Pharmacokinetics of Infused Antithrombin Concentrate in Children with Disseminated Intravascular Coagulation Secondary to Sepsis † 794

Antithrombin (AT) is the major plasma serine protease inhibitor in humans. Acquired AT deficiency has been reported in association with disseminated intravascular coagulation (DIC), purpura fulminans and veno-occlusive disease of the liver. Treatment of hereditary deficiency of AT with AT concentrate is well-established. Recent literature suggests that AT concentrate may be useful in acquired AT deficiency, especially at doses resulting in supraphysiological levels in plasma. The use of AT concentrate in children with consumption coagulapathies is, at best anecdotal, and little is known regarding the pharmacokinetics of infused AT in children in this setting. This study investigated the pharmacokinetics of infused AT in children with DIC secondary to sepsis. Three children with clinical and/or laboratory evidence of DIC and sepsis were given a loading dose of AT (150 IU/kg) followed by continuous infusion to keep AT activity at approximately 250%. A fourth child received a single dose of AT. Markers of thrombin and plasmin activation and AT(immunologic and chromogenic assay) were measured at Time (T) = 0, 30, 60, 120, 240 and 360 minutes, then approximately every six hours until the patient was discharged from the study. Pharmacokinetic parameters were calculated using standard equations. Results: Initial administration of AT resulted in mean peak AT activity of 275% (range 266-290%) and peak plasma concentration of 742 μg/mL (range 615-1065 μg/mL). Infusion of 10 IU/kg/hr AT resulted in variable steady state AT activity (174-418%), and steady state plasma concentration (C_ss) (570 - 900 μg/mL). Elimination rate constant(k_e) values (0.043-0.089 hr^-1) were similarly variable. Apparent volume of distribution ranged from 18.4-34.6 mL/kg, and total clearance (CL) ranged from 1.37-11 mL/kg/hr. In the patient who received a single dose of AT, elimination kinetics were estimated, with a t_1/2 of 13.3 hours, and a CL of 2.03 mL/kg/hr. Strong concordance between measurement of AT by chromogenic and immunologic assay was demonstrated (r² = 0.962). AT elimination was influenced by alterations in hepatic function; the patient with the highest C_ss (900 μg/mL) and lowest CL (1.37 mL/kg/hr) developed overt hepatic failure while on study. This preliminary data suggests that stable elevation of AT activity may be acheived by continuous infusion of AT concentrate. This data may be utilized to provide initial parameters for administration of AT in patients with consumptive coagulopathy.