COVID-19 vaccinations are especially important for patients with complement-mediated hemolytic anemias such as cold agglutinin disease (CAD) but with meticulous monitoring for complications, according to a new study published in the journal Frontiers in Immunology.

The study reports the cases of 2 patients with CAD and 2 with paroxysmal nocturnal hemoglobinuria who experienced hemolytic flares after COVID-19 infections or vaccinations. It also presents a review of the most recent literature.

Patients and healthcare professionals may have reservations about vaccinating patients with complement-mediated hemolytic anemias such as CAD due to potential complications.

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However, the authors of the present study reported that the flares that happened during a COVID-19 infection were more severe, needed more intervention, and led to more complications including deaths than flares occurring as a result of a COVID-19 vaccination.

Read more about CAD etiology

“We report that most episodes occurred within the first 10 days after COVID-19 infection/vaccination and suggest laboratory monitoring,” Bruno Fattizzo and the coauthors of the study wrote.

Patient education is of great importance to ensure the signs and symptoms of hemolytic flares are promptly recognized and patients are referred to medical attention, the authors said. This includes transfusions, steroids, and/or rituximab in patients with CAD and “should be based on the severity of the hemolytic exacerbation as well as of that of COVID-19 infection.”

CAD is a rare genetic disease where the body’s immune system mistakenly attacks its own erythrocytes at cold temperatures. This immune response is mediated by the complement system.

There is also a complex pathophysiological interplay between COVID-19 infections and the activation of the complement system, which explains why hemolytic flares occur in diseases such as CAD after a COVID-19 infection or vaccination. 


Fattizzo B, Pasquale R, Bellani V, Barcellini W, Kulasekararaj AG. Complement mediated hemolytic anemias in the COVID-19 era: case series and review of the literature. Front Immunol. 2021;25(12). doi:10.3389/fimmu.2021.791429