David Green, MD, PhD reviewing Kavanagh D et al. Blood 2016 Sep 23.

Recombinant type I interferons exert a dose-dependent direct toxic effect on the endothelium, resulting in microvascular thrombosis.

Endothelial cell injury accompanied by microvascular thrombosis (thrombotic microangiopathy or TMA) is associated with thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, cancer, autoimmune diseases, and a variety of drugs, including interferons. Whether interferons directly injure the endothelium or require other mediators to induce disease has been uncertain.

To determine whether recombinant type I interferons are a direct cause of TMA, investigators studied patients with multiple sclerosis receiving treatment with interferon-β and conducted experiments using a mouse model of interferon toxicity.

The findings were as follows:

Patients who developed TMA received higher weight-adjusted doses of interferon than those who did not develop microangiopathy (P<0.001); all patients with TMA had received doses >50 mcg/week.

Anti-interferon antibodies were not observed in any patients.

TMA occurred with all subtypes of recombinant type I interferons.

In the mouse model, transgenic overexpression of interferon was associated with a dose-dependent spectrum of microvascular disease. Knocking out the receptor for interferon prevented the development of TMA.

CITATION(S):

Kavanagh D et al. Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature. Blood 2016 Sep 23; [e-pub].

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