title: Effects of peri-operative bridging with low molecular weight heparins on coagulation during interruption of vitamin K antagonists: A mechanistic study.
abstract: BACKGROUND
  Bridging with low molecular weight heparins (LMWH) is used in patients undergoing invasive procedures that require interruption of vitamin K antagonists (VKA). Little is known on the mechanisms underlying observed thrombotic and bleeding events. In this exploratory study we investigated the interactive effects of the co-administration of VKA, LMWH and surgery on coagulation.
  
  
  METHODS
  Blood was sampled daily from day -3 to day +5 in 13 patients. In addition to measurement of INR, anti-Xa activity, thrombin generation (TG) testing and assessment of its protein determinants was performed.
  
  
  RESULTS
  At the time of intervention the mean INR was 1.0 (SD 0.1, range 0.9-1.2); the mean residual anti-Xa level was 0.19 units/ml (SD 0.20 units/ml, range<0.05-0.60). The intervention caused a 2-3 fold increase in TG at day 0. Factor (F) XI had the strongest correlation with TG (peak and endogenous thrombin potential (ETP)) (r=0.6; p=0.02). Thrombomodulin-induced reduction of ETP increased from 10.0% (SD 9.2) at day -3 to 18.2% (SD 9.5) at day 0, p=0.02. After surgery, FVIII (175.9%(SD 58.9% to 246.7% (SD 71.4%); p=0.002) and fibrinogen (4.3 g/L (SD 1.1 g/L) to 5.6 g/L (SD 1.7 g/L); p=0.003) were significantly increased.
  
  
  CONCLUSIONS
  Residual anti-Xa activity was present in 84.6% of patients at the day of the intervention. Three prothrombotic mechanisms were exposed: FXI dependent TG, reduced activity of the activated protein C pathway and postoperative rises in FVIII and fibrinogen. For the perioperative management the value of TG merits further study.
authors.affiliation: Laboratory for Clinical Thrombosis and Hemostasis, Maastricht University, Universiteitssingel 50 6229 ER Maastricht, The Netherlands. Electronic address: p.eijgenraam@ziggo.nl.
authors.forename: Pieter
authors.initials: P
authors.lastname: Eijgenraam
authors.affiliation: Laboratory for Clinical Thrombosis and Hemostasis, Maastricht University, Universiteitssingel 50 6229 ER Maastricht, The Netherlands; Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre+, Joseph Bechlaan 113 6229GR Maastricht, The Netherlands.
authors.forename: Hugo
authors.initials: H
authors.lastname: Ten Cate
authors.affiliation: Central diagnostic laboratory, Maastricht University Medical Centre+, Joseph Bechlaan 113 6229GR Maastricht, The Netherlands.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Henskens
authors.affiliation: Philips Group Innovation Research, High Tech Campus 34, 5656 AE Eindhoven, The Netherlands.
authors.forename: Rene
authors.initials: R
authors.lastname: van den Ham
authors.affiliation: Laboratory for Clinical Thrombosis and Hemostasis, Maastricht University, Universiteitssingel 50 6229 ER Maastricht, The Netherlands; Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre+, Joseph Bechlaan 113 6229GR Maastricht, The Netherlands.
authors.forename: Arina
authors.initials: A
authors.lastname: Ten Cate-Hoek
mesh_terms: D000074:Acenocoumarol / Q000627:therapeutic use*; D000368:Aged; D000925:Anticoagulants / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects; D001780:Blood Coagulation Tests; D005169:Factor VIII / Q000032:analysis; D005260:Female; D005340:Fibrinogen / Q000032:analysis; D006470:Hemorrhage / Q000097:blood / Q000209:etiology; D006495:Heparin, Low-Molecular-Weight / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019990:Perioperative Care; D013514:Surgical Procedures, Operative; D013923:Thromboembolism / Q000097:blood / Q000209:etiology; D014812:Vitamin K / Q000037:antagonists & inhibitors
chemical_list: D000925:Anticoagulants; D006495:Heparin, Low-Molecular-Weight; D014812:Vitamin K; D005169:Factor VIII; D005340:Fibrinogen; D000074:Acenocoumarol
keywords: Acenocoumarol; Blood coagulation factors; Coagulation; General surgery; Low-molecular-weight-heparin