Patients with paroxysmal nocturnal hemoglobinuria (PNH) who receive vaccination for COVID-19 may be at risk of severe hemolysis, according to a report published as a letter to the editor in the journal Blood by researchers from Johns Hopkins University and the University of Michigan Medical School.

The researchers explained that an increase in complement associated with the immune response to COVID-19 may be involved in organ damage and microthrombosis and that the presence of the SARS-CoV-2 spike protein may increase complement production. The authors noted that the mRNA-based vaccines enable a brief period of spike protein production.

Reactions are typically mild for most recipients of COVID-19 vaccines. However, the researchers postulated, in patients with PNH, a deficiency in complement-regulatory proteins in their blood cells could potentially be linked to serious consequences with these vaccines.

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In their report, the researchers described outcomes for 6 patients with PNH who received COVID-19 vaccines, of whom 4 had experienced significant adverse reactions, while 2 did not. All patients in the study had received either the Pfizer-BioNTech COVID-19 vaccine or the Moderna COVID-19 vaccine. All but 1 patient had received both planned COVID-19 vaccine doses. COVID-19 vaccination history was based on self-reporting.

None of the patients in the analysis had been given transfusions in the prior year, and all had PNH granulocyte clones at or above 80%. Most of the patients in this report had received prior treatment with the complement inhibitor ravulizumab, excluding 1 of the patients who had experienced a severe reaction. For the 5 patients who received ravulizumab, the most recent dose was given 4 to 7 weeks prior to the last vaccine dose.

Severe reactions that occurred began during the period from the day of vaccine administration to 5 days afterward. Reactions lasted up to 6 days. Fever occurred in 4 cases, and 3 patients had severe hemolysis, marked by a reduction in hemoglobin of 2 to 4 g/dL.

In an assay involving the addition of SARS-CoV-2 spike protein subunit 1 to erythrocytes from a patient with PNH and a control patient, there was no increase in hemolysis seen with the spike protein subunit. The researchers indicated that clinical hemolysis following vaccination was likely not directly attributable to the spike protein.

“As SARS-CoV-2 leads to a severe inflammatory state, the benefits of vaccinating patients with PNH likely outweigh the risks; however, clinicians and patients should be aware of this serious adverse effect, and patients should be educated to report any symptoms postvaccination,” the researchers wrote in their report.

Disclosures: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.


Gerber GF, Yuan X, Yu J, et al. COVID-19 vaccines induce severe hemolysis in paroxysmal nocturnal hemoglobinuria. Blood. Published online May 4, 2021. doi:10.1182/blood.2021011548