Complement blockade for TA-TMA: lessons learned from large pediatric cohort treated with eculizumab

Jodele, Sonata; Dandoy, Christopher E.; Lane, Adam; Laskin, Benjamin L.; Teusink‐Cross, Ashley; Myers, Kasiani C.; Wallace, Gregory; Nelson, Adam; Bleesing, Jack J.; Chima, Ranjit S.; Hirsch, Russel; Ryan, Thomas; Benoit, Stefanie; Mizuno, Kazuharu; Warren, Mikako; Davies, Stella M.

doi:10.1182/blood.2019004218

Cited by 105 publications

(174 citation statements)

References 41 publications

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“…A few reports of agents with some evidence base in complement-mediated TMAs have been published in the COVID-19 literature. Complement inhibition is currently in favour for the treatment of most of the non-DIC TMA syndromes following a number of uncontrolled case reports or patient series showing dramatic responses that would not have been obtained with anticoagulation alone 97 – 100 . These reports are consistent with results in another complement-mediated disorder, paroxysmal nocturnal haemoglobinuria 101 .…”

Section: Implications For Treatmentmentioning

confidence: 99%

Emerging evidence of a COVID-19 thrombotic syndrome has treatment implications

et al. 2020

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Reports of widespread thromboses and disseminated intravascular coagulation (DIC) in patients with coronavirus disease 19 (COVID-19) have been rapidly increasing in number. Key features of this disorder include a lack of bleeding risk, only mildly low platelet counts, elevated plasma fibrinogen levels, and detection of both severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and complement components in regions of thrombotic microangiopathy (TMA). This disorder is not typical DIC. Rather, it might be more similar to complement-mediated TMA syndromes, which are well known to rheumatologists who care for patients with severe systemic lupus erythematosus or catastrophic antiphospholipid syndrome. This perspective has critical implications for treatment. Anticoagulation and antiviral agents are standard treatments for DIC but are gravely insufficient for any of the TMA disorders that involve disorders of complement. Mediators of TMA syndromes overlap with those released in cytokine storm, suggesting close connections between ineffective immune responses to SARS-CoV-2, severe pneumonia and life-threatening microangiopathy.

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Section: Implications For Treatmentmentioning

confidence: 99%

Emerging evidence of a COVID-19 thrombotic syndrome has treatment implications

et al. 2020

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“…[2][3][4][5][6][7] Complement dysregulation plays an important role in TA-TMA and complement blockade with eculizumab, a monoclonal antibody directed against C5, improves survival after TA-TMA. [8][9][10] However, some patients with TA-TMA do not have a clinical response to eculizumab, suggesting that other mechanisms of endothelial injury may be involved in the pathogenesis of thrombotic microangiopathies and could potentially serve as therapeutic targets.…”

Section: Introductionmentioning

confidence: 99%

Interferon-complement loop in transplant-associated thrombotic microangiopathy

et al. 2020

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Transplant-associated thrombotic microangiopathy (TA-TMA) is an important cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The complement inhibitor eculizumab improves TA-TMA, but not all patients respond to therapy, prompting a search for additional targetable pathways of endothelial injury. TA-TMA is relatively common after HSCT and can serve as a model to study mechanisms of tissue injury in other thrombotic microangiopathies. In this work, we performed transcriptome analyses of peripheral blood mononuclear cells collected before HSCT, at onset of TA-TMA, and after resolution of TA-TMA in children with and without TA-TMA after HSCT. We observed significant upregulation of the classical, alternative, and lectin complement pathways during active TA-TMA. Essentially all upregulated genes and pathways returned to baseline expression levels at resolution of TA-TMA after eculizumab therapy, supporting the clinical practice of 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 that resolved after complement blockade. In summary, we observed activation of multiple complement pathways in TA-TMA, in contrast to atypical hemolytic uremic syndrome (aHUS), where complement activation occurs largely via the alternative pathway. Our data also suggest a key relationship between increased interferon signaling, complement activation, and TA-TMA. We propose a model of an “interferon-complement loop” that can perpetuate endothelial injury and thrombotic microangiopathy. These findings open opportunities to study novel complement blockers and combined anti-complement and anti-interferon therapies in patients with TA-TMA and other microangiopathies like aHUS and lupus-associated TMAs.

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“…Currently, there are no universally accepted biomarkers for the prediction of TA-TMA, although platelet activation, neutrophil extracellular traps and complement activation are suggested to play key roles (21). The relationship between elevated sC5b-9 levels at the time of TA-TMA diagnosis and poor survival was reported a few years ago (10), which has been followed by several studies demonstrating the possible link between complement activation and TA-TMA, and facilitated subsequent therapeutic decisions and analysis to predict response to treatment (7,22). Importantly, according to recent observations in a large pediatric cohort use of anti-C5 complement inhibitory drug seems to be an effective therapeutic strategy for high-risk TA-TMA patients after HSCT (22).…”

Section: Discussionmentioning

confidence: 99%