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Synergistic effects of ADAMTS13 deficiency and complement activation in pathogenesis of thrombotic microangiopathy

Liang Zheng, Di Zhang, Wenjing Cao, Wenchao Song and X. Long Zheng

Key Points

  • Mice with Adamts13-/-or a heterozygous mutation of complement factor H at residue of 1206 (cfhW/R) do not develop thrombotic microangiopathy

  • However, mice carrying Adamts13-/-cfhW/Ror cfhR/Rdevelop thrombotic microangiopathy with a significantlyincreased mortality rate

Abstract

Severe deficiency of plasma ADAMTS13 activity is the primary cause of thrombotic thrombocytopenic purpura (TTP) while an overwhelming activation of complement via analternative pathway results in an atypical hemolytic uremic syndrome (aHUS), two prototypes of thrombotic microangiopathy. However, clinical and pathogenic distinctions between TTP and aHUS are often quite challenging. Clinical reports have suggested that complement activation may play a role in the development of TTP caused by severe deficiency of plasma ADAMTS13 activity. However, the experimental evidence to support this hypothesis is still lacking. Here, we show that mice with either Adamts13-/- or a heterozygous mutation of complement factor H (cfh) at amino acid residue of 1206 (i.e. cfhW/R) alone remain asymptomatic despite the presence of occasional microvascular thrombi in various organ tissues. However, mice carrying both Adamts13-/- and cfhW/R exhibit thrombocytopenia, low plasma haptoglobin, increased fragmentation of erythrocytes in peripheral blood smear, increased plasma levels of lactate dehydrogenase activity, BUN, and creatinine, as well as an increased mortality rate, consistent with the development of thrombotic microangiopathy. Moreover, mice with a homozygous mutation of cfh (i.e. cfhR/R) with or without Adamts13-/-developed severe thrombotic microangiopathy. The mortality rate in mice with Adamts13-/-cfhR/R was significantly higher than that in mice with cfhR/R alone. Histological and immunohistochemical analyses demonstrated the presence of disseminated platelet-rich thrombi in terminal arterioles and capillaries of major organ tissues in thesemice that were sacrificed or died. Together, our results support a synergistic effect of severe ADAMTS13 deficiency and complement activation in pathogenesis of thrombotic microangiopathy in mice.

  • Submitted April 8, 2019.
  • Revision received August 12, 2019.
  • Accepted August 2, 2019.