. Because we used a single TSH value obtained during the index period for assignment to groups, there remains a small possibility that this methodology could have misclassified some patients. In addition, multicenter analysis would have increased the power of the study and improved the generalizability of the findings. The study could also have benefitted from consideration of the effect of thyroid hormone replacement therapy, with subanalysis to stratify the Euthyroid cohort into those who were receiving thyroid hormone replacement therapy and those who were not. While such a subanalysis would be informative, previous studies have demonstrated normalization of coagulation laboratory tests with thyroid hormone replacement (3). Future research might expand on the current study by including multicenter patient data or by examining TEE risk in the context of a prospective, randomized clinical trial.
In conclusion, compared with the euthyroid state, overt hypothyroidism confers an increased risk for a subsequent TEE over the next 10 years among individuals younger than 35 years.
Acknowledgments
The authors wish to thank Daniel De Francisco Cabral of the University of New Mexico Clinical and Translational Sciences Center for his tireless work exporting the data for this study from the Cerner PowerInsight database.
Financial Support: This study was partially supported by the UNM HSC Clinical & Translational Science Center, NCATS grant # 8UL1TR000041.
Author Contributions: J.A.M. performed background research, obtained IRB approval, worked with statistician to perform statistical analysis, and wrote the draft manuscript. F.Q. performed the statistical analysis for the study. M.R.B. obtained funding, conceived the study design, obtained IRB approval, provided overall direction for the study, and approved the final manuscript.
Glossary
Abbreviations
- FT4
free T4
- OR
odds ratio
- RR
relative risk
- TAFI
thrombin-activatable fibrinolysis inhibitor
- TEE
thromboembolic events
- TFPI
tissue factor pathway inhibitor
- TSH
thyrotropin (thyroid-stimulating hormone)
- UNM HSC
University of New Mexico Health Sciences Center
Additional Information
Disclosure Summary: The authors have no multiplicity of interest to disclose.
Data Availability: The datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.
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