Autoimmune hemolytic anemia in adults: primary risk factors and diagnostic procedures

ABSTRACT

Introduction

Autoimmune hemolytic anemia (AIHA) is due to autoantibodies against erythrocytes that may arise either because of primary tolerance breakage or along with several associated conditions, including genetic predispositions, congenital syndromes, environmental triggers, autoimmune diseases, immunodeficiencies, and neoplasms.

Areas covered

This review evaluated the risk of AIHA development in associated conditions and summarized disease-intrinsic risk factors for relapse and outcome. Diagnostic procedures were analyzed to properly identify primary and secondary forms. A Medline including clinical trials, meta-analyses, guidelines, consensus, and case reports, published in the last 30 years were performed.

Expert opinion

The several associated conditions listed above constitute a risk for AIHA development and should be considered since disease course and therapy may be different. Particularly, AIHA developing after transplant or novel checkpoint inhibitors is an emerging complex entity whose proper therapy is still an unmet need. Concerning intrinsic risk factors, the severity of anemia at onset correlated with the recurrence of relapses, refractoriness, and fatal outcome. This finding reflects the presence of several mechanisms involved in AIHA, i.e. highly pathogenic antibodies, complement activation, and failure of marrow compensation. With the advent of novel target therapies (complement and various tyrosine kinase inhibitors), a risk-adapted therapy for AIHA is becoming fundamental.

KEYWORDS:

• Warm autoimmune hemolytic anemia
• cold agglutinin disease
• autoantibodies
• bone marrow responsiveness index
• checkpoint inhibitors
• complement
• direct antiglobulin test
• risk factors
• rituximab
• secondary autoimmune hemolytic anemia

Article highlights

• Autoimmune hemolytic anemia (AIHA) may be primary or secondary to several conditions including autoimmune and lymphoproliferative diseases, immunodeficiencies, infections, drugs, congenital syndromes, and neoplasms.

• Associated conditions represent a risk factor for the development of AIHA and should be properly diagnosed to harness therapy.

• Several immunopathologic mechanisms are involved in determining the severity of the disease including the type and thermal characteristics of antibodies, the degree of complement activation, and the failure of bone marrow compensation.

• The most important disease-specific risk factor for refractoriness is the severity of anemia at the onset. Evans’ syndrome, acute renal failure, and infections have been associated with increased mortality.

• AIHA developing after transplant or novel anti-cancer drugs such as checkpoint inhibitors is an emerging complex setting requiring proper diagnosis and therapy.

• A risk adapted therapy is an unmet need for severe and refractory AIHAs.

Declaration of interest

W Barcellini received consulting honoraria from Alexion, Incyte, Bioverativ, Momenta, and B Fattizzo received consulting honoraria Momenta and Apellis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.