Effects of peri-operative bridging with low molecular weight heparins on coagulation during interruption of vitamin K antagonists: A mechanistic study

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. Materials and 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.