Your immune system is your body’s army, protecting you from foreign invaders like viruses and bacteria. When there’s miscommunication between your genes and your immune system, the body can confuse its own tissues for bad guys and launch a misguided attack. This is what happens in paroxysmal nocturnal hemoglobinuria (PNH) — a rare disease in which your immune system attacks your red blood cells (RBCs).

In PNH, red blood cells may be destroyed either inside or outside the blood vessels. In this article, we’ll discuss the differences between these two types of RBC destruction.

Understanding Intravascular and Extravascular Hemolysis in PNH

To understand how paroxysmal nocturnal hemoglobinuria affects your body, it’s important to grasp three key terms:

• Hemolysis — The destruction of red blood cells
• Hemoglobin — The protein in red blood cells that delivers oxygen to all the body’s organs and tissues
• Hemoglobinuria — The presence of hemoglobin in urine, often giving it a dark color

In PNH, red blood cells are destroyed, leading to low RBC levels and various health issues. For instance, anemia occurs when you don’t have enough hemoglobin and healthy red blood cells. Anemia can lead to fatigue, pallor (loss of color in the face), headaches, shortness of breath, and other PNH symptoms.

Hemolysis can happen in different ways and places within your body. Intravascular hemolysis (IVH) and extravascular hemolysis (EVH) refer to where and how red blood cells are destroyed.

Intravascular Hemolysis

Intravascular hemolysis takes place inside the blood vessels. You can think of blood vessels as rivers through which your blood flows. Veins, capillaries, and arteries are all types of blood vessels. In IVH, red blood cells are attacked and broken down while traveling within these vessels.

Intravascular hemolysis (IVH) takes place inside the blood vessels. Extravascular hemolysis (EVH) happens outside the blood vessels, usually in the spleen or liver.

Extravascular Hemolysis

Extravascular hemolysis happens outside the blood vessels, usually in the spleen or liver. These organs act like recycling centers for red blood cells. In EVH, red blood cells are attacked and destroyed in these organs after leaving the bloodstream.

Causes of Intravascular and Extravascular Hemolysis in PNH

The complement system is one part of your immune system. It’s made up of a group of proteins that work together in a complement-mediated cascade — one protein activates the next, and so on, in a chain reaction.

Paroxysmal nocturnal hemoglobinuria happens because of a mutation (variant) in the PIGA gene. This gene normally makes proteins CD55 and CD59, which protect red blood cells from being targeted by the complement system. However, the mutation keeps the gene from making CD55 and CD50. Without these protective proteins, red blood cells look like dangerous invaders to the complement system, leaving them vulnerable to attack.

The complement system plays different roles in intravascular and extravascular hemolysis, depending on which components of the pathway are involved and where the destruction takes place.

C5 in the Blood Vessels

In IVH, the key player is the membrane attack complex (MAC). One of the complement proteins involved in the MAC is called C5. Without protection from CD55 and CD59, the MAC targets and destroys red blood cells directly in the blood vessels. This causes the release of hemoglobin into the blood and then the urine.

A protein called C5 is responsible for destroying red blood cells in IVH. Other immune system proteins are involved in EVH.

C3 in the Spleen and Liver

Despite the lack of protection from CD55 and CD59, some red blood cells still manage to avoid destruction in the bloodstream. However, when they reach the spleen or liver, they’re identified as abnormal and attacked there. This process involves another complement protein, called C3. C3 proteins tell your spleen and liver that the cells should be attacked. It’s a slower process than the MAC complex’s assault in the bloodstream in IVH. As a result, EVH may cause less severe PNH symptoms.

Symptoms and Severity of Intravascular and Extravascular Hemolysis

Intravascular and extravascular hemolysis differ not only in where they happen in the body but also in what symptoms they can cause.

IVH Often Leads to More Severe Symptoms That Happen Fast

In general, IVH is usually more severe because it causes a sudden release of large amounts of hemoglobin directly into the bloodstream. The surge can overwhelm your body’s ability to clear the hemoglobin, leading to a range of symptoms. IVH symptoms can include:

• Dark urine
• Fatigue
• Abdominal pain
• Blood clots
• Anemia
• Low hemoglobin levels
• Kidney problems

Without proper treatment, the symptoms of intravascular hemolysis in PNH can significantly affect your daily life. For example, fatigue can be intense, and the risk of blood clots can lead to serious, life-threatening complications, such as strokes or deep vein thrombosis (blood clots in the large veins of the limbs).

EVH May Cause Milder but Long-Lasting Symptoms

Many of the PNH symptoms seen in IVH can also happen in extravascular hemolysis, but they’re usually not as severe. This is because it takes longer for red blood cells to be broken down in the spleen and liver. EVH can cause symptoms like fatigue and anemia, but it’s less likely to lead to kidney failure or a sudden, life-threatening crisis. EVH may also cause abdominal pain and loss of appetite due to enlargement of the spleen.

Although EVH in PNH may be less severe overall, it can still cause chronic symptoms that wear you down over time. Constant anemia from EVH can lead to chronic fatigue and weakness that may have far-reaching effects on your overall quality of life.

Treatments for Intravascular vs. Extravascular Hemolysis in PNH

A major challenge in the treatment of paroxysmal nocturnal hemoglobinuria is that different types of hemolysis require different approaches. The most commonly available PNH treatments target intravascular hemolysis but may be less effective for extravascular hemolysis.

C5 Inhibitors for IVH in PNH

Complement inhibitors are a type of immunotherapy that work by targeting certain parts of the complement system. C5 inhibitors protect red blood cells from destruction by the MAC complex, and they’re largely effective at reducing or preventing intravascular hemolysis in many people living with PNH.

C5 inhibitor drugs approved by the U.S. Food and Drug Administration (FDA) to treat PNH include:

• Crovalimab-akkz (PiaSky)
• Eculizumab (Soliris)
• Ravulizumab (Ultomiris)

Treatments for EVH in PNH

C5 inhibitors are less effective at treating EVH because they don’t stop the spleen and liver from using C3 proteins to break down red blood cells. However, a new class of drugs called proximal complement inhibitors targets C3-driven EVH in those organs.

Drugs known as C5 inhibitors may work well to reduce IVH, but you can still have symptoms caused by EVH. Other medications may be better at reducing EVH.

Proximal complement inhibitors approved by the FDA for PNH include:

• Danicopan (Voydeya)
• Iptacopan (Fabhalta)
• Pegcetacoplan (Empaveli)

Sometimes, complement-mediated treatments for EVH and IVH aren’t enough to properly manage PNH. Depending on the severity of your disease and symptoms, you may need to receive blood transfusions as well.

New and emerging therapies for treating intravascular and extravascular hemolysis are on the horizon. Talk with your health care team or a hematology specialist (blood specialist) about what new treatments are available to you. They can also help you learn about clinical trials for EVH and IVH if you’re interested in taking part in research on new therapies for PNH.

Talk With Others Who Understand

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

Have you talked with your PNH specialist about what type of hemolysis you have? Has it made a difference in your treatment plan? Share your experience in the comments below, or start a conversation on your Activities page.