The effect of levothyroxine on expression of inflammation-related genes in healthy subjects: a controlled randomized crossover study.

An excess of thyroid hormone leads to a prothrombotic state; however, the underlying pathophysiological mechanisms remain unknown. As evidence points towards an extensive "cross-talk" between the inflammatory and coagulation cascade, inflammation has been claimed as a possible mechanism through which different risk factors trigger venous thrombus formation. We aimed to study changes in expression of inflammation-related genes of the leukocyte RNA expression profile in healthy subjects in response to supraphysiological doses of levothyroxine. In a randomized single-blinded crossover design, 12 healthy volunteers (aged 18-40 years) received levothyroxine and no medication, both for 14 days with a wash-out period of at least 28 days between the periods. Blood was sampled at baseline and day 14 of each study period. MRNA was isolated from whole blood and used for multiplex ligation-dependent probe amplification to study the expression of inflammation-related genes. Compared to the control situation no significant changes were found in the expression of proinflammatory cytokines and mediators after the intake of levothyroxine. The results of this study show that high thyroid hormone levels do not lead to an altered inflammatory profile. This provides evidence against a major role of the inflammatory system as mediator in the effect of thyroid hormone on the coagulation system. The mechanisms by which thyroid hormone may influence coagulation proteins remain to be elucidated.

Acquired von Willebrand syndrome in patients with overt hypothyroidism: a prospective cohort study.

Numerous case reports have been published on acquired von Willebrand syndrome (aVWS) in patients with hypothyroidism, but no prospective studies have been published. The aim of this study was to investigate laboratory and clinical characteristics of aVWS in patients with newly diagnosed overt hypothyroidism. An observational cohort study was performed between May 2007 and February 2012. Consecutive hypothyroid patients before or within the first 48 h of replacement therapy were enrolled. At inclusion, blood was sampled for coagulation tests and bleeding history was documented by means of a standardized bleeding questionnaire. Repeat samples were obtained after restoration of euthyroidism. The prevalence of aVWS, defined as von Willebrand factor antigen (VWF:Ag) ≤50% and/or VWF ristocetin activity (VWF:RCo) ≤50%, was calculated. Patients with aVWS were subsequently divided into severe (VWF:Ag and/or VWF:RCo ≤10%), moderate (VWF:Ag and/or VWF:RCo between 10 and 30%) or mild (VWF:Ag and/or VWF:RCo between 30 and 50%). A total of 90 patients were included among whom a prevalence of aVWS of 33% was found. There were no patients with severe aVWS. Eight patients (9%) had moderate aVWS and 21 (23%) had mild aVWS. Bleeding score was negatively correlated with both VWF:Ag (ß -0.32, P = 0.03) and VWF:RCo (ß -0.32, P = 0.02). After restoration of euthyroidism, VWF:Ag had significantly increased by 44%, VWF:RCo by 36%, factor VIII by 39%, and endogenous thrombin potential by 10%. aVWS has a high prevalence in hypothyroid patients. Highest bleeding scores in patients with lower VWF levels suggest clinical relevance.

Thyroid dysfunction and fibrin network structure: a mechanism for increased thrombotic risk in hyperthyroid individuals.

CONTEXT: Hyperthyroidism is associated with increased thrombosis risk, and fibrin clot structure determines susceptibility to vascular thrombotic events. OBJECTIVE: Our objective was to investigate clot formation and lysis in hyperthyroidism using observational and interventional studies. DESIGN: Ex vivo fibrin clot structure/fibrinolysis and plasma levels of thrombotic/inflammatory markers were investigated in hyperthyroid individuals (n = 24) and matched controls (n = 19), using turbidimetric assays, ELISA, and confocal and electron microscopy. The effects of normalizing thyroid function were analyzed (n = 19) and the role of short-term exogenous hyperthyroidism in healthy volunteers studied (n = 16). RESULTS: Hyperthyroid subjects displayed higher clot maximum absorbance compared with controls (0.41 ± 0.03 and 0.27 ± 0.01 arbitrary units, respectively; P < 0.01), and longer clot lysis time (518 ± 23 and 461 ± 18 sec, respectively; P < 0.05), which correlated with free T(4) levels. Plasma levels of fibrinogen and plasminogen activator inhibitor-1 were significantly higher in patients compared with controls. Normalizing thyroid function in 19 subjects was associated with lower maximum absorbance and shorter lysis time, accompanied by reduction in fibrinogen, plasminogen activator inhibitor-1, and D-dimer levels. Complement C3, but not C-reactive protein, levels were higher in hyperthyroid subjects compared with controls (0.92 ± 0.05 and 0.64 ± 0.03 g/liter, respectively; P < 0.01), correlated with clot structure parameters, and decreased after intervention. Confocal and electron microscopy confirmed more compact clots and impaired fibrinolysis during hyperthyroidism. Exogenous hyperthyroidism in healthy volunteers had no effect on any of the clot structure parameters. CONCLUSIONS: Endogenous hyperthyroidism is associated with more compact clots and resistance to fibrinolysis ex vivo, related to the degree of hyperthyroidism and C3 plasma levels, and these changes are modulated by achieving euthyroidism. Altered clot structure/lysis may be one mechanism for increased thrombotic risk in hyperthyroidism.

Incidence of venous thromboembolism in patients with Cushing's syndrome: a multicenter cohort study.

CONTEXT: Venous thrombosis has frequently been reported in patients with endogenous Cushing's syndrome (CS). OBJECTIVE: The aim of this study was to evaluate the incidence of venous thromboembolism (VTE) in patients with CS prior to treatment and after surgery. DESIGN AND SETTING: We conducted a multicenter cohort study at all university medical centers in The Netherlands. PATIENTS: Consecutive patients diagnosed with endogenous CS of benign origin between January 1990 and June 2010 were eligible for inclusion. Patients surgically treated for nonfunctioning pituitary adenoma served as controls for the incidence of postoperative VTE in ACTH-dependent CS. MAIN OUTCOME MEASURES: We documented all objectively confirmed VTE during 3 yr prior to, and 3 yr after treatment onset. The incidences of VTE were expressed as incidence rates. RESULTS: A total of 473 patients (mean age 42 yr, 363 women) were included (360 ACTH-dependent pituitary CS). The total number of person-years was 2526. Thirty-seven patients experienced VTE during the study period, resulting in an incidence rate of 14.6 [95% confidence interval (CI) 10.3-20.1] per 1000 person-years. The incidence rate for first-ever VTE prior to treatment was 12.9 (95% CI 7.5-12.6) per 1000 person-years (17 events). The risk of postoperative VTE, defined as risk within 3 months after surgery, was 0% for ACTH-independent and 3.4% (95% CI 2.0-5.9) for ACTH-dependent CS (12 events in 350 patients); most events occurred between 1 wk and 2 months after surgery. Compared with the controls, the risk of postoperative VTE in patients undergoing transsphenoidal surgery was significantly greater (P = 0.01). CONCLUSIONS: Patients with CS are at high risk of VTE, especially during active disease and after pituitary surgery. Guidelines on thromboprophylaxis are urgently needed.