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*

Abstract

Thrombocytopenia-associated multiple organ failure (TAMOF) is a poorly understood syndrome in critically ill children. 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. We hypothesized that children with TAMOF syndrome have decreased ADAMTS-13 activity which can be replenished with PEx. In the first of two consecutive studies, relationships between platelet count, VWF multimers, ADAMTS-13 activity, plasminogen activator inhibitor-1 (PAI-1) and prothrombin time (PT) were analyzed in children with and without TAMOF. In the second study, children with severe TAMOF (platelet counts<100,000/mm3 and ≥3 organ failure) were randomized to PEx or standard therapy. In the first study, children with TAMOF (n=28) had decreased ADAMTS-13 activity, but similar PAI-1 activity and PT 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). Children with TAMOF syndrome can have VWF mediated thrombotic microangiopathy. Similar to adult experience, PEx can replenish ADAMTS-13 activity and reverse organ failure in these children.

Global Epidemiology of Pediatric Severe Sepsis: The Sepsis Prevalence, Outcomes, and Therapies Study

“…The hospital mortality rate of 25% confirms that severe sepsis remains a critical public 23 (12-28) 20 (5-26) 21 25 (19-28) 26 (20-28) 25 (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) 22 (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) ,0.001…”

“…Hospital mortality was 25% and did not differ by age or between developed and resourcelimited countries. Median ventilator-free days were 16 (IQR, 0-25), and vasoactive-free days were 23 (IQR,(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Sixty-seven percent of patients had multiorgan dysfunction at sepsis recognition, with 30% subsequently developing new or progressive multiorgan dysfunction.…”

“…Consequently, debate remains about the optimal approach to both basic and adjuvant therapies. For example, vasoactive strategies, immune stimulation, and plasma exchange would all benefit from further evaluation in rigorous pediatric trials (21,24,25). The low frequency of pediatric sepsis at any one institution necessitates broad-ideally international-collaboration across many sites to achieve adequate enrollment and generalizability (26).…”

Preserved Expression of mRNA Coding von Willebrand Factor-Cleaving Protease ADAMTS13 by Selenite and Activated Protein C

“…This deficiency is associated with an increase in ulVWF and is postulated to cause TMA in patients (9,23,26). The impact of ADAMTS13 deficiency in thrombocytopenia and organ failure is supported by the observation that plasma exchange reversed organ dysfunction in thrombocytopenia-associated multiple organ failure in children (27) and renal deposition of thrombi enriched from activated platelets and VWF in a porcine sepsis model (28). Also, an inverse relationship between severity of inflammation and ADAMTS13 activity is described in clinical studies (29,30).…”

Daily estimation of the severity of multiple organ dysfunction syndrome in critically ill children

“…These data support the concept that the PELOD score and its progression in the PICU can be an outcome measure of interest. Measurement of organ dysfunction with scores such as the PELOD can be useful both for administrative PICU management [29][30][31] and as a secondary outcome measure of studies conducted in the ICU, 12,32 particularly the PICU, 21,33 where the death rate is low. Two recent examples can be given.…”