In late October 2026, the investigators behind the HAT trial answered a cautionary review in the pages of the Annals of Translational Medicine, addressing a question that touches the heart of sickle cell care: what a rising share of sickle hemoglobin means when a patient takes hydroxyurea alongside regular transfusions. They agreed that a smaller transfusion volume should never justify tolerating a higher pre-transfusion HbS level, while explaining that the combination had nonetheless pushed total HbS percentages upward. Their reasoning rests on a quiet biological trade, in which the body's ow
Hydroxyurea plus transfusion raises total HbS% in sickle cell disease, and researchers say that may not mean more harm
Total HbS rises, but individual cells carry less of it
In late October 2026, the investigators behind the HAT trial answered a cautionary review in the pages of the Annals of Translational Medicine, addressing a question that touches the heart of sickle cell care: what a rising share of sickle hemoglobin means when a patient takes hydroxyurea alongside regular transfusions. They agreed that a smaller transfusion volume should never justify tolerating a higher pre-transfusion HbS level, while explaining that the combination had nonetheless pushed total HbS percentages upward. Their reasoning rests on a quiet biological trade, in which the body's own fetal hemoglobin keeps more of its cells alive between transfusions, each carrying a lighter load of the troublesome protein. Whether that trade is a gain or a hidden cost remains an open question, and the authors have offered the stored samples of their trial as a means of finding out.
A short letter in the Annals of Translational Medicine, published in late October 2026, takes up a question that looks like a technical footnote but sits close to how sickle cell disease is treated. When a patient takes hydroxyurea and also receives regular blood transfusions, what does a higher measured level of sickle hemoglobin actually mean?
The letter comes from the investigators behind the HAT trial, which combined hydroxyurea with chronic transfusion therapy. They are replying to a review by Rai, Capellera-Garcia and Manwani, who raised a caution about the combined approach. The trial authors agree with the central point: a lower transfusion volume alone should never justify accepting a higher pre-transfusion percentage of hemoglobin S, or HbS%.
They then clarify what the study did and did not do. The pre-transfusion HbS targets were not changed. What they did observe was a significant rise within individual participants, a median increase of 8.6% in HbS% while on the combination.
Their explanation is mechanistic. Hydroxyurea raises the body's own production of fetal hemoglobin. With more of it, more recipient red cells are still circulating when the next transfusion arrives, so the total HbS% climbs. The authors argue that the number hides something important: each recipient cell carries less HbS than it otherwise would, which may ease the disease's damage.
They do not claim the question is settled. Like Rai and colleagues, they call for more research to find the right balance between a modestly higher total HbS% and hydroxyurea's benefits. Banked samples from before and after patients began the combination are available to support that work.
The letter ends by widening the frame to the growing pipeline of disease-modifying agents for sickle cell disease, and to the value of testing how such agents interact with established treatments directly. The piece was commissioned by the journal rather than externally peer reviewed. The trial was funded by the AABB Foundation and the Clinical and Translational Science Institute at Children's National, and the authors declare no conflicts of interest. The test to watch is whether anyone uses those samples to check whether a higher total HbS under hydroxyurea truly means less HbS per cell, and no greater harm.
A short letter in the Annals of Translational Medicine, published in late October 2026, answers a question that sounds like a technical footnote but sits close to the center of how sickle cell disease is treated: when a patient takes hydroxyurea and also receives regular blood transfusions, what does a higher measured level of sickle hemoglobin really mean?
The letter is the reply of the investigators behind the HAT trial, which combined hydroxyurea with chronic transfusion therapy. It responds to a review by Rai, Capellera-Garcia and Manwani, who surveyed the literature on this combined approach and raised a caution. The trial authors thank them and agree with the central point: a lower transfusion volume, taken alone, should not be a reason to accept a higher pre-transfusion percentage of hemoglobin S, or HbS%.
The trial authors then clarify what they did and did not do. Their study did not change the pre-transfusion HbS targets. What they did observe was a significant rise within individual participants: a median increase of 8.6% in HbS% while on the combination. The trial itself, led by Nickel and colleagues, was published in Transfusion in 2025 under the title "Adding hydroxyurea to chronic transfusion therapy for sickle cell anemia reduces transfusion burden."
Their explanation is mechanistic. Hydroxyurea increases the body's own production of fetal hemoglobin, or HbF. With more HbF in the patient's own red cells, more of those recipient cells are still present when the next scheduled transfusion arrives. The total measured HbS% therefore climbs. But the authors argue the number alone hides something: each individual recipient red cell carries less HbS than it otherwise would, which could reduce the pathology of the disease.
They do not claim the matter is settled. Echoing Rai and colleagues, they say more research is needed to find the right balance between tolerating a modestly higher total HbS% and capturing hydroxyurea's rheological and anti-inflammatory benefits. To support that work, they note that banked research samples from before and after patients started the combination are available from the trial.
The letter closes by widening the frame. A growing number of disease-modifying agents are under investigation for sickle cell disease, and understanding how they interact with established approaches, chronic transfusion among them, will matter. The authors say the HAT trial shows the value of testing combination strategies directly.
Some context on the document itself: the piece was commissioned by the journal's editorial office and did not go through external peer review. The trial was funded by the AABB Foundation, formerly the National Blood Foundation, through its early-career research grants, and by the Clinical and Translational Science Institute at Children's National, supported by the NIH National Center for Advancing Translational Sciences. The authors declare no conflicts of interest.
What to watch for is whether anyone uses the banked samples to test the authors' argument, that a higher total HbS% under hydroxyurea reflects less HbS per cell rather than greater harm.
Citations marquantes
The reduction in transfusion volume should not, on its own, justify tolerating a higher pre-transfusion HbS%, though the study did not alter targets (paraphrase).— HAT trial authors, Annals of Translational Medicine
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