Warm Autoimmune Haemolytic Anaemia
Warm autoimmune haemolytic anaemia is a rare condition where the body’s immune system mistakenly attacks and destroys its own red blood cells, leading to profound fatigue and other serious symptoms that can severely impact daily life.
Table of contents
- What is Warm Autoimmune Haemolytic Anaemia?
- Disease Codes and Alternative Names
- What Causes This Condition?
- Signs and Symptoms
- How is it Diagnosed?
- Treatment Options
- Outlook and Management
What is Warm Autoimmune Haemolytic Anaemia?
Warm autoimmune haemolytic anaemia (wAIHA) is a rare, potentially life-threatening disease that occurs when the body’s immune system produces autoantibodies—harmful antibodies that mistakenly attack the body’s own tissues—against healthy red blood cells[1][2]. While antibodies normally protect the body from harmful invaders like bacteria and viruses, in wAIHA, immunoglobulin G (IgG) antibodies (the most common type of antibody) mistakenly mark red blood cells for destruction[2].
Red blood cells have the vital job of delivering oxygen throughout the body. Normally, these cells have a life span of 115 to 120 days[3][5]. However, in wAIHA, the red blood cells are destroyed as fast as they are produced, leaving very few in the bloodstream[5]. This process of premature red blood cell destruction is called haemolysis[2].
The condition is called “warm” because these antibodies bind to red blood cells at normal body temperature (37-40°C), unlike cold autoimmune haemolytic anaemia where destruction occurs at cooler temperatures[1][5]. Warm autoimmune haemolytic anaemia is the most common type of autoimmune haemolytic anaemia, comprising approximately 70% to 80% of all adult cases and about 50% of paediatric cases[3].
The destruction of red blood cells leads to anaemia, a condition marked by low levels of red blood cells, which hinders oxygen delivery to every organ in the body[2]. The premature destruction can happen either inside blood vessels (intravascularly) or in organs like the spleen and liver (extravascularly) where immune cells remove the damaged cells[3].
Disease Codes and Alternative Names
wAIHA, wAHA, warm antibody autoimmune haemolytic anaemia, autoimmune hemolytic anemia, primary/idiopathic autoimmune haemolytic anaemia, autoimmune haemolytic anaemia syndrome
90033
3A20.0
What Causes This Condition?
The underlying cause of wAIHA can be classified into two main categories. About half of all cases are called primary or idiopathic, meaning no specific underlying cause can be identified[1][3][4]. The exact reason why some people spontaneously start producing excessive amounts of these harmful autoantibodies is not known, though in some cases it has been associated with prior infections, transplants or transfusions[5].
The remaining cases are secondary, meaning the condition develops in connection with another recognizable underlying disorder[1][3]. Several autoimmune diseases can trigger secondary wAIHA, including lupus, rheumatoid arthritis, Sjogren’s syndrome, thyroid disease, ulcerative colitis, and Hashimoto’s disease[1]. Blood cancers such as chronic lymphocytic leukaemia and lymphoma can also be associated with wAIHA[1][4].
Certain medications can trigger the development of warm autoimmune haemolytic anaemia. These include antibiotics such as penicillins, cephalosporins (particularly ceftriaxone and cefotetan), and ciprofloxacin, as well as nonsteroidal anti-inflammatory drugs (NSAIDs), and certain other medications like quinidine and alpha methyldopa[4].
Viruses can sometimes cause wAIHA to develop, though typically the anaemia resolves once the infection is treated. Common viruses linked to wAIHA include Epstein-Barr virus, measles, mumps, rubella, atypical pneumonia, and varicella (the virus that causes chickenpox)[1].
The way these autoantibodies destroy red blood cells involves recognition by immune cells in the spleen. The IgG antibodies attach to red blood cells, leaving their FC portion exposed. This portion is recognized by FC receptors on monocytes and macrophages (types of immune cells) in the spleen. These cells remove portions of the red blood cell membrane, causing the cells to become spherocytes—sphere-shaped cells that are less flexible than normal red blood cells[4]. These spherocytes are then trapped and destroyed in the spleen, which often causes the spleen to enlarge[4].
Signs and Symptoms
The signs and symptoms of wAIHA can vary from mild to severe and may develop gradually over several weeks or, in some cases, within just a few days[1][5]. The severity of symptoms depends on how rapidly red blood cells are being destroyed and how well the body can compensate by producing new ones[9].
The most common symptoms of wAIHA include tiredness, dizziness, and jaundice (yellowing of the skin and eyes)[1][5]. Jaundice occurs because the breakdown of red blood cells releases a substance called bilirubin, which can make the skin and whites of the eyes appear yellow[9].
Other symptoms include weakness, fever, rapid heartbeat (tachycardia), heart palpitations (feeling like your heart is racing or pounding), shortness of breath (dyspnoea), pale skin colour (pallor), headaches, muscle pain, dark-coloured urine, backache, nausea and vomiting, difficulty breathing, diarrhoea, and a sore tongue[1][5].
In chronic cases, people may develop gallstones and cholecystitis (inflammation of the gallbladder)[3]. There may also be confusion, enlargement of the spleen (splenomegaly), and signs of heart failure in severe cases[5]. Individuals with wAIHA may have an increased risk of developing blood clots, strokes, and heart issues[5].
How is it Diagnosed?
Diagnosis of warm autoimmune haemolytic anaemia is usually straightforward, based on the presence of haemolytic anaemia and evidence of antibodies attached to red blood cells[6]. The key diagnostic test is the direct antiglobulin test (DAT), also known as the direct Coombs test, which looks for antibodies attached to the surface of red blood cells[4][9]. In wAIHA, this test is typically positive for IgG antibodies and sometimes also for C3d (a component of the immune system called complement)[6][9].
Laboratory findings commonly include anaemia (decreased haemoglobin levels), reticulocytosis (increased numbers of young red blood cells, showing the body is trying to compensate), elevated levels of lactate dehydrogenase (LDH) and unconjugated bilirubin (indicating cell breakdown), and decreased haptoglobin levels (a protein that binds free haemoglobin)[3][9]. Blood tests may also show that serum aspartate aminotransferase levels are disproportionately higher than serum alanine aminotransferase[3].
When examining blood under a microscope, doctors often see spherocytes—small, sphere-shaped red blood cells that have lost part of their membrane[9]. The average size of red blood cells (mean corpuscular volume or MCV) is typically normal[4].
It is important to note that the DAT may sometimes yield false-negative results. This can occur if the antibodies involved are IgA (which are not detected by most routine tests), if the antibodies have low affinity for red blood cells, or if the amount of antibody bound to red blood cells is below the detection threshold of the test[6]. In such cases, more specialized testing may be needed.
Treatment Options
The treatment of wAIHA aims to stop the destruction of red blood cells, increase red blood cell counts, and manage any underlying conditions that may be triggering the disease[1]. Because the condition varies considerably between individuals, treatment must be personalized[6].
Corticosteroids (steroid medications) are the first-line treatment for most cases of warm autoimmune haemolytic anaemia[6][8][9]. These medications work by suppressing the immune system’s production of antibodies. Common corticosteroids used include prednisone, prednisolone, and methylprednisolone[8]. Treatment typically starts with high doses that are then gradually reduced over a period of six to twelve months[6]. Corticosteroids are highly effective, with over 85% of patients responding to initial treatment[9]. However, less than one-third maintain their response when the medication is reduced[9].
Rituximab is increasingly used as a second-line treatment for patients who do not respond adequately to corticosteroids or who relapse when steroids are reduced[6][8][9]. This medication is a type of monoclonal antibody, originally developed to treat blood cancers but now also used for autoimmune disorders[8]. Rituximab can provide complete remission in over 75% of patients failing corticosteroids, and these remissions may be long-lasting[9]. Recent evidence supports its use even as first-line therapy in combination with corticosteroids, with studies showing that 75% of patients treated with both medications had a satisfactory response after 12 months, compared to 36% of those given prednisolone alone[8].
Splenectomy (surgical removal of the spleen) may be considered when other treatments are ineffective[8][9]. Removing the spleen can help prevent the premature destruction of red blood cells, as this is where much of the destruction occurs. Splenectomy is effective in approximately two out of three cases and may offer long-term remission in over two-thirds of patients[6][9]. However, the spleen is part of the immune system, and people who have had their spleen removed may be more vulnerable to infections[8].
For patients who do not respond to rituximab, other options include immunosuppressive drugs such as azathioprine, cyclophosphamide, cyclosporin, and mycophenolate mofetil[6][8]. Over 50% of patients failing rituximab respond to these medications or to erythropoiesis-stimulating agents (medications that help the body produce more red blood cells)[9].
Additional treatment options include intravenous immunoglobulins (IVIG), though only a few patients respond to this treatment and responses tend to be temporary[6][8]. Other medications that may be used include danazol[6][8].
Newer treatments showing promise include fostamatinib, rilzabrutinib, and FcRn inhibitors (medications that block a specific receptor involved in antibody recycling)[9].
Blood transfusions should be avoided unless absolutely necessary, as the risk of destruction of transfused blood is high[8]. However, transfusions may be essential for patients with severe anaemia affecting the heart or lungs. When transfusions are needed, packed red blood cells should be administered slowly, and the least incompatible blood should be used[8].
Prophylactic folic acid is recommended because active haemolysis can deplete folate stores in the body[8][9].
If wAIHA is secondary to another condition or medication, treating the underlying disease or discontinuing the responsible medication is an important part of management[8].
Outlook and Management
Warm autoimmune haemolytic anaemia is highly manageable with appropriate treatment, but it can be fatal if left untreated[1]. Immediate intervention is essential when the condition is diagnosed. The disease often requires long-term management, as relapses are common when treatments are reduced or stopped[5].
The condition is rare, affecting approximately 1 to 3 out of every 100,000 people each year[1][3][6]. It can affect anyone but most commonly occurs in females over the age of 40[1]. In children, wAIHA is very rare, with an estimated incidence of 0.2 per 100,000 per year, and mortality is lower in children (4%) than in adults (11%)[6].
Many people living with wAIHA experience symptoms that can significantly impact daily life, including profound fatigue that can limit normal activities[2]. The chronic nature of the condition and the need for ongoing treatment mean that individuals may experience disability-related impacts from the disease[5].
With modern treatment approaches, many patients can achieve good control of their disease, though some may require multiple treatment changes over time as initial therapies lose effectiveness or cause side effects[9]. Regular monitoring by healthcare professionals is important to adjust treatment as needed and watch for complications.
