PCCs are recommended in various guidelines for the emergency reversal of oral anticoagulation therapy, particularly in the presence of major bleeding and/or elevated INR [1
]. Despite these recommendations, the use of PCC remains low in many surgical units where emergency physicians continue to use human plasma because of its widespread availability, its low cost, its reasonable efficacy and lack of awareness of the guidelines [1
]. In contrast, PCC has been used for several years in our surgical unit, since before the introduction of recent guidelines recommending its use, both for anticoagulation reversal and for adjunctive treatment of acute hemorrhage, due to its high clinical efficacy.
PCCs may offer advantages over FFP for urgent reversal of oral anticoagulation therapy [24
]. Comparative studies have suggested that PCCs may provide more effective and rapid correction of INR than FFP, with a greater increase in clotting factors [25
]. PCCs can also be infused faster than human plasma, have a reduced volume of administration (and therefore, unlike FFP, are not associated with volume overload), are associated with a shorter preparation time (since some PCCs can be stored and reconstituted at room temperature, whereas FFP needs to be thawed prior to use), and do not require blood-group matching [1
In this study, PCC effectively normalized the INR in patients requiring emergency reversal of anticoagulation therapy. Moreover, the effect on the INR was similar to that reported in other studies in which PCCs (including Beriplex P/N®
) had been administered with vitamin K to reverse over-anticoagulation, treat anticoagulant-related bleeding, prepare anticoagulant-treated patients for emergency surgery, or manage other miscellaneous conditions in patients receiving oral anticoagulants [8
]. In particular, the relatively low dose of PCC (about 22 IU/kg) used here in the anticoagulant reversal group (baseline INR 2.8) is comparable with that used by Pabinger et al. during a recent prospective trial [30
], in which 93% of emergency coagulant reversal patients with baseline INR 2 to 3.9 achieved INR ≤1.3 after receiving 25 IU/kg of the same PCC. The mean INR of 1.5 achieved with PCC administration in anticoagulation reversal patients was below the target threshold of 1.7. PCC infusion also facilitated surgical procedures in this group, as evidenced by the absence of major perioperative bleeding and low use of concomitant blood component replacement therapy. Our data add further to the evidence for using PCC in vitamin K antagonist reversal at a time when guidelines continue to discuss this issue and PCC is still not available in many European centers.
PCC also restored the INR to nearly normal values (mean of 1.4 compared with a target of 1.2) in patients with acute severe bleeding. Furthermore, the bleeding episodes ceased within three hours of PCC administration in 30 out of 38 (79%) patients (4/11 patients with surgical bleeding and 26/27 patients with diffuse bleeding). This is a particularly important observation, as clinical data demonstrating the efficacy of PCC in patients with severe bleeding not associated with oral anticoagulation therapy are scarce, despite reports dating back more than a decade of their potential and their routine use in massive hemorrhage in many European countries [20
]. In a recent observational study conducted within a UK tertiary hospital, significant improvements in clotting times were reported with PCC in all but two of 20 patients with life-threatening bleeding [38
]. Only five of these patients were receiving oral anticoagulants; the remaining patients had severe perioperative or post-operative bleeds. Further expansion of this retrospective review demonstrated a considerable reduction in administration of other blood products during the 24 hours following PCC administration with partial or complete hemostasis achieved in 14 of 18 cases (78%) [39
]. Moreover, 83% of these patients received PCC at a lower dose (≤1,500 IU) than we used in the present study, so it is also an economically viable option.
The retrospective nature of the present study results in limitations, most notably the lack of a control group. Patients received conservative therapies in addition to PCC, and the contribution of these to the reversal of anticoagulation or cessation of bleeding cannot be ruled out. Also no blood sample of prothrombin was drawn immediately after PCC administration, reflecting that these data were collected in a real-life clinical situation, rather than being part of a prospective clinical trial. However, controlled studies are difficult to conduct in this setting - in particular in the situation where patients are suffering considerable blood loss, it would be unethical to include a control group receiving no hemostatic therapy. Additional units of FFP administered to bleeding patients were unlikely to be responsible for the increase in Quick results observed. INR values measured at baseline or after PCC administration were not significantly different between patients who did or did not receive FFP between the baseline and after PCC time points. Similarly, other additional conservative therapies, including intravenous vitamin K, were administered to some but not all patients, based on our experience with PCCs in emergency surgical patients over many years. Furthermore, intravenous administration of vitamin K would not be expected to have an impact within this four-hour period. No significant effects of these additional treatments on INR were seen in any patient group.
Another alternative to FFP for treatment of life-threatening bleeding is activated recombinant factor VII (rFVIIa). This is approved for use as a bypassing agent
in hemophiliac patients who have inhibitor antibodies to factor VIII or IX, but its use in a broader range of applications in life-threatening hemorrhage has been extensively reported [40
]. However, rFVIIa only replaces a single factor, and its principle mechanisms of action are dependent on adequate levels of other coagulation factors, in particular factors II and X, and fibrinogen [24
The data obtained in this study do not provide information on the speed of INR correction following administration of PCC; they merely represent clotting measurements at a specific time in a given setting (mainly after surgery has been performed and the patient has been transferred to the surgical ward for post-surgical care). However, the data do suggest that correction of INR and cessation of bleeding can be achieved with PCC in less than three hours. In a recent pharmacokinetic study, administration of PCC (Beriplex P/N®
; dose 50 IU factor IX/kg) to 15 healthy volunteers resulted in a maximal increase in coagulation factors II, VII, IX and X within five minutes of administration, suggesting that PCC has a rapid onset of action [41
]. This increase in clotting factors remained stable over the next six hours and declined slowly over the next six days. One factor that will influence the speed of INR correction with PCCs is body temperature. Hypothermia inhibits the synthesis of fibrinogen and the initiation phase of thrombin generation [42
] so normothermia is important for effective hemostasis [42
]; all patients were normothermic at the beginning of PCC application in our study.
The magnitude of INR reduction in bleeding patients was not as large as that seen in the anticoagulation reversal group. This is likely to be due largely to a lower baseline INR in the bleeding group (1.7 vs 2.8 in the anticoagulation reversal group), but it could also be attributed to a higher volume application in the reversal patients, different consumption of coagulation factors or cardiocirculatory instability following activation of coagulation.
The dose of PCC administered was significantly higher in bleeding patients than in anticoagulation reversal patients. This was probably because bleeding patients were incurring major blood loss, whereas anticoagulation reversal patients were only receiving PCC as bleeding prophylaxis. Therefore, higher doses were administered in an attempt to control a more urgent and immediate clinical situation. As described above, the target INR in bleeding patients was also lower than in the anticoagulation reversal patients, necessitating higher PCC doses in an attempt to achieve the lower target.
Measurements of serum creatinine and bilirubin did not suggest any detrimental effects of PCCs on kidney or liver function. With the exception of hemoglobin in bleeding patients and CRP in reversal patients, laboratory safety parameters were not increased from baseline values following infusion of PCC. The increase in hemoglobin concentrations in the bleeding group may be explained by the higher and more frequent use of RBC concentrates compared with the anticoagulation reversal group and by the eventual cessation of bleeding in these patients. Unsurprisingly, baseline hemoglobin levels were lower in bleeding patients due to the severe blood loss incurred. Baseline serum creatinine and bilirubin concentrations were also lower in bleeding patients, most likely for the same reason. The significant increase of CRP concentration in the anticoagulation reversal patients is probably due to the operative procedure that followed optimization of coagulation. In contrast, bleeding patients did not show an increase in CRP after PCC application, despite receiving higher doses of PCC on average. It therefore seems highly unlikely that PCCs induce inflammatory activation.
Although there is a small, and to a certain degree inherent, risk of thromboembolic events when PCCs are used for anticoagulation reversal [2
], there was no evidence of any thromboembolic complications in this study. There was also no evidence of viral transmission, something that is very rarely reported with PCC therapy, in any of the patients in this study [2
]. Effective virus inactivation and reduction processes are reported for the study drug, which make transmission of infective agents, including prions, less likely [19
]. These results and those reported in other similar studies suggest that Beriplex P/N®
has a favorable safety profile with a low risk of thromboembolic complications [8