LAUSR

Idarucizumab can completely reverse the biological activity of dabigatran within a few minutes [1]. Several reports have documented thrombolytic therapy following antagonism of dabigatran with idarucizumab, and various arrangements have been made in different countries [2, 3]. Direct measurements of dabigatran concentration or activated clotting times are used to determine the effectiveness of dabigatran, but little is known about paradoxical elevation of plasma dabigatran after reversal with idarucizumab. We report a case of stroke in a patient who received intravenous thrombolytic therapy following dabigatran antagonism with idarucizumab and repeated measurements of plasma dabigatran before and after antagonism. A 74-year-old man with a body weight of 72 kg was emergently admitted to our hospital with sudden onset of severe left-sided hemiparesis. He had a medical history of atherothrombotic stroke due to right internal carotid artery stenosis and paroxysmal atrial fibrillation and had been receiving dabigatran twice-daily at 110 mg. On the day of onset, he had taken dabigatran at 07:30. The time of lastknown normal status was at 09:00, and he was brought to our emergency room at 11:20 (Fig. 1a). The patient displayed left-sided spatial neglect, left-sided hemiparesis, and sensory loss with a National Institutes of Health Stroke Scale (NIHSS) score of 6. Brain MRI showed fresh infarcts in the territories of the right middle cerebral artery and left posterior cerebral artery (Fig. 2a, b). No major cerebral arteries showed occlusion on MR angiography. Activated partial thromboplastin time (APTT) was 41 s and creatinine clearance level was 67.6 ml/min. We decided to administer intravenous alteplase at 0.6 mg/kg (official dosage in Japan) after antagonism of dabigatran by idarucizumab administration at noon in accordance with recent Japanese consensus clinical guidelines [2]. APTT returned to 30 s just after administration of idarucizumab and further decreased to 27 s after 2 h. 24-h follow-up MRI showed no other fresh cerebral infarcts (Fig. 2c) and no signs of hemorrhagic transformation of the infarcts (Fig. 2d). The total plasma level of dabigatran was measured from stored samples the following day, revealing levels of 35 ng/ml just before idarucizumab and 92 ng/ml after 2 h (Fig. 1b). By day 17, hemiparesis had improved to mild (NIHSS 2) and the patient was discharged for early rehabilitation. We encountered a case with safe performance of intravenous thrombolysis immediately after antagonism of dabigatran using idarucizumab who displayed a paradoxical increase in total plasma level of dabigatran after antagonism, although APTT completely normalized. Total dabigatran plasma level is measured by high-performance liquid chromatography coupled with mass spectrometry and calibrated to plasma samples specifically supplemented with the drug under examination. The measured level of total dabigatran includes plasma protein-bound dabigatran and idarucizumab-bound dabigatran in addition to the pharmacologically active unbound dabigatran. Additional measurement of unbound dabigatran plasma alone requires ultrafiltration to separate. Idarucizumab is mostly distributed in blood, while dabigatran freely distributes in both blood and tissues, with equilibrium between these compartments. When idarucizumab binds to dabigatran in the blood and the active dabigatran concentration in blood decreases, dabigatran in tissues redistributes into the blood to maintain equilibrium. Idarucizumab then also inactivates the dabigatran. In this way, the total plasma concentration of dabigatran is elevated, while the plasma concentration of active dabigatran nears the lower limit of quantification after idarucizumab administration [4]. Such an increase in total drug concentration * Masahito Takagi [email protected]