Cold agglutinin disease: Improved understanding of pathogenesis helps define targets for therapy (2023)

Cold agglutinin disease: Improved understanding of pathogenesis helps define targets for therapy (1)

Imagine not being able to stay outdoors during winter. Or having to put on gloves to open the fridge. New knowledge and better treatment give hope to people who suffer from a rare cold disease.

For most of us, feeling a little cold is not a big issue. This is a different story for people who suffer from a rare cold disease. They can experience a lot of pain, become anemic and suffer serious damage to their health from the cold. Even small changes in temperature can make the disease flare up, and many patients have symptoms even when they are not feeling cold.

Researchers estimate that 100 people suffer from this disease in Norway. Most often, the disease is discovered when patients are in their 70s, while in some cases it is discovered in people as young as 40 years old.

The disease is called chronic cold agglutinin disease (CAD) and is a disease of the bone marrow. For a long time, no one knew about it, and it was not acknowledged as a disease. However, recent discoveries have provided new knowledge about its causes, and it is now on the World Health Organization's list of diseases.

"The fact that we now know more about the mechanisms behind the disease, what happens in the body and why, means that patients can receive more targeted treatment," Ulla Randen says. She is an associate professor at the Institute of Clinical Medicine at the University of Oslo.

Patients used to get other diagnoses and treatments

Since researchers and clinicians did not know about the mechanisms behind the rare cold disease and it was not recognized as a disease, it was difficult to treat patients.

(Video) Demystifying Cold Agglutinin Disease

"In the past, patients have been diagnosed incorrectly, with everything from lymphoma to autoimmune diseases. They received treatments for those diagnoses. However, the treatments did not achieve the desired effect in these patients. The treatments also have a number of side effects," Randen says and adds:

"Some patients did not receive any diagnosis at all."

Ulla Randen therefore wanted to study the condition and get to the bottom of what the patients were suffering from.

"We discovered that this disease differs from known forms of lymphoma and other types of reactive conditions. We went on to describe and reclassify the disease," she says.

Cooling activates antibodies in the blood

Many of us may have a few antibodies in our blood called cold agglutinins. For the most part, they do not cause problems. However, patients with CAD have many such antibodies, which is abnormal.

In patients, the antibodies are activated when the blood cools down. When that happens, the blood begins to clot or agglutinate, as it is also called.

"When this occurs, the blood cannot circulate all the way to the smallest blood vessels in the fingertips, toes, in the ears and on the tip of the nose. These body parts therefore become bluish-white and painful because you don't have blood circulation there," the associate professor explains.

For those affected, only small changes in temperature can activate these antibodies. A smaller temperature drop, such as the temperature in the blood falling below 32 degrees Celsius, may be enough. This can occur when patients get cold, but also under normal conditions when the blood passes through the outer parts of the head, arms and legs.

As a result, the antibodies can cause trouble even when it is not particularly cold.

(Video) Following the Diagnostic Pathway for Cold Agglutinin Disease

"We looked at the blood and bone marrow samples of patients in Norway and found that everyone had a group of immune cells that produce these antibodies," Ulla Randen says.

Many become anemic and need a blood transfusion

The clots in the blood dissolve again when the blood returns to warmer parts of the body.

"The problem is that the red blood cells get a small tag on them when they clot. The cleansing systems in the liver and spleen recognize the tag and destroy the blood cells. Since this cleansing system constantly destroys blood cells, patients become anemic, i.e., they lose red blood cells," she explains.

Half of the patients with CAD that suffer from anemia need blood transfusion.

Treatment with immunotherapy has a good effect

With these new discoveries, patients can receive better treatment. One type of immunotherapy has proven to have a good effect in most people who are affected, according to Randen.

"There is a drug called Rituximab that attacks the population of immune cells that make the body produce the abnormal antibodies," she says.

In addition, patients get various combinations of chemotherapy.

The aim of the treatment is to remove the immune cells that make abnormal antibodies.

"This treatment had a very good effect. Seven out of ten patients could lead a more normal life," she says.

(Video) Cold Agglutinin Disease Laboratory Evaluation and Treatment Options

The new treatment improves patients' quality of life greatly. Many feel their energy is back and can spend time outdoors without pain or symptoms even when it is cold.

"Some patients could finally go skiing again!" the researcher says.

So far, the effects of the treatment seem to last over time.

"But we do not know if patients are completely cured. With new immunotherapy, some people report that the disease disappears completely. However, these kinds of diseases are a bit insidious. There may be some cells hiding somewhere, which means that the disease can flare up again," Randen points out.

Different treatment options

There are several possible treatments for CAD. Sigbjørn Berentsen has conducted research on several types of treatment and has treated many patients with the disease. He is one of the clinicians who has collaborated with Ulla Randen.

The treatment with immunotherapy and chemotherapy does not turn out equally for everyone who has cold agglutinin disease, he explains.

"The possible disadvantage of chemotherapy is that you may shut down the immune system completely. Then there is a risk of different types of infections," Berentsen says.

Doctors must assess the general health of each patient and weigh treatment options against how much they are affected by the disease, he explains.

"Elderly, frail patients should in some cases be given a milder version of the treatment. Other patients have so few and mild symptoms that they do not need treatment. In those cases, we go for a 'watch and wait' option and follow up on the patient over time to see how the disease develops," Berentsen explains.

(Video) Management of Cold Agglutinin Disease in the Emergency Department: A Case-Based Discussion

"No one had actually collected all the data that we had on patients in Norway until we started working on this project. Since this is a small patient group, we need to collect all the data that we can access, in order to do different analyses," Randen says.

The researchers collected bone marrow samples, both tissue samples and cells that are collected from the bone marrow with a syringe. The researchers could then look at a single cell at a time. The method they used is called flow cytometry.

"This is a method by which you recognize different cell types and count them. By using this, we discovered that these were separate clones, or identical groups, of immune cells. We also did genetic analyses to check if the antibodies were the same. Under the microscope, we could see that they differ from the clones known from other types of lymphoma and reactive conditions. This is how we ended up discovering that we were talking about a separate disease," the associate professor explains.

The study is published in the journal Hemato.

More information: Sigbjørn Berentsen et al, Cold Agglutinin Disease: Improved Understanding of Pathogenesis Helps Define Targets for Therapy, Hemato (2022). DOI: 10.3390/hemato3040040

Provided byUniversity of Oslo

Citation: Cold agglutinin disease: Improved understanding of pathogenesis helps define targets for therapy (2023, February 7) retrieved 11 February 2023 from

(Video) Cold Agglutinin Disease Animation - Mechanism of Disease

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What is the pathogenesis of cold agglutinin disease? ›

Pathologic cold agglutinins occur at titers over 1:1000 and react at 28-31°C and sometimes at 37°C. Cold agglutinin disease usually results from the production of a specific IgM antibody directed against the I/i antigens (precursors of the ABH and Lewis blood group substances) on red blood cells (RBCs).

What is a cold agglutinin test useful for the diagnosis of? ›

A cold agglutinin test may be used to help detect cold agglutinin disease and determine the cause of a person's hemolytic anemia.

What is the drug therapy for cold agglutinin disease? ›

Sutimlimab, a new drug for treatment of CAD, is an artificially produced antibody that binds to a protein called C1s. This binding results in inhibition of complement, a system of active proteins that is part of the immune system and promotes red blood cell destruction in CAD.

What effect could cold agglutinin disease have on a routine full blood count? ›

While RBC agglutination causes clinical symptoms of hemolytic anemia, agglutination caused by cold agglutinin is a notorious pre-analytical and analytical factor that leads to spurious automated complete blood count (CBC) results [2].

What is the significance of cold agglutinin? ›

Cold agglutinins – Cold agglutinins are antibodies that recognize antigens on red blood cells (RBCs) at temperatures below normal core body temperature. They can cause agglutination of the RBCs (picture 1) and extravascular hemolysis, resulting in anemia, typically without hemoglobinuria.

What is cold agglutinin disease pathology outlines? ›

Cold agglutinin disease (CAD) is a rare autoimmune disease characterized by the presence of high concentrations of circulating cold sensitive antibodies, usually IgM and autoantibodies that are also active at temperatures below 30 °C (86 °F), directed against red blood cells, causing them to agglutinate and undergo ...

Is cold agglutinin serious? ›

CAD can lead to severe and even life-threatening heart conditions in emergency scenarios. Related to its name — “cold” agglutinin disease — CAD causes most intense symptoms in cold climates or chilly weather.

How do you deal with a cold agglutinin? ›

The author recommends that B cell–directed approaches remain the first choice in most patients requiring treatment. The 4-cycle bendamustine plus rituximab combination is highly efficacious and sufficiently safe and induces durable responses in most patients, but the time to response can be many months.

Is cold agglutinin disease an autoimmune disease? ›

Cold agglutinin disease (CAD) is a rare autoimmune disorder characterized by the premature destruction of red blood cells (hemolysis). Autoimmune diseases occur when one's own immune system attacks healthy tissue. More specifically, CAD is a subtype of autoimmune hemolytic anemia.

Who treats cold agglutinin disease? ›

Hematologists. Hematologists specialize in the treatment of blood disorders and are familiar with CAD. They can guide the diagnostic process and treat affected patients to maintain their red blood cells at optimal levels.

What treatments are FDA approved for cold agglutinin disease? ›

FDA has approved Enjaymo (sutimlimab-jome) infusion to decrease the need for red blood cell transfusion due to hemolysis (red blood cell destruction) in adults with cold agglutinin disease (CAD).

How do you treat cold agglutinin naturally? ›

No treatment is necessary in mild cases of cold agglutinin disease. Avoiding cold temperatures or living in regions with warmer climates can help to prevent the binding of autoantibodies to red blood cells. Folic acid supplements are also advisable because this vitamin is essential for the formation of red blood cells.

What leads to the production of agglutinin? ›

A body might produce agglutinins to attack the erythrocytes due to allergies to foods, inhalants, chemicals and infections. A person suffering from this condition will likely have cooler body parts such as fingers, nose, and ears attacked more often than warmer areas such as armpits.

What is the antibody usually associated with cold agglutinin disease? ›

Autoimmune hemolytic anemia is caused by autoantibodies that react with red blood cells at temperatures ≥ 37° C (warm antibody hemolytic anemia) or < 37° C (cold agglutinin disease). Hemolysis is extravascular. The direct antiglobulin (direct Coombs) test establishes the diagnosis and may suggest the cause.

What causes cold autoimmune hemolytic anemia? ›

Autoimmune hemolytic anemia is caused by autoantibodies that react with red blood cells at temperatures ≥ 37° C (warm antibody hemolytic anemia) or < 37° C (cold agglutinin disease). Hemolysis is extravascular. The direct antiglobulin (direct Coombs) test establishes the diagnosis and may suggest the cause.

What happens when a patient with cold agglutinins body temperature fails? ›

Cold agglutinins are particular cold-reactive antibodies that react with red blood cells when the blood temperature drops below normal body temperature causing increased blood viscosity and red blood cell clumping.


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