Plasma Levels of Free Thyroxine and Risk of Major Bleeding in Bariatric Surgery

Introduction

Thyroid hormone affects metabolism in virtually every organ system. Several studies have indicated that thyroid hormone also influences the hemostatic balance and that these changes are associated with a risk of venous thromboembolism (VTE) or bleeding. Higher plasma levels of free thyroxine (FT₄) have been associated with an increased VTE risk [1,2,3]. Conversely, lower levels of FT₄ seem to be associated with a bleeding tendency [4,5]. An observational cohort study of consecutive hypothyroid patients showed a high prevalence of acquired von Willebrand syndrome [6]. In a case-control study in subjects using vitamin K antagonist (VKA) treatment, patients with an FT₄ level within the lower part of the reference range had an increased risk of major bleeding compared to those with higher FT₄ levels, suggesting that FT₄ levels play a role in the etiology of major bleeding in VKA users.

Bleeding is one of the major short-term complications after bariatric surgery (weight loss surgery). The Medical Center Slotervaart is a referral center for bariatric surgery in the Netherlands. In the majority of patients, a Roux-en-Y gastric bypass is performed. This population is homogenous and the number of operations each year is considerable. In all patients undergoing preoperative screening for bariatric surgery, plasma FT₄ and thyroid-stimulating hormone (TSH) are measured. From previous work, we know that more than 2% of these patients experience major bleeding after bariatric surgery (unpubl. data). Given the earlier literature on increased risk of major bleeding in patients with FT₄ levels within the lower part of the reference range, we hypothesized that lower levels of preoperative FT₄ are also associated with an increased risk of major bleeding after bariatric surgery. This may help to identify patients before surgery who may benefit from extra monitoring during and after surgery.

Methods

Results

Patients

We screened all 2,872 patients amongst whom 72 patients (2.5%) with major bleeding were identified (cases) and 288 control patients were selected. The reasons for exclusion of cases and controls are depicted in figure 1. Of the 72 patients with major bleeding, 58 had a definite major bleeding, and in 14 patients the bleeding was classified as possible. All major bleedings were surgical site bleedings. The characteristics of the cases and controls are summarized in table 1. The prevalence of heart failure, renal insufficiency, bleeding disorder, prior VTE, and myocardial infarction was ≤5% in both groups. Five cases (7%) had a history of ischemic stroke compared to 3 controls (1%). The frequency of any former bleeding, prior abdominal surgery and usage of NSAIDs did not differ between the cases and the controls. Fifteen cases (21%) used one platelet aggregation inhibitor compared to 13 controls (5%). All patients with a medical history of hypothyroidism used levothyroxine [5 cases (7%) and 15 controls (5%)]. The laparoscopic procedure had to be converted to open surgery in 2 patients with major bleeding (2.8%) and in 1 control (0.3%).

Table 1

Characteristics of patients

View Table

View Full Size

Flowchart of selection of patients for this study. PAI = Platelet aggregation inhibitor.

Citation: European Thyroid Journal 5, 2; 10.1159/000446431

• Download Figure
• Download figure as PowerPoint slide

Levels of FT₄ and the Risk of Major Bleeding

The median (IQR) time between FT₄ measurement and bariatric surgery was 3 months (2-5). The median (IQR) FT₄ level was 13 pmol/l (12-14) for both cases and controls (reference values: 9-19 pmol/l). The median (IQR) TSH level was 1.74 mU/l (1.18-2.21) in the cases and 1.89 mU/l (1.38-2.63) in the control patients. Table 2 provides a description of the types of major bleeding events. ORs (95% CI) for developing major bleeding within 1 month after bariatric surgery for different cutoff values of FT₄ are shown in table 3. For patients with an FT₄ level <11 pmol/l, the crude OR (95% CI) for developing major bleeding was 1.48 (0.46-4.80) compared with patients with higher FT₄ levels. For all other cutoff values, the ORs were approximately 1 (ORs ranging from 0.95 to 1.12). Restricted analyses for definite major bleeding and adjustment for age, BMI, or the use of any platelet aggregation inhibitor did not materially change the results. Excluding patients using levothyroxine also did not change the results (data not shown).

Table 2

Major bleeding events

View Table

Table 3

Risk of major bleeding in patients undergoing bariatric surgery with different levels of FT₄

View Table

Discussion

Although an effect of FT₄ levels <11 pmol/l cannot be excluded, we can conclude that low levels of FT₄ within the reference ranges do not seem to be a risk factor for developing major bleeding within 1 month after bariatric surgery.

Previous literature suggests that not only hypothyroidism leads to an increased risk of bleeding, but also lower levels of FT₄ within the reference range. An observational cohort study of consecutive hypothyroid patients showed a high prevalence of acquired von Willebrand syndrome [6]. In a recent case-control study in subjects using VKA treatment, patients with an FT₄ level within the lower part of the reference range (cutoff of 13 or 14 pmol/l) had a 3- to 5-fold increased risk of major bleeding compared to those with higher FT₄ levels [8].

There are several potential explanations for the differences observed in our current study and the study in patients using VKA treatment. First, both populations are clearly different: our study population was younger (median age of 48 and 44 years versus 66.5 and 70.9 years in the cases and the controls, respectively) and most importantly, all patients were on VKAs while we excluded patients on VKAs. Furthermore, our study population consisted of patients with obesity that is associated with hypercoagulability and an increased VTE risk [9]. All major bleeding events were attributed to a surgical procedure in contrast to the (mainly) spontaneous bleeding events in patients on VKAs. Second, an explanation for the increased risk of major bleeding in the study of Debeij et al. [8] could be that lower levels of FT₄ influence VKA stability, which was observed in a pilot study [10]. However, the same study observed that patients with subclinical hypothyroidism had a diminished sensitivity for VKAs, which would make them less prone to bleeding. The literature on overt hypothyroidism also argues against this explanation since overt hypothyroidism seems to diminish the effect of VKAs by decreasing the clearance of coagulation factors [11].

In the present study, 21% of the cases used one platelet aggregation inhibitor compared to 5% of the controls. Since in the literature it was suggested that the use of platelet aggregation inhibitors could influence FT₄ levels [12], we also performed our analyses with the use of any platelet aggregation inhibitor added to the model. However, this did not change our results.

There are several limitations to this case-control study. The relatively low values of FT₄ in the population undergoing bariatric surgery are striking [median (IQR): 13 (12-14) pmol/l in both cases and controls]. The median FT₄ level in the study of Debeij et al. [8] was 17.7 pmol/l, and in the MEGA Study [1], which was a large case-control study investigating risk factors for VTE, the median FT₄ level was 16.6 pmol/l in the controls. The literature about the association between (morbid) obesity and levels of FT₄ is limited, but it seems that lower levels of FT₄ are associated with higher BMI, suggesting that thyroid function (also within the normal range) could be one of several factors acting in concert to determine body weight in a population [13,14]. If low levels of FT₄ within the reference ranges influenced bleeding risk, this would result in a higher bleeding risk for the entire population in our study, which consisted of patients who were (morbidly) obese. Another prominent finding in our study is the small IQR of the rounded FT₄ levels in both the cases and controls, which hindered the possibility to perform an analysis in as many categories under the 50th percentile of FT₄ as was performed in the study by Debeij et al. [8]. An explanation for the lack of an observed association between FT₄ and major bleeding could be, in addition to the relatively low values of FT₄, the presence of other stronger risk factors such as the use of a platelet aggregation inhibitor. Nevertheless, the results of this study cannot be generalized to other patient populations, e.g. lean subjects. Another limitation of this study is the adjudication of the major bleeding events due to the inconclusive definition of major bleeding according to the ISTH criteria regarding surgical procedures (details provided in online suppl. material) [7]. As a result, 19% of all major bleeding events were adjudicated as possible major bleeding. However, the results of the analyses in all major bleeding events are in accordance with the analyses in solely the definite major bleeding events. Because of the study size, the confidence intervals presented were relatively wide and therefore we cannot exclude a small effect for patients with a FT₄ <11 pmol/l. However, for the other cutoff values, the power of the study is sufficient to rule out a strongly increased risk of major bleeding. It could be argued that the level of FT₄ at the time of screening for bariatric surgery is not representative for the FT₄ level at the time of the surgery itself and the moment of the occurrence of major bleeding. The patients underwent surgery after a median of 3 months after screening for bariatric surgery and thus the measurement of FT₄. Levels of FT₄, however, are stable over time [15,16]. Furthermore, such misclassification would be random and lead to an underestimation of the risk.

In conclusion, this study shows that in patients undergoing bariatric surgery, lower levels of FT₄ are not associated with an increased risk of major bleeding. We cannot exclude a small effect for patients with a FT₄ <11 pmol/l. This study also points out the relatively low levels of FT₄ in obese subjects undergoing bariatric surgery. For future research, the clinical relevance of low levels of FT₄ within the reference range could be of interest in other (surgical) patient populations. In addition, further investigation could determine whether FT₄ levels contribute to the prediction of major bleeding in prediction models.

Disclosure Statement

This work was supported by the SKWOSZ (Foundation for Clinical Scientific Research at Medical Center Slotervaart).