Off-Label Antithrombin Use In Pediatrics: Evaluation Of Safety, Efficacy and Usage Patterns

Antithrombin (AT) is a naturally occurring anticoagulant, and occupies a critical role in regulating thrombin generation. AT concentrate (ATC) is indicated for patients with hereditary AT deficiency but off-label use for acquired heparin resistance in patients receiving anticoagulation for thrombotic disease is not uncommon. Use of ATC in children in this and other settings such as extracorporeal membrane oxygenation (ECMO) and ventricular assist devices (VAD) appears to be expanding. However, no guidelines exist with respect to proper indications and monitoring, and scant safety and efficacy data is available. The objective of this study was to review our substantial institutional experience with off-label pediatric use of ATC regarding indications for use, dosing practice, dosing effect, adverse events, and patient outcomes.

An institutional review board (IRB)-approved retrospective chart review is being performed on all pediatric patients who received human-plasma derived ATC at Texas Children’s Hospital from 2001 to 2013. Data collection includes demographic, clinical and laboratory data. We are currently reporting on the first 100 consecutive patients examined using descriptive statistics and ANOVA for group comparisons.

One hundred patients with median age 5 months (range 0 to 216 months) received 536 doses of ATC (median 4 doses per patient, range 1 to 29) between February 2012 and May 2013. Clinical scenarios for ATC use included heparin (unfractionated (UFH) or low molecular weight (LMWH)) therapy for thrombosis in 47%, ECMO in 38%, VAD in 5% and other settings in 10% of the 100 consecutive patients analyzed. Neither dosing nor dose response (measured as AT activity level post- versus pre-ATC dose) differed significantly between these patient groups. For the group of patients who received AT for thrombosis and heparin therapy, only 57% had subtherapeutic levels (anti-Xa activity <0.3 units/mL for UFH or <0.5 units/mL for LMWH) at the time of ATC initiation. Of these, only 22% achieved therapeutic levels within 12 hours after the first ATC dose. Among all the groups, 33% of children had bleeding events within 72 hours after ATC administration, most commonly reported as oozing from line sites (n=15). There was no association between AT activity levels measured after ATC administration and bleeding events. The 2 patients that developed intracranial hemorrhage were on ECMO. There were no allergic reactions. End of hospitalization mortality was 28%.

In this high-risk cohort of pediatric patients, off-label ATC was most commonly given in the setting of heparin therapy for thrombosis and low AT levels, but often without apparent evidence for inadequate heparinization as measured by low anti-Xa activity. Although ATC administration led to a significant rise in AT activity for most patients, interindividual response to ATC varied greatly, with some patients demonstrating little to no response. Furthermore, among patients who exhibited clear signs of heparin resistance, the first administration of ATC potentiated an adequate heparin effect in only a small minority. Finally, ATC administration was associated with high rate of minor bleeding complications and rare major bleeding events. These findings raise significant questions about the safety, efficacy and appropriate use of ATC in pediatrics and highlight the need for its further prospective study.

Off Label Use: Antithrombin concentrate.