Bleeding is a serious complication after pediatric
cardiopulmonary bypass (CPB) that is associated with an increase in perioperative morbidity and mortality. Four-factor
prothrombin complex concentrates (4F-PCCs) have been used off-label to supplement transfusion protocols for
bleeding after CPB in adults; however, data on their use in neonates are limited. In this study, we hypothesized that 4F-PCCs administered ex vivo to neonatal plasma after CPB will increase
thrombin generation.
METHODS: Fifteen neonates undergoing complex cardiac repairs requiring CPB were enrolled in this prospective study. Arterial blood was obtained after
anesthesia induction but before CPB (baseline), after CPB following
heparin reversal, and after our standardized transfusion of a quarter of a platelet
apheresis unit (approximately 20 mL·kg) and 3 units of cryoprecipitate. Kcentra (CSL Behring), a 4F-PCC with nonactivated
factor VII (FVII), and
factor 8 inhibitor bypassing activity (
FEIBA; Baxter Healthcare Corporation), a 4F-PCC with activated FVII, were added ex vivo to plasma obtained after CPB to yield concentrations of 0.1 and 0.3 IU·mL. Calibrated automated thrombography was used to determine
thrombin generation for each sample.
RESULTS: The addition of Kcentra to plasma obtained after CPB resulted in a dose-dependent increase in the median (99% confidence interval) peak amount of
thrombin generation (42.0 [28.7-50.7] nM for Kcentra 0.1 IU·mL and 113.9 [99.0-142.1] nM for Kcentra 0.3 IU·mL). The rate of
thrombin generation was also increased (15.4 [6.5-24.6] nM·min for Kcentra 0.1 IU·mL and 48.6 [29.9-66.6] nM·min for Kcentra 0.3 IU·mL). The same was true for
FEIBA (increase in peak: 39.8 [27.5-49.2] nM for
FEIBA 0.1 IU·mL and 104.6 [92.7-124.4] nM for
FEIBA 0.3 IU·mL; increase in rate: 17.4 [7.4-28.8] nM·min
FEIBA 0.1 IU·mL and 50.5 [26.7- 63.1] nM·min
FEIBA 0.3 IU·mL). In the posttransfusion samples, there was a significant increase with Kcentra in the median (99% confidence interval) peak amount (41.1 [21.0-59.7] nM for Kcentra 0.1 IU·mL and 126.8 [106.6- 137.9] nM for Kcentra 0.3 IU·mL) and rate (18.1 [-6.2 to 29.2] nM·min for Kcentra 0.1 IU·mL and 53.2 [28.2-83.1] nM·min for Kcentra 0.3 IU·mL) of
thrombin generation. Again, the results were similar for
FEIBA (increase in peak: 43.0 [36.4-56.7] nM for
FEIBA 0.1 IU·mL and 109.2 [90.3-136.1] nM for
FEIBA 0.3 IU·mL; increase in rate: 25.0 [9.1-32.6] nM·min for
FEIBA 0.1 IU·mL and 59.7 [38.5-68.7] nM·min for
FEIBA 0.3 IU·mL). However,
FEIBA produced in a greater median reduction in lag time of
thrombin generation versus Kcentra in samples obtained after CPB (P = 0.003 and P = 0.0002 for
FEIBA versus Kcentra at 0.1 and 0.3 IU·mL, respectively) and in samples obtained after transfusion (P < 0.0001 for
FEIBA versus Kcentra at 0.1 and 0.3 IU·mL).
CONCLUSIONS: After CPB,
thrombin generation in neonatal plasma was augmented by the addition of 4F-PCCs. The peak amount and rate of
thrombin generation were enhanced in all conditions, whereas the lag time was shortened more with
FEIBA. Our findings suggest that the use of 4F-PCCs containing activated FVII may be an effective adjunct to the initial transfusion of platelets and cryoprecipitate to augment coagulation and control
bleeding in neonates after CPB.