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Table 3 Pre-clinical studies investigating the use of PCCs and aPCCs to reverse dabigatran-induced anticoagulation

From: Efficacy of prothrombin complex concentrates for the emergency reversal of dabigatran-induced anticoagulation

Reference Study design Dose Main results Conclusion
Dabigatran (mg/kg) PCC (IU/kg)
Zhou et al., 2011 [54] Murine intracerebral haemorrhage model 9.0 100 Haematoma volume: PCC effectively prevented haematoma growth and significantly reduced 24-h mortality
 Post-dabigatran: 17.0 ± 4.1 mm3
 Post-PCC: 11.7 ± 3.0 mm3
Mortality:
 Control animals: 30 %
 PCC-treated mice: 4 %
Pragst et al., 2012 [55] Leporine standardised kidney injury model 0.4 20, 35 or 50 Blood loss: PCC resulted in a dose-dependent reduction in blood loss and acceleration in haemostasis. At the highest dose, blood loss was normalised in all animals. All doses of PCC successfully treated dabigatran-induced anticoagulation at plasma concentrations similar to those seen in patients receiving dabigatran
 Control: 1.0–7.2 ml
 Post-dabigatran: mean 29 ml
 Post-PCC: decreased by 5.44 ml per 10 IU/kg PCC
No change in aPTT
PT shortened by 0.335 s per 10 IU/kg PCC
Herzog et al., 2014 [56] Leporine arterial venous shunt model 0, 0.075, 0.2, 0.45 0, 5 or 300 Bleeding time: Dabigatran-induced bleeding was effectively reversed by PCC. The thromboembolic risk associated with PCC administration appeared to be reduced due to the persistence of dabigatran in the plasma
 Increasing PCC doses shortened time to haemostasis for rabbits treated with 0.2 mg/kg dabigatran
 No dose of PCC could reverse the effects of 0.45 mg/kg dabigatran on time to haemostasis
Thrombosis:
 The frequency of pulmonary thrombi decreased progressively with increasing concomitant dabigatran dose
Grottke et al., 2014 [49] Porcine liver trauma model 30 (daily oral dose) then intravenous infusion to reach supratherapeutic plasma concentration PCC: PCC: Both PCC and aPCC diminished the effects of dabigatran, restoring ROTEM® parameters and PT to 80–90 % of baseline
 30 or 60  No effect on aPTT
aPCC: aPCC:
 30 or 60  No effect on aPTT
Honickel et al., 2015 [57] Porcine polytrauma model 30 (daily oral dose) then intravenous infusion to reach supratherapeutic plasma concentration aPCC: 50 IU/kg aPCC associated with significant reduction in blood loss vs placebo group and those treated with 25 IU/kg aPCC (50 IU/kg) is effective in reducing blood loss in anticoagulated pigs
 25 or 50
Lower-dose aPCC (25 IU/kg) had an initial effect that was not sustained, suggesting stoichiometric excess of prothrombin vs dabigatran may be required
Honickel et al., 2015 [18] Porcine polytrauma model 30 (daily oral dose) then intravenous infusion to reach supratherapeutic plasma concentration 30 or 60 Significant decreases in PT, CT and CFT Three-factor and four-factor PCCs are similarly effective for dabigatran reversal
Honickel et al., 2015 [58] Porcine polytrauma model 30 (daily oral dose) then intravenous infusion to reach supratherapeutic plasma concentration 25, 50 or 100 50 and 100 IU/kg PCC associated with significant reductions in blood loss vs placebo group and those treated with 25 IU/kg PCC can be effective in reducing blood loss in anticoagulated pigs
High doses may induce a procoagulant state
Low doses may be ineffective
High-dose PCC (100 IU/kg) led to overcorrection of thrombin generation
  1. aPCC activated prothrombin complex concentrate, aPTT activated partial prothrombin time, CFT clot formation time, CT clotting time, PCC prothrombin complex concentrate, PT prothrombin time