In PNH, Severe Hemolysis Post COVID-19 Vaccination is Possible
—An absence of complement regulatory proteins in patients with paroxysmal nocturnal hemoglobinuria could trigger adverse reactions to COVID-19 vaccines in this population.
Overactivation of the complement cascade is likely a critical driver of the immune response to COVID-19 infection and, in turn, its sequelae, including end-organ damage.1-3 Although reactions to mRNA-based COVID-19 vaccines are generally mild, heightened complement amplification with these vaccines could hypothetically lead to more severe reactions in conditions like paroxysmal nocturnal hemoglobinuria (PNH), in which blood cells lack complement regulatory proteins.1
In a recent report published in the journal Blood, Gloria Gerber, MD, a hematology fellow at Johns Hopkins Medicine in Baltimore, and her co-investigators described several cases of pharmacodynamic breakthrough hemolysis induced by COVID-19 vaccines in PNH patients on a complement inhibitor.1 The investigators also assessed whether the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein directly triggers post-vaccination hemolysis.
Case reports from Johns Hopkins
Six patients (3 women and 3 men), 25 to 63 years of age, were identified from self-reports of having had received the COVID-19 vaccine.1 These patients had PNH granulocyte clones of ≥80% and had not received transfusions in the previous year. All reactions were evident from the day of administration to 5 days later and resolved after 1 to 6 days.
Three patients, including 1 who had received Pfizer-BioNTech BNT162b2 and 2 who had received Moderna mRNA-1273, experienced severe hemolysis with a 2 to 4 g/dL decrease in hemoglobin. Dr. Gerber and her colleagues pointed out that the hemolysis occurring after COVID vaccination, as observed in these 3 patients who were on a complement inhibitor, suggests pharmacodynamic breakthrough (as opposed to pharmacokinetic breakthrough due to insufficient drug levels). Three occurrences of breakthrough hemolysis 4 weeks from the last ravulizumab infusion make suboptimal complement inhibition unlikely, the authors commented in their report.
An additional patient, who had received the Pfizer vaccine, presumably had a thrombotic manifestation, particularly a possible small bowel microvascular thrombosis.
Two other patients received the Pfizer vaccine without any clinical or laboratory indications of hemolysis.
What mechanism controls post-vaccination hemolysis?
To evaluate whether a direct effect of the SARS-CoV-2 spike protein mediates the development of hemolysis after COVID-19 vaccination, acidified normal human serum pre-intubated with various concentrations of spike protein subunit 1 was added to type O-positive erythrocytes from 1 PNH patient and from 1 healthy control subject. Erythrocytes were incubated at 37 ºC for 1 hour.
The research team found that spike protein subunit 1 didn’t increase hemolysis of PNH erythrocytes, compared with the acidified normal human serum alone, and didn’t appear to bind erythrocytes. This finding suggested that hemolysis post-vaccination was not precipitated directly by the SARS-CoV-2 spike protein.
The authors concluded that strong complement amplification as a consequence of the COVID-related inflammatory state may have been responsible for the hemolysis experienced by several of the Johns Hopkins patients described in the Blood report. They pointed out that this has been observed with other vaccines, as well as with infections and surgeries.
“Our previous work in Blood4 showed that SARS-CoV-2 spike proteins lead to complement dysregulation by binding heparan sulfate and disrupting complement factor H,” says senior author Robert A. Brodsky, MD, The Johns Hopkins Family Professor of Oncology Research, and Director of the Division of Hematology at Johns Hopkins Medicine. “This doesn’t happen on red cells because red cells express very little heparan sulfate and don’t bind the spike proteins. PNH red cells, however, already have complement dysregulation due to the absence of CD55 and CD59. Thus, the ‘breakthrough hemolysis’ here is due to the immune response to the spike protein rather than directly interfering with complement on the surface of red cells.”
What should doctors take away?
Dr. Brodsky and his fellow investigators noted several points that clinicians who treat patients with PNH should keep in mind in the context of COVID-19 vaccination and the risk of hemolysis:
- Patients should be instructed to report any symptoms they experience after receiving the COVID-19 vaccination.
- Patients should maintain optimal hydration.
- The benefits of COVID-19 vaccination still outweigh the risk for most patients.
- Most reactions manifest within the first 5 days after vaccination.
- Vaccine-related adverse events appear to be time-limited and can be addressed with supportive care and transfusions, as appropriate.
The research team also recommended that vaccines should be administered within 4 weeks of the last ravulizumab infusion and within 1 week of the eculizumab infusion.
“Breakthrough hemolysis in PNH can be either pharmacokinetic, in that drug levels aren’t high enough, or pharmacodynamic, due to complement-amplifying conditions,” Dr. Brodsky says. “By receiving the vaccine closer to the last infusion, there’s less chance for pharmacokinetic breakthrough; however, it won’t necessarily prevent pharmacodynamic breakthrough.”
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References
- 1. Gerber GF, Yuan X, Yu J, et al. COVID-19 vaccines induce severe hemolysis in paroxysmal nocturnal hemoglobinuria. Blood. 2021 May 4. doi:10.1182/blood.2021011548. [Epub ahead of print].
- 2. Sokol J, Nehaj F, Mokan M, Lisa L, Stasko J. COVID19 infection in a patient with paroxysmal nocturnal hemoglobinuria: a case report. Medicine (Baltimore). 2021;100(20):e25456. doi:10.1097/MD.0000000000025456.
- 3. Polycarpou A, Howard M, Farrar CA, et al. Rationale for targeting complement in COVID-19. EMBO Mol Med. 2020;12(8):e12642. doi:10.15252/emmm.202012642.
- 4. Yu J, Yuan X, Chen H, Chaturvedi S, Braunstein EM, Brodsky RA. Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor D inhibition. Blood. 2020;136(18):2080-2089. doi:10.1182/blood.2020008248.