title: Augmentation of thrombin generation in neonates undergoing cardiopulmonary bypass.
abstract: BACKGROUND
  Factor concentrates are currently available and becoming increasingly used off-label for treatment of bleeding. We compared recombinant activated factor VII (rFVIIa) with three-factor prothrombin complex concentrate (3F-PCC) for the ability to augment thrombin generation (TG) in neonatal plasma after cardiopulmonary bypass (CPB). First, we used a computer-simulated coagulation model to assess the impact of rFVIIa and 3F-PCC, and then performed similar measurements ex vivo using plasma from neonates undergoing CPB.
  
  
  METHODS
  Simulated TG was computed according to the coagulation factor levels from umbilical cord plasma and the therapeutic levels of rFVIIa, 3F-PCC, or both. Subsequently, 11 neonates undergoing cardiac surgery were enrolled. Two blood samples were obtained from each neonate: pre-CPB and post-CPB after platelet and cryoprecipitate transfusion. The post-CPB products sample was divided into control (no treatment), control plus rFVIIa (60 nM), and control plus 3F-PCC (0.3 IU ml(-1)) aliquots. Three parameters of TG were measured ex vivo.
  
  
  RESULTS
  The computer-simulated post-CPB model demonstrated that rFVIIa failed to substantially improve lag time, TG rate and peak thrombin without supplementing prothrombin. Ex vivo data showed that addition of rFVIIa post-CPB significantly shortened lag time; however, rate and peak were not statistically significantly improved. Conversely, 3F-PCC improved all TG parameters in parallel with increased prothrombin levels in both simulated and ex vivo post-CPB samples.
  
  
  CONCLUSIONS
  Our data highlight the importance of prothrombin replacement in restoring TG. Despite a low content of FVII, 3F-PCC exerts potent procoagulant activity compared with rFVIIa ex vivo. Further clinical evaluation regarding the efficacy and safety of 3F-PCC is warranted.
authors.affiliation: Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Guzzetta
authors.forename: F
authors.initials: F
authors.lastname: Szlam
authors.forename: A S
authors.initials: AS
authors.lastname: Kiser
authors.forename: J D
authors.initials: JD
authors.lastname: Fernandez
authors.forename: A D
authors.initials: AD
authors.lastname: Szlam
authors.forename: T
authors.initials: T
authors.lastname: Leong
authors.forename: K A
authors.initials: KA
authors.lastname: Tanaka
mesh_terms: D001779:Blood Coagulation Factors / Q000627:therapeutic use*; D002315:Cardiopulmonary Bypass; D003198:Computer Simulation; D015942:Factor VIIa / Q000627:therapeutic use*; D005260:Female; D006470:Hemorrhage / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008954:Models, Biological; D011994:Recombinant Proteins / Q000097:blood / Q000627:therapeutic use; D013917:Thrombin / Q000627:therapeutic use*
chemical_list: D001779:Blood Coagulation Factors; D011994:Recombinant Proteins; C025667:prothrombin complex concentrates; C103587:recombinant FVIIa; D015942:Factor VIIa; D013917:Thrombin
keywords: bleeding; cardiopulmonary bypass; coagulation/anticoagulation; neonate; thrombin