Cold agglutinin disease (CAD) is a type of cold autoimmune haemolytic anaemia/cAIHA (ORPHA:228312). In CAD the body produces antibodies that cause its immune system to mistakenly attack and destroy its own red blood cells when exposed to cold temperatures (below 30˚C).^1,2

Red blood cells usually have a lifespan of about 120 days, but in autoimmune haemolytic anaemias, they can be destroyed as fast as they are produced. This results in a low number of red blood cells in the bloodstream, which can lead to symptoms ranging from mild to potentially life-threatening.

CAD can present without an underlying cause (this is known as primary idiopathic CAD) or arise due to other health conditions (secondary CAD). These conditions include other autoimmune disorders, infections and cancers involving blood cells (haematologic malignancies).^1,4 The treatment and disease length for primary and secondary CAD can differ. Primary and lymphoma-associated CAD are generally long lasting (chronic) conditions, whereas CAD caused by an infection is usually short (acute).

There is another type of cold autoimmune haemolytic anaemia, called Paroxysmal cold haemoglobinuria/PCH (ORPHA:90035), where a different type of antibody causes red blood cell destruction at cold temperatures. PCH mainly occurs in children. There is also a condition (warm autoimmune haemolytic anaemia/wAIHA) where the red blood cell destruction occurs at warm temperatures of 37-40˚C.³

Synonyms: CAD, CAS, chronic cold agglutinin disease, cold agglutinin hemolytic anemia, cold antibody hemolytic anemia, cold antibody disease, cold agglutinin syndrome.^1,2

Universal rare disease classifications provide a common language for recording, reporting and monitoring diseases. Please visit the Rare Disease Classifications page for more information about these internationally recognised classifications.

ORPHA:56425 Cold agglutinin disease

ICD-11: 3A20.1 Autoimmune haemolytic anaemia, cold type

The signs and symptoms of CAD can be mild to severe, and may come on suddenly or gradually.^1,2,5,6 The symptoms are likely to get worse in the cold. Symptoms include coldness in the fingers, toes and nose which may turn white, blue or red (acrocyanosis or Raynaud phenomenon). This can occur even at mild cold temperatures for some individuals. People with CAD also experience many typical anaemia symptoms such as weakness, fatigue, dizziness, headaches, pale skin colour (pallor), rapid heartbeat (tachycardia), shortness of breath (dyspnoea), and yellowing of skin and eyes (jaundice). In severe cases there may also be enlargement of the liver and spleen (hepatosplenomegaly), nausea or vomiting, dark urine, back and leg pain, ulcers on the fingers or toes, and signs of heart failure.

Individuals with CAD have an increased risk of developing blood clots, strokes, and heart issues.⁵

Please speak to your medical team to learn more about the symptoms and complications of CAD.

Rare diseases are often serious and progressive, exhibiting a high degree of symptom complexity, leading to significant disability. Majority of the estimated two million Australians living with a rare disease meet the Australian Government’s definition for disability (in accordance to the Australian Public Service Commission and Australian Bureau of Statistics), and many experience severe and permanent disability impacts. If you or someone you care for is experiencing disability-related impacts from a rare condition, please speak with a health or disability professional for advice. Information about relevant disability support can be found at the RARE Portal’s Disability Support Information page.

Haemolytic anaemia may be considered based on a clinical examination of the symptoms and standard blood tests showing a high proportion of young compared to old red blood cells, and misshapen red blood cells.^6,10 More blood or urine tests can also be performed to look for other signs of red blood cell destruction (haemolysis) and clumping of red blood cells (agglutination).

CAD is an autoimmune condition in which the body’s immune system produce antibodies that target its own red blood cells (autoantibodies).¹ These particular autoantibodies are called cold agglutinins.⁵ At cold temperatures in the body, these autoantibodies stick to red blood cells and cause the cells to stick together and form large clumps of red blood cells. Immune cells then recognise these clumps as abnormal and destroy them. The temperature at which this happens varies between different people.

Some people spontaneously start producing excessive amounts of cold agglutinins (primary CAD).^1,2 In other cases, the body produces cold agglutinins because of another condition, such as an infection, immunoproliferative disease, connective tissue disorder, or other illness (secondary CAD).⁴ It is unknown why the body begins to produce cold agglutinin antibodies in primary CAD and many cases of secondary CAD.

Haemolytic anaemia may be considered based on a clinical examination of the symptoms and standard blood tests showing a high proportion of young compared to old red blood cells, and misshapen red blood cells.^6,10 More blood or urine tests may also be performed to look for other signs of red blood cell destruction (haemolysis) and clumping of red blood cells (agglutination). These tests may include complete blood count (CBC), a bilirubin test, haptoglobin test, and a lactate dehydrogenase (LD) test.

Once haemolytic anaemia is confirmed, a direct antiglobulin test (DAT, also known as Coomb’s test) can be used to determine if there are autoantibodies sticking to red blood cells and the types of autoantibodies. This test can diagnose cold autoimmune haemolytic anaemia and distinguish it from warm autoimmune haemolytic anaemia (which involves a different type of antibody).^2,6 Further blood tests and a urine test may be required to distinguish CAD from other types of cold autoimmune haemolytic anaemias.

After being diagnosed with CAD, more tests are often performed to check for any other conditions that might be causing secondary CAD, such as other types of autoimmune haemolytic anaemias and paroxysmal nocturnal hemoglobinuria.^1,2,4

Please speak to your medical team to learn more about the available diagnostic pathways for CAD.

Primary CAD is often chronic (long-term or recurring). Chronic CAD is often managed with medications such as steroids and/or biological medications that lower the activity of the immune system.^6,7 This weakens the immune system’s response to cold agglutinins (autoantibodies) on red blood cells and slows red blood cell destruction. These medications might need to be taken for a long time.

Secondary CAD treatment involves managing the symptoms of CAD (symptomatic management) and treatment of the underlying condition. Treatment varies greatly depending upon a person’s specific case of secondary CAD. In many cases, treatment of the underlying condition can resolve CAD symptoms.^4,6

The range and severity of cold sensitivity can vary greatly. Depending upon the individual case, it can be important for some people with CAD to avoid cold temperatures as much as possible.

Please speak to your medical team to learn more about the possible treatment or management options for your condition. Treatment will depend on an individual’s specific condition and symptoms. It is also important to stay connected to your medical team so that you can be made aware of any upcoming clinical trial opportunities.

Healthcare professionals involved in the treatment of CAD may include general practitioners (GP), paediatricians, haematologists, immunologists and rheumatologists.¹⁰ The need for different healthcare professionals may change over a person’s lifetime and extend beyond those listed here. 

Clinical care for rare diseases often involves a multidisciplinary team of medical, care and support professionals. Please note that the information provided here is as a guide and that RVA does not necessarily monitor or endorse specific clinics or health experts.

For many rare diseases, palliative care services may be relevant and useful. Palliative care services are available for people (adults, children and their families) living with a life-limiting illness and is not only for end-of-life care. It can also help at any stage of illness from diagnosis onwards, and will look different for different people. Palliative care services provide assistance, support, resources and tools to help people manage their illness and the symptoms, ease pain, and improve comfort and quality of life. If this is relevant to you and you wish to find out more information about palliative care and how it can help you, please visit:

• Australian Institute of Health and Welfare: Palliative care Overview
• Australian Government Department of Health, Disability and Ageing: Palliative care
• Palliative Care Australia

We are not aware of any clinical care guidelines for CAD in Australia. If you know of any relevant care guidelines, please let us know via the Contribute page.

The following guidance is available from international experts outside Australia; however, there may be information that is not relevant or applicable to the Australian context, and may not be up to date:

• Diagnosis and treatment of autoimmune hemolytic anemia in adults: Recommendations from the First International Consensus Meeting developed by a group of international experts from Europe and USA, published in 2020.
• The diagnosis and management of primary autoimmune haemolytic anaemia developed by the British Society for Haematology in collaboration with UK based experts, published in 2016.
• Guidelines on the management of drug-induced immune and secondary autoimmune, haemolytic anaemia developed by the British Society for Haematology in collaboration with UK based experts, published in 2017.

Individuals living with rare diseases may have complex medical issues and disabilities, which are not always visible. It is often useful to refer to their medical history as well as personal information such as a medical card, doctor’s letter, or if available, a rare disease passport, for relevant information.

It may be important to consider the following when managing individuals living with CAD at emergency departments/services:

• It has been recommended that anti-pyretics (anti-fever medications) be used to treat fevers instead of actively cooling the person (such as with a cold compress or cold bath).⁷
• For both primary and secondary CAD, blood transfusions might be necessary in emergencies to provide healthy red blood cells quickly. Due to the autoimmune and temperature sensitive nature of CAD, extra precautions may need to be considered when giving transfusions of any type to individuals with CAD.^9,12

More details on emergency protocols for CAD, including transfusion guidelines, can be found at:

• Diagnosis and treatment of autoimmune hemolytic anemia in adults: Recommendations from the First International Consensus Meeting developed by a group of international experts, published in 2020.
• Emergency Transfusion Guidelines for Autoimmune Hemolytic Anemia developed in Canada, published in 2005.

There are specific considerations around participating in rare disease research, including clinical trials. It is important to be mindful of issues such as data privacy, research ethics, consent and differences in research regulations between Australia and other countries. For more information, please visit the RARE Portal’s Considerations for Participating in Health and Medical Research page.

If you are interested in finding clinical trials for your condition, please visit the following websites; however, there may not be any clinical trials available:

• Australian Clinical Trials
• ClinicalTrials.gov

It is best to discuss your interest in research, including clinical trials,  with your medical team to determine suitability and eligibility.

There are currently no known organisations for CAD in Australia. If you are aware of any relevant Australian organisations, please let us know via the Contribute page. 

International Organisation:

Cold Agglutinin Disease Foundation Inc. (United States)
Website: https://coldagglutinindisease.org/

Please note that RVA does not monitor or endorse each group/organisation’s operational governance and activities. When engaging with a group, please consider the information on the RARE Portal’s Finding Helpful Peer and Community Supports page.

CAD vary between individuals, and each person’s experience is unique.  

If you would like to share your personal story with RVA, please visit the Rare Voices Australia: Share Your Story page. RVA will consider your story for publishing on our website and inclusion on the RARE Portal.

For information on available government and social services that provide support for individuals with a rare disease, please visit the National and State Services pages.

People living with a rare disease often face unique challenges such as diagnostic delays, misdiagnoses, limited treatment options, and limited access to rare disease specialists and support. These challenges may impact people’s emotional wellbeing and quality of life. Many find it helpful to seek mental health and wellbeing support to cope with ongoing stress and uncertainty. Connecting with people who have shared experiences through a support group may also be helpful. Information about relevant mental health and wellbeing support can be found at:

• Mental Health and Wellbeing Support for Australians Living with a Rare Disease
• The National and State Services pages underneath the ‘Mental Health’ sections listed

Further information on CAD can be found at: 

• Genetic and Rare Diseases (GARD) Information Center: Cold agglutinin disease
• National Organization for Rare Disorders (NORD): Cold Agglutinin Disease

Royal College of Pathologists of Australia (RCPA): Cold Agglutinins

The Royal Children’s Hospital Melbourne: Anaemia Clinical Practice Guidelines

Orphanet: Cold agglutinin disease

Human Phenotype Ontology (HPO): Cold agglutinin disease

This page has been developed by Rare Voices Australia (RVA)’s RARE Portal team.

If you are aware of any additional information that may benefit stakeholders with an interest in this page, or if you notice any broken links or inaccurate information, please let us know via the Contribute page.