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

- At the day of the intervention clinical relevant residual anti-Xa activity is measured in the majority of patients.
- There is a perioperative rise in TG driven by FXI elevation, an impaired APC pathway and a rise in FVIIII and fibrinogen.
- For the perioperative hemostasis management the value of TG, to monitor the hemostatic balance, merits further study.

BackgroundBridging 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 methodsBlood 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.ResultsAt 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.ConclusionsResidual 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.