title: Effect of rivaroxaban on prothrombin fragment 1+2 compared with warfarin in patients with acute cardioembolic stroke: Insight from its serial measurement.
abstract: BACKGROUND
  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.
  
  
  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.affiliation: Hirosaki Stroke and Rehabilitation Center, Hirosaki 036-8104, Japan.
authors.forename: Joji
authors.initials: J
authors.lastname: Hagii
authors.affiliation: 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.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Tomita
authors.affiliation: Hirosaki Stroke and Rehabilitation Center, Hirosaki 036-8104, Japan.
authors.forename: Norifumi
authors.initials: N
authors.lastname: Metoki
authors.affiliation: Division of Blood Transfusion Medicine, Hirosaki University Hospital, Hirosaki 036-8563, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Tamai
authors.affiliation: Hirosaki Stroke and Rehabilitation Center, Hirosaki 036-8104, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Saito
authors.affiliation: Hirosaki Stroke and Rehabilitation Center, Hirosaki 036-8104, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shiroto
authors.affiliation: Hirosaki Stroke and Rehabilitation Center, Hirosaki 036-8104, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Hitomi
authors.affiliation: Hirosaki Stroke and Rehabilitation Center, Hirosaki 036-8104, Japan.
authors.forename: Takaatsu
authors.initials: T
authors.lastname: Kamada
authors.affiliation: Hirosaki Stroke and Rehabilitation Center, Hirosaki 036-8104, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Seino
authors.affiliation: Hirosaki Stroke and Rehabilitation Center, Hirosaki 036-8104, Japan.
authors.forename: Koki
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Hirosaki Stroke and Rehabilitation Center, Hirosaki 036-8104, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Sasaki
authors.affiliation: Hirosaki Stroke and Rehabilitation Center, Hirosaki 036-8104, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Yasujima
authors.affiliation: 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.
authors.forename: Ken
authors.initials: K
authors.lastname: Okumura
mesh_terms: D000208:Acute Disease; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000627:therapeutic use; D002543:Cerebral Hemorrhage / Q000097:blood / Q000150:complications / Q000188:drug therapy; D065427:Factor Xa Inhibitors / Q000097:blood / Q000627:therapeutic use*; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D006470:Hemorrhage; D006801:Humans; D008297:Male; D010446:Peptide Fragments / Q000097:blood*; D011516:Prothrombin; D011517:Prothrombin Time; D000069552:Rivaroxaban / Q000097:blood / Q000627:therapeutic use*; D020521:Stroke / Q000097:blood* / Q000150:complications / Q000188:drug therapy*; D014859:Warfarin / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D005338:Fibrin Fibrinogen Degradation Products; D010446:Peptide Fragments; C036309:fibrin fragment D; C045879:prothrombin fragment 1.2; D014859:Warfarin; D011516:Prothrombin; D000069552:Rivaroxaban
keywords: Bleeding; Prothrombin fragment 1+2; Rivaroxaban; Stroke; Warfarin