Chronic, uncontrolled complement activity results in continuous endothelial damage and ongoing risk of TMA1-4

TMA lesions from repeated endothelial injury can progress toward irreversible tissue damage1-3,18

  • Elevated Baseline of
    Complement Activity

  • Chronic
    Complement Activity

  • Complement Mediated
    TMA

  • Ischemia

  • Progressive Organ
    Damage

Individual with aHUS

  • The assembly of multiple C5b-9 complexes on the surface of endothelial cells causes endothelial injury and platelet activation4,19,26,27
  • Binding of C5a to the C5a receptor results in a decrease in the endothelium's anticomplement and antithrombogenic properties4,26,28,29
  • Disrupted endothelial cells:
    • Release complement-activating microparticles, resulting in a vicious cycle of endothelial activation, complement amplication, and ongoing endothelial injury4,30
    • Release prothrombotic coagulation proteins, activate platelets, and recruit leukocytes, resulting in the formation of thrombi in small blood vessels throughout the body4
  • Uncontrolled complement activity causes ongoing vascular endothelial injury, resulting in TMA lesions and progressive organ damage1-3,18
  • Biomarkers of complement activation, inflammation, endothelial cell activation and damage, coagulation, and renal damage (eg, Ba, sTNFR1, sVCAM-1, D-dimer, U-Cystatin C) are similarly elevated among patients with aHUS receiving or not receiving plasma exchange or plasma infusion8

Continuous complement amplification and endothelial damage put patients with aHUS at ongoing risk of life-threatening complications1-3,18

1. Laurence J. Atypical hemolytic uremic syndrome (aHUS): making the diagnosis. Clin Adv Hematol Oncol. 2012;10(suppl 17):1-12. 2. Legendre CM, Licht C, Muus P, et al. N Engl J Med. 2013;368:2169-2181. 3. Sellier-Leclerc A-L, Frémeaux-Bacchi V, Dragon-Durey MA, et al; French Society of Pediatric Nephrology. Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2007;18:2392-2400. 4. Noris M, Mescia F, Remuzzi G. STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nat Rev Nephrol. 2012;8:622-633. 8. Cofiell R, Kukreja A, Bedard K, et al. Poster presented at the 55th Annual Meeting of the American Society of Hematology; December 7-10, 2013; New Orleans, LA. Abstract 2184. 18. Nester CM, Thomas CP. Atypical hemolytic uremic syndrome: what is it, how is it diagnosed, and how is it treated? Hematology Am Soc Hematol Educ Program. 2012;2012:617-625. 19. Barbour T, Johnson S, Cohney S, et al. Thrombotic microangiopathy and associated renal disorders. Nephrol Dial Transplant. 2012;27:2673-2685. 26. Fang CJ, Richards A, Liszewski MK, et al. Advances in understanding of pathogenesis of aHUS and HELLP. Br J Haematol. 2008;143:336-348. 27. Loirat C, Frémeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60. 28. Gastoldi S, Noris M, Macor P, et al. C5a/C5aR interaction mediates complement activation and thrombosis on endothelial cells in atypical hemolytic uremic syndrome (aHUS). Immunobiology. 2012;217:1145-1146. 29. Salant DJ. Targeting complement C5 in atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2011;22:7-9. 30. Renner B, Klawitter J, Goldberg R, et al. Cyclosporine induces endothelial cell release of complement-activating microparticles. J Am Soc Nephrol. 2013;24:1849-1862.