Use of Antithrombin Concentrate for Acquired Antithrombin Deficiency in Acutely Unwell Children Receiving Unfractionated Heparin

Antithrombin (AT) is essential as a cofactor for unfractionated heparin (UFH) to deliver its anticoagulant effect. AT deficiency may result in inadequate anticoagulation with UFH at usual doses. Acquired AT deficiency is common in acutely unwell children due to either decreased production (especially in infants with liver immaturity) or increased consumption. It is known that children require higher doses of UFH than adults to achieve and maintain therapeutic levels of anticoagulation. 1 2 3 In infants and children, the levels of AT are lower than in adults (may be as low as 10–30%) and AT may be consumed in illness. 3 In a study by Andrew et al, it was shown that children 12 months of age (20 U/kg/h) to achieve the same anticoagulant effect as measured by activated partial thromboplastin time (APTT). 4 In another study, the median UFH dose required to achieve therapeutic anti-factor Xa (anti-Xa) levels in 83 infants was 33 U/kg/h and 39% of infants required at least one dose of AT supplementation (50–200 IU/kg) to achieve therapeutic heparin anti-Xa levels. 5 However, the UFH requirement may also be increased by nonspecific binding of UFH to acute phase reactants. Both reduced levels of AT and accelerated heparin clearance are barriers to effective anticoagulation in children. Although the APTT is a cheap and easily available test that is commonly used for the monitoring of UFH, it may not provide an accurate measure of anticoagulant effect of heparin as a result of various confounding factors including both preanalytical and analytical variables. 6 The anti-Xa assay is not as significantly affected by these confounding factors and so has been proposed as a better assay for monitoring UFH. Consequently, it is our standard practice to use the anti-Xa level to monitor UFH rather than the APTT in both pediatric and adult patients. Based on comparisons using an anti-Xa chromogenic assay within our hospital, an APTT of 60 to 100 seconds (using SynthASil reagent on ACL TOP 500 Instrumentation Laboratory) corresponds to the recommended anti-Xa therapeutic range of 0.3 to 0.7 IU/mL. In this retrospective single-center observational study in a tertiary pediatric intensive care unit in United Kingdom, we set out to determine whether AT supplementation could elevate AT levels, achieve therapeutic anticoagulation based on heparin anti-Xa, and reduce UFH dosage. This was undertaken as a service evaluation project and approved by the Trust Clinical Effectiveness Unit. We studied children with acquired AT deficiency who were acutely unwell following acute thrombosis, cardiac surgery due to congenital heart disease, and those requiring extracorporeal membrane oxygenation (ECMO) for severe respiratory or cardiac failure or both. From January 2016 to March 2019, all patients 40 U/kg/h and was found to have a low AT level. ATC was then administered to achieve an AT level of at least 0.5 IU/mL. However, if a child needed UFH > 50 U/kg/h, even if the AT was > 0.5 IU/mL, a dose of ATC was given to elevate the AT level to achieve an AT level > 0.7 IU/mL. In addition, in children with suspected low AT levels based on clinical scenarios such as chylothorax or on ECMO, the AT level was measured to ensure it was not too low. In these children, if the AT levels were found to be very low (i.e., 100 seconds) in 60% (21/35), while only 40% (14/35) had heparin anti-Xa level within the therapeutic range (0.3–0.7 U/mL) with an overall median of 0.27 U/mL (range: 0.05–0.59). Within 4 to 6 hours following administration of ATC, there were significant increases in both AT (from 0.24 IU/mL 0.03–0.57 to 0.63 IU/mL 0.29–1.27, p 12 months of age were 30.5 U/kg/h (26.5–34.5) and 30.3 U/kg/h (26.1–34.5), respectively, and fell to 18.9 U/kg/h (16.8–20.9) and 17.7 U/kg/h (15.0–20.4) following the ATC administration. Notably, in that published study 3 the mean dose of ATC was 241 IU/kg compared with approximately 50 IU/kg in our study and also in the report from Diaz and colleagues. 8 With this higher dose of ATC, Ryerson et al achieved a mean AT level of 0.93 IU/mL from a baseline level of 0.40 IU/mL 3 compared with 0.63 IU/mL from 0.24 IU/mL in our study and 0.79 IU/mL from 0.61 IU/mL in the study by Diaz et al. 8 Following the higher dose of ATC administration in the Ryerson study, 3 the mean anti-Xa increased from 0.23 to 0.41 U/mL and all children ≤12 months of age achieved therapeutic heparin anti-Xa levels (mean 0.43 U/mL with 95% CI of 0.33–0.53). Although it was not clear how many children > 12 months achieved therapeutic heparin anti-Xa, the mean was 0.35 U/mL (95% CI: 0.26–0.44). The doses of ATC used in our study and in those of Diaz et al 8 failed to achieve the age-normal AT concentration in many children (median: 0.63 and 0.79 IU/mL, respectively). All children in the Ryerson study 3 were on ECMO and 50% were 50 U/kg/h except in children with chylothorax, the very large doses of UFH used in our study could therefore be due to much lower AT levels (median: 0.24 IU/mL range: 0.03–0.57) in our cohort of children at baseline compared with 0.40 IU/mL in Ryerson et al 3 and 0.61 IU/mL in Diaz et al. 8 Although off-label use of ATC is increasing in both adult and pediatric practice, especially for ECMO, congenital AT deficiency is the only approved indication at present. The level of evidence base for use of ATC to support therapeutic anticoagulation with UFH is weak and mostly retrospective, including the current study. Conducting prospective randomized clinical studies in the pediatric population is extremely challenging and so accumulation of experience from large centers managing specific disease setting is important. The major limitations of this study are small sample size, its retrospective design, and lack of a control group or prespecified ATC dosing regimen. However, despite being retrospective, almost all relevant clinical and laboratory data were available and patients represented a spectrum of indications to receive UFH. In conclusion, AT deficiency, be it congenital or acquired, may limit anticoagulant therapy with UFH in sick children and that can be significantly improved after ATC replacement. Only 9% of children in our study had minor bleeding and none had recurrence of thrombosis. In children who fail to achieve therapeutic heparin anti-Xa levels despite using UFH > 40 U/kg/h or those with chylothorax and associated thrombosis and unable to change to alternative anticoagulant, we believe it is reasonable to check AT levels and replace AT if the levels are < 0.40 IU/mL. Authorship D.R.J.A. was involved in study concept and design, data collection, analysis, and interpretation of data, and prepared the first draft of the manuscript. M.G. and S.M. supported in data collection and revised the manuscript. M.L. was involved in interpretation of the data and revising the manuscript. All authors approved the final manuscript.