title: Inhibition of factor IXa by the pegnivacogin system during cardiopulmonary bypass: a potential substitute for heparin. A study in baboons.
abstract: OBJECTIVE
  Heparin and protamine are standard for anticoagulation and reversal for cardiopulmonary bypass (CPB). The REGADO biosciences protocol 1 (REG1) anticoagulant system, consisting of the Factor IXa (FIXa)-inhibitor pegnivacogin and its reversal agent (anivamersen), has been studied in patients undergoing coronary catheterization and in CPB in sheep and pigs. Prior to first human use in CPB, we wanted to test the safety and efficacy of REG1 in a primate model.
  
  
  METHODS
  Fourteen baboons undergoing 2 h of CPB followed by 1 h of reperfusion were studied. Three received heparin/protamine and 11 received 1 of 2 doses of pegnivacogin followed by anivamersen. Thrombin-generating capacity was tested in additional in vitro experiments.
  
  
  RESULTS
  Targeted drug levels and near-complete FIXa inhibition were achieved. Bypass was run uneventfully in all animals without any clotting in the circuit and bleeding was minimal in the two groups. However, in contrast to heparin-treated baboons, those receiving pegnivacogin/anivamersen displayed thrombi in the bypass cannulae upon cannulation and kidney cortical infarcts. Inter-species comparisons revealed that in the presence of high levels of FIXa inhibition, tissue factor-mediated thrombin generation in baboons was much higher than that in other species.
  
  
  CONCLUSIONS
  These data highlight the limitations of the baboon model for assessing factor-specific coagulation inhibitors during CPB. The justification for Phase 1 human studies using REG1 for CPB is unclear.
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou Department of Cardiovascular Surgery, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Bel
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou Department of Cardiovascular Surgery, Paris, France.
authors.forename: Wasseem
authors.initials: W
authors.lastname: Borik
authors.affiliation: Department of Haematology, Royal Brompton Hospital, London, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Davidson
authors.affiliation: Molecular Imaging Research Center, Commissariat à l'Energie Atomique, Fontenay-aux-Roses, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Helies
authors.affiliation: Molecular Imaging Research Center, Commissariat à l'Energie Atomique, Fontenay-aux-Roses, France CEA-INSERM U986, Commissariat à l'Energie Atomique, Fontenay-aux-Roses, France.
authors.forename: Lev
authors.initials: L
authors.lastname: Stimmer
authors.affiliation: Department of Cardiovascular Surgery, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Fremes
authors.affiliation: Regado Biosciences, Basking Ridge, NJ, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Zelenkofske
authors.affiliation: Regado Biosciences, Basking Ridge, NJ, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Rusconi
authors.affiliation: Cardiovascular Thrombosis, Duke Clinical Research Institute, Durham, NC, USA.
authors.forename: John
authors.initials: J
authors.lastname: Alexander
authors.affiliation: Department of Cardiothoracic Surgery, Royal Brompton Hospital, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Alexander
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou Department of Cardiovascular Surgery, Paris, France Université Paris Descartes, Sorbonne Paris Cité; INSERM U 970, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Menasché
authors.affiliation: Department of Cardiothoracic Surgery, Royal Brompton Hospital, London, UK j.pepper@rbht.nhs.uk.
authors.forename: John
authors.initials: J
authors.lastname: Pepper
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D052157:Aptamers, Nucleotide / Q000627:therapeutic use*; D002315:Cardiopulmonary Bypass; D003029:Coagulants / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D015949:Factor IXa / Q000037:antagonists & inhibitors; D005260:Female; D006493:Heparin / Q000627:therapeutic use; D007431:Intraoperative Complications / Q000517:prevention & control*; D009841:Oligonucleotides / Q000627:therapeutic use; D010215:Papio; D019990:Perioperative Care / Q000379:methods; D011183:Postoperative Complications / Q000517:prevention & control; D019106:Postoperative Hemorrhage / Q000517:prevention & control*; D011479:Protamines / Q000627:therapeutic use; D013927:Thrombosis / Q000209:etiology / Q000517:prevention & control*; D016896:Treatment Outcome
chemical_list: D000925:Anticoagulants; D052157:Aptamers, Nucleotide; D003029:Coagulants; D009841:Oligonucleotides; D011479:Protamines; C515724:RB 006; C515725:RB 007; D006493:Heparin; D015949:Factor IXa
keywords: Anticoagulation; Cardiopulmonary bypass; Factor lX; Pegnivacogin/Anivamersen; Thrombin generation