Report highlights step-by-step process for accurate CAD diagnosis

Other causes of immune-induced blood cell destruction should also be excluded

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A step-by-step process is needed to accurately diagnose cold agglutinin disease (CAD) and other forms of autoimmune hemolytic anemia (AIHA), according to a report.

This process involves the detection of blood cell destruction, establishing whether this is due to an immune attack, and finally zeroing in on the specific type of immune attack.

Simultaneously, other potential causes of immune-induced blood cell destruction should be excluded, researchers say.

This step-by-step process was highlighted in the study “Collage of cases and brief review of the laboratory diagnosis and molecular testing in autoimmune haemolytic anaemia,” which was published in the Journal of Family Medicine and Primary Care.

AIHA refers to a group of rare autoimmune disorders marked by the production of self-reactive immune antibodies that wrongly attack red blood cells, making them aggregate and marking the cells for destruction (hemolysis). This results in low levels of red blood cells, or anemia.

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It can be classified as CAD, warm AIHA, or mixed AIHA, depending on whether the antibodies bind more easily to red blood cells at lower temperatures, higher temperatures, or both. CAD is a rare form of AIHA, while warm AIHA is the most common type.

AIHA is said to be primary when its cause is unknown, and secondary when it occurs due to an underlying condition, which includes blood cancers, infections, or other autoimmune diseases.

Now, a sextet of scientists in India described five cases of people diagnosed with different forms of AIHA, highlighting the step-by-step process needed to establish a correct diagnosis.

“The categorization of AIHA as cold or warm or mixed type has a significant bearing on the treatment options available,” the researchers wrote, emphasizing the importance of determining the correct diagnosis.

This stepwise approach first involves “the diagnosis of haemolysis followed by the establishment of immune nature with the aid of direct agglutination tests (DAT),” the team wrote.

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DAT assesses whether IgG and/or C3d are attached to red blood cells

DAT, also known as a direct Coombs test, assesses whether a type of antibody called IgG and/or C3d — a protein that’s part of an immune cascade called the complement — are attached to a patient’s red blood cells.

Hemolysis in warm AIHA is associated with self-reactive IgG antibodies, but is independent of activation of the complement cascade. In turn, CAD is driven by self-reactive antibodies called cold agglutinins that are of another type called IgM. Also, it is dependent on complement activation, which leads to the formation of C3d that can bind to cells and tissues.

As such, CAD is typically marked by a DAT positive for C3d, and an absence of IgGs, while warm AIHA patients test positive for IgGs, and may or may not test positive for C3d.

“However, the DAT positive report should also be viewed with caution,” the researchers wrote.

That’s because other conditions may also be associated with a positive DAT, including liver diseases — in which antibodies or complement proteins may passively bind to red blood cells — cancer, autoimmune diseases like systemic lupus erythematosus, and kidney diseases.

“In absence of these causes, diagnosis of AIHA can be rendered without a doubt,” the researchers wrote.

The described cases included three people with warm AIHA, one with CAD, and one with mixed AIHA.

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The CAD case was a 42-year-old man who sought medical attention due to symptoms that included shortness of breath, fatigue, unusual sensitivity to cold, and abnormally bluish skin on his extremities.

Initial blood tests revealed anemia and several markers of hemolysis, and his blood sample showed red blood cell clumping at room temperature. All these signs suggested AIHA and a DAT was conducted.

The test came back positive for C3d and negative for IgG antibodies, and the man was also found to have high levels of cold agglutinins. These findings and the exclusion of other potential causes confirmed a CAD diagnosis.

After establishing the diagnosis, the man received off-label treatment with rituximab (sold as Rituxan, among others), a therapy that works by killing antibody-producing immune cells. His CAD was brought into remission after four doses of the therapy, and his condition “improved on clinical and laboratory parameters,” the researchers wrote.