Autoimmune Haemolytic Anaemia

Autoimmune haemolytic anaemia is a rare blood disorder where the immune system mistakenly attacks and destroys the body’s own red blood cells, leading to a shortage of these vital oxygen-carrying cells. Though uncommon, affecting only 1 to 2 people per 100,000 each year, prompt diagnosis and treatment are essential, as the condition is highly manageable but can be serious if left untreated.

Table of contents

• What is autoimmune haemolytic anaemia?
• Types of autoimmune haemolytic anaemia
• Who is affected?
• Symptoms
• Causes and related conditions
• How is it diagnosed?
• Treatment options
• Long-term outlook

What is autoimmune haemolytic anaemia?

Autoimmune haemolytic anaemia (AIHA) occurs when the body’s immune system mistakes red blood cells as foreign or unwanted substances and produces antibodies (protective proteins) that attack and destroy them.^[1] Red blood cells normally carry oxygen throughout the body and typically live for about 100 to 120 days. In AIHA, these cells are destroyed much faster than the bone marrow can produce new ones, sometimes surviving only a few days in serious cases.^[3]

When red blood cells break down, their internal contents are released into the bloodstream and tissues, causing characteristic symptoms. This premature destruction of red blood cells leads to anaemia, which is a condition where there are too few red blood cells to carry adequate oxygen to the body’s tissues.^[1]

AIHA is classified into two main categories based on whether an underlying cause can be identified. Primary AIHA develops without any obvious underlying condition and is sometimes called idiopathic, meaning the cause is unknown. This accounts for approximately 50% to 60% of cases.^[2] Secondary AIHA is linked to another condition, such as a viral illness, other autoimmune diseases, medications, or underlying blood cancers like lymphoma.^[1]

Types of autoimmune haemolytic anaemia

AIHA is further classified into different types based on the temperature at which the antibodies become active and attack red blood cells.^[1]

Warm autoimmune haemolytic anaemia is the most common type, accounting for the majority of AIHA cases. In this form, IgG antibodies attach to and destroy red blood cells at normal body temperature or above. Symptoms typically develop gradually over several weeks, though in some cases they can appear within days.^[1]

Cold autoimmune haemolytic anaemia, also known as cold agglutinin disease, affects 10% to 20% of AIHA cases. This type involves IgM antibodies that become active and attack red blood cells when blood is at cooler temperatures compared to the body’s core temperature. The specific temperature threshold at which these antibodies activate varies between individuals.^[1] This form is extremely rare, with about 1 person per million developing it each year, usually between the ages of 40 and 80.^[6]

Paroxysmal cold haemoglobinuria is a rare type of cold antibody haemolytic anaemia. Destruction of red blood cells results from exposure to cold, even when cold exposure is limited to a small area of the body, such as drinking cold water or washing hands in cold water. It occurs most often after a viral illness or in otherwise healthy people.^[5]

Who is affected?

AIHA is a rare condition, affecting approximately 1 to 2 out of every 100,000 people each year.^[1] While AIHA can affect anyone at any age, it most commonly occurs in females over the age of 40.^[1]

The condition is very rare in infancy and childhood, with an estimated incidence of 0.2 per 100,000 children per year. In children, AIHA is primary in 37% of cases and associated with immune disorders in 53% of cases. Mortality is lower in children at 4%, but rises to 10% if the haemolytic anaemia is associated with immune thrombocytopenia, a condition called Evans syndrome.^[10]

Symptoms

Many people with AIHA experience symptoms related to having too few red blood cells and the breakdown of these cells. Some people have no symptoms, especially when the destruction of red blood cells is mild and develops gradually.^[5]

Common symptoms of AIHA include tiredness, weakness, rapid heartbeat, shortness of breath or difficulty breathing, pale skin, fever, headaches, muscle pain, and heart palpitations. Many people also experience jaundice, which is yellowing of the skin and the whites of the eyes caused by the accumulation of bilirubin, a substance produced when red blood cells break down.^[1] Dark brown or tea-coloured urine may also occur due to the release of haemoglobin (the oxygen-carrying protein in red blood cells) when cells are destroyed.^[2]

Some people may experience nausea, vomiting, diarrhea, or a sore tongue. When destruction persists for a few months or longer, the spleen may enlarge, resulting in a sense of abdominal fullness and, occasionally, discomfort.^[5]

Symptoms specific to warm autoimmune haemolytic anaemia most commonly include tiredness, dizziness, jaundice, and heart palpitations.^[1]

In cold autoimmune haemolytic anaemia, additional symptoms often include cold hands and feet, bluish or greyish colouring in the hands and feet, chest pain, and pain in the backs of the legs. The condition can also cause Raynaud’s phenomenon, where fingers and toes change colour in response to cold. In rare cases, more serious complications can include arrhythmia (irregular heartbeat), heart murmur, heart failure, and rarely gangrene.^[1]

People with paroxysmal cold haemoglobinuria may have severe pain in the back and legs, headache, vomiting, and diarrhea, with dark brown urine.^[5]

Causes and related conditions

In approximately half of all cases, the cause of autoimmune haemolytic anaemia is unknown. When no cause can be identified, it is called idiopathic autoimmune haemolytic anaemia.^[1] In other cases, AIHA develops secondary to another condition.^[2]

Several autoimmune diseases are associated with secondary AIHA. These include lupus (systemic lupus erythematosus), rheumatoid arthritis, Sjogren’s syndrome, thyroid disease, ulcerative colitis, and Hashimoto’s disease.^[1]

AIHA can also be caused by blood cancers and lymphoproliferative disorders, such as chronic lymphocytic leukaemia, lymphoma, and other cancers.^[2]

Certain viral infections can trigger AIHA, though the anaemia typically goes away once the infection is treated. Common viruses that may be linked to AIHA include Epstein-Barr virus, measles, mumps, rubella, atypical pneumonia, varicella (the virus that causes chickenpox), HIV, hepatitis, cytomegalovirus, and Mycoplasma pneumoniae.^[1]

Medications can also trigger AIHA in some cases. These include certain antibiotics such as penicillin, nonsteroidal anti-inflammatory drugs, methyldopa, quinine, and sulfonamides.^[6] AIHA can rarely occur following bone marrow or solid organ transplant.^[2]

In a very small number of cases, autoimmune haemolytic anaemia appears to run in families. In those cases, the condition appears to be inherited in a recessive pattern, meaning both parents must carry the gene for a child to be affected.^[3]

How is it diagnosed?

Doctors diagnose AIHA through a combination of clinical assessment and laboratory tests. When a patient presents with anaemia, doctors follow a stepwise approach to identify the cause.^[4]

Initial blood tests may reveal signs of haemolysis, including a low red blood cell count, raised reticulocyte count (immature red blood cells), raised unconjugated bilirubin, increased lactate dehydrogenase (LDH, an enzyme released when cells are damaged), and reduced haptoglobin (a protein that binds free haemoglobin).^[4]

Examination of a blood smear under a microscope may show specific features such as polychromasia (variation in red blood cell colour), spherocytes (small, round red blood cells), or agglutination (clumping of cells).^[4]

The key diagnostic test for AIHA is the direct antiglobulin test (DAT), also known as the direct Coombs test. This test detects antibodies attached to the surface of red blood cells. In warm AIHA, the DAT is typically positive with anti-IgG testing. In cold forms, the DAT is usually positive for C3d, a component of the complement system (a part of the immune system).^[4]

It is important to note that the DAT may occasionally yield false-negative results in certain situations. This can occur with IgA antibodies not detected by routine tests, low-affinity IgG antibodies, or when the amount of antibody on red blood cells is below the detection threshold. More sensitive techniques may be needed in these cases. Approximately 10% of AIHA cases remain DAT negative, and diagnosis is made after excluding other causes of haemolysis and based on clinical response to therapy.^[10]

Once AIHA is confirmed, doctors search for secondary causes by evaluating for underlying conditions such as autoimmune diseases, lymphoproliferative disorders, infections, or medication use.^[4]

Treatment options

Treatment for AIHA varies depending on the type of anaemia, its severity, and whether there is an underlying condition that needs to be addressed. The main goals of treatment are to stop the destruction of red blood cells, increase red blood cell count, and treat any underlying conditions.^[18]

Mild cases of autoimmune haemolytic anaemia often require no treatment and resolve on their own.^[3]

Corticosteroids are the first-line treatment for most cases of warm AIHA. These medications suppress the immune system’s production of antibodies. High doses of corticosteroids, such as prednisone or prednisolone, are given initially, then the dose is gradually reduced over a period of 6 to 12 months. Corticosteroids are effective in 70% to 85% of patients, though as many as half may need repeat treatment.^[10] Recent evidence supports combining the drug rituximab with corticosteroids as first-line therapy in severe warm AIHA, with studies showing better long-term remission rates compared to corticosteroids alone.^[11]

Rituximab is a type of drug called a monoclonal antibody that targets B-cells (a type of immune cell that produces antibodies). It was originally developed for blood cancers but is now widely used for AIHA. Rituximab is given in low doses, either alone or in combination with corticosteroids. It is effective in approximately 80% to 90% of cases of warm AIHA.^[10] For cold agglutinin disease, rituximab is now recommended as first-line treatment, either alone or combined with other medications such as bendamustine.^[4]

For patients who do not respond to corticosteroids and rituximab, other treatment options include:^[10]

• Splenectomy (surgical removal of the spleen), which may be effective in approximately two out of three cases, with a presumed cure rate of up to 20%
• Immunosuppressive drugs such as azathioprine, cyclophosphamide, cyclosporin, or mycophenolate mofetil
• Intravenous immunoglobulin (IVIG), though responses are often temporary
• Other medications such as danazol
• Plasma exchange in certain situations
• Alemtuzumab or high-dose cyclophosphamide as last-resort options

Complement inhibitors are newer medications that have shown utility in stabilizing AIHA patients with acute severe haemolysis. These drugs block part of the immune system involved in destroying red blood cells. A complement inhibitor called sutimlimab has shown promise in clinical trials for cold agglutinin disease and is entering advanced testing phases.^[4]

Blood transfusions may be necessary in cases of severe anaemia, especially for patients with chest pain or seriously compromised heart and lung function. However, transfusions do not treat the underlying cause and provide only temporary relief. When transfusions are needed, doctors use the least incompatible blood available and administer it slowly to minimize rapid destruction of the transfused cells.^[11]

If AIHA is secondary to another condition, treating the underlying disease is essential. For medication-induced AIHA, stopping the offending drug is usually sufficient for the anaemia to resolve.^[11]

Supportive care, including folic acid supplementation, is recommended because active haemolysis can deplete folate and cause additional blood cell problems.^[11]

Long-term outlook

The long-term outlook for people with autoimmune haemolytic anaemia varies depending on several factors, including the type of AIHA, severity of the condition, presence of underlying diseases, and response to treatment.^[3]

AIHA is highly manageable with appropriate treatment, but it can be fatal if left untreated. Immediate medical intervention is essential when symptoms develop.^[1] The overall mortality rate for adults with AIHA is approximately 11%.^[10]

The prognosis for children with autoimmune haemolytic anaemia is generally very good with proper treatment.^[3] Mortality is lower in children at 4%, though it increases to 10% when AIHA occurs together with immune thrombocytopenia (Evans syndrome).^[10]

Many patients achieve good disease control with treatment, though some may experience relapses requiring additional or different therapies. With advances in treatment options, including newer targeted therapies and complement inhibitors, outcomes continue to improve.^[13]

Regular follow-up with healthcare providers is important to monitor disease activity, adjust treatments as needed, and watch for complications or side effects of therapy.