Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood autoimmune disorder that causes your immune system to attack and destroy your red blood cells (RBCs) — also called erythrocytes. Specifically, mutations in the PIGA gene prevent your RBCs from making proteins that protect them from your immune system. As a result, your complement system — part of your immune system — attacks and destroys your RBCs.

In this article, we’ll discuss the role of complement in your immune system and in PNH and how blocking it helps treat this disease. Doctors and researchers continue to find new ways to block different pathways in the complement system to prevent RBC breakdown and PNH symptoms.

1. The Complement System Is an Important Part of Your Immune System

Your immune system has two main components — the innate immune system and the adaptive immune system. Your innate immune system is activated first whenever germs enter the body. It’s made of several cells and proteins, including the proteins of the complement system (or complement, for short). The innate immune system and complement system mobilize instantly because they attack anything that’s not recognized as “self,” or part of your own body.

On the other hand, your adaptive immune system takes time to be activated because it needs to produce antibodies, proteins tailored to target the specific pathogen (disease-causing organism) that’s trying to invade.

The complement system is made of nearly 50 plasma proteins that work together as your body’s first line of defense against invaders. It produces inflammation that calls in other immune cells to help fight off infection.

2. In PNH, Complement Destroys Red Blood Cells

Your immune system is an important part of keeping you healthy, but some health conditions are triggered when it recognizes your cells as foreign invaders. Normally, your RBCs have proteins on their surface that prevent complement from reacting and attacking them.

In PNH, the genes that provide the instructions for making and placing the complement regulators on the cell surface are mutated. This means that your RBCs no longer have them — as a result, your complement system breaks down your RBCs, known as hemolysis.

PNH causes two types of hemolysis. One is intravascular hemolysis, which occurs when RBCs are destroyed in your blood vessels. The second is extravascular hemolysis, which occurs when RBCs are destroyed in your spleen and liver.

3. Complement Includes C3 and C5 Proteins

In the complement system, the protein C3 is broken down by an enzyme known as C3 convertase into proteins C3a and C3b. The C3a protein interacts with other immune cells to produce inflammation.

C3b attaches to C3 convertase to form another enzyme known as C5 convertase, which breaks apart the complement protein C5. The C5a protein works alongside C3a to produce inflammation.

C5b, C3b, and several other complement proteins work together to form the membrane attack complex. This powerful complex works by punching holes into bacteria and other pathogens, causing them to burst (which scientists refer to as lysis).

Some complement proteins also participate in another process known as opsonization. The C3b protein attaches to the outside of pathogens, tagging them as foreign invaders as a signal to your immune system. This triggers immune cells known as macrophages to “eat” the pathogen, destroying it.

4. PNH Symptoms Are Caused by RBC Destruction

As your complement system continues to break down RBCs, your body will try to replace them. New blood cells form in your bone marrow (the spongy tissue found inside your bones). However, bone marrow usually can’t keep up, leading to a shortage of RBCs.

Hemolytic anemia is a condition that develops when your RBC count is too low because they’re destroyed too quickly. It’s responsible for causing common PNH symptoms, such as shortness of breath, weakness, and fatigue.

Many people with PNH also have abnormal platelets or cell fragments that help with blood clotting. They’re at an increased risk of thrombosis (blood clots in large veins) — especially in the abdomen.

Hemoglobin is the protein found on your RBCs that is responsible for carrying oxygen. When RBCs are destroyed by the complement system, they release hemoglobin into your bloodstream. The free hemoglobin eventually ends up in your urine — called hemoglobinuria — which makes it red or dark brown.

5. Newer Treatments for PNH Block Complement

Previously, doctors treated PNH with regular RBC transfusions. Doctors and researchers have since developed several PNH treatments that target different parts of the complement system, blocking its activity. These drugs fall under the category of complement inhibitors. While there’s currently no cure for PNH, complement inhibitors have significantly improved the quality of life and life span of people living with the disease.

Eculizumab and Ravulizumab

Monoclonal antibodies are lab-engineered proteins that target and block a specific part of the immune system to treat diseases. The U.S. Food and Drug Administration (FDA) has approved three of these therapies for treating PNH:

• Crovalimab-akkz (Piasky)
• Eculizumab (Soliris) and the interchangeable medication eculizumab-aeeb (Bkemv)
• Ravulizumab-cwvz (Ultomiris)

Pegcetacoplan

The FDA approved pegcetacoplan (Empaveli) in 2021 as the first complement C3 inhibitor for treating PNH. It works by blocking the breakdown of C3 into C3a and C3b.

Iptacopan

Iptacopan (Fabhalta) is a drug for complement inhibition. The FDA approved this treatment in 2023. It works by blocking factor B, a protein involved in the alternative pathway.

Iptacopan has been shown to raise hemoglobin levels by preventing complement-mediated hemolysis. It also reduces PNH symptoms such as fatigue. Iptacopan is the first PNH treatment available as a pill taken by mouth.

Talk With Others Who Understand

On myPNHteam, the social network for people with paroxysmal nocturnal hemoglobinuria and their loved ones, hundreds of members come together to ask questions, give advice, and share their stories with others who understand life with PNH.

Are you taking a complement inhibitor for PNH? Share your experience in the comments below, or start a conversation by posting on your Activities page.