Hemolysis is driven by the classical complement pathway in Cold Agglutinin Disease (CAD)

In CAD, activated C1 drives chronic hemolysis through the classical pathway1,2

Continued C1 activation of the classical complement pathway leaves patients in a chronic hemolytic state1,2

Diagram depicting IgM autoantibodies binding to RBCs and activating C1 triggering chronic hemolysis and inflammation in CAD


*C1 amplifies the activation of C3, resulting in extravascular hemolysis and chronic inflammation.

Complement activity can activate C5, leading to intravascular hemolysis and chronic inflammation.

Watch the mechanism of CAD

Cold agglutinin disease (CAD) is a rare, severe blood disorder. It’s a form of autoimmune hemolytic anemia, which means the immune system mistakenly attacks and destroys red blood cells.

In cold agglutinin disease, certain abnormal bone marrow cells produce antibodies called cold agglutinins, which activate a part of the immune system known as the complement pathway. This activation results in the constant destruction of red blood cells, known as hemolysis.

Here’s how it works:

  • • The cold agglutinin antibody mistakenly attaches to a red blood cell and activates the complement pathway
  • • The pathway starts with a protein called C1 binding to the red blood cell. This leads to a complex chain of events that marks the red blood cell for destruction
  • • At the end of the pathway, the marked cell is destroyed. This destruction is known as hemolysis

In people with CAD, the destruction of red blood cells, or C1-activated hemolysis, is happening all the time. It can cause anemia, along with severe fatigue. That’s because red blood cells are destroyed prematurely and are not able to do the vital job of carrying oxygen throughout your body. If your organs and tissues don’t get enough oxygen, they can’t function normally—making you feel tired.

Recent studies have shown that CAD may be more serious than previously thought. A 10-year review of the medical histories of people with CAD showed that they had a higher risk of stroke, heart attack, or blood clots. Additionally, patients with CAD are also at risk of experiencing sudden drops in their hemoglobin that may require emergency treatment

Though researchers are getting closer, there are currently no treatments approved specifically for cold agglutinin disease. Research is being done every day to find more answers for people living with this rare condition.

Sanofi Genzyme is committed to transforming the care of people living with rare blood disorders.

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CAD can impact
patients' lives

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CAD can have
serious consequences

CAD=Cold Agglutinin Disease; IgM=immunoglobulin M; RBC=red blood cell.
References: 1. Berentsen S. Complement activation and inhibition in autoimmune hemolytic anemia: focus on cold agglutinin disease. Semin Hematol. 2018;55(3):141-149. doi:10.1053/j.seminhematol.2018.04.002 2. Noris M, Remuzzi G. Overview of complement activation and regulation. Semin Nephrol. 2013;33(6):479-492. doi:10.1016/j.semnephrol.2013.08.001