Project description:Transplant-associated thrombotic microangiopathy (TA-TMA) is a significant cause of mortality after hematopoietic stem cell transplant (HSCT). Complement blockade is an effective therapeutic strategy for TA-TMA, but some patients with severe disease lack a complete response, prompting a search for additional targetable endothelial injury pathways. We performed transcriptome analysis of peripheral blood mononuclear cells collected prior to HSCT and at onset of TA-TMA and observed significant up-regulation of classical and alternative complement pathways during active TA-TMA. At resolution of TA-TMA after eculizumab therapy, essentially all up-regulated genes and pathways returned to baseline expression levels, supporting the clinical practice of successfully discontinuing complement blockade after resolution of TA-TMA. Further analysis of the global transcriptional regulatory network showed a notable interferon signature associated with TA-TMA with increased STAT1 and STAT2 signaling. To confirm our observations, we documented a high incidence of clinically significant TMA in children with hemophagocytic lymphohistiocytosis (HLH), an interferon gamma-driven disease, outside the setting of transplantation. We also confirmed increased interferon signaling in a separate cohort of patients by measuring CXCL9 and CXCL10 in urine. Our data suggest a key relationship between increased interferon signaling, complement activation, and TMA in two distinct clinical settings, HLH and TA-TMA. Combined anti-complement and anti-interferon treatment may facilitate disease control in patients with refractory TA-TMA. These data cast light on the occurrence of TMA in persons receiving therapeutic interferons, and possibility of TMA in other interferon-driven diseases where interferon may be a novel therapeutic target.

2020-03-30 | GSE134979 | GEO

Clinical value of the renal pathologic scoring system in complement-mediated thrombotic microangiopathy.

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| S-EPMC9848373 | biostudies-literature

Partial Complement Factor H Deficiency Associates with C3 Glomerulopathy and Thrombotic Microangiopathy.

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Interferon-complement loop in transplant-associated thrombotic microangiopathy.

Project description: Not available