Sickle cell disease, transfusional iron overload, and an ABO-incompatible unrelated donor

Ferritin is an acute-phase reactant and correlates poorly with total body iron, so the liver iron concentration and cardiac T2* are more informative. A liver iron of 7 mg/g dry weight indicates moderate overload, and a cardiac T2* of 18 ms is in the mild-to-moderate range; values below 10 ms would signal substantial cardiac iron and high risk during conditioning. Obtain a cardiac evaluation with echocardiography, endocrine testing for diabetes and gonadal dysfunction, liver function tests and hepatitis serologies, and a detailed neurovascular history. Pulmonary function is normal, which is favorable.

Iron overload increases the risk of sinusoidal obstruction syndrome, infection, and cardiotoxicity. If transplantation is planned, start or continue chelation before conditioning if there is time, and consider pre-transplant erythrocytapheresis to lower HbS and iron burden. Avoid unnecessary transfusions that add iron. The conditioning regimen should be chosen with hepatic and cardiac reserve in mind. This assessment also frames consent: the family should understand that transplant is being offered to prevent recurrent stroke and sickle complications, not because she is currently unstable.

This is a major ABO mismatch: donor red cells are group A and the recipient has a high anti-A titer, so donor red cells in the graft could be hemolyzed. Reduce the isohemagglutinin titer before infusion, typically by plasma exchange or large-volume plasma exchange, with a common target below 1:16–1:32, and RBC-deplete the graft. Some centers also use donor-type plasma exchange after transplant. Post-transplant, transfuse group O red cells until donor erythroid engraftment is documented, then switch to group A; monitor the DAT and hemolysis markers. Platelet transfusions may need to be group O or AB depending on the product's plasma content.

The CMV mismatch is donor-positive to recipient-negative, which increases the risk of primary CMV infection. Use leukoreduced or CMV-safe blood products, monitor CMV PCR weekly during the at-risk period, and use preemptive therapy when viremia is detected. Some centers use prophylactic antiviral therapy. Counsel the family that these measures reduce but do not eliminate risk.

Explain that a matched unrelated donor transplant can stabilize or cure sickle cell disease and reduce recurrent stroke risk, but it carries real risks. Myeloablative busulfan-based conditioning offers robust engraftment but has greater toxicity; reduced-intensity or reduced-toxicity regimens are used in some centers and may lower organ toxicity but can increase graft failure or mixed chimerism. The choice depends on the center's experience and her organ function.

GVHD remains the major cause of transplant-related death with unrelated donors. Discuss acute and chronic GVHD, prophylaxis, and the possibility of chronic morbidity. Infertility is highly likely with myeloablative conditioning; offer sperm or oocyte cryopreservation before therapy if time permits, and discuss hormonal replacement. Also discuss gene therapy as an emerging alternative for sickle cell disease, with its own risks and limited long-term data. Frame the discussion around her goals, the family's values, and the alternative of continuing chronic transfusion with chelation. Document the consent discussion and involve a transplant psychologist.