Thyroid Disorders and Hemostasis.

Lower levels of free thyroxine (whether this is endogenous or exogenous) lead to a hypocoagulable state, and higher levels of free thyroxine lead to a hypercoagulable state. In this narrative review, the effects of different levels of thyroid hormones on clinical end points are described. Hypothyroidism is associated with an increased bleeding risk, whereas hyperthyroidism leads to an increased risk of venous thrombosis. Besides, effects of thyroid hormone on the heart may indirectly influence hemostasis. Hyperthyroidism leads to a higher incidence of atrial fibrillation and atrial flutter, and, at least partly by that mechanism, a higher risk of cerebral arterial thrombosis. In addition, compression effects of goiter on developing venous thrombosis are described. This is caused by local stasis of blood due to tumor expansion.

Bone Mineral Density Loss and Fracture Risk After Discontinuation of Anti-osteoporotic Drug Treatment: A Narrative Review.

The number of patients on long-term anti-osteoporotic drug therapy is rising. Unfortunately, there are few data to guide decisions about duration of pharmacologic therapy for osteoporosis. Many practitioners discontinue therapy after a period of 5 years because of the risk of rare but severe side effects that may occur in long-term users. The objective of this narrative review was to describe the effects of discontinuation of anti-osteoporotic drugs and to investigate what is not yet known on this topic. For each anti-osteoporotic agent, PubMed was searched for evidence from randomized clinical trials in patients with osteoporosis on osteoporotic drugs lasting ≥ 3 years, followed by ≥ 1 year of follow-up after discontinuation of therapy and reported at least one item of the following: changes in bone mineral density, bone turnover markers and/or the risk of vertebral and/or nonvertebral fractures after discontinuation of therapy. The% change in bone mineral density (BMD) after 1 year of discontinuation of therapy is - 0.4% or less at the hip and femoral neck in both alendronate- and zoledronic acid-treated patients. In the other reported agents (risedronate, ibandronate, raloxifene, teriparatide, denosumab and romosozumab) this percentage of bone loss at the femoral neck and total hip was at least 1%, with the largest decrease in BMD after discontinuation of denosumab and romosozumab. In all studies reporting bone turnover markers, a substantial rapid rise in these markers was observed after discontinuation of therapy, with a large rebound increase to far above baseline levels in the denosumab-treated patients. There were few data on fracture risk after discontinuation of therapy; data showed that discontinuing alendronate, zoledronic acid and especially denosumab significantly increases the risk of vertebral fractures. In conclusion, osteoporosis should be considered more as a chronic condition. Therefore, in modern fracture risk management, continuous monitoring and treatment is required, as is the case with other chronic diseases, to sustain the benefits of therapy, especially in denosumab- and romosozumab-treated patients. The exception is alendronate and zoledronic acid, in these patients a discontinuation of drug therapy of 1 year or more might be acceptable.

Coagulation and fibrinolysis in hyperparathyroidism secondary to vitamin D deficiency.

INTRODUCTION: Abnormal coagulation tests have been observed in patients with primary hyperparathyroidism (HPT) suggesting a prothrombotic effect of parathyroid hormone (PTH). Vitamin D deficiency (VIDD) is the most frequent cause of secondary HPT. Aim of our study was to investigate the influence of HPT secondary to moderate-to-severe VIDD and vitamin D replacement on the coagulation and fibrinolysis system. SUBJECTS AND METHODS: Prospective cohort study of patients with vitamin D <25 nmol/L with and without HPT, and a control group of patients on vitamin D suppletion. At baseline and after 2 months of vitamin D suppletion (900,000 IU in 2 months), endocrine and coagulation markers were measured. RESULTS: 59 patients with VIDD of which 34 had secondary HPT and 36 controls were included. After 2 months of suppletion, vitamin D increased by 399% (VIDD with HPT), 442% (all patients with VIDD) and 6% (controls). PTH decreased by 34% (VIDD with HPT, P < 0.01 for decrease), 32% (all VIDD, P < 0.01) and increased by 8% in the controls (P-values: <0.01 for relative changes between VIDD with HPT or all VIDD patients vs controls). Relative changes in PT, aPTT, fibrinogen, Von Willebrand factor, factors VII, VIII and X, thrombin generation, TAFI, clot-lysis time and d-dimer were not different between patients with VIDD with HPT or all VIDD vs controls. DISCUSSION: Secondary HPT due to VIDD does not have a prothrombotic effect. In contrast with previous reports, PTH does not seem to influence coagulation or fibrinolysis, which is relevant because of the high prevalence of VIDD.

Effects of Supra-Physiological Levothyroxine Dosages on Liver Parameters, Lipids and Lipoproteins in Healthy Volunteers: A Randomized Controlled Crossover Study.

Eprotirome, a liver specific thyroid hormone agonist, was shown to induce significant increases in markers of liver injury along with a modest decrease in atherogenic lipids and lipoproteins. To get more insight into whether these effects on liver parameters were compound specific or the effect of mimicking thyrotoxicosis, we studied the effects of supra-physiological levothyroxine dosages on liver parameters, lipids and lipoproteins. We used data of a single-blinded, randomized controlled crossover trial. Herein, healthy volunteers received levothyroxine or no medication for 14 days. Thyroid hormone excess did not induce clinically relevant changes in liver parameters, while significant reductions in total cholesterol, low-density lipoprotein-cholesterol as well as apolipoprotein-B levels were observed in the intervention periods compared with the control periods. Supra-physiological thyroid hormone levels did not induce clinically relevant increases in markers of liver injury after 2 weeks of exposure, while it reduced total cholesterol, low-density lipoprotein cholesterol and apolipoprotein B levels. This suggests that the effects of eprotirome on liver parameters in previous studies were either off-target and compound specific or due to drug-drug interaction at the level of the liver. The results of our study are relevant for the development of novel thyroid hormone agonists to reduce atherogenic lipoproteins.

The Hypercoagulable state in Hyperthyroidism is mediated via the Thyroid Hormone ß Receptor pathway.

OBJECTIVE: Hyperthyroidism is associated with a hypercoagulable state, but the underlying mechanism is unknown. Patients with resistance to thyroid hormone (RTH) due to defective thyroid hormone receptor ß (TRß) exhibit elevated circulating thyroid hormones (TH) with refractoriness to TH action in TRß-expressing tissues. We tested the hypothesis that the hypercoagulable state in hyperthyroidism is mediated via the TRß. DESIGN: We conducted a cross-sectional study from November 2013 to January 2015 in 3 hospitals in the Netherlands and the United Kingdom. METHODS: Patients with RTH due to defective TRß (n=18), patients with hyperthyroidism (n=16) and euthyroid subjects (n=18) were included. TH concentrations and markers of coagulation and fibrinolysis were measured. Data are expressed as median [interquartile range]. RESULTS: Free thyroxine (FT4) levels were slightly higher in hyperthyroid patients than in RTH patients (53.9 [30.5-70.0] and 34.9 [28.4-42.2]pmol/l, respectively, P=0.042). Both groups had raised FT4 levels compared to euthyroid subjects (14.0 [13.0-15.8] pmol/l, P≤0.001). Levels of von Willebrand factor (VWF), factor (F) VIII, fibrinogen, and D-dimer were significantly higher in hyperthyroid patients than in RTH patients (VWF 231 [195-296] vs. 111 [82-140]%, FVIII 215 [192-228] vs. 145 [97-158]%, fibrinogen 3.6 [3.0-4.4] vs. 2.8 [2.5-3.2]g/L, D-dimer 0.41 [0.31-0.88] vs. 0.20 [0.17-0.26]mg/L, respectively, P≤0.001), while there were no differences between RTH patients and euthyroid controls. CONCLUSIONS: Parameters of coagulation and fibrinolysis were elevated in hyperthyroid patients compared to patients with RTH due to defective TRß, whereas these parameters were not different between euthyroid controls and RTH patients, despite elevated FT4 concentrations in RTH patients. This indicates that the procoagulant effects observed in hyperthyroidism are mediated via the TRß.

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

BACKGROUND: In a recent study of patients using vitamin K antagonists, those with low free thyroxin (FT4) levels within the normal range had a 3- to 5-fold increased risk of major bleeding. We tested the hypothesis that low levels of preoperative FT4 within the reference range are associated with an increased risk of major bleeding during and after bariatric surgery. METHODS: The charts of 2,872 consecutive patients undergoing bariatric surgery were retrospectively screened for bleeding episodes. Patients with major bleeding until 1 month after surgery were compared to randomly selected control patients without bleeding, in a ratio of 1:4. We evaluated the association between preoperative FT4 levels and the risk of major bleeding by logistic regression. RESULTS: Seventy-two cases (2.5%) with major bleeding were identified and 288 controls were selected. The median plasma level of FT4 was 13 pmol/l (interquartile range: 12-14) in the cases as well as in the controls. No clear effect was observed of low levels of FT4 on the risk of major bleeding: odds ratio 1.48 (95% CI: 0.46-4.80) for patients with an FT4 level <11 pmol/l, 1.03 (0.49-2.18) for patients with an FT4 level <12 pmol/l, and 1.12 (0.65-1.94) for patients with an FT4 level <13 pmol/l as compared to patients with FT4 values greater than or equal to these cutoff levels. INTERPRETATION: We did not observe an increased risk of major bleeding with low levels of FT4 in patients undergoing bariatric surgery.