Therapy Of Pediatric

Numerous case reports describe the occurrence of new or recurrent thromboem-bolic events during continued or repeated use of heparin in adult patients with acute HIT. Further, thrombocytopenia usually persists if heparin is not stopped. Thus, all heparin should be discontinued in patients strongly suspected of having HIT, including heparin "flushes," heparin-coated catheters, and heparin-containing blood products (Severn et al., 2002b) (see Chapter 12). As in adults, low molecular weight heparin (LMWH) should not be used to treat acute HIT in children (see Chapter 12).

Because HIT is a prothrombotic ("hypercoagulability") state with high risk of thromboembolic complications, alternative anticoagulation is usually required after stopping heparin. In adults, there are prospective studies of anticoagulation for HIT patients using danaparoid, lepirudin, or argatroban. However, in children, experience with these agents is anecdotal and heterogeneous. Expert opinions are available in reviews (Young, 2004; Balasa, 2005; Bidlingmaier et al., 2006; Hursting et al., 2006; Risch et al., 2006).

Danaparoid use has been reported in 39 patients (with additional aspirin, thrombolysis, or lepirudin given in some cases). In two children, danaparoid was stopped because of apparent cross-reactivity, with further anticoagulation with lepirudin. Fourteen patients received lepirudin (one combined with aspirin). Eight children were treated with LMWH. Three infants received aspirin, three were given argatroban plus aspirin, one argatroban and fondaparinux, and 15 were treated with argatroban alone. Nineteen children received oral anticoagulants and six received thrombolytics. [Note, however, that oral anticoagulants should not be given during acute HIT (see Chapters 2 and 12).] In five children, no anticoagulant was given. In 15 cases, alternative anticoagulation is not mentioned.

A. Danaparoid

Danaparoid (see Chapter 13) is a mixture of low molecular weight glycosamino-glycans that catalyze the inactivation of factor Xa (FXa) by antithrombin (formerly, antithrombin III). It has relatively minor anti-factor IIa activity. Dosing schedules for adults (appropriately weight-adjusted for the child) can be used for guidance. For antithrombotic prophylaxis, 10 IU/kg body weight given twice daily by subcutaneous injection is recommended. For therapeutic anticoagulation in pedia-tric HIT patients, an initial i.v. bolus of 30 IU/kg is followed by continuous infusion of 1.2-2.0 IU/kg/h (Monagle et al., 2004). The anti-FXa level should be measured during treatment for optimal dosing. Target levels of anti-FXa activity are 0.4-0.6 IU/mL for standard and 0.5-0.8 IU/mL for higher danaparoid doses (Severin et al., 2002b).

B. Lepirudin

Lepirudin (see Chapter 14) is a direct inhibitor of free and clot-bound thrombin through noncovalent, irreversible binding. In adults with HIT complicated by thrombosis, the approved dose is an initial bolus of 0.4 mg/kg followed by continuous i.v. infusion (0.15 mg/kg/h) adjusted by activated partial thromboplastin time (aPTT). The usual target aPTT ratio should be 1.5-2.5 times the normal laboratory mean aPTT. Dosing in children is based on anecdotal experience. Schiffmann et al. (1997) gave a bolus of lepirudin (0.2 mg/kg) and a continuous infusion (ranging between 0.1 and 0.7 mg/kg/h) adjusted by aPTT. Severin et al. (2002b) achieved therapeutic anticoagulation with a continuous infusion of 0.1 mg/ kg/h in a 15-yr-old boy, and with an infusion rate of about 0.15 mg/kg/h in an 8-yr-old girl. In an 11-yr-old girl, 0.15-0.22 mg/kg/h was given. In a premature infant, Nguyen and coworkers (2003) gave a 0.2 mg/kg bolus followed initially by 0.1 mg/kg/h infusion rate; the dose was adjusted daily based on the aPTT, and 0.03-0.05 mg/kg/hr provided adequate anticoagulation. Since pharmacokinetics depend largely on renal function, we recommend starting lepirudin with an i.v. infusion of 0.10 mg/kg/h (if renal function is normal) and to adjust the dose according to aPTT 4 h later, without initial bolus. This minimizes both risk of overdosing and anaphylaxis (see Chapter 14).

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