Cold Type Haemolytic Anaemia

Cold type haemolytic anaemia is a rare blood disorder where the immune system mistakenly attacks and destroys red blood cells when exposed to cold temperatures, causing symptoms that range from mild fatigue to serious complications.

Table of contents

• What is cold type haemolytic anaemia?
• Other names for this condition
• How common is the condition?
• Signs and symptoms
• What causes cold type haemolytic anaemia?
• How is it diagnosed?
• Treatment options
• Living with cold type haemolytic anaemia

What is cold type haemolytic anaemia?

Cold type haemolytic anaemia is a rare form of autoimmune haemolytic anaemia, which is a condition where the immune system attacks healthy red blood cells^[1]. In this condition, cold temperatures activate the immune system to make special proteins called autoantibodies that flag red blood cells for destruction^[1].

Red blood cells are essential because they carry oxygen throughout the body. The oxygen powers cells to make the energy the body needs to function. Normally, red blood cells live for about 120 days, giving bone marrow enough time to make new ones to replace the old^[1]. However, with cold type haemolytic anaemia, red blood cells can be destroyed in just a few days^[16].

The process begins when temperatures drop to approximately 37 to 39 degrees Fahrenheit (3 to 4 degrees Celsius)^[1]. At these cold temperatures, the autoantibodies cause red blood cells to clump together, making them easy targets for destruction by another part of the immune system called macrophages^[1]. This results in complement activation and predominantly intravascular haemolysis, which means the red blood cells are broken down in the bloodstream^[4].

Other names for this condition

CAD, CAS, chronic cold agglutinin disease, cold agglutinin hemolytic anemia, cold antibody hemolytic anemia, cold antibody disease, cold agglutinin syndrome, cold autoimmune hemolytic anemia

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How common is the condition?

Cold type haemolytic anaemia is very rare. Approximately one in a million people get diagnosed each year^[1]. In the United States, the number of people living with this condition ranges from 300 to 3,000^[1].

The condition is most common in women between the ages of 40 and 80. Most diagnoses occur in people in their mid to late 60s^[1]. In contrast, when the condition occurs in children, it is typically after an infection, mild, and short-lived^[4].

Signs and symptoms

The symptoms of cold type haemolytic anaemia can be mild to severe and may come on suddenly or gradually^[5]. The symptoms are likely to get worse in cold weather or environments^[1]. In mild cases, symptoms may set in so slowly that a person may have the condition for several years before receiving a diagnosis^[1].

A common complaint is painful fingers and toes with purplish discoloration associated with cold exposure^[3]. Symptoms include coldness in the fingers, toes and nose which may turn white, blue or red, a condition known as acrocyanosis or Raynaud phenomenon^[5]. This can occur even at mild cold temperatures for some individuals. In chronic cases, patients are more symptomatic during the colder months^[2].

People with this condition also experience many typical anaemia symptoms such as:

• Weakness and fatigue
• Dizziness
• Headaches
• Pale skin colour (pallor)
• Rapid heartbeat (tachycardia)
• Shortness of breath (dyspnoea)
• Sweating

Additional symptoms may include jaundice, which is a yellowing of the skin and the whites of the eyes^[1]. As red blood cells get destroyed, they release a yellowish substance called bilirubin. Bilirubin build-up leads to jaundice and can also cause dark brown-coloured urine^[1].

In severe cases, there may also be enlargement of the liver and spleen (hepatosplenomegaly), nausea or vomiting, back and leg pain, ulcers on the fingers or toes, and signs of heart failure^[5]. Individuals with this condition have an increased risk of developing blood clots, strokes, and heart issues^[5].

What causes cold type haemolytic anaemia?

Cold type haemolytic anaemia can be classified as primary or secondary. Primary cold type haemolytic anaemia occurs without an obvious underlying condition and is usually associated with a clonal lymphoproliferative disorder, which means abnormal B-cell clones in the bone marrow produce harmful antibodies^[4].

In 90% of cases, the autoantibody involved is immunoglobulin M (IgM). Rarely, it may involve monoclonal immunoglobulin G (IgG), immunoglobulin A (IgA), or other antibody types^[3].

Secondary cold type haemolytic anaemia is linked to other conditions or triggers, including:

Infections: Cold agglutinins develop in more than 60% of patients with infectious mononucleosis, though haemolytic anaemia is rare^[2]. Other infections that can trigger the condition include:

• Mycoplasma infections
• Viral infections such as Epstein-Barr virus (EBV), cytomegalovirus (CMV), mumps, varicella, rubella, adenovirus, HIV, influenza, and hepatitis C
• Bacterial infections such as Legionnaire disease, syphilis, listeriosis, and Escherichia coli
• Parasitic infections such as malaria and trypanosomiasis

Blood cell cancers: These include Waldenström macroglobulinemia, lymphoma, chronic lymphoid leukaemia, and myeloma^[2].

Other autoimmune disorders: Cold type haemolytic anaemia has been described in patients with systemic sclerosis, with the degree of anaemia being associated with increasing disease activity^[2].

Transplantation: The condition has been reported in patients after living-donor liver transplantation treated with tacrolimus and after bone marrow transplantation with cyclosporine treatments. It is thought that such medications may interfere with normal immune regulation^[2].

In children, cold type haemolytic anaemia is typically post-infection, mild, and self-limited^[4].

How is it diagnosed?

Diagnosis of cold type haemolytic anaemia involves several tests. A common finding is a positive direct antiglobulin test (DAT), which shows antibodies attached to red blood cells. Specifically, the test is typically negative for IgG but positive for C3d^[4].

Other laboratory findings include:

• Undetectable haptoglobin (a protein that binds free haemoglobin)
• Elevated lactate dehydrogenase (LDH)
• Unconjugated hyperbilirubinemia (elevated bilirubin)
• Elevated absolute reticulocyte count (showing the body is trying to make new red blood cells)
• Undetectable C3 and C4 (complement proteins)
• High cold agglutinin titre, typically 1024 at 4°C^[4]

Peripheral blood smears may reveal clumps of red blood cells, which are typical of the condition^[3]. A bone marrow biopsy may be performed to look for underlying blood cancers or lymphoproliferative disorders^[4].

Treatment options

Treatment of cold type haemolytic anaemia depends on the severity of symptoms and whether there is an underlying condition causing the disorder^[6].

Lifestyle measures: Most patients can manage their disorder successfully just by wearing appropriate clothing and avoiding cold exposure^[6]. This may include avoiding cold food and beverages and wearing gloves to remove food from the refrigerator or freezer. Special protective clothing is sometimes necessary in extreme cases^[6].

Medication therapy: For patients with serious symptoms, active treatment may be needed. The idiopathic variety of the condition is generally benign with prolonged survival, and only patients who have serious symptoms related to anaemia or have a Raynaud-type syndrome that constitutes a threat to health or quality of life require active therapy^[6].

Rituximab has become the most accepted first-line therapy for the condition. In prospective studies, approximately 50% of patients showed partial response to rituximab, though complete response was rare. Response duration ranged from 2 to 42 months^[6]. In relatively fit patients who are severely affected, rituximab may be combined with bendamustine, which improves response rates but at the expense of tolerability^[4].

A complement inhibitor called sutimlimab was approved by the US Food and Drug Administration in 2022. It is indicated to decrease the need for red blood cell transfusion in patients with haemolysis associated with cold type haemolytic anaemia^[6].

Other therapies that have been used include the complement inhibitor eculizumab and the anti-CD38 monoclonal antibody daratumumab in patients with treatment-resistant disease^[6].

Glucocorticoids (steroids) are generally not useful in IgM-induced cold type haemolytic anaemia but may occasionally work in selected patients^[6].

Blood transfusions: Red blood cell transfusion is indicated in severe, acute disease. When transfusions are needed, the blood should be warmed^[4].

Treatment of underlying conditions: In cases of secondary cold type haemolytic anaemia, therapy is directed at the underlying disorder. Acute post-infectious cases usually resolve spontaneously^[6].

Living with cold type haemolytic anaemia

Living with cold type haemolytic anaemia requires careful attention to temperature exposure. Staying warm and keeping safe during winter may help avoid or lessen symptoms^[15].

Limiting outdoor time: Try to stay indoors as much as possible where it is warmer. When going outside, check the temperature, including the wind chill, and try to plan outings when it is warmest^[15].

Proper clothing: Dress in loose layers rather than wearing one heavy clothing item. Warm air can be more easily trapped between each layer. Synthetic fabrics help stay warm even when they get wet, while cotton becomes cold when damp^[15].

Protecting extremities: It may be particularly important to avoid cold temperatures on the head and face. Wear a warm hat or hood to prevent body heat from escaping. Wear gloves that contain an insulated inner lining and an outer waterproof layer. Water-resistant shoes or boots are essential for protecting the feet^[15].

Vehicle considerations: If driving, consider buying a remote starter for the car to warm it up before entering. Keep an emergency kit in the car with blankets and extra clothes in case of breakdown^[15].

The impacts of the condition on daily life can range from mild to severe. With mild cases, people may have the condition for several years before receiving a diagnosis. However, the condition can lead to severe and even life-threatening heart conditions in emergency scenarios^[1].

Spontaneous exacerbations and remissions in the course of the disease are to be expected^[6]. Regular monitoring by a healthcare team is important to manage the condition effectively.