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Low-Dose Tissue Plasminogen Activator Thrombolysis in Children

Wang, Michael M.D.; Hays, Taru M.D.; Balasa, Vinod M.D.; Bagatell, Rochelle M.D.; Gruppo, Ralph M.D.; Grabowski, Eric F. M.D., Sc.D.; Valentino, Leonard A. M.D.; Tsao-Wu, George M.D.; Manco-Johnson, Marilyn J. M.D.; Pediatric Coagulation Consortium

Journal of Pediatric Hematology/Oncology: May 2003 - Volume 25 - Issue 5 - pp 379-386
ORIGINAL ARTICLES: Hematology

Purpose: To compare results of low-dose tissue plasminogen activator (TPA) in children with arterial and venous thrombi relative to standard published dosing.

Methods: Subjects consisted of all consecutive children with objectively confirmed thrombi for whom TPA thrombolysis was clinically ordered by the authors. Initial dosing used published standard dose (0.1–0.5 mg/kg per hour). With experience, a low-dose regimen (0.01–0.06 mg/kg per hour) was given in an attempt to derive a minimal effective dose.

Results: Thirty-five children were treated with TPA. Either standard or low-dose infusions of TPA resulted in complete thrombolysis of 28 of 29 (97%) acute thrombi, while all 6 chronic thrombi had a partial response. In contrast to the recommended adult-derived dosages of 0.1 to 0.5 mg/kg per hour, the authors found that initial doses of less than 0.01 mg/kg per hour were effective in 12 of 17 patients with acute thrombosis. Neonates required 0.06 mg/kg per hour. Route of administration (local or systemic) did not affect efficacy. Major bleeding occurred in only one extremely preterm infant. Minor bleeding, primarily oozing at intravenous sites, occurred in 27% of children during TPA infusions. Prophylactic unfractionated or low-molecular-weight heparin was infused concomitant with TPA in 42% of the children and did not increase the risk of bleeding.

Conclusions: TPA in very low doses appears to be safe and effective for thrombolysis of acute thromboses in most children, given appropriate patient selection.

The optimal use, dosage, efficacy, and bleeding toxicity of tissue plasminogen activator (TPA) thrombolysis in children are unknown. Currently, anticoagulation using unfractionated heparin or low-molecular-weight heparin (LMWH) constitutes standard therapy for children with thrombosis (1). However, pediatric hematologists are regularly asked about the use of TPA in a growing number of children who present with a wide variety of thrombi. Interest in TPA is due to the recognition that successful thrombolysis is associated with more rapid and complete restoration of blood flow and less tissue infarction (2). Thrombolytic therapy has been shown to be more efficacious than anticoagulation alone in adults with pulmonary embolism (3) and acute coronary thrombosis (4) and for prevention of postthrombotic syndrome (PTS) secondary to iliofemoral thrombosis (5). Children exhibit low rates of death, pulmonary embolism, thrombus propagation, thrombus recurrence, or bleeding toxicity with anticoagulant therapy; however, PTS, a clinical spectrum of swelling, pain, skin changes, and stasis ulcers that occurs as a sequela to obstructed venous flow, has been reported in 10% to 20% of children with venous thrombosis (6–9).

Several case reports and small series of pediatric patients have shown that TPA has lysed thrombi in critically ill infants and children (10–18). To be clinically beneficial, novel therapies in children must show improved efficacy with little or no increase in toxicity. A recent review of the literature determined that bleeding complications requiring packed red cell transfusions occur in 20% of children receiving TPA thrombolysis (19). Weiner et al. (10) reported intracranial hemorrhage in two of seven newborns receiving TPA. A perception of increased TPA-associated bleeding has limited the use of thrombolysis in children, and a recent report with standard doses (0.5 mg/kg per hour average dose) also revealed significant bleeding complications (20).

Our increased appreciation that children do suffer thrombi and the rise in frequency of therapy-related thrombotic complications necessitate an investigation of the management of pediatric thromboses that includes careful investigation of TPA. Currently the dose and duration of TPA given to children are extrapolated from adult data (21), modified by limited anecdotal experience. To design future trials evaluating TPA therapy in children, we collected clinical data through a multi-institutional North American consortium, the Pediatric Coagulation Consortium (PCC).

From the Department of Pediatrics at the Children's Hospital and the University of Colorado Health Sciences Center, Denver, Colorado, U.S.A. (M.W., T.H., M.J.M-J.), Children's Hospital Medical Center, Cincinnati, Ohio, U.S.A. (V.B., R.G.), University of Arizona, Tucson, Arizona, U.S.A. (R.B.), Massachusetts General Hospital, Boston, Massachusetts, U.S.A. (E.F.G.), Rush Children's Hospital, Chicago, Illinois, U.S.A. (L.A.V.), and Alaska Center for Pediatrics, Anchorage, Alaska, U.S.A. (G.T-W.). The Pediatric Coagulation Consortium comprises investigators of the Hemophilia Research Society and the American Society of Pediatric Hematology/Oncology.

Submitted for publication August 6, 2002; accepted September 13, 2002.

Address correspondence and reprint requests to Marilyn J. Manco-Johnson, M.D., Mountain States Regional Hemophilia and Thrombosis Center, University of Colorado Health Sciences Center, P.O. Box 6507, MS F416, Aurora, CO 80045–0507, U.S.A. E-mail: marilyn.manco-johnson@uchsc.edu.

© 2003 Lippincott Williams & Wilkins, Inc.