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Circulating dsDNA, endothelial injury, and complement activation in thrombotic microangiopathy and GVHD

Nicholas J. Gloude, Pooja Khandelwal, Nathan Luebbering, Dana T. Lounder, Sonata Jodele, Matthew N. Alder, Adam Lane, Alyss Wilkey, Kelly E. Lake, Bridget Litts and Stella M. Davies

Key points

  • dsDNA production peaks 14 days after HSCT, likely a result of IL-8 driven neutrophil recovery.

  • dsDNA production may serve as a mechanistic link between endothelial injury, TA-TMA, and GVHD.

Abstract

TA-TMA is a common and poorly recognized complication of HSCT associated with excessive complement activation, likely triggered by endothelial injury. An important missing piece is the link between endothelial injury and complement activation. We hypothesized that neutrophil extracellular traps (NETs) mechanistically link endothelial damage with complement activation and subsequent TA-TMA. Neutrophil activation releases granule proteins together with double stranded DNA (dsDNA), to form extracellular fibers known as NETs. NETs have been shown to activate complement, and can be assessed in humans by quantification of dsDNA in serum. We measured levels of dsDNA, as a surrogate for NETs in 103 consecutive pediatric allogeneic transplant recipients at day 0, +14, +30, +60, and +100. A spike in dsDNA production around day +14 during engraftment was associated with subsequent TA-TMA development. Peak dsDNA production around day +14 was associated with IL-8 driven neutrophil recovery. Increased dsDNA levels at days +30, +60, and +100 were also associated with increased mortality and GI GVHD. NETs may serve as a mechanistic link between endothelial injury and complement activation. NET formation may be one mechanism contributing to the clinical overlap between GVHD and TA-TMA.

  • Submitted May 26, 2017.
  • Accepted July 4, 2017.