Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature

David Kavanagh, Sarah McGlasson, Alexa Jury, Jac Williams, Neil Scolding, Chris Bellamy, Claudia Gunther, Diane Ritchie, Daniel P. Gale, Yashpal S. Kanwar, Rachel Challis, Holly Buist, James Overell, Belinda Weller, Oliver Flossmann, Mark Blunden, Eric P. Meyer, Thomas Krucker, Stephen J.W. Evans, Iain L. Campbell, Andrew P. Jackson, Siddharthan Chandran and David P.J. Hunt

Key points

  • Type I interferon therapies can cause a dose-dependent thrombotic microangiopathy.

  • Recombinant type I interferon therapies should be stopped at the earliest opportunity in patients who develop thrombotic microangiopathy.


Many drugs have been reported to cause thrombotic microangiopathy (TMA), yet evidence supporting a direct association is often weak. In particular TMA has been reported in association with recombinant type I interferon therapies, with recent concern regarding the use of interferon in multiple sclerosis patients. However a causal association has yet to be demonstrated. Here we adopt a combined clinical and experimental approach to provide evidence of a such an association between type I interferon and TMA. We show the clinical phenotype of cases referred to a national centre is uniformly consistent with a direct dose-dependent drug-induced TMA. We then show that dose-dependent microvascular disease is seen in a transgenic mouse model of interferon toxicity. This includes specific microvascular pathological changes seen in patient biopsies, and is dependent on transcriptional activation of the interferon response through the type I interferon receptor (IFNAR). Together our clinical and experimental findings provide evidence of a causal link between type I interferon and thrombotic microangiopathy. As such, recombinant type I interferon therapies should be stopped at the earliest stage in patients who develop this complication, with implications for risk mitigation.

  • Submitted May 16, 2016.
  • Accepted August 30, 2016.