Table 3 Pre-clinical studies investigating the use of PCCs and aPCCs to reverse 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 0.335Â s per 10Â 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: | 50Â IU/kg aPCC associated with significant reduction in blood loss vs placebo group and those treated with 25Â IU/kg | aPCC (50Â IU/kg) is effective in reducing blood loss in anticoagulated pigs |
 25 or 50 | |||||
Lower-dose aPCC (25Â 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 100Â IU/kg PCC associated with significant reductions in blood loss vs placebo group and those treated with 25Â 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 (100Â IU/kg) led to overcorrection of thrombin generation | |||||