Understanding
complement pathway
inhibition

Even with current treatments, RBCs remain vulnerable to complement-mediated hemolysis1-3

There are multiple mechanisms of hemolysis.3

Watch the video to learn more.

According to a retrospective analysis (N=93), up to 89% of patients treated with C5 inhibition showed varying signs of ongoing hemolysis.4*

*An international, retrospective analysis of 93 patients with PNH was conducted to classify hematologic response to eculizumab based on hemoglobin levels and residual hemolysis (Debureaux ASH Abstract 2019). The calculation of hematologic response is from the last 6 months, inclusive of major, good, partial, minor, and non-responders.4
Hemolysis is the destruction of RBCs and occurs in PNH through 2 mechanisms:
IVH, which occurs inside blood vessels, and EVH, which occurs in the liver and spleen5,6

The lectin, classical, and alternative complement pathways all converge at the point of C3

The lectin, classical, and alternative complement pathways all converge at the point of C3

LECTIN
PATHWAY
CLASSICAL
PATHWAY
ALTERNATIVE
PATHWAY
Proximal
complement
inhibition
C3
Amplification loop
Inflammation
C3a
C3b
EVH happens when C3-loaded PNH RBCs are recognized and destroyed by macrophages7
C3-loading is the process in which proteins such as C3b “tag” a cell’s surface, marking them for destruction (complement-mediated EVH).5
Terminal
complement
inhibition
C5
Once C5 is activated, various complement
proteins bind to create the MAC, anchoring
into and puncturing the membrane of the
PNH red blood cell, causing the cell to burst in circulation6
C5a
Inflammation
C5b
MAC
IVH is initiated by terminal
complement activation of
the MAC5
C5 inhibition targets terminal complement activation of the MAC8
C3, upstream of C5 in the
complement cascade, may be
central to the control of
hemolysis in PNH8
Proximal
complement
inhibition
C3
Amplification loop
Inflammation
C3a
C3b
EVH happens when C3-loaded PNH RBCs are recognized and destroyed by macrophages7
C3-loading is the process in which proteins such as C3b “tag” a cell’s surface, marking them for destruction (complement-mediated EVH).5
C5
Once C5 is activated, various complement
proteins bind to create the MAC, anchoring
into and puncturing the membrane of the
PNH red blood cell, causing the cell to burst
in circulation7
Terminal
complement
inhibition
C5
Inflammation
C5a
C5b
MAC
IVH is initiated by
terminal complement
activation of the MAC5
C5 inhibition targets terminal complement activation of the MAC8
C3, upstream of C5 in the
complement cascade, may be
central to the control of
hemolysis in PNH8
Back to Top
Addressing ongoing hemolysis may play a significant role in reducing PNH disease activity8
Watch the video
to learn more

ARC=absolute reticulocyte count; EVH=extravascular hemolysis; IVH=intravascular hemolysis; LDH=lactate dehydrogenase; MAC=membrane attack complex; PNH=paroxysmal nocturnal hemoglobinuria; RBC=red blood cell; ULN=upper limit of normal.


References: 1. Brodsky RA, et al. Haematologica. 2021;106(1):230-237. 2. Hill A, et al. Haematologica. 2010;95(4):567-573. 3. Risitano AM, et al. Blood. 2009;113(17):4094-4100. 4. Debureaux PE, et al. Abstract presented at: 61st American Society of Hematology Annual Meeting; December 7-10, 2019; San Diego, CA. 5. Brodsky RA. Blood. 2014;124(18):2804-2811. 6. Risitano AM. Immunobiology. 2012;217(11):1080-1087. 7. Hill A, et al. Nat Rev Dis Primers. 2017;3:17028. 8. Risitano AM, et al. Front Immunol. 2019;10:1157.