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K-dependent proteins . The PCCs include 3-factor PCCs ( 3F-PCCs ) that contain factors II , IX and X ; and 4-factor PCCs ( 4F-PCCs ) that contain factors II , IX , VII and X , and varying levels of anticoagulant protein C and protein S . 8 , 11 – 13 Although multiple factor concentrates exist as therapeutic alternatives for allogeneic blood products , 4F-PCC was developed specifically for warfarin reversal , and contains factors II , VII , IX and X , as well as protein C and protein S , and small amounts of heparin . PCCs were initially developed for patients with haemophilia B , and initially was a 3F-PCC that contained factors II , IX and X but minimal factor VII levels , which is still available in some countries . Only one aPCC is available in most countries ; this is called factor eight ( VIII ) inhibitor bypassing activity ( FEIBA ) and contains mostly activated factor VII along with mainly non-activated factors II , IX and X . The advantages of the PCCs are they are stored at room temperature , have a long shelf life , do not require cross matching , are lyophilised and reconstituted with a small volume , and undergo significant purification , and so have a minimal risk of viral transmission and transfusion-related acute lung
11 , 12 injury .
Data supporting PCCs for DOAC reversal Studies supporting PCC administration for reversing DOAC anticoagulant effects in humans are based primarily on reports examining anticoagulation reversal in volunteers with clinically relevant endpoints . This includes laboratory testing of coagulation with standard haemostatic tests and restoration of thrombin generation as determined by endogenous thrombin potential . Other important supporting data for PCC reversal of DOACs include an increasing number of case reports and evaluation of ex vivo studies . Specific studies are reported as follows .
Animal studies for factor concentrates and DOAC reversal Although there are multiple animal studies evaluating PCC reversal of DOACs , there exists species variability and issues with non-human models . Therefore , animal data extrapolation to managing patients must be interpreted cautiously , especially with the increasing human data currently available . As an
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example , Lee et al examined databases on PCCs , aPCCs and recombinant activated factor VII ( rFVIIa ) in a literature review to compare their abilities to reverse DOACs . 14 They searched MEDLINE and EMBASE databases and found 11 animal studies and two human trials that met their specific predefined inclusion criteria . In animal studies , inconsistencies in the reversal abilities of PCC , aPCC and rFVIIa can be attributed to species variability and non-human differences in the affinity among various haemostatic factors and tissue factors . 14 Moreover , the authors note that differences in the affinity between species-specific clotting factors and anticoagulants that were initially designed to inhibit human factors may impose additional obstacles when comparing factor concentrates . 14
In vitro / ex vivo studies Marlu et al . evaluated the effect of haemostatic factor concentrates on reversing the anticoagulant effects and thrombin generation from ten males who received rivaroxaban ( 20mg ) or dabigatran ( 150mg ) in one oral administration with a two-week washout period in between . 15 Blood samples were collected before DOAC administration and two hours after using the factor concentrates including PCCs , aPCCs and rFVIIa , and evaluated thrombin generation parameters including the endogenous thrombin potential – area under the curve ( ETP-AUC ), peak thrombin generation , the lag-time , and time to peak . These important parameters are sensitive indicators of the ability to generate thrombin and thus clot formation . The authors reported that PCC consistently corrected ETP-AUC , whereas rFVIIa only modified the kinetic parameters . Activated PCC corrected all parameters for both of the anticoagulants . Although this study is widely quoted , the authors stated that clinical evaluation is needed regarding severe hemorrhage associated with the DOACs , and a careful risk – benefit evaluation regarding their use in this context is required . 15 Similar results were reported in another study examining the reversal of supra-therapeutic concentrations of Xa inhibition in human whole blood . 16 More importantly , there are human volunteer studies in anticoagulated patients that have shown the effectiveness of PCC dosing , and will be discussed in the following sections .
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Human studies : volunteers The first human volunteer study that evaluated the potential of 4F-PCCs to reverse the anticoagulant effect of rivaroxaban was reported by Eerenberg et al . They performed a randomised , double-blind , placebo-controlled evaluation of 12 male volunteers who received rivaroxaban 20mg twice daily ( n = 6 ) or dabigatran 150mg twice daily ( n = 6 ) for 2.5 days to achieve a steady state , followed by either a single bolus of 50IU / kg PCC or a similar volume of saline . 17 Rivaroxaban treatment prolonged the prothrombin time ( 15.8 ± 1.3 versus 12.3 ± 0.7 seconds ), which was completely and rapidly reversed to 12.8 ± 1.0 by 50IU / kg PCC . ETP was inhibited by rivaroxaban from 92 ± 22 % before anticoagulant administration , to 51 ± 22 %. Following PCC administration , the ETP normalised to 114 ± 26 %. Dabigatran increased the activated partial thromboplastin time , ecarin clotting time , and thrombin time . Administration of PCC did not restore either of the coagulation tests . 17
A follow-up study by Levi et al evaluated both a 4F-PCC and a 3F-PCC . This study was performed because until late 2013 , only 3F-PCCs and not 4F-PCCs were available in the United States . 18 This study was an open-label , single-centre , parallel-group comparison of the effect of a 3F-PCC ( Profilnine SD ) with that of a 4F-PCC ( Beriplex / Confidex / Kcentra ) on the pharmacodynamics of rivaroxaban in 35 volunteers who received four days of rivaroxaban 20mg twice daily to obtain supra-therapeutic steady-state concentrations . Volunteers were randomised to receive a single 50IU / kg bolus dose of 4F-PCC , 3F-PCC or saline four hours after the morning dose of rivaroxaban on day 5 , and the effects of these interventions on prothrombin time and thrombin generation were determined . Within 30 minutes , 4F-PCC reduced mean prothrombin time by 2.5 – 3.5 seconds , whereas 3F-PCC produced only a 0.6 – 1.0 second reduction . By contrast , 3F-PCC reversed rivaroxaban-induced changes in thrombin generation more than 4F-PCC , likely related to residual heparin in the 4F-PCC , protein C and S , and the sensitivity of the thrombin generation assay . 18
Human studies : volunteers with bleeding determination One novel investigation reported the
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