Sickle cell diseaseHBB

In brief

What it is

Haemoglobin is four protein chains folded around four iron atoms, and in an adult two of those chains are β-globin, written by HBB on the short arm of chromosome 11. In sickle cell disease one base of that gene is changed — an adenine for a thymine — so the sixth residue of β-globin is valine where it should be glutamate. Glutamate carries a negative charge and sits comfortably on the surface of the molecule. Valine is greasy, and the patch it leaves is hydrophobic: deoxygenated haemoglobin molecules carrying it stack into long fibres ^1,2.

So the disease is a polymer. Fibres grow inside the red cell and distort it from within, and the crescent on the blood film is the shape a cell takes when it is being pushed out of true from the inside. Those cells break open, and they also jam. The primer that defines the field lists three processes rather than one: polymerisation with haemolysis, vaso-occlusion, and activation of the immune system ².

There is more than one genotype under the name. Two copies of the sickle change is sickle cell anaemia, HbSS, and the most severe form. One sickle gene with a haemoglobin C gene, or with a β-thalassaemia gene, gives disease that is usually milder and still real. One sickle gene with one normal gene is sickle cell trait, which is not the disease, and the difference between those last two sentences is the whole of the next paragraph but one ^2,7.

The numbers are large and rising. 7.74 million people were living with sickle cell disease in 2021, 41% more than in 2000, and about 515,000 children are born with it each year — up 13.7%, driven mostly by population growth in western and central sub-Saharan Africa and the Caribbean ³. Part of the rise is a success rather than a failure: as child mortality falls in high-burden countries, babies who once died undiagnosed in infancy now live long enough to be counted ¹¹.

How the understanding got here

This disease has an unusual history, in that the cause was known long before anything could be done about it. Herrick described the cells in 1910. Pauling and Itano showed the protein was abnormal in 1949, four years before the structure of DNA was published, and Ingram found the single substitution in 1957. The first drug shown to change the course of the illness was reported in 1995 — thirty-eight years after the lesion had been named ^1,4,12,15.

The gap is not a mystery. You cannot un-substitute an amino acid in a protein the marrow is making by the kilogram, so everything that worked, worked around the lesion. Penicillin covered the spleen the disease had already destroyed. Transfusion diluted the sickle cells with normal ones. Hydroxyurea raised fetal haemoglobin, which cannot join the polymer. The treatments approved at the end of 2023 are the same idea carried to its end: break the switch that turns fetal haemoglobin off after birth, or add a β-globin gene that will not sickle ^5,6,12,14,16.

Part of the delay was not scientific. Around 80% of the world's severe inherited haemoglobin disorders are born in low- and middle-income countries, which is not where the research money is ¹¹. Nearly every trial that built the modern standard of care was run in the United States or Europe; the first large randomised trial of hydroxyurea in sub-Saharan Africa reported in 2019 ^12,17.

What it does to the body

Two engines run at once and they damage different things. Haemolysis empties red cells into the plasma, and free haemoglobin consumes nitric oxide, the molecule that tells a blood vessel to relax; the vasculature is held tighter than it should be. Vaso-occlusion is the other engine: rigid cells, activated white cells and platelets plug small vessels, the tissue downstream goes short of oxygen, and that is the pain. Immune activation sits across both ².

The pain is the disease as patients live it, and it is the outcome almost every trial counts. It is also the part of the disease with the thinnest evidence behind its treatment. The American Society of Hematology's 2020 guideline on acute and chronic sickle cell pain reached 18 recommendations and had to make most of them conditional, because the certainty of the evidence was low and benefits and harms were closely balanced; the panel closed by asking for randomised trials of chronic opioid therapy, of non-opioid drugs and of non-drug approaches ²⁸.

Over years the damage stops being episodic and becomes structural. Chronic complications can reach every organ, chronic kidney disease among the commonest, and they accumulate while the acute events are being managed ². Under United States standard of care a Markov model built for a cost-effectiveness submission put the mean age at death at 43.6 years — a modelled figure, not a measured one, and still the number the field argues around ⁸.

Where the damage lands, organ by organ:

Spleen

The organ that filters deformed red cells is destroyed by them. Repeated infarction leaves most children functionally asplenic in early childhood, which is why a trial of twice-daily penicillin V in 215 children under three cut pneumococcal infection by 84% and was stopped eight months early, with three deaths in the placebo arm and none on penicillin ^2,14.

Brain

Stroke in childhood, and silent infarcts that appear only on imaging. Transcranial Doppler finds the children at risk and transfusion prevents the stroke; stopping the transfusion undoes the protection within months, and in carefully selected children hydroxyurea can hold the velocities instead ^16,18,19.

Lungs

Acute chest syndrome — fever, chest pain and a new infiltrate — is one of the commonest ways the disease kills, and one of the clearest places a treatment shows up. In the hydroxyurea trial episodes fell from 51 to 25 ^2,12.

Kidneys

Chronic kidney disease is among the commonest chronic complications ². The kidney also carries the starkest fact about the trait: renal medullary carcinoma is now defined by it. The 2022 WHO classification reserves that name for tumours arising in people with sickle trait or disease and classes morphologically identical SMARCB1-deficient tumours without a haemoglobinopathy separately ²⁹.

Bone and marrow

Infarction of marrow is where much of the pain originates, and in infants it presents in the hands and feet. Dactylitis was one of the outcomes the malaria chemoprophylaxis trials counted, which is a good indication of how early in life this part of the disease starts ^2,30.

The red cell membrane

Before any parasite arrives, the sickle cell is already mechanically spent. Ektacytometry across normal, trait and HbSS cells shows reduced deformability under both shear and osmotic gradients, raised point-of-sickling values, altered osmotic fragility, loss of surface area and shedding of membrane as extracellular vesicles — a spectrum, worst by far in HbSS ³¹.

What is done about it

Four things change the course of the disease, and they are not equally available anywhere: hydroxyurea, transfusion, haematopoietic stem cell transplantation, and since 2023 gene therapy. Everything else is supportive and most of it matters — penicillin and vaccination in early childhood, folate, analgesia, hydration, and the treatment of each complication as it arrives ^2,14.

Two drugs approved on surrogate endpoints in 2019 have since failed to hold. They are set out below rather than quietly dropped, because a reader who was prescribed one of them is owed an account of what happened ^13,25.

Each panel below takes one treatment and the trial behind it.

What else gets in

Two parasites live inside the red blood cell, and sickle cell disease has a strange relationship with both. Plasmodium falciparum is the reason the gene exists at all. Babesia, its close relative in the same phylum, arrives in the transfusions that treat the disease ^9,37.

The pattern is the same for both, and it is counter-intuitive twice over. The sickle red cell is a poor host, so parasite numbers stay low. The patient is in more danger anyway — because what threatens life here is not the parasite burden but the anaemia a small burden can precipitate in someone with no haematological reserve and, usually, no working spleen ^10,31,38.

How it is found and followed

The diagnosis is a laboratory one and it is not technically hard: separate the haemoglobins and see which are present. The hard parts are getting the test to the newborn, and getting the newborn into care afterwards ^2,14.

Universal newborn screening exists in some countries and is difficult to deliver in exactly the low-income, high-burden settings where most affected children are born. Screening is also only worth as much as what follows it; the reason it became standard is that there was something to give the child once it was found ^2,11,14.

After diagnosis, the test that changes the most is the one for stroke risk. The test most often not thought of is the one for a parasite ^16,37.

• Haemoglobin analysisHigh-performance liquid chromatography, isoelectric focusing or electrophoresis, which separate HbS from HbA, HbC and HbF and so distinguish disease from trait ².Newborn screening, which is universal in some countries and hard to deliver where the disease is commonest ².Definitive for genotype.A screening programme is only as good as the follow-up attached to it: the penicillin that makes screening worth doing has to reach the child by about four months ¹⁴.
• Transcranial DopplerUltrasound of blood velocity in the internal carotid and middle cerebral arteries, in children ¹⁶.To find the children at high risk of a first stroke, defined as a time-averaged mean velocity of 200 cm per second or more ¹⁶.In the trial that established it, transfusing the children it flagged cut first strokes by 92% — eleven cerebrovascular events in the standard-care arm against one — and the trial was stopped early ¹⁶.It identifies risk, it does not treat it; the benefit came from the transfusion programme that followed, with everything chronic transfusion brings ^16,32.
• Blood film and parasite testingIn a transfused patient with unexplained haemolysis, the film is read for intra-erythrocytic parasites and sent for Babesia nucleic acid testing ^32,37.Because transfusion-transmitted babesiosis presents almost exactly like a delayed haemolytic transfusion reaction ³⁷.Parasitaemia can be under 0.5% and still be the cause; serology and PCR settle it ³².Screening is aimed at Babesia microti. A patient with sickle cell disease has been infected with Babesia duncani, which those tests do not detect ⁴².

The complications, one by one

What was believed, and is not

Nothing in this entry is more instructive than the list of things that were confidently believed, written into guidelines or approvals, and then measured. Two are drugs that reached patients. Two are facts about how dangerous one copy of the gene is and how many people the disease kills. One is a treatment duration, and one is a question that is still open while being cited as settled ^3,7,13,25.

What is strange about it

The gene is common because it was useful. One copy made a child more likely to survive falciparum malaria, so in malarial regions the change spread, and two copies is the bill that arrives. It is the textbook case of balanced polymorphism, and the textbook usually skips the part where the protection is real, the disease is real, and nobody chose either ^9,10.

Pauling and Itano published Sickle cell anemia, a molecular disease in 1949, four years before the structure of DNA was described. The idea of a disease caused by a defect in one molecule existed before anybody knew what a gene was made of ⁴.

The body keeps a spare haemoglobin and then stops making it. Fetal haemoglobin cannot join the sickle polymer, and almost every treatment that has worked in sixty years is a different way of getting more of it: hydroxyurea raises it with a chemotherapy drug nobody designed for this, and gene editing raises it by deliberately breaking the enhancer of the gene whose job is to switch it off ^5,12.

The cheapest interventions are the hardest to deliver. Penicillin for toddlers costs almost nothing and cut deaths in a randomised trial in 1986. Hydroxyurea is a generic tablet that cut deaths from 3.6 to 1.1 per 100 patient-years across four African countries in 2019. The donor screening that would prevent the transfusion-transmitted co-infection on this page does not exist in most of the countries where the disease does ^14,17,45.

And the measure everyone argues about is a word rather than a number. Crisis rates are the currency of every trial here, and the trials each minted their own ³⁶.

Where it connects

Sources

45 sources, numbered as they are cited. Every one was checked against PubMed or its publisher before it was cited here; the note under each says what it shows and what it does not.

1. 1
   Ingram VM. Gene mutations in human haemoglobin: the chemical difference between normal and sickle cell haemoglobin.Nature · 1957 · 180(4581):326–328doi:10.1038/180326a0 · PMID 13464827

   One residue, located: valine where β-globin should carry glutamic acid.

2. 2
   Kato GJ, Piel FB, Reid CD, et al. Sickle cell disease.Nat Rev Dis Primers · 2018 · 4:18010doi:10.1038/nrdp.2018.10 · PMID 29542687

   The primer the field works from: polymerisation, haemolysis, vaso-occlusion, immune activation, and the complication list.

3. 3
   GBD 2021 Sickle Cell Disease Collaborators. Global, regional, and national prevalence and mortality burden of sickle cell disease, 2000–2021: a systematic analysis from the Global Burden of Disease Study 2021.Lancet Haematol · 2023 · 10(8):e585–e599doi:10.1016/S2352-3026(23)00118-7 · PMID 37331373

   The prevalence and birth figures, and the eleven-fold correction between cause-specific and total mortality.

4. 4
   Pauling L, Itano HA, Singer SJ, Wells IC. Sickle cell anemia, a molecular disease.Science · 1949 · 110(2865):543–548doi:10.1126/science.110.2865.543 · PMID 15395398

   The phrase in the title was new, and it arrived four years before the double helix.

5. 5
   Frangoul H, Locatelli F, Sharma A, et al. Exagamglogene autotemcel for severe sickle cell disease.N Engl J Med · 2024 · 390(18):1649–1662doi:10.1056/NEJMoa2309676 · PMID 38661449

   CRISPR-Cas9 on the BCL11A enhancer; 29 of 30 evaluable patients crisis-free for at least 12 months.

6. 6
   Kanter J, Walters MC, Krishnamurti L, et al. Biologic and clinical efficacy of LentiGlobin for sickle cell disease.N Engl J Med · 2022 · 386(7):617–628doi:10.1056/NEJMoa2117175 · PMID 34898139

   Lovo-cel: a lentiviral anti-sickling β-globin; all 25 evaluable patients free of severe vaso-occlusive events. Funded by Bluebird Bio.

7. 7
   Nelson DA, Deuster PA, Carter R, et al. Sickle cell trait, rhabdomyolysis, and mortality among U.S. Army soldiers.N Engl J Med · 2016 · 375(5):435–442doi:10.1056/NEJMoa1516257 · PMID 27518662

   47,944 soldiers: no excess death (HR 0.99), and a rhabdomyolysis risk (HR 1.54) the same size as smoking.

8. 8
   Lopez A, Gargano M, Yang H, et al. Cost-effectiveness of exagamglogene autotemcel in sickle cell disease with recurrent vaso-occlusive crises in the United States.J Med Econ · 2026 · 29(1):547–562doi:10.1080/13696998.2026.2624971 · PMID 41730016

   A manufacturer-funded Markov model: mean age at death 74.5 against 43.6, and $3.34M less lifetime cost. A model, not an observation.

9. 9
   Harp KO, Botchway F, Dei-Adomakoh Y, et al. Hemoglobin genotypes modulate inflammatory response to Plasmodium infection.Front Immunol · 2020 · 11:593546doi:10.3389/fimmu.2020.593546 · PMID 33424841

   HbS and HbC both reduce the severity and fatality of malaria, by a mechanism still described as poorly understood.

10. 10
    Uyoga S, Olupot-Olupot P, Connon R, et al. Sickle cell anaemia and severe Plasmodium falciparum malaria: a secondary analysis of the Transfusion and Treatment of African Children trial (TRACT).Lancet Child Adolesc Health · 2022 · 6(9):606–613doi:10.1016/S2352-4642(22)00153-5 · PMID 35785794

    33% against 78% parasitaemia, PfHRP2 8 against 346 ng/mL, no excess mortality — and a warning about the anaemic crisis a light infection can cause.

11. 11
    Weatherall DJ. The inherited diseases of hemoglobin are an emerging global health burden.Blood · 2010 · 115(22):4331–4336doi:10.1182/blood-2010-01-251348 · PMID 20233970

    Where the burden is, and why falling child mortality makes the counted burden rise.

12. 12
    Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia.N Engl J Med · 1995 · 332(20):1317–1322doi:10.1056/NEJM199505183322001 · PMID 7715639

    The Multicenter Study of Hydroxyurea. 299 adults, stopped early; crises 2.5 against 4.5, acute chest syndrome 25 against 51.

13. 13
    Kim MS, Prasad V. FDA approval based on novel surrogate endpoints: lessons from the voluntary withdrawal of voxelotor in sickle cell disease.Am J Hematol · 2025 · 100(5):922–924doi:10.1002/ajh.27635 · PMID 39981741

    The approval rested on a haemoglobin rise. The withdrawal is the lesson about approving on one.

14. 14
    Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral penicillin in children with sickle cell anemia. A randomized trial.N Engl J Med · 1986 · 314(25):1593–1599doi:10.1056/NEJM198606193142501 · PMID 3086721

    215 children under three; 84% fewer pneumococcal infections, three deaths on placebo and none on penicillin, stopped eight months early.

15. 15
    Herrick JB. Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. 1910.Reprinted Yale J Biol Med · 2001 · 74(3):179–184PMID 11501714

    The first description, in Walter Clement Noel, a dental student from Grenada. A shape, recorded.

16. 16
    Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography.N Engl J Med · 1998 · 339(1):5–11doi:10.1056/NEJM199807023390102 · PMID 9647873

    STOP. 130 children at 200 cm/s or above; 11 cerebrovascular events against 1, a 92% reduction, stopped early.

17. 17
    Tshilolo L, Tomlinson G, Williams TN, et al. Hydroxyurea for children with sickle cell anemia in sub-Saharan Africa.N Engl J Med · 2019 · 380(2):121–131doi:10.1056/NEJMoa1813598 · PMID 30501550

    REACH. 635 children in four countries: pain, infection, transfusion, malaria and death all down, malaria halved.

18. 18
    Adams RJ, Brambilla D; Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) Trial Investigators. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease.N Engl J Med · 2005 · 353(26):2769–2778doi:10.1056/NEJMoa050460 · PMID 16382063

    What happens when the transfusions stop: 14 of 41 reverted to high-risk velocities and two had strokes, at a mean of 4.5 months.

19. 19
    Ware RE, Davis BR, Schultz WH, et al. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia — TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial.Lancet · 2016 · 387(10019):661–670doi:10.1016/S0140-6736(15)01041-7 · PMID 26670617

    138 cm/s against 143: non-inferior and post-hoc superior, in children already stabilised and without severe vasculopathy.

20. 20
    Niihara Y, Miller ST, Kanter J, et al. A phase 3 trial of L-glutamine in sickle cell disease.N Engl J Med · 2018 · 379(3):226–235doi:10.1056/NEJMoa1715971 · PMID 30021096

    The approval trial. 230 patients, median crises 3.0 against 4.0 (P=0.005); funded by Emmaus Medical, which sells it.

21. 21
    Wang J, Lu H. Benefit-risk of voxelotor, crizanlizumab, and l-glutamine in sickle cell disease: a systematic review.Am J Med Sci · 2026doi:10.1016/j.amjms.2026.08.010 · PMID 42628795

    Searched to April 2026, eight studies, and no pooled estimate possible — the honest reading of all three drugs at once.

22. 22
    Opoka RO, Bangirana P, Idro R, et al. Lack of mortality in 22 children with sickle cell anemia and severe malarial anemia.Pediatr Blood Cancer · 2018 · 65(1)doi:10.1002/pbc.26745 · PMID 28834130

    The series that contradicted the retrospective reports: no excess mortality at admission or at two years.

23. 23
    Alkindi S, Al Subhi A, Pathare A. Rapid withdrawal of voxelotor can precipitate sickle cell disease related crisis.Ann Hematol · 2025 · 104(9):4855–4857doi:10.1007/s00277-025-06503-x · PMID 40627162

    Eight of 11 patients crised within a median of 4.7 days of stopping; five needed transfusion.

24. 24
    Andemariam B, Shah N, Ershler WB, et al. Safety and effectiveness of voxelotor in individuals with sickle cell disease in the RETRO and PROSPECT US registries.Blood Adv · 2026 · 10(9):3032–3043doi:10.1182/bloodadvances.2025018992 · PMID 41701977

    The surrogate behaved and the pain rates did not follow. PROSPECT had enrolled 265 participants when the drug was withdrawn in September 2024.

25. 25
    Abboud MR, Cançado RD, De Montalembert M, et al. Crizanlizumab with or without hydroxyurea in patients with sickle cell disease (STAND): primary analyses from a placebo-controlled, randomised, double-blind, phase 3 trial.Lancet Haematol · 2025 · 12(4):e248–e257doi:10.1016/S2352-3026(24)00384-3 · PMID 40088922

    252 patients, 21 countries: 2.49 and 2.04 crises a year against 2.30 on placebo, both p>0.999. The confirmatory trial said no.

26. 26
    Mendez-Marti S, Thein SL. Now where do we STAND with crizanlizumab?Lancet Haematol · 2025 · 12(4):e232–e233doi:10.1016/S2352-3026(25)00033-X · PMID 40088923

    The commentary printed alongside STAND, asking the question in its title.

27. 27
    Frangoul H, de la Fuente J, Chopra Y, et al. Exa-cel in children with transfusion-dependent β-thalassemia or sickle cell disease.N Engl J Med · 2026 · 395(10):947–958doi:10.1056/NEJMoa2603387 · PMID 42274009

    Ages 5 to 11. Eight of eight followed at least 16 months crisis-free; every child had a grade 3 or 4 adverse event.

28. 28
    Brandow AM, Carroll CP, Creary S, et al. American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain.Blood Adv · 2020 · 4(12):2656–2701doi:10.1182/bloodadvances.2020001851 · PMID 32559294

    18 recommendations, most of them conditional on low-certainty evidence. The commonest symptom has the thinnest evidence base.

29. 29
    Luo W, Zheng Y, Huang W, et al. Renal medullary carcinoma and SMARCB1-deficient medullary-like renal cell carcinoma.Ann Diagn Pathol · 2026 · 82:152621doi:10.1016/j.anndiagpath.2026.152621 · PMID 41666682

    The 2022 WHO classification reserves the name for people with sickle trait or disease, and separates the identical tumour without one.

30. 30
    Oniyangi O, Omari AA. Malaria chemoprophylaxis in sickle cell disease.Cochrane Database Syst Rev · 2019 · 2019(11):CD003489doi:10.1002/14651858.CD003489.pub2 · PMID 31681984

    Beneficial, on two trials and 223 children — and carrying an update-pending notice since 2019.

31. 31
    Beri D, Rodriguez M, Singh M, et al. Babesiosis and sickle red blood cells: loss of deformability, altered osmotic fragility, and hypervesiculation.Blood · 2025 · 145(19):2202–2213doi:10.1182/blood.2024027602 · PMID 39869831

    Ektacytometry across AA, AS and SS cells: the mechanical cost of infection on a spectrum, worst in SS, which is why the illness is hyperhaemolysis rather than a fever.

32. 32
    Costa V, Mercure-Corriveau N, Gourneau J, et al. Transfusion-transmitted babesiosis in a patient with sickle cell disease undergoing chronic red cell exchange.Transfusion · 2023 · 63(3):652–655doi:10.1111/trf.17244 · PMID 36637364

    65 units in six months, 58 screened, one seropositive donor among the seven that were not, and parasitaemia under 0.5%.

33. 33
    Turkistani S, AlHarbi A, Khan M, et al. Real-world experience of L-glutamine in sickle cell disease: a retrospective observational study.Pharmacy (Basel) · 2025 · 13(3):84doi:10.3390/pharmacy13030084 · PMID 40560029

    15 patients on maximum tolerated hydroxyurea: crises 4 to 3 at P=0.44, reticulocytes up 61.9%, cost above SAR 2 million a year.

34. 34
    Ebeid FSE, Aly NH, Shaheen NM, et al. Safety and efficacy of L-glutamine in reducing the frequency of acute complications among patients with sickle cell disease: a randomized controlled study.Ann Hematol · 2024 · 103(9):3493–3506doi:10.1007/s00277-024-05877-8 · PMID 39028356

    60 Egyptian children on stable hydroxyurea; fewer cumulative crises (P=0.008) and hospitalisations (P<0.001) over 24 weeks.

35. 35
    Shakibazad N, Momenzadeh M, Amiri B, et al. The GLOBE trial: efficacy and safety of L-glutamine plus hydroxyurea versus hydroxyurea alone in sickle cell anemia — a double-blind, randomized study.Turk J Haematol · 2026 · 43(2):155–162doi:10.4274/tjh.galenos.2026.09709 · PMID 41664386

    53 children, six months: crises 1.00 against 1.65, acute chest syndrome 0.19 against 0.77, HbF up 6.2% against 1.6%.

36. 36
    Frangoul H, Locatelli F, Eckrich MJ, et al. Impact of different definitions of vaso-occlusion on efficacy assessments in sickle cell disease clinical trials.Adv Ther · 2025 · 42(5):2490–2499doi:10.1007/s12325-025-03162-2 · PMID 40146367

    Seven trials, seven definitions of the same word. Why the crisis rates on this page cannot be compared with each other.

37. 37
    Karkoska K, Louie J, Appiah-Kubi AO, et al. Transfusion-transmitted babesiosis leading to severe hemolysis in two patients with sickle cell anemia.Pediatr Blood Cancer · 2018 · 65(1)doi:10.1002/pbc.26734 · PMID 28766838

    The diagnostic trap: it looks like a delayed haemolytic transfusion reaction, and that diagnosis is treated with immunosuppression.

38. 38
    Cursino-Santos JR, Singh M, Senaldi E, et al. Altered parasite life-cycle processes characterize Babesia infection in human sickle cell anemia.Haematologica · 2019 · 104(11):2189–2199doi:10.3324/haematol.2018.214304 · PMID 30923098

    The parasite does badly in HbSS cells and normally in trait cells: the malaria shield does not transfer to the cousin.

39. 39
    Frimpong A, Thiam LG, Arko-Boham B, et al. Safety and effectiveness of antimalarial therapy in sickle cell disease: a systematic review and network meta-analysis.BMC Infect Dis · 2018 · 18(1):650doi:10.1186/s12879-018-3556-0 · PMID 30541465

    912 children, seven regimens: parasitaemia and clinical malaria down, hospitalisation, transfusion, crisis and mortality unchanged.

40. 40
    Amato M, Siller A, Schennach H. Babesiosis and its significance in transfusion medicine from a European point of view.Transfus Med Hemother · 2025 · 53(1):23–43doi:10.1159/000550246 · PMID 41684703

    Chronic asymptomatic infection for up to two years, donor seroprevalence 0.38% in endemic US regions, the FDA's 2019 regional testing recommendation, and a mortality approaching 20% in immunocompromised recipients.

41. 41
    Tonnetti L, Eder AF, Dy B, et al. Transfusion-transmitted Babesia microti identified through hemovigilance.Transfusion · 2009 · 49(12):2557–2563doi:10.1111/j.1537-2995.2009.02317.x · PMID 19624607

    18 definite or probable infections in two years with five deaths; two recipients had sickle cell disease and four were asplenic.

42. 42
    Bloch EM, Herwaldt BL, Leiby DA, et al. The third described case of transfusion-transmitted Babesia duncani.Transfusion · 2012 · 52(7):1517–1522doi:10.1111/j.1537-2995.2011.03467.x · PMID 22168221

    HbSS, B. microti tests negative, B. duncani at 1:1024. Screening aimed at one species misses the other.

43. 43
    Yi W, Bao W, Rodriguez M, et al. Robust adaptive immune response against Babesia infection marked by low parasitemia in a murine model of sickle cell disease.Blood Adv · 2018 · 2(23):3462–3478doi:10.1182/bloodadvances.2018026468 · PMID 30518538

    Low parasitaemia and a competent adaptive response in sickle cell mice, despite disorganised splenic architecture.

44. 44
    Vannier E, Hunfeld KP, Smith RP, Krause PJ. Management of human babesiosis — approaches and perspectives.Expert Rev Anti Infect Ther · 2025 · 23(9):739–752doi:10.1080/14787210.2025.2526843 · PMID 40596759

    Atovaquone with azithromycin, or clindamycin with quinine; and red cell exchange, whose efficacy and indications the authors list as an open question.

45. 45
    Bloch EM, Drews SJ, Jacobs JW. Infectious risks of transfusion: a 10-year look back and perspectives.Transfus Clin Biol · 2026doi:10.1016/j.tracli.2026.09.004 · PMID 42749151

    Ten years of making transfusion safer — and the statement that none of it reaches the low- and middle-income countries where most of these patients are transfused.