Joji Hagii1, Hirofumi Tomita2, Norifumi Metoki1, Yoshiko Tamai3, Shin Saito1, Hiroshi Shiroto1, Hiroyasu Hitomi1, Takaatsu Kamada1, Satoshi Seino1, Koki Takahashi1, Satoko Sasaki1, Minoru Yasujima1, Ken Okumura4. 1. Hirosaki Stroke and Rehabilitation Center, Hirosaki 036-8104, Japan. 2. Department of Cardiology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; Department of Hypertension and Stroke Medicine, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan. 3. Division of Blood Transfusion Medicine, Hirosaki University Hospital, Hirosaki 036-8563, Japan. 4. Department of Cardiology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; Department of Hypertension and Stroke Medicine, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan. Electronic address: okumura@hirosaki-u.ac.jp.
Abstract
INTRODUCTION: Patients with intracerebral hemorrhage during rivaroxaban treatment have small hematoma and favorable outcomes compared with those with warfarin. We investigated its possible mechanism, focusing on prothrombin fragment 1+2 (F1+2), a marker of thrombin generation. MATERIALS AND METHODS: In 65 patients with acute cardioembolic stroke (median 77years), rivaroxaban was initiated at 5days after the onset. Plasma F1+2 level (normal range, 69-229pmol/L), prothrombin time (PT), and rivaroxaban concentration evaluated by anti-Xa activity were serially measured. RESULTS: Median plasma F1+2 was 276 (IQR, 195-454) pmol/L before starting rivaroxaban, and significantly decreased to 196 (141-267) and 192 (151-248) on 7 and 28days after rivaroxaban, respectively (both p<0.05). Serial measurements of PT and rivaroxaban concentration at trough, 2, 4, and 6h after taking rivaroxaban showed a positive correlation (R2=0.69, p<0.01). PT at 4h after rivaroxaban was significantly prolonged compared with trough (16.6 versus 11.5s, p<0.0001). F1+2 at 4h was also decreased compared with trough (160 (123-245.5) versus 196 (141-266.5), p=0.04), but no patients showed F1+2 below the normal range at 4h. In other 34 patients with warfarin treatment (77years), median PT-INR and F1+2 were 2.06 (1.75-2.50) and 75 (48-111) (p<0.0001 versus 4h after rivaroxaban). Notably, of those with PT-INR≥2.0 (18/34), 12 (12/18, 67%) showed F1+2 below the normal range. CONCLUSIONS: Rivaroxaban retains a normal thrombin generation even at its peak level with prolonged PT, whereas warfarin at therapeutic levels inhibits thrombin generation. This may partly explain different outcomes in patients complicated with bleeding events.
INTRODUCTION:Patients with intracerebral hemorrhage during rivaroxaban treatment have small hematoma and favorable outcomes compared with those with warfarin. We investigated its possible mechanism, focusing on prothrombin fragment 1+2 (F1+2), a marker of thrombin generation. MATERIALS AND METHODS: In 65 patients with acute cardioembolic stroke (median 77years), rivaroxaban was initiated at 5days after the onset. Plasma F1+2 level (normal range, 69-229pmol/L), prothrombin time (PT), and rivaroxaban concentration evaluated by anti-Xa activity were serially measured. RESULTS: Median plasma F1+2 was 276 (IQR, 195-454) pmol/L before starting rivaroxaban, and significantly decreased to 196 (141-267) and 192 (151-248) on 7 and 28days after rivaroxaban, respectively (both p<0.05). Serial measurements of PT and rivaroxaban concentration at trough, 2, 4, and 6h after taking rivaroxaban showed a positive correlation (R2=0.69, p<0.01). PT at 4h after rivaroxaban was significantly prolonged compared with trough (16.6 versus 11.5s, p<0.0001). F1+2 at 4h was also decreased compared with trough (160 (123-245.5) versus 196 (141-266.5), p=0.04), but no patients showed F1+2 below the normal range at 4h. In other 34 patients with warfarin treatment (77years), median PT-INR and F1+2 were 2.06 (1.75-2.50) and 75 (48-111) (p<0.0001 versus 4h after rivaroxaban). Notably, of those with PT-INR≥2.0 (18/34), 12 (12/18, 67%) showed F1+2 below the normal range. CONCLUSIONS:Rivaroxaban retains a normal thrombin generation even at its peak level with prolonged PT, whereas warfarin at therapeutic levels inhibits thrombin generation. This may partly explain different outcomes in patients complicated with bleeding events.
Authors: Christina Christersson; Lars Wallentin; Ulrika Andersson; John H Alexander; Marco Alings; Raffaele De Caterina; Bernard J Gersh; Christopher B Granger; Sigrun Halvorsen; Michael Hanna; Kurt Huber; Elaine M Hylek; Renato D Lopes; Byung-Hee Oh; Agneta Siegbahn Journal: Heart Date: 2018-09-12 Impact factor: 5.994