Cold agglutinin disease is a condition that causes low red blood cell (RBC) counts. Symptoms can include fatigue, weakness, or shortness of breath.
Cold agglutinin disease is a type of autoimmune hemolytic anemia. This is where the immune system mistakenly attacks RBCs, causing them to break down in a process known as hemolysis. As a result, this reduces the amount of RBCs and leads to anemia. As such, cold agglutinin disease can cause symptoms such as weakness, fatigue, and shortness of breath.
A person may not necessarily require treatment for cold agglutinin disease. In other cases, people may require medication to modulate their immune system or treatment for an underlying condition. They may also need to try and avoid potential triggers, such as colder temperatures.
Cold agglutinin disease is a rare form of autoimmune hemolytic anemia. This refers to a rare RBC and immune disorder where the immune system targets and destroys RBCs. Cold agglutinin disease accounts for about 15% of all autoimmune hemolytic anemia cases.
Cold agglutinin disease occurs when the immune system produces antibodies that mistakenly target RBCs. The antibodies attach to RBCs and mark them for other immune cells to destroy through a process known as hemolysis.
Hemolysis is a natural bodily process that usually occurs when RBCs become too old. However, with cold agglutinin disease, the immune system targets healthy RBCs prematurely. The destruction of RBCs leads to anemia or reduced RBC count in the blood.
Health experts refer to the condition as cold agglutinin disease, as the antibodies that attach to the RBCs operate
Cold agglutinin disease causes the premature destruction of RBCs. Typically, RBCs live for about 120 days before the spleen destroys them.
Due to the early death of RBCs, the person’s body cannot maintain healthy levels, leading to anemia. When a person has anemia, their body lacks oxygen. This can manifest as several symptoms, such as:
- weakness
- fatigue
- shortness of breath (dyspnea)
- dizziness
- pale skin color (pallor)
- palpitations
- headaches
- chest pain
As RBCs break down, they release a protein called hemoglobin. This protein helps carry oxygen to various parts of the body.
Once released into the bloodstream, hemoglobin starts to break down into bilirubin. Excess bilirubin can cause jaundice, a yellowing of the skin and eyes, or dark brown urine.
Following exposure to cold temperatures, a person may also notice unusual sweating. They may also experience a painful discoloration in their fingers, toes, wrists, or ankles when cold. The discoloration may be bluish or reddish.
Cold agglutinin disease is an autoimmune disorder in which the immune system mistakenly attacks healthy cells. In the case of cold agglutinin, antibodies — known as autoantibodies when they attack healthy cells — bind to RBCs.
Once autoantibodies bind to RBCs, another part of the immune system — known as
Research suggests that the underlying creation of IgMκ antibodies that lead to cold agglutinin disease may relate to lymphoproliferative disorders. This term refers to conditions that cause an uncontrolled production of lymphocytes, a type of white blood cell.
The National Organization for Rare Disorders (NORD) notes that secondary agglutinin disease can occur in some people. Secondary agglutinin disease often occurs due to:
- transmissible infections, such as:
- connective tissue disorders, such as lupus or rheumatoid arthritis
- immunoproliferative diseases, such as non-Hodgkin’s lymphoma or chronic lymphocytic leukemia
NORD states that as many as 70% of people living with the condition may have the secondary form.
However, a 2022 review separates and suggests a distinction between primary and secondary forms of cold agglutinin disease. Secondary forms of the disease are known as cold agglutinin syndrome.
Cold agglutinin disease often affects people between 40 and 80 years, with a median age of onset of 65. It affects people assigned female at birth roughly twice as often as those assigned male at birth.
People living with certain underlying health conditions or infections have an increased risk of developing cold agglutinin syndrome.
As the name implies, exposure to colder climates can worsen symptoms. Some suggest that living in a colder environment may increase risk. However, a 2020 observational study suggests that not enough data supports these claims. The claims come primarily from individual cases.
Diagnosis can be challenging due to the rarity of the condition. Doctors may not be familiar with cold agglutinin disease or mistakenly attribute symptoms to other potential, more common causes.
Diagnosis often involves several steps, including reviewing personal and family medical history, assessment of symptoms, and testing. Blood tests can help a doctor identify potential signs of cold agglutinin disease, such as:
- elevated bilirubin levels
- large number of immature RBCs, suggesting an increased production of RBCs
- increased levels of lactate dehydrogenase, a chemical byproduct that occurs when RBCs get destroyed
- reduced levels of haptoglobin, a component of blood that decreases following RBC destruction
If a doctor suspects cold agglutinin disease, they will likely order specialized testing. A Coombs test can look for the presence of antibodies binding to RBCs.
Positive results from a Coombs test may spark the need for additional testing known as thermal amplitude testing. This checks the reaction of the antibodies at different temperatures. Stronger reactions at cooler temperatures could indicate cold agglutinin disease.
Other tests to help diagnose cold agglutinin disease
Generally, treatment for cold agglutinin disease may involve medications that modulate the immune system. This helps decrease the production of antibodies against RBCs.
A 2020 study notes that people often respond well to rituximab monotherapy. This therapy often takes about 11 to 12 months to work. It provides moderate effectiveness to about 50% of people and rarely eliminates symptoms. Doctors may enhance the effects with other medications, such as bendamustine or fludarabine, but they can cause toxicity in some people.
Most other treatment options are still under investigation with clinical trials or a need for studies. Future treatments may provide more effective therapy for the condition.
During the diagnostic process, doctors will check whether the condition is due to an underlying condition. In these cases, treatment will aim to manage this condition.
Cold agglutinin disease is a rare form of autoimmune hemolytic anemia. It occurs when the immune system produces cold agglutinin antibodies.
These antibodies mistakenly attack healthy RBCs and are more active at colder temperatures. They attach to RBCs, which causes the immune system to target and destroy them. This can result in a low RBC count, or anemia, causing symptoms such as fatigue.
Treatment often involves avoiding colder temperatures and medications to reduce the immune response. In other cases, doctors may treat an underlying condition that is causing cold agglutinin disease.