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The Cold Hard Facts About Warm Antibody Hemolytic Anemia

December 6, 2021

December 2021

Warm Autoimmune Hemolytic Anemia

  • Prevalence (U.S.): 1-3 adults per 100,000 people
  • Number of FDA-approved treatments: 0
  • Social media hashtags: #WAIHA, #WAIHAWarriors
  • Resources: wAIHA Warriors is an online community for
    people living with wAIHA, providing educational resources
    and a clinical trials hub to connect patients with trials.

Warm antibody hemolytic anemia (wAIHA) is the most common form of autoimmune hemolytic anemia (AIHA). The “warm” in its name refers to the autoantibodies generated by the body, which are active only at body temperatures of 37 degrees Celsius or higher and attach to and prematurely destroy red blood cells (RBCs).

It contrasts with another type of autoimmune hemolytic anemia, cold agglutinin disease (CAD), in which hemolysis is caused by another type of autoantibody that also tags the RBCs for destruction, but acts at cold temperatures around 3 degrees Celsius. A third subtype of AIHA, paroxysmal cold hemoglobinuria, involves autoantibodies that mark RBCs for destruction, in this case by the complement system. Recently, paroxysmal cold hemoglobinuria has become recognized as one of the most common causes of acute AIHA in young children.

Typically, RBCs live for approximately 115 to 120 days before they are removed from circulation in the spleen. The decreased life span of RBCs can be due to an inherent abnormality of the cell itself or to an external factor – in the case of wAIHA or CAD, antibodies.

The autoantibodies are polyclonal and poly-specific, meaning that they react with multiple RCB antigens rather than with a specific one and are usually directed against high-incidence antigens, explained Theodosia Kalfa, MD, PhD, of the Cancer and Blood Diseases Institute in Cincinnati, Ohio.

The antibody-dependent cell-mediated cytotoxicity of the RBCs is mediated by macrophages and other lymphocytes in the lymphoid organs and the spleen, added Dr. Kalfa, who is also a pediatric hematologist at the Cincinnati Children’s Hospital Medical Center. Whether the bone marrow can compensate for some of the erythrocyte population depletion determines the clinical severity of the disease. When the rate of hemolysis cannot be compensated by increased RBC production, hemolytic anemia results.

Immunopathogenesis of wAIHA

Approximately one to three adults per 100,000 per year are affected by wAIHA,1 which accounts for about 70% to 80% of adult autoimmune hemolytic anemia cases and about 50% of pediatric cases.2

Irina Murakhovskaya, MD, associate professor in the department of oncology and the division of hematology at Montefiore Medical Center in New York City, explained that, “about half the time, wAIHA is idiopathic in adults, with no overt associated condition.” Also, in approximately half of cases, wAIHA is secondary to other disorders including lymphoproliferative disorders, autoimmune diseases such as lupus and rheumatoid arthritis, viral infections such as HIV or hepatitis C, and certain drugs such as cephalosporins and piperacillin.

“The most common neoplasm that results in wAIHA is chronic lymphocytic leukemia, followed by non-Hodgkin lymphoma,” said Dr. Murakhovskaya. She added that new emerging etiologies of wAIHA include solid organ or hematopoietic cell transplantation, anti-cancer treatment with immune checkpoint inhibitors including anti-PD1 antibodies, and COVID-19 infection.3

In the pediatric population, about 40% of wAIHA cases are idiopathic, appearing in previously healthy children. Additional underlying causes in children are similar to those in adults, including primary immune disorders and autoimmune diseases, malignancies, infections, and transplantation. Dr. Kalfa noted that the risk is particularly high after post-transplant tacrolimus treatment for immunosuppression.

Besides autoantibodies, phagocytes, cytotoxic CD8+ T-cells and other immune cells can play a role in the pathogenesis of wAIHA. A current working hypothesis posits that wAIHA is triggered by molecular mimicry of foreign antigens from viruses or other exogenous infectious and noninfectious agents (including certain drugs) that cross-react with RBC self-antigens (most frequently Rh proteins). Another potential mechanism for the autoimmune hemolysis of wAIHA is the polyclonal activation of B lymphocytes by a virus that triggers the emergence of so-called “forbidden clones.”2

Workup to a Diagnosis

“Patients ultimately diagnosed with warm autoimmune hemolytic anemia, when they present to a hematologist, typically have symptoms of anemia,” said Dr. Murakhovskaya. “Their symptoms are generally non-specific, such as fatigue, headache, and dyspnea.”

Those with mild or moderate anemia may not have overt symptoms, and the anemia is instead discovered as a result of the diagnosis of another disorder such as lupus. Patients that come in with severe anemia may have yellow skin due to jaundice, discolored urine, and elevated bilirubin and lactate dehydrogenase (LDH) levels. Those patients with severe hemolysis are at risk of deep vein thrombosis or pulmonary embolism.

Patients are assessed for bilirubin and LDH levels as well as a reticulocyte and peripheral blood cell count. “This combination of anemia, reticulocytosis, and elevated bilirubin and LDH should lead to consideration of hemolytic anemia,” said Dr. Murakhovskaya. “Reticulocytopenia, which is an abnormal decrease of reticulocytes, can also be present and is typically a poor prognostic factor in those with wAIHA,” she added.

The next step in the diagnostic process is evaluation of peripheral blood smear to assess for presence of “basketball-like” RBCs. RBCs have a biconcave discoid, a disc with an indented center with a dumbbell-like shape when viewed from the side. If spherocytes are present as well, the next analysis is the direct antiglobulin test (DAT), also called the Coombs test, to assess for the presence of immunoglobulin G (IgG) autoantibodies and complement system activation.

“Since AIHA can be a life-threatening, fast-progressing disease and requires prompt diagnosis and initiation of treatment, the first question to be answered on presentation of a patient with evidence of hemolytic anemia is whether it is an immune-mediated hemolytic anemia,” Dr. Kalfa explained, a question that is answered by results from the DAT and indirect antiglobulin test. These should be the first tests to be ordered when wAIHA is suspected.

Patients whose tests reveal only the presence of complement activation likely have CAD or paroxysmal nocturnal hemoglobinuria, as opposed to wAIHA, while the presence of IgG antibodies – in conjunction with other clinical factors – suggests a wAIHA diagnosis. However, a negative DAT may also occur when anti–RBC IgG antibodies bind to the erythrocytes, leading to hemolysis, but at levels below the threshold of detection for the commonly used DAT reagents.

“Patients with severe hemolysis who present with severe anemia are the tip of the iceberg,” said David Kuter, MD, PhD, director of clinical hematology at Massachusetts General Hospital and professor of medicine at Harvard Medical School in Boston. “The bottom of the iceberg are those patients who have no symptoms that we may never see, or those who come in and are diagnosed with mild hemolysis but who do not want therapy.”

Drs. Kuter, Murakhovskaya, and Kalfa emphasized that wAIHA cannot be diagnosed based on a positive DAT test alone. If a patient has evidence of hemolysis and has had a negative DAT result, additional tests are necessary to confirm wAIHA or another hemolytic disorder. “About 80% of patients with wAIHA have IgG autoantibodies and will have a positive DAT, which tests for IgG antibodies,” explained Dr. Kuter. In about 20% of cases, the autoantibodies are either IgA or IgM and another more precise antibody test is needed to identify the presence of these antibodies.

Therapeutic Options

There are no U.S. Food and Drug Administration (FDA)–approved therapies indicated for wAIHA. A course of glucocorticosteroids is the standard initial therapy for patients diagnosed with wAIHA. For patients with mild to moderate hemolysis, the recommended dose is prednisone 1 to 2 mg/kg per day for three days. Patients with severe hemolysis typically receive a high dose of steroids, such as methylprednisolone 250 to 1,000 mg per day for three days. Up to 80% of patients respond to steroids, typically within four to seven days of therapy initiation, according to Dr. Murakhovskaya.

“If a patient’s disease has not responded within three weeks of therapy, we consider that patient to have refractory disease and move on to a second-line therapy,” she told ASH Clinical News. Patients typically stay on steroids for several months with a gradual taper, because faster tapers have been associated with an increased incidence of relapse, according to Dr. Murakhovskaya.

“The good news is that many patients have a response to steroids,” said Dr. Kuter. “The bad news is that many patients’ disease does not go into remission, and they will require additional therapies or need to stay on steroids for the long term.” Patients whose disease responds to steroids can be weaned off if they have stable RBC counts without overt symptoms. They are monitored and typically will not require additional therapy unless they show signs of relapse.

For patients whose disease does not respond to steroids within two to three weeks, the next option is a course of rituximab, typically 375 mg/m2 for four weeks, which usually induces responses in 80% of patients and long-term remissions in about 60% to 70%. “Rituximab is rarely used up front because it takes about a month to work while steroids begin to work within days,” said Dr. Kuter. Patients who relapse can subsequently be treated successfully with additional courses of rituximab.

Another option for patients with severe hemolysis is high-dose intravenous Ig. Patients with severe disease, particularly in cases of brisk hemolysis and precipitous anemia, may require RBC transfusions, which can be lifesaving. “It’s important to understand that RBC transfusions are discouraged for the average patient with wAIHA, but are important in some cases and not contraindicated,” said Dr. Murakhovskaya.

“There is also a minority of patients who can receive a single course of steroids and will not have a disease relapse again, and then there are patients who have chronic relapsing disease and require ongoing therapy. Some of these patients can be maintained on low-dose prednisone, only requiring rescue therapy when they experience intermittent flares,” said Dr. Murakhovskaya.

For the approximately 25% of patients whose disease does not respond to rituximab, splenectomy is a possible treatment option for patients who are eligible. If a splenectomy does not produce the desired response, or if a patient is too medically sick to undergo surgery, additional therapy options include immunosuppressive drugs such as azathioprine, cyclosporine, bortezomib, and daratumumab.

New Options – and Challenges – on the Horizon

Researchers are exploring several new options for patients with wAIHA, although the rarity and heterogeneity of the disease all but preclude large randomized, prospective clinical trials. Fostamatinib, an oral spleen tyrosine kinase inhibitor approved by the FDA for the treatment of chronic immune thrombocytopenia, is currently being tested in a phase III trial in patients with wAIHA. Additional agents being studied for wAIHA include antibodies that target the neonatal Fc receptor, such as IMVT-1401 and ALXN1830.

“I think the main challenge with wAIHA is the fact that it is a rare disease and the index of suspicion has to be high for the diagnosis,” said Dr. Murakhovskaya. “It’s very important to recognize the condition because it can be a medical emergency, with a mortality rate of about 5% to 10% in retrospective studies.”

Dr. Kuter stressed that, with wAIHA, many patients are stable and, despite mild hemolysis, do not require therapy. “We need to avoid long-term steroid use. We have patients who die due to chronic steroid exposure, rather than from the disorder,” he said. “I have been taking part in clinical trials and innovation for wAIHA for more than two decades. We have no licensed therapies for wAIHA, but with new agents now in trials and others on the way, I am hopeful we will have better options for our patients.” —By Anna Azvolinsky


  1. National Organization for Rare Disorders. Warm Autoimmune Hemolytic Anemia. Accessed November 3, 2021.
  2. Kalfa TA. Warm antibody autoimmune hemolytic anemia. Hematology Am Soc Hematol Educ Program. 2016;1:690-697.
  3. GE, Doley PB, Munker R. Autoimmune hemolytic anemia associated with the use of immune checkpoint inhibitors for cancer: 68 cases from the Food and Drug Administration database and review. Eur J Haematol. 2019;102(2):157-162.


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