Argatroban, a direct thrombin inhibitor, is approved in the United States in adults as an anticoagulant for prophylaxis or treatment of thrombosis in heparin-induced thrombocytopenia (HIT) and in adults with or at risk for HIT undergoing percutaneous coronary intervention. The authors conducted a literature analysis to characterize the uses, dosing patterns, and safety of argatroban anticoagulation in pediatric patients. A comprehensive literature search identified nine articles describing 34 patients aged 1 week to 16 years who received argatroban anticoagulation for prophylaxis or treatment of thrombosis, cardiac catheterization, hemodialysis, extracorporeal membrane oxygenation or ventricular assist device support, or cardiopulmonary bypass. Most (85%) patients had HIT, a history of HIT, and/or HIT antibodies. For HIT thromboprophylaxis or treatment, argatroban dosing varied widely (0.1-12 mcg/kg/min), with no obvious relationship between patient age and dosage requirement. Overall, in these pediatric patients, therapeutic levels of anticoagulation were achieved despite the wide range of doses used. For pediatric patients undergoing cardiac catheterization, argatroban doses lower than those recommended in adults appeared to provide therapeutic anticoagulation. There was an unacceptably high bleeding risk with argatroban anticoagulation during pediatric cardiopulmonary bypass. Due to the limitations of case reports and/or case series, prospective studies with pharmacokinetic analyses are needed to evaluate the use of argatroban in pediatric patients.
Based on this clinical experience, together with the established linear pharmacokinetics and pharmacodynamics of argatroban, appropriate dosage increments may be proposed for argatroban-treated patients with HIT. Incremental adjustments of 0.5 micro g/kg/min are reasonable for most patients. Smaller adjustments (e.g., 0.25 micro g/kg/min) should be used when modifying lower doses, such as those recommended for use in hepatically impaired patients.
We retrospectively characterized major bleeding events and their risk factors among 269 patients with clinically diagnosed heparin-induced thrombocytopenia (HIT) treated using argatroban (2 microg x kg(-1) x min(-1) initially, adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5-3 times the baseline) in a prospective multicenter study. Patients received a median (range) dose of 1.9 (0.2-9.7) microg x kg(-1) x min(-1) for 5.6 (0.1-61) days. Average aPTTs during therapy were 61.6 (37-183) seconds. Major bleeding, most commonly gastrointestinal, occurred in 19 patients (7.1%) during therapy. Another patient suffered from intracranial hemorrhage 4 days after argatroban cessation. Bleeding was fatal in 2 patients (0.7%); each received multiple anticoagulants and thrombolytic therapy. Major bleeding was more likely to occur in patients with HIT-related thrombosis (odds ratio = 2.9, P = 0.039), pulmonary impairment (odds ratio = 20.3, P < 0.001), or an aPTT >100 seconds (odds ratio = 3.7, P = 0.010). Major bleeding rates associated with average aPTTs of <45, 45-67.5, 67.6-90, and >90 seconds, respectively, were 5.0% (1 of 20 patients), 5.6% (9 of 162 patients), 8.7% (6 of 69 patients), and 22% (4 of 18 patients). No significant effect of patient demographics, other baseline illnesses including hepatic or renal impairment, argatroban dose, or treatment duration was detected on major bleeding. Risk factors for major bleeding in argatroban-treated patients with HIT include baseline HIT-related thrombosis and pulmonary impairment. For minimizing bleeding risk during argatroban therapy for HIT, the aPTT should be routinely monitored and maintained at <90 seconds.
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