Unfractionated Heparin Activity Measured by Anti-Factor Xa Levels Is Associated With the Need for Extracorporeal Membrane Oxygenation Circuit/Membrane Oxygenator Change

Abstract

Rationale Traditional measures of anticoagulation, including activated clotting time (ACT), have been poorly correlated with circuit thrombosis in pediatric patients supported with extracorporeal membrane oxygenation (ECMO). Objective Investigate whether anti-Factor Xa levels are associated with the need for change of circuit/membrane oxygenator secondary to thrombus formation in pediatric patients. Design and Settings Retrospective single institution study. Patients and Methods Retrospective record review of 62 pediatric patients supported with ECMO from 2009-2011. Data on standard demographic characteristics, indications for ECMO, duration of ECMO, ACT measurements, anti-Factor Xa measurements, and heparin infusion rate (HIR) were collected. Generalized linear models were used to associate anti-Factor Xa concentrations and need for change of either entire circuit/membrane oxygenator secondary to thrombus formation. Measurements and Main Results Sixty two patients met study inclusion criteria. No circuit change was required in 45/62 (Group NC). 17/62 patients required change of circuit/membrane oxygenator due to thrombus formation (Group CC). Multivariate analysis of daily anti-Factor Xa measurements throughout duration of ECMO support estimated a mean anti-Factor Xa concentration of 0.20 IU/ml [95% CI: (0.16, 0.24)] in Group NC that was significantly higher than the estimated 0.13 IU/ml [95% CI: (0.12, 0.14)] in Group CC (p = 0.001). A 0.01 IU/ml decrease in anti-Factor Xa increased odds of need for circuit/membrane oxygenator change by 5% (OR = 1.105 95% CI: 1.00, 1.10), p=0.044). Based upon the observed anti-Factor Xa concentrations, Group CC had 41% increased odds for requiring circuit/ membrane oxygenator change compared to Group NC (OR=1.41, 95% CI: 1.01, 1.96, p = 0.044). Mean daily ACT measurement (p = 0.192) was not different between groups, but mean daily HIR (p <0.001) was significantly different between the two groups. Conclusion Higher anti-Factor Xa concentrations were associated with freedom from circuit/membrane oxygenator change due to thrombus formation in pediatric patients during ECMO support. ACT measurements did not differ significantly between groups with or without circuit/membrane oxygenator change. This is the first study to link anti-Factor Xa concentrations with a clinically relevant measure of thrombosis in pediatric patients during ECMO support. Further prospective study is warranted.

Quantitative measurement of heparin in comparison with conventional anticoagulation monitoring and the risk of thrombotic events in adults on extracorporeal membrane oxygenation

“…In hospitalized patients who required heparin for cardiovascular indications, aPTT and antiXa levels were discordant the majority of the time; high aPTT/in-range antiXa discordance predicted major bleeding and mortality (4). In pediatric ECMO patients, lower antiXa levels (but not ACT or aPTT levels) were associated with circuit thrombosis, although hemostatic changes that occur during early life makes it difficult to generalize this observation to adults (5). …”

Overview of Pharmacological Considerations in Extracorporeal Membrane Oxygenation

“…Anticoagulation monitoring studies have demonstrated a lack of correlation between the anti-Xa test and ACT or aPTT in all patient populations. 55,56 Irby and colleagues 57 demonstrated an association between subtherapeutic anti-Xa levels and an increased need for oxygenator exchanges, suggesting potential benefi ts of the anti-Xa test. The relationship between ACT and aPTT has also shown inconsistencies; better correlations have been found between heparin doses and aPTT than between heparin doses and ACT.…”

Interference in the anti‐Xa heparin activity assay due to hemolysis and icterus during pediatric extracorporeal life support

“…Heparin is difficult to monitor in these patients for a variety of reasons including low antithrombin levels, low coagulation factor levels, lupus inhibitors, hemolysis, and icterus. The activated clotting time has been used for ECLS unfractionated heparin monitoring, but has been called into question due to its lack of correlation with heparin dose, anti‐Xa heparin activity, partial thromboplastin time (PTT), bleeding, or circuit thrombosis . The PTT has also been used to monitor unfractionated heparin during ECLS, but it has been reported to show high levels of discordance with anti‐Xa heparin activity assays, due to low or high coagulation factor levels, lupus inhibitors, contact factor deficiencies, and other causes …”

“…The activated clotting time has been used for ECLS unfractionated heparin monitoring, but has been called into question due to its lack of correlation with heparin dose, anti-Xa heparin activity, partial thromboplastin time (PTT), bleeding, or circuit thrombosis. [1][2][3][4][5][6] The PTT has also been used to monitor unfractionated heparin during ECLS, but it | 881 KHAN ANd CHANdLER has been reported to show high levels of discordance with anti-Xa heparin activity assays, due to low or high coagulation factor levels, lupus inhibitors, contact factor deficiencies, and other causes. [7][8][9][10] Anti-Xa heparin activity assays are becoming a standard approach for monitoring heparin during ECLS.…”