Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Sep;111(3):326-336.
doi: 10.1111/ejh.14026. Epub 2023 Jun 12.

Molecular pharmacology in complement-mediated hemolytic disorders

Marta Bortolotti  1   2 , Wilma Barcellini  1 , Bruno Fattizzo  1   2
Affiliations
Review

Molecular pharmacology in complement-mediated hemolytic disorders

Marta Bortolotti et al. Eur J Haematol. 2023 Sep.

Abstract

In the last decade, a deeper understanding of the pathogenesis of complement mediated hemolytic disorders, such as paroxysmal nocturnal hemoglobinuria (PNH), cold agglutinin disease (CAD), warm type autoimmune hemolytic anemia (AIHA) with complement activation (wAIHA), and atypical hemolytic uremic syndrome (aHUS), paved the way to the therapeutic shift from purely supportive approaches to complement-targeted therapies. This resulted in a significant improvement in disease management, survival, and quality of life. In this review, we will provide a snapshot of novel therapies for complement-mediated hemolytic anemias with a focus on those ready to use in clinical practice. C5 inhibitors eculizumab and the long-acting ravulizumab, are the established gold standard for untreated PNH patients, whilst the C3 inhibitor pegcetacoplan should be considered for suboptimal responders to anti-C5 drugs. Several additional compounds targeting the complement cascade at different levels (other C5 inhibitors, factor B and D inhibitors) are under active investigation with promising results. In CAD, immunosuppression with rituximab remains the first-line. However, recently FDA and EMA approved the anti-C1s monoclonal antibody, sutimlimab, that showed dramatic responses and whose regulatory approval is soon awaited in many countries. Other drugs under investigation in AIHA include the C3 inhibitor pegcetacoplan, and the anti-C1q ANX005 for warm AIHA with complement activation. Finally, aHUS is an indication for complement inhibitors. Eculizumab and ravulizumab have been approved, whilst other C5 inhibitors, and novel lectin pathway inhibitors are under active investigation in this disease.

Keywords: atypical hemolytic uremic syndrome; cold agglutinin disease; complement inhibitors; paroxysmal nocturnal hemoglobinuria; warm autoimmune hemolytic anemia.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

References

REFERENCES

    1. Kinoshita T, Inoue N, Takeda J. Defective glycosyl phosphatidylinositol anchor synthesis and paroxysmal nocturnal hemoglobinuria. Adv Immunol. 1995;60:57-103. doi:10.1016/s0065-2776(08)60584-2
    1. Brodsky RA. How I treat paroxysmal nocturnal hemoglobinuria. Blood. 2021;137(10):1304-1309. doi:10.1182/blood.2019003812
    1. Parker CJ. Hemolysis in PNH. In: Young NS, Moss J, eds. PNH and the GPI-Linked Proteins. Academic Press; 2000.
    1. Risitano AM, Kulasekararaj AG, Lee JW, et al. Danicopan: an oral complement factor D inhibitor for paroxysmal nocturnal hemoglobinuria. Haematologica. 2021;106(12):3188-3197. doi:10.3324/haematol.2020.261826
    1. Taylor RP, Lindorfer MA. Mechanisms of complement-mediated damage in hematological disorders. Semin Hematol. 2018;55(3):118-123. doi:10.1053/j.seminhematol.2018.02.003

MeSH terms

Substances

Grants and funding

LinkOut - more resources