Mechanism of disease

To understand PNH, it is essential to understand the complement system, a part of the innate immune response which enhances the body’s ability to fight bacterial pathogens.2

The complement system is divided into two main parts with differing functions: a proximal part, which plays an important role in targeting pathogens, such as bacteria, for phagocytosis, and a terminal part, which is involved in lysis of certain bacteria.3

The alternative pathway is always active and plays the most important role in PNH.3 All three of these biochemical pathways can cause the activation of complement protein C3.3 

In the proximal part of the complement system, activated C3 is split into two fragments: C3a and C3b.5 C3b acts as a marker of foreign bodies, and in a process known as opsonisation it binds to bacteria to target them for elimination by phagocytic cells.5

Figure adapted from Duval A et al. Am J Hematol. 2023;98:S5–S19.6

In the terminal complement pathway, C5 convertase facilitated cleavage of C5 into C5a and C5b.5 C5b combines with a number of other complement factors to form the membrane attack complex, also known as MAC.5,7 The role of the MAC is to damage the membrane of pathogens causing them to be lysed and die; the MAC plays a key role in PNH.3
In healthy individuals’ red blood cells (RBCs), platelets and leukocytes have complement regulators on their surface that protect them from attack from MAC formation.5,8 In PNH, however, an acquired mutation (not inherited) in a gene called PIG-A leads to the reduced expression or absence of the complement inhibitors (CD55/CD59) on the surface of the blood cells.3 Complement regulation is impaired, leaving RBCs highly susceptible to attack from the MAC. This leads to premature RBCs destruction in the form of IVH through uncontrolled activation of the terminal complement.3
Figure adapted from information presented in Lee JW, et al. Expert Review of Clinical Pharmacology. 2022;(7):851–8613 and Risitano AM, et al. Frontiers in Immunology. 2019;10:1157.8

The lack of terminal complement regulation also results in activation of platelets and leukocytes, and together with IVH, this leads to a prothrombotic state.3 Together, terminal complement-mediated IVH and activation of leukocytes and platelets put patients at risk of life-threatening thromboembolic events, organ damage and the debilitating symptoms associated with PNH.3

Targeted blockade of the terminal part of the complement pathway through inhibition of C5 is the standard of care treatment for PNH.5,10 C5 inhibition blocks the terminal complement pathway and prevents the formation of the MAC.10 This approach prevents terminal complement mediated IVH and reduces the risk of thrombosis and the devastating consequences of PNH.10

C5 inhibitors have transformed the natural history of PNH, reducing thromboembolic risk and improving survival, organ function and disease-related symptoms.*10
*Disclaimer: this retrospective study compared results from 389 patients with PNH, treated with eculizumab and/or ravulizumab, between 2002 and 2022 vs population mortality data taken from the human mortality database for the UK (1841–2020), stratified based on age and sex. The observed survival was not a prespecified endpoint, and the study was not powered to detect differences. This analysis excluded patients receiving an allogeneic HSCT, bone marrow dysfunction or those with clonal evolution to MDS or AML.9
Effectively blocking the terminal complement pathway can result in a small proportion of RBCs being prematurely marked for extravascular haemolysis (EVH) in the spleen or liver mediated by the proximal complement.11
Figure adapted from information presented in Lee JW, et al. Expert Review of Clinical Pharmacology. 2022;(7):851–8613 and Brodsky RA. Blood. 2014;124(18):2804-2811.12

EVH can lead to anaemia, as RBCs are destroyed faster than they are formed. However, for most patients with PNH receiving C5 inhibition therapy, anaemia (if present) is asymptomatic.3,13 Unlike IVH, EVH is rarely life-threatening and does not usually require intervention, only clinically significant EVH requires treatment.*10,13

EVH, when it becomes clinically significant, is defined as residual symptomatic anaemia with or without the need for transfusion while on a C5 inhibitor, with low haemoglobin and increased absolute reticulocyte count, when other causes of symptomatic anaemia are eliminated.11 Selective inhibition of the alternative pathway is critical in managing clinical significant EVH.11

However, residual anaemia can be caused by several factors beyond EVH, including bone marrow dysfunction, low nutritional folate or iron overload, relative erythropoietin deficiency and more.14 In PNH, to confirm whether residual anaemia is due to EVH, other causes should be eliminated.11,15
*The terms “clinically significant EVH” used in the VOYDEYA® ALPHA trial and “residual haemolytic anaemia” used in the SmPC refer to the same patient population. For simplicity, the term EVH will be used interchangeably throughout this document for both of the above terms. EVH in PNH is a mechanistic effect of complete terminal complement inhibition. Only EVH deemed clinically significant needs to be treated.
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Kulasekararaj AG, et al. Paroxysmal nocturnal hemoglobinuria: Where are we going. American Journal of Hematology. 2023. Walport MJ. Advances in Immunology. New England Journal of Medicine. 2001. Lee JW, Brodsky RA, Nishimura JI, Kulasekararaj AG. The role of the alternative pathway in paroxysmal nocturnal hemoglobinuria and emerging treatments. Expert Rev Clin Pharmacol. 2022;15(7):851-861. doi:10.1080/17512433.2022.2109462.  Merle NS, et al. Complement System Part I - Molecular Mechanisms of Activation and Regulation. Frontiers in Immunology. 2015;6:262;​ Berentsen S, et al. Novel Insights Into the Treatment of Complement-mediated Hemolytic Anemias. Therapeutic Advances in Hematology. 2019;10:1–20. Duval A et al. Complement Biology for Hematologists. American Journal of Hematology. 2023;98:S5–S19. Barratt J 2021 et al. Complement Factor D as a Strategic Target for Regulating the Alternative Complement Pathway. Frontiers in Immunology. 2021. Risitano AM, et al. Anti-Complement Treatment for Paroxtsmal Nocturnal Hemoglobinuria: Time for Proximal Complement Inhibition? A Position Paper from the SAAWP of the EBMT. Frontiers in Immunology. 2019;10:1157. Kelly RJ, Holt M, Vidler J, et al. Treatment outcomes of complement protein C5 inhibition in 509 UK patients with paroxysmal nocturnal hemoglobinuria. Blood. 2024;143(12):1157-1166. doi:10.1182/blood.2023021762. Kulasekararaj AG, et al. The Importance of Terminal Complement Inhibition in Paroxysmal Nocturnal Hemoglobinuria. Therapeutic Advances in Hematology. 2022;13:20406207221091046. Lee JW, et al. Addition of Danicopan to Ravulizumab or Eculizumab in Patients with Paroxysmal Nocturnal Haemoglobinuria and Clinically Significant Extravascular Haemolysis (ALPHA): a Double-blind, Randomised, Phase 3 Trial. The Lancet Haematology. 2023;10:e955 – e965. Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood. 2014;124(18):2804-2811. doi:10.1182/blood-2014-02-522128. Hill A, et al. Paroxysmal nocturnal haemoglobinuria. Nature Review Disease Primers. 2017;3:17028. Kulasekararaj AG, et al. Monitoring of Patients with Paroxysmal Nocturnal Hemoglobinuria on a Complement Inhibitor. American Journal of Hematology. 2021;7(96):E232–E235. Roth A. Treatment of paroxysmal nocturnal hemoglobinuria in the era of eculizumab. European Journal of Haematology 2011. 87 (473–479). advance I am a healthcare professional registered in the EU I am not a
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