Effect of rivaroxaban on prothrombin fragment 1 + 2 compared with warfarin in patients with acute cardioembolic stroke: Insight from its serial measurement

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 m ethods In 65 patients with acute cardioembolic stroke (median 77 years), rivaroxaban was initiated at 5 days after the onset. Plasma F1 + 2 level (normal range, 69 – 229 pmol/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 28 days after rivaroxaban, respectively (both p < 0.05). Serial measurements of PT and rivaroxaban concentration at trough, 2, 4, and 6 h after taking rivaroxaban showed a positive correlation (R2 = 0.69, p < 0.01). PT at 4 h after rivaroxaban was significantly prolonged compared with trough (16.6 versus 11.5 s , p < 0.0001). F1 + 2 at 4 h 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 4 h . In other 34 patients with warfarin treatment (77 years), median PT-INR and F1 + 2 were 2.06 (1.75 – 2.50) and 75 (48 – 111) (p < 0.0001 versus 4 h 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.