Research into new anticoagulants for preventing and treating thromboembolic disorders has focused on targeting single enzymes in the coagulation cascade, particularly Factor Xa and thrombin, inhibition of which greatly decreases thrombin generation. Based on the results of phase III clinical trials, rivaroxaban, a direct Factor Xa inhibitor, has been approved in many countries for the management of several thromboembolic disorders. Owing to its predictable pharmacokinetic and pharmacodynamic characteristics, fixed-dose regimens are used without the need for routine coagulation monitoring. In situations where assessment of rivaroxaban exposure may be helpful, anti-Factor Xa chromogenic assays (in tandem with standard calibration curves generated with the use of rivaroxaban calibrators and controls) could be used. It is important to note that test results will be affected by the timing of blood sampling after rivaroxaban intake. In addition, the anti-Factor Xa method measures the drug concentration and not the intensity of the drug’s anticoagulant activity, and a higher than expected rivaroxaban plasma level does not necessarily indicate an increased risk of bleeding complications. Therefore, clinicians need to consider test results in relation to the pharmacokinetics of rivaroxaban and other patient risk factors associated with bleeding.
Abstract-The present study was designed to analyze the thrombomodulin proximal promoter region spanning nucleotides Ϫ293 to Ϫ12 to search for polymorphisms that could modify thrombomodulin gene expression in patients with venous thromboembolic disease. The study population comprised 205 patients and 394 healthy subjects of similar age and sex distribution. No polymorphisms and only 1 point mutation (G-33A) were found. The G-33A mutation was present at the heterozygous state in 2 patients and in 1 control. Being more frequent in the patients (0.97%) than in the controls (0.25%), the G-33A mutation might be a risk factor for venous thrombosis. To investigate the effect of this mutation on the thrombomodulin promoter activity, the proximal promoter region of the gene (bearing or not bearing the G-33A mutation) was inserted into a promotorless expression vector, upstream of the firefly luciferase gene, and transiently transfected into EA.hy926 endothelial cells. Under the conditions of the assay, the G-33A mutation mildly decreased the promoter activity. This study confirms that abnormalities of the thrombomodulin proximal promoter are not frequent in patients with venous thromboembolism.
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