In this randomized placebo-controlled animal model study, PCC significantly alleviated suture hole bleeding after CPB. Such bleeding may simulate the diffuse oozing occurring in many CPB patients who experience excessive postoperative blood loss. The PCC-mediated reduction in suture hole bleeding was accompanied by normalization of SBT and a pronounced increase in peak thrombin generation.
This pilot study is limited by its relatively small size. The results need to be confirmed in further investigations, and the optimal PCC regimen for use in CPB remains to be delineated. The thrombogenic potential of PCC in CPB must also be characterized.
PCC displayed haemostatic efficacy in this study notwithstanding a reduction in median platelet concentration to 254×109
. In a recent study of haemodilutional coagulopathy and trauma in pigs,22
PCC displayed haemostatic efficacy, despite an even more pronounced platelet reduction to a mean of 133×109
Additionally, in a clinical study of 16 consecutive intensive care unit patients, cessation of bleeding was achieved after PCC administration in all cases, despite a mean nadir platelet level of 149×109
Since decreases in platelet function and number are a hallmark of CPB, one potential attraction of PCC might be that its effectiveness does not appear to be limited by comparatively low platelet counts.
A report of two cardiac surgery patients with liver dysfunction documented successful normalization of INR and cessation of excessive bleeding after infusion of Beriplex P/N.8
In a retrospective study, Beriplex P/N was administered to seven cardiac surgery patients, five undergoing coronary artery bypass graft and two valve procedures, who were experiencing bleeding refractory to FFP, platelets, and cryoprecipitate.9
Beriplex P/N shortened PT by 25% and activated partial thromboplastin time by 38%, and partial or complete haemostasis was achieved in all six patients with recorded results for bleeding. In a newly reported randomized trial of 40 patients undergoing semi-urgent cardiac surgery with CPB, Beriplex P/N was more effective than FFP for reversal of oral anticoagulant therapy.10
In previous clinical trials, Beriplex P/N has also proven effective for emergency reversal of oral anticoagulant therapy outside the setting of CPB.13,25
Additionally, Beriplex P/N showed haemostatic efficacy among patients with clotting factor deficits due to severe liver disease who required rapid haemostasis because of bleeding or the need for urgent surgical or invasive diagnostic procedures.26
In trauma, as in CPB, administered fluids can produce dilutional coagulopathy. In a porcine trauma model, PCC reduced blood loss from traumatic bone and spleen injuries compared with FFP14
and accelerated haemostasis after spleen trauma compared with recombinant activated FVII (rFVIIa).22
In those studies, PCC also increased peak thrombin generation vs
FFP and rFVIIa. Reduction in blood loss also resulted from combination treatment with PCC and fibrinogen in a porcine model of haemodilutional coagulopathy and uncontrolled liver bleeding.27
Similarly, in a rabbit model of dilutional coagulopathy, PCC reduced blood loss and augmented peak thrombin generation after kidney trauma compared either with saline placebo or rFVIIa.28
Importantly, at effective dosages, PCC, unlike rFVIIa, showed no evidence of thrombogenicity in that study, as evaluated using the Wessler stasis model. Available clinical evidence also suggests that the thrombogenic potential of PCC is low. In a pharmacovigilance study, the estimated incidence of thrombotic events among patients receiving PCC was 1.0 per 105
infusions (CI, 0.1–3.6 per 105
rFVIIa has been evaluated in a recent randomized clinical trial of 179 cardiac surgery patients with postoperative bleeding.30
The primary study endpoint was the incidence of critical serious adverse events, defined as either death or thromboembolic complications. Owing to a trend towards increasing critical serious adverse events after rFVIIa treatment (odds ratio, 1.67; CI, 0.50–5.47), the investigators cautioned that further clinical trials are required.
The pig has been extensively utilized as a model for evaluating haemostasis after administration of human PCC14,21,22
and human rFVIIa.22,31–38
Certain uncertainties are inherent in such studies. The activity, bioavailability, or both of the human protein might be attenuated in the porcine host.34
Assays of PT or thrombin generation optimized for measurements of human samples may yield disparate results in the pig. For instance, PT measured with a porcine-specific assay is greater by over three-fold than with the standard assay designed for human specimens.37,39
The porcine-specific assay revealed a nearly 50% prolongation of PT during hypothermia, while no effect was detectable by the standard assay method.39
It is possible that the use of the standard assay may account for the relatively small impact of CPB on PT in the present study, despite the substantial increase in blood loss observed after CPB and saline infusion. In any case, large absolute differences in PT assay values may not translate into major differences in the observed relative effects of human haemostatic proteins in the pig model. Thus, despite an over three-fold absolute PT difference at baseline, the average relative shortening of PT by 90 µg kg−1
human rFVIIa was comparable when measured by standard assay (64%) vs
the porcine-specific method (51%).37
The thrombin generation assay used in the present study was optimized for human samples, and the possibility cannot be excluded of differences in results compared with those that might have been generated by a porcine-specific method. Nonetheless, assay differences could not have affected bleeding, and the observed increase in thrombin generation by PCC relative to saline was accompanied by a corresponding decrease in blood loss. Furthermore, in two pig studies of dilutional coagulopathy and trauma, human PCC augmented thrombin generation compared with human rFVIIa and with both standard- and high-dose porcine PCC.14,22
In both studies, corresponding acceleration of haemostasis by PCC vs
those control agents was demonstrated.
In light of the data reviewed above, PCC appears to be a versatile haemostatic agent suitable for use in indications involving multiple clotting factor deficiencies. Further clinical studies are needed to define the appropriate role for PCC in CPB. The present results provide encouragement to embark upon such studies.