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Intensive plasma exchange increases a disintegrin and metalloprotease with thrombospondin motifs-13 activity and reverses organ dysfunction in children with thrombocytopenia-associated multiple organ failure*

Nguyen, Trung C. MD; Han, Yong Y. MD; Kiss, Joseph E. MD; Hall, Mark W. MD; Hassett, Andrea Cortese PhD; Jaffe, Ron MD; Orr, Richard A. MD; Janosky, Janine PhD; Carcillo, Joseph A. MD

doi: 10.1097/CCM.0b013e318186aa49
Pediatric Critical Care
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Background: Thrombocytopenia-associated multiple organ failure (TAMOF) is a poorly understood syndrome in critically ill children. A disintegrin and metalloprotease with thrombospondin motifs (ADAMTS-13), formerly known as von Willebrand factor (VWF) cleaving protease, is decreased in adults with VWF-mediated thrombotic microangiopathy, and intensive plasma exchange (PEx) both replenishes ADAMTS-13 and improves outcome in these patients.

Objectives: To determine whether: 1) critically ill children with TAMOF syndrome have decreased ADAMTS-13 activity, 2) ADAMTS-13 activity correlates with platelet counts and VWF antigen, 3) the autopsies from patients who died with reduced ADAMTS-13 activity have VWF-rich microthrombi, and 4) intensive PEx will restore ADAMTS-13 activity and facilitate organ failure resolution.

Design: First study: Observational.

Second study: Randomized control trial.

Setting: Single center university pediatric intensive care unit.

Patients: First study: thirty-seven consecutive children (17 males and 20 females; ages ranging from 9 days to 23 years) identified with ≥2 organs dysfunction were enrolled. Seventy-six percent of these children had thrombocytopenia (platelet counts <100,000/mm3). Five additional critically ill children without MOF were also enrolled. In the second study, children with severe TAMOF (platelet counts <100,000/mm3 and >3 organ failure) were randomized to PEx or standard therapy. Primary physicians and parents agreed to enrollment in 10 of the 20 eligible patients with ages ranging from 1 year to 18 years. Five patients received PEx and 5 patients received standard therapy.

Results: First study: children with TAMOF (n = 28) had decreased ADAMTS-13 activity, but similar plasminogen activator inhibitor-1 activity and prothrombin time compared to children with MOF without thrombocytopenia (n = 9, p < 0.05). All non-survivors (n = 7) had TAMOF, reduced ADAMTS-13 activity, and VWF-rich microvascular thromboses at autopsy. In the second study, PEx (n = 5, median 12 days, 4–28 days) restored ADAMTS-13 activity and organ function, compared to standard therapy (n = 5, p < 0.05).

Conclusions: Children with TAMOF syndrome can have VWF-mediated thrombotic microangiopathy. Similar to adult experience, PEx can replenish ADAMTS-13 activity and reverse organ failure.

From the Section of Critical Care (TCN), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Critical Care (YYH), Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI; Division of Hematology/Oncology and the Department of Medicine (JEK), University of Pittsburgh School of Medicine, Pittsburgh, PA; The Institute for Transfusion Medicine (JEK, ACH), Pittsburgh, PA; Division of Critical Care (MWH), Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH; Department of Family Medicine and Epidemiology (JJ), University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA; Departments of Pathology (RJ), Critical Care Medicine and Pediatrics (RAO, JAC), University of Pittsburgh School of Medicine, Pittsburgh, PA.

Supported in part by grant NICHD/NIH 5T32-HD40686 (TCN, YYH), AHA Beginning grant-in-aid (TCN), Department of Anesthesiology, University of Pittsburgh School of Medicine Charles Research Fellowship (MWH), and NCRR 3M01RR0056GCRC (JAC).

The authors have not disclosed any potential conflicts of interest.

For information regarding this article, E-mail: tcnguyen@texaschildrenshospital.org

© 2008 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins