title: Challenges with heparin-based anticoagulation during cardiopulmonary bypass in children: Impact of low antithrombin activity.
abstract: BACKGROUND
  Antithrombin is one of the main natural coagulation system inhibitors. It is potentiated by heparin, and may be a key component of heparin response, particularly in infants aged <1 year. We sought to determine the impact of baseline antithrombin activity on response to heparin and thrombin generation during cardiopulmonary bypass (CPB).
  
  
  METHODS
  Secondary analysis was performed using linear regression analyses, which combined patients from a trial of individualized versus weight-based heparin management for 90 infants aged <1 year undergoing cardiac surgery.
  
  
  RESULTS
  Mean baseline antithrombin activity was 0.69 ± 0.16 U/mL, and it was lower in neonates than in older infants (0.57 ± 0.15 vs 0.77 ± 0.12 U/mL; P < .001). Lower baseline antithrombin activity was associated with lower postheparin anti-Xa activity (EST [SE]: +0.47 (0.19) U/mL per 100 U/kg heparin; P = .01) and higher heparin doses during surgery (EST [SE]: +51 (17) U/kg per hour; P = .003). The administration of fresh frozen plasma attenuated the effect of low baseline antithrombin activity (interaction P value = .009). Patients with lower anti-Xa activity recorded during CPB had higher levels of thrombin-antithrombin complex (EST [SE]: +12.8 (4.7) ng/mL per -1 U/mL anti-Xa; P = .006); prothrombin activation fragment 1.2 (EST [SE]: +0.13 (0.07) log pg/mL per -1 U/mL anti-Xa; P = .06); and D-dimer (EST [SE]: -0.25 (0.09) log ng/mL per -1 U/mL anti-Xa; P = .009) in the postoperative period after adjustment for baseline antithrombin activity, duration of CPB, amount of fresh frozen plasma and heparin used throughout surgery in multivariable models.
  
  
  CONCLUSIONS
  Low circulating antithrombin activity is associated with lower heparin efficacy, which ultimately leads to a lower ability to suppress thrombin generation during CPB. Determination of risk factors for heparin resistance, and potentially, antithrombin replacement therapy, may individualize and improve anticoagulation treatment.
authors.affiliation: Labatt Family Heart Centre, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Cedric
authors.initials: C
authors.lastname: Manlhiot
authors.affiliation: Labatt Family Heart Centre, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Colleen E
authors.initials: CE
authors.lastname: Gruenwald
authors.affiliation: Labatt Family Heart Centre, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Holtby
authors.affiliation: Division of Haematology/Oncology, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Leonardo R
authors.initials: LR
authors.lastname: Brandão
authors.affiliation: Division of Pediatric Hematology/Oncology, Department of Pediatrics, McMaster University, McMaster Children's Hospital, Hamilton, Ontario, Canada.
authors.forename: Anthony K
authors.initials: AK
authors.lastname: Chan
authors.affiliation: Labatt Family Heart Centre, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Glen S
authors.initials: GS
authors.lastname: Van Arsdell
authors.affiliation: Labatt Family Heart Centre, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada. Electronic address: brian.mccrindle@sickkids.ca.
authors.forename: Brian W
authors.initials: BW
authors.lastname: McCrindle
mesh_terms: D000367:Age Factors; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects; D058833:Antithrombin Proteins / Q000378:metabolism*; D001777:Blood Coagulation / Q000187:drug effects*; D001780:Blood Coagulation Tests; D016913:Blood Component Transfusion; D016063:Blood Loss, Surgical / Q000517:prevention & control; D006348:Cardiac Surgical Procedures / Q000009:adverse effects; D002315:Cardiopulmonary Bypass / Q000009:adverse effects; D004351:Drug Resistance; D015951:Factor Xa / Q000378:metabolism; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D006493:Heparin / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016014:Linear Models; D008297:Male; D015999:Multivariate Analysis; D010446:Peptide Fragments / Q000097:blood; D010949:Plasma; D019106:Postoperative Hemorrhage / Q000517:prevention & control; D011516:Prothrombin; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D013917:Thrombin / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000925:Anticoagulants; D058833:Antithrombin Proteins; D005338:Fibrin Fibrinogen Degradation Products; D010446:Peptide Fragments; C036309:fibrin fragment D; C045879:prothrombin fragment 1.2; D011516:Prothrombin; D006493:Heparin; D013917:Thrombin; D015951:Factor Xa
keywords: antithrombin; congenital heart disease; heparin; surgery; thrombosis