Two Cases of Pediatric Hit Requiring Unusually High Doses of Direct Thrombin Inhibitors: Does a Subset of Such Patients Exist?.

Experience in pediatrics with heparin-induced thrombocytopenia (HIT) with or without thrombosis is currently limited. In the past two years, however, we have cared for two children with HIT who have required unusually high doses of direct thrombin inhibitors in order to maintain a PTT in the 50–80 sec range. Neither child had any recognizeable congenital or acquired risk factor(s) for hypercoagulability, including activated protein C resistance, prothrombin mutation G20210A, deficiency of protein C or S, anticardiolipin antibodies, or elevated levels of homocysteine or lipoprotein (a).

Case 1: A 6 year old girl presented with persistant headache, left-sided weakness, and right lateral gaze paresis. Head CT and MR showed saggital and transverse sinus thrombosis, as well as the presence of two intraparenchymal hemorrhages. Treatment in the first 24 hrs consisted of catheter-directed thromborhexis to recanalize the left transverse sinus and prevent the otherwise anticipated development of complete obstruction to drainage from the right cerebral cortex, followed by low-dose unfractionated heparin (10 U/kg/hr) to inactivate thrombus-bound thrombin released acutely by the thromborhexis. While full anticoagulation was sought by hr 48, this was achieved only over several days owing to a high heparin requirement (45 U/kg/hr) to obtain therapeutic heparin levels. Neurologic status improved over the next several days. However, on day 14 our patient suffered acute loss of vision, following by a drop in platelet count and identification of HIT antibody. She was placed on argatroban, but to attain a therapeutic PTT, required an inordinately high dose (15μg/kg/min, vs “usual” dose of 2). When she was switched to r-hirudin, an unusually high dose (0.7 mg/kg/hr, vs “usual” dose of 0.2) was again required.

Case 2: A 2-and-a-half year old girl was admitted for ECMO following development of respiratory failure due to necrotizing strep. pneumoniae. After 5 days on unfractionated heparin, her platelet count dropped, she developed skin necrosis, and HIT antibody was identified. She was placed on r-hirudin, but also required an unusually high dose (0.52 mg/kg/hr) to achieve a therapeutic PTT. We are aware of two other pediatric cases of such high requirements for direct thrombin inhibitors at other institutions, although a review of the literature makes clear that most instances of pediatric HIT are managed satisfactorily with doses/kg consistent with adult practice. We hypothesize that a subset of chidren with HIT require a significantly higher dose of direct thrombin inhibitors on the basis of a relatively enhanced ability to generate thrombin in the presence of HIT antibody. Studies of thrombin generation and inhibition in our two patients are in progress.