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PubMed This is a summary of 17 peer-reviewed journal articles Updated
Hematology · Warm Autoimmune Hemolytic Anemia

Primary vs. Secondary wAIHA & Related Conditions

At a Glance

Warm autoimmune hemolytic anemia (wAIHA) is classified as primary when the cause is unknown, and secondary when triggered by an underlying condition like lupus, blood cancer, or infection. Identifying secondary wAIHA is crucial because the underlying disease must be treated to stop the anemia.

When you are diagnosed with warm Autoimmune Hemolytic Anemia (wAIHA), one of the first questions your hematologist will try to answer is whether the condition is Primary or Secondary. This distinction is crucial because it determines whether treatment should focus solely on the anemia or if another “hidden” condition must also be addressed [1][2].

Primary vs. Secondary wAIHA

  • Primary (Idiopathic) wAIHA: This occurs when the immune system starts attacking red blood cells for no identifiable reason [1]. It is essentially a “glitch” in the immune system where the root cause remains unknown.
  • Secondary wAIHA: This occurs when the immune system is “tricked” into attacking red blood cells because of an underlying medical condition, a recent infection, or a specific medication [3][4]. Approximately 50% of wAIHA cases are found to be secondary [1].

Common Secondary Triggers

If you have secondary wAIHA, your doctor will look for these common underlying causes:

  • Autoimmune Diseases: Most notably Systemic Lupus Erythematosus (SLE) [3][4].
  • Blood Cancers: Such as Chronic Lymphocytic Leukemia (CLL) or other types of lymphoma [3][5].
  • Infections: Viruses like SARS-CoV-2 (COVID-19) or parasites like Babesia (from tick bites) can trigger an immune attack [6][7].
  • Medications: Certain drugs, including some antibiotics (like ceftriaxone) or newer cancer treatments called immune checkpoint inhibitors, can occasionally trigger wAIHA [8].

Why the Distinction Matters

In secondary wAIHA, treating the anemia with steroids may only be a temporary fix. Often, the hemolysis (blood destruction) will only fully resolve once the underlying cause is treated [2][7]. For example, if a patient has CLL-related wAIHA, the doctor will likely use a treatment plan that targets the leukemia cells at the same time as the anemia [2][9].

Related Conditions: Evans Syndrome

Sometimes, the immune system doesn’t stop at attacking red blood cells. Evans Syndrome is a condition where a patient has wAIHA occurring at the same time as, or sequentially with, Immune Thrombocytopenia (ITP) [10].

In simple terms, ITP is when the immune system destroys platelets (the cells that help your blood clot) [10]. Evans Syndrome is considered very rare, much less common than wAIHA alone, affecting only a small subset of patients [10]. Because it involves two separate immune attacks, it is often more complex to manage and requires a very thorough search for an underlying immunological or rheumatological condition [11][12].

Look-Alike Conditions

Not all cases of “broken” red blood cells are caused by an autoimmune attack. Your doctor must rule out other “look-alikes” that require very different treatments:

  • Paroxysmal Nocturnal Hemoglobinuria (PNH): A rare genetic condition where red blood cells are missing a protective “shield.” Unlike wAIHA, the DAT test (Coombs test) for PNH is typically negative [13][14].
  • Cold Agglutinin Disease (CAD): Similar to wAIHA, but the antibodies react to cold temperatures rather than warmth. This is an important distinction because standard wAIHA treatments (like steroids) often don’t work for CAD [15][16]. Because the antibodies react to cold temperatures, patients with CAD need to strictly avoid cold exposure in their daily life [15].
  • Hereditary Spherocytosis: A genetic condition where the red blood cells are naturally shaped like balls rather than discs, making them fragile [17].

Common questions in this guide

What is the difference between primary and secondary wAIHA?
Primary wAIHA happens when the immune system attacks red blood cells for an unknown reason. Secondary wAIHA occurs when an underlying issue, such as another autoimmune disease, blood cancer, or infection, triggers the immune system to mistakenly attack the cells.
What conditions can trigger secondary wAIHA?
Secondary wAIHA is frequently triggered by other autoimmune diseases like lupus, or blood cancers such as chronic lymphocytic leukemia. Certain infections, like COVID-19, and some medications can also cause the condition.
What is Evans Syndrome?
Evans Syndrome is a rare condition where a patient has wAIHA and immune thrombocytopenia at the same time. This means the immune system is destroying both red blood cells and platelets, which are the cells that help your blood to clot.
Are there other conditions that look like wAIHA?
Yes, conditions like cold agglutinin disease, paroxysmal nocturnal hemoglobinuria, and hereditary spherocytosis can cause similar red blood cell destruction. Your doctor will perform specific tests to rule these out because they require very different treatments than wAIHA.
Why does it matter if my wAIHA is primary or secondary?
Knowing if your wAIHA is secondary helps your doctor create an effective treatment plan. If an underlying condition is causing the anemia, the blood destruction often will not fully resolve until that root cause is treated.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Do my lab results suggest that my wAIHA is 'primary,' or have we identified an underlying trigger or 'secondary' condition?
  2. 2.Based on my current blood counts, is there any evidence of Evans syndrome, such as low platelets in addition to my low red blood cell count?
  3. 3.Are there other conditions, like Cold Agglutinin Disease or PNH, that we need to rule out with further testing?
  4. 4.If we find an underlying cause for my wAIHA, how will that change our treatment strategy for the anemia itself?

Questions For You

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References

References (17)
  1. 1

    Epidemiology of Secondary Warm Autoimmune Haemolytic Anaemia-A Systematic Review and Meta-Analysis.

    Tranekær S, Hansen DL, Frederiksen H

    Journal of clinical medicine 2021; (10(6)) doi:10.3390/jcm10061244.

    PMID: 33802848
  2. 2

    A Retrospective Study of the Combination of Rituximab, Cyclophosphamide and Dexamethasone for the Treatment of Relapsed/Refractory Warm Antibody Autoimmune Hemolytic Anemia.

    Piatek CI, Bocian H, Algaze S, et al.

    Acta haematologica 2020; (143(3)):244-249 doi:10.1159/000501538.

    PMID: 31665725
  3. 3

    Treatment of autoimmune hemolytic anemia: real world data from a reference center in Mexico.

    Jaime-Pérez JC, Aguilar-Calderón P, Salazar-Cavazos L, et al.

    Blood research 2019; (54(2)):131-136 doi:10.5045/br.2019.54.2.131.

    PMID: 31309092
  4. 4

    Warm Autoimmune Hemolytic Anemia as the Initial Presentation of Systemic Lupus Erythematosus (SLE): A Case Report.

    Kanderi T, Kim J, Chan Gomez J, et al.

    The American journal of case reports 2021; (22()):e932965 doi:10.12659/AJCR.932965.

    PMID: 34897265
  5. 5

    Autoimmune Hemolytic Anemia in Chronic Lymphocytic Leukemia: A Comprehensive Review.

    Autore F, Pasquale R, Innocenti I, et al.

    Cancers 2021; (13(22)) doi:10.3390/cancers13225804.

    PMID: 34830959
  6. 6

    Warm Autoimmune Hemolytic Anemia Associated With Asymptomatic SARS-CoV-2 Infection.

    Liput JR, Jordan K, Patadia R, Kander E

    Cureus 2021; (13(3)):e14101 doi:10.7759/cureus.14101.

    PMID: 33927918
  7. 7

    Warm Autoimmune Hemolytic Anemia Secondary to Babesia Microti Infection: A Case Report.

    Bleik P, Matubia V

    Cureus 2023; (15(12)):e50294 doi:10.7759/cureus.50294.

    PMID: 38205493
  8. 8

    Ceftriaxone-induced hemolytic anemia with severe renal failure: a case report and review of literature.

    Leicht HB, Weinig E, Mayer B, et al.

    BMC pharmacology & toxicology 2018; (19(1)):67 doi:10.1186/s40360-018-0257-7.

    PMID: 30359322
  9. 9

    Treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma presenting simultaneously with acquired hemophilia and warm autoimmune hemolytic anemia.

    Williams C, Cable C, Choi J

    Proceedings (Baylor University. Medical Center) 2017; (30(3)):343-345 doi:10.1080/08998280.2017.11929642.

    PMID: 28670081
  10. 10

    Diagnosis and management of Evans syndrome in adults: first consensus recommendations.

    Fattizzo B, Marchetti M, Michel M, et al.

    The Lancet. Haematology 2024; (11(8)):e617-e628 doi:10.1016/S2352-3026(24)00144-3.

    PMID: 38968944
  11. 11

    Female adolescent with recurrent anemia and thrombocytopenia: Answers.

    Lozano Chinga M, Afify Z, Lowichik A, et al.

    Pediatric nephrology (Berlin, Germany) 2022; (37(9)):2069-2071 doi:10.1007/s00467-022-05486-5.

    PMID: 35275276
  12. 12

    Evans Syndrome in Childhood: Long Term Follow-Up and the Evolution in Primary Immunodeficiency or Rheumatological Disease.

    Rivalta B, Zama D, Pancaldi G, et al.

    Frontiers in pediatrics 2019; (7()):304 doi:10.3389/fped.2019.00304.

    PMID: 31396497
  13. 13

    Abdominal pain in combination with an unexplained hemolytic anemia are crucial signs to test for paroxysmal nocturnal hemoglobinuria: A case report.

    Elias NS, Riedl J, Stouten K, et al.

    Clinical case reports 2019; (7(1)):175-179 doi:10.1002/ccr3.1771.

    PMID: 30656036
  14. 14

    Paroxysmal nocturnal hemoglobinuria: a complement-mediated hemolytic anemia.

    DeZern AE, Brodsky RA

    Hematology/oncology clinics of North America 2015; (29(3)):479-94.

    PMID: 26043387
  15. 15

    Acrocyanosis revealing chronic lymphocytic leukemia.

    Lesesve JF

    Clinical case reports 2016; (4(4)):404-5 doi:10.1002/ccr3.529.

    PMID: 27099738
  16. 16

    [Autoimmune hemolytic anemia in children].

    Becheur M, Bouslama B, Slama H, Toumi NE

    Transfusion clinique et biologique : journal de la Societe francaise de transfusion sanguine 2015; (22(5-6)):291-8.

    PMID: 26575109
  17. 17

    Warm Autoimmune Hemolytic Anemia.

    Brodsky RA

    The New England journal of medicine 2019; (381(7)):647-654 doi:10.1056/NEJMcp1900554.

    PMID: 31412178

This page explains the primary causes and related conditions of wAIHA for educational purposes only. Always consult your hematologist to understand the specific triggers, underlying conditions, and look-alike diseases affecting your health.

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