Acquired coagulopathy following trauma is an important determinant of outcome. Coagulopathic patients, including those with head injury, experience worse outcomes than patients with the same injury severity but no clotting disturbance.9
Therefore, a major clinical need exists for modalities that quickly and effectively reverse the dilutional coagulopathy occurring over the course of trauma treatment. Pharmacological treatment options consist of antifibrinolytics, fresh whole blood and plasma, FFP, cryoprecipitate, and coagulation factor concentrates.2,9,33
This is the first study to compare PCC with FFP for correction of coagulopathy under conditions of haemodilution and haemorrhage in a porcine trauma model.
Time to haemostasis and blood loss following either femur or spleen injury were both significantly diminished by PCC compared with FFP treatment. The ineffectiveness of FFP with respect to these primary endpoints appears to reflect persistent coagulation factor deficiency after administration of a standard FFP dose (15 ml kg−1
) comparable to the typical adult dose used in clinical practice, as well as after a much higher dose (40 ml kg−1
In the absence of ongoing coagulation factor consumption or loss, a dose of 10–15 ml kg−1
FFP is expected to raise factor levels by 25% in humans.33
In the porcine model, smaller increases were observed, possibly due to the use of human coagulation factor-deficient plasma in the porcine coagulation factor assays. The availability of species-specific coagulation factor-deficient plasma would be needed to assess the contribution, if any, of assay method to the relatively small increases in coagulation factor levels following FFP administration. On the other hand, the normalization of FII, FVII, and FX levels by PCC in the study animals suggests that assay inaccuracy may not explain the lack of FFP effect in restoring levels of those coagulation factors. In any case, high-dose FFP proved to be no more effective than the standard dose in speeding haemostasis and restricting blood loss after bone injury.
In patients, greater restoration of coagulation factor levels with FFP is hampered by the risk of fluid overload. Additionally, during preparation of FFP for clinical use, coagulation factors are diluted by ~15% with citrate, and further losses are believed to occur during freezing and thawing.35,36
Due to the high coagulation factor concentrations in PCC, FII, FVII, and FX rebounded fully to baseline levels after PCC administration in the model system. The small FIX rise produced by PCC was similar in magnitude to that by 15 ml kg−1
porcine FFP. This observation reflects the comparatively low FIX dose in the administered 0.8 ml kg−1
PCC volume. Whereas the doses of the other three coagulation factors in the administered PCC volume were 2–4-fold those in 15 ml kg−1
porcine FFP, the corresponding dose of FIX was 33% lower. In any case, PCC did produce a small but statistically significant increase in FIX which, in concert with full normalization of the other three coagulation factors, proved sufficient to enhance haemostasis.
Another advantage of PCC is viral safety. Most FFP preparations are not subjected to viral inactivation. Prepared from plasma screened by polymerase chain reaction, Beriplex P/N is pasteurized and nanofiltrated to eliminate viruses.30,37
In clinical trials there has been no evidence of viral transmission following Beriplex P/N administration.20,31
Although the coagulation factor increase was relatively small, FFP did partially reverse the haemodilution-induced PT prolongation. PCC, however, entirely normalized PT. These findings are consistent with prior data. In a prospective audit of FFP transfusion in patients with mild PT prolongation (13–17 s), halfway normalization of PT was accomplished in only 15% of cases and full correction in <1%.38
In contrast, Beriplex P/N administration effectively normalized PT in critically ill patients with moderately reduced coagulation activity.39
In a porcine model of dilutional coagulopathy similar to that in the present study, PCC plus fibrinogen normalized PT, while normal saline was ineffective.40
It is generally recognized that both PT and aPTT are insensitive measures for detecting hypocoagulant conditions.36
The value of SBT in monitoring the coagulation system and directing therapeutic inventions remains to be established. In this study, the SBT results closely coincided with those for time to haemostasis and volume of blood loss after bone or spleen trauma. While platelet function is a major determinant of SBT, the coagulation cascade may also play a role. In rats, the direct thrombin inhibitor melagatran has been shown to prolong SBT, and the prolongation could be reversed by PCC.41
TGAs are being actively investigated for their utility in characterizing and monitoring both hypocoagulable and hypercoagulable states. In the present study, TGA data were consistent with the bleeding endpoint results. Thus, PCC normalized the thrombin peak, whereas FFP had negligible effect.
TGA has been used to monitor the response to FFP administration in surgery patients.36
Thrombin generation parameters and fibrinogen levels were higher in post-transfusion plasma from patients who stopped bleeding than from those with ongoing haemorrhage. An in vitro
study has demonstrated the ability of PCC to restore thrombin generation in plasma from orally anticoagulated patients.42
TGA has also been used to monitor the effects of activated PCC.25,43,44
Both platelet count and fibrinogen concentration were substantially reduced by haemodilution and did not recover in response to PCC or FFP treatment. However, the platelet number and fibrinogen concentration were not below the thresholds to sustain the competence of the coagulation system, as demonstrated by the ability of PCC to control femur and spleen bleeding.
The porcine model of dilutional coagulopathy employed in the present study has been previously established for evaluating the effectiveness of i.v. fluids in normalizing coagulation function and reducing bleeding resulting from a subsequent haemorrhagic challenge in the form of a standardized experimental femur or spleen injury.29
The model simulates clinical situations in which, after initial traumatic haemorrhagic shock and resuscitation, haemostasis has been secured, but dilutional coagulopathy needs to be corrected to prevent excessive bleeding during further surgical interventions the patient may require. A similar porcine dilutional coagulopathy model has been described, in which placebo or coagulation factors were administered prior to a standardized hepatic laceration, and subsequent blood loss and survival were assessed.40
In this porcine trauma model of dilutional coagulopathy and haemorrhage, PCC proved superior to FFP in normalizing PT, SBT, and peak thrombin generation and controlling bleeding. These findings support a potential role for PCC in coagulopathic trauma and surgery patients. In view of the unmet clinical need for more efficacious haemostatic agents in such patients, clinical studies are now justified to confirm the observed favourable effects of PCC in the present preclinical model system.