Stem cell transplant prep brings complications for woman with PNH
Breakthrough hemolysis controlled with complement inhibitor
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A woman with paroxysmal nocturnal hemoglobinuria (PNH) developed severe breakthrough hemolysis — when red blood cell destruction resumes despite treatment to prevent the process — while preparing for a stem cell transplant.
A case report said the woman, who was being treated with the complement inhibitor Empaveli (pegcetacoplan), was helped after doctors temporarily switched her to Ultomiris (ravulizumab).
The researchers identified several possible reasons for the episode, including the removal of Empaveli during plasma exchange, a blood transfusion that was not compatible with her blood type, treatment with intravenous immunoglobulin, and a possible infection.
“Our case illustrates that careful consideration be given to re-dosing complement inhibitors immediately following [therapeutic plasma exchange], to compensate for potential removal of the drug during the procedure, as well as avoiding plasma-incompatible transfusions in high-risk settings,” the researchers wrote.
The report, “Breakthrough Hemolysis in Paroxysmal Nocturnal Hemoglobinuria: Mechanistic Insights and Management Strategies,” was published in Transfusion.
Complement inhibitors
PNH is caused by mutations in the PIGA gene in blood-forming stem cells. These mutations cause blood cells to lack proteins that normally protect them from the complement system, part of the immune system that helps destroy potentially harmful cells.
Without that protection, the complement system can attack and destroy red blood cells (hemolysis). When destruction occurs within blood vessels, it is known as intravascular hemolysis and can lead to symptoms such as anemia (low red blood cell count), dark-colored urine, kidney damage, and potentially life-threatening blood clots.
Complement inhibitors have substantially changed PNH treatment. Treatment with inhibitors against the complement C5 protein, such as Soliris (eculizumab) and PiaSky (crovalimab), can control intravascular hemolysis but may not prevent red blood cell destruction outside the blood vessels.
Newer inhibitors that act earlier in the complement pathway, such as Empaveli, can suppress both forms of hemolysis. However, breakthrough hemolysis can still occur and may be especially severe if proximal complement suppression becomes incomplete.
Stem cell transplant replaces the blood-forming stem cells in people with PNH. The woman in the case report was preparing to undergo an allogenic stem cell transplant, which uses cells from a donor.
Blood testing before the transplant showed the 45-year-old woman had antibodies against HLA proteins on the donor’s cells, increasing the risk that her immune system would reject the transplant, so she began a desensitization protocol aimed at lowering these antibodies.
The protocol included therapeutic plasma exchange (TPE), a procedure that cleans the blood by removing and replacing the plasma — the liquid part of blood that contains water, salts, and proteins, including antibodies. At the time of her first TPE, she was being treated with antibiotics for a suspected skin infection around her catheter site.
The procedure was followed by intravenous immunoglobulin (IVIG), a treatment containing antibodies purified from healthy donors that can help neutralize harmful antibodies and reduce abnormal immune activity.
After the first TPE, the woman received a platelet transfusion for a dental procedure, followed by IVIG. About three hours after the platelet transfusion, during the IVIG infusion, she developed back pain and her urine turned dark red. Tests showed acute intravascular hemolysis, meaning red blood cells were being rapidly destroyed inside the blood vessels, and she also showed signs of acute kidney injury.
Since the platelet transfusion contained plasma that was not fully compatible with the woman’s blood type, the researchers said it may have helped trigger complement activation and hemolysis.
Her condition initially stabilized with intravenous fluids and another dose of Empaveli. She underwent a second TPE 48 hours later, followed again by IVIG and Empaveli. Severe hemolysis returned, accompanied by worsening kidney injury. Empaveli was stopped, and Ultomiris was started to help control the hemolysis.
During the woman’s first five days in the hospital, she needed seven red blood cell transfusions and one platelet transfusion. Her condition then began to improve, with less evidence of red blood cell destruction and no further worsening of kidney function. Because of the severe hemolysis and kidney problems, doctors stopped preparations for the transplant.
No single cause of the breakthrough hemolysis could be confirmed. The researchers said several factors may have contributed, including potential removal of Empaveli from the bloodstream during the TPE blood-cleaning procedure, a platelet transfusion with plasma not fully matched to her blood type, the IVIG antibody treatment itself, and an active or suspected infection.
The researchers said the case highlights the need to consider whether plasma exchange may reduce the amount of complement inhibitor in the bloodstream, and to limit exposure to incompatible plasma during transfusions.
Breakthrough hemolysis “remains a significant issue especially in PNH patients on [Empaveli],” the team wrote, adding that patients should be closely monitored so treatment can be adjusted quickly and factors that may worsen hemolysis can be addressed.
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