Challenges with heparin-based anticoagulation during cardiopulmonary bypass in children: Impact of low antithrombin activity

Cedric Manlhiot, Colleen E. Gruenwald, Helen M. Holtby, Leonardo R. Brandão, Anthony K. Chan, Glen S. Van Arsdell, Brian W. McCrindle

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)444-450
Number of pages7
JournalJournal of Thoracic and Cardiovascular Surgery
Volume151
Issue number2
DOIs
StatePublished - Feb 1 2016
Externally publishedYes

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Antithrombins
Expressed Sequence Tags
Cardiopulmonary Bypass
Heparin
Thrombin
Postoperative Period
Thoracic Surgery
Linear Models
Regression Analysis
Newborn Infant
Weights and Measures

Keywords

  • antithrombin
  • congenital heart disease
  • heparin
  • surgery
  • thrombosis

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine

Cite this

Challenges with heparin-based anticoagulation during cardiopulmonary bypass in children : Impact of low antithrombin activity. / Manlhiot, Cedric; Gruenwald, Colleen E.; Holtby, Helen M.; Brandão, Leonardo R.; Chan, Anthony K.; Van Arsdell, Glen S.; McCrindle, Brian W.

In: Journal of Thoracic and Cardiovascular Surgery, Vol. 151, No. 2, 01.02.2016, p. 444-450.

Research output: Contribution to journalArticle

Manlhiot, Cedric ; Gruenwald, Colleen E. ; Holtby, Helen M. ; Brandão, Leonardo R. ; Chan, Anthony K. ; Van Arsdell, Glen S. ; McCrindle, Brian W. / Challenges with heparin-based anticoagulation during cardiopulmonary bypass in children : Impact of low antithrombin activity. In: Journal of Thoracic and Cardiovascular Surgery. 2016 ; Vol. 151, No. 2. pp. 444-450.
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T2 - Impact of low antithrombin activity

AU - Manlhiot, Cedric

AU - Gruenwald, Colleen E.

AU - Holtby, Helen M.

AU - Brandão, Leonardo R.

AU - Chan, Anthony K.

AU - Van Arsdell, Glen S.

AU - McCrindle, Brian W.

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N2 - 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.

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