Coagulation After Intravenous Methylprednisolone Administration

High-dose Intravenous Methylprednisolone Therapy in Patients With Graves' Orbitopathy is Associated With the Increased Activity of Factor VIII

The alterations of coagulation and fibrinolysis parameters have been described in patients with endogenous Cushing's syndrome (CS) and those treated with glucocorticosteroids (GCs). The change in hemostatic process is associated with an increased risk of venous thromboembolic events (VTE) and pulmonary embolism (PE). Anticoagulation prophylaxis reduces thromboembolic complications in endogenous and exogenous hypercortisolism. The impact of the intravenous GCs therapy on hypercoagulability, however, remains unclear and perplexing. According to the European Group On Graves' Orbitopathy (EUGOGO), patients with active, severely symptomatic and sight-threatening Graves' orbitopathy (GO) should be treated with high dose intravenous methylprednisolone (IVMP) pulses. There are, however, reports of fatal side effects that may be associated with this therapy (e.g.: PE, myocardial infarction, severe cerebrovascular events, acute liver damage and sudden death). For this reason, the cumulative dose of IVMP should not exceed 8 g within each treatment course, and pulses should not be given on consecutive or alternate days, except for the case of dysthyroid optic neuropathy. Nevertheless, even smaller cumulative therapy may be associated with fatal cardiovascular complications. Hence the aim of our study was to evaluate the effects of IVMP therapy on hemostatic process in patients with GO. All of patients were treated according to EUGOGO recommendations with standard doses of methylprednisolone with standard recommended schedule. Inclusion criterion for the therapy was according to EUGOGO guidelines moderate-to-severe and active GO (12 pulses of IVMP 6x0.5g followed by 6x0.25g every week).

The end point of the study was a change in hemostatic variables' levels in laboratory tests. There were short- and long-term hemostatic changes analysed during IVMP therapy: comparisons of laboratory tests before, 24h and 48h after selected pulses, and between the beginning of 1st, 6th and 12th IVMP pulses, respectively. Hemostatic variables that were evaluated: factor [F] II, FV, FVII, FVIII, fibrinogen, antithrombin, activated partial thromboplastin time, prothrombin time, platelets and D - dimer. Moreover, analyses were performed concerning clinical data (such as age, sex, body mass index, smoking, duration time of GO, presence of hypertension, basal markers of thyroid function) between independent groups (patients with initially increased/reduced selected markers versus without increased/reduced selected markers).

Inclusion Criteria:

• active, moderate-to-severe Graves' orbitopathy according to EUGOGO classification
• euthyroidism for at least 1 month
• completion of at least first six IVMP pulses

Exclusion Criteria:

• medical history of thromboembolic events
• cardiovascular morbidity (chronic heart failure, cardiovascular heart disease)
• uncontrolled hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg)
• liver disease (>3x increase of alanine aminotransferase and/or aspartate aminotransferase)
• active inflammation
• nephritic syndrome
• active neoplastic disease
• previous GCs therapy within the last 6 months
• trauma/surgery within the last 3 months
• pregnancy or a bedridden state
• use of: heparin, vitamin K antagonists, antiplatelet drugs, contraceptives or hormone replacement therapy