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Determinar a gravidade da anemia falciforme é um desafio. Qualquer estimativa deve considerar o nível de hemoglobina fetal (a hemoglobina mais prevalente nos dois últimos trimestres de gestação em humanos), a presença de alfa-talassemia e a idade. A terapêutica com hidroxiureia (HU) provou, do ponto de vista da eficácia laboratorial e clínica, melhorar os sinais e sintomas da anemia falciforme, reduzindo consequentemente a taxa de mortalidade, principalmente através do aumento do nível de hemoglobina fetal (HbF) para um intervalo de 10 a 40%. Praticamente todos os doentes tratados terão o benefício associado à gravidade da doença. No entanto, existe uma variabilidade significativa entre os doentes, mesmo que seja administrada a dose máxima tolerada de HU, e alguns doentes terão uma mielossupressão excessiva com doses relativamente baixas.

Some authors (McDade, J and Ware, R.E.) hypothesised in 2009 that "genetic polymorphisms may play an important role in the observed inter-patient variability for both Hydroxyurea response and toxicity".

Em 2016, Habara, A. e Steinberg, M.H. afirmaram que a heterogeneidade fenotípica da doença falciforme era apenas parcialmente explicada pela variabilidade genética da expressão da hemoglobina fetal e pela co-herança da alfa-talassemia. Outros trabalhos propuseram e mais tarde demonstraram a associação inesperada do papel do BCL11A na expressão do gene da HbF.

In 2022, Sales RR. et al. published a systematic review to assess whether genetic polymorphisms affect HbF levels in patients with Sickle Cell Anaemia treated with HU. In addition, pathway analysis of single nucleotide polymorphisms (SNPs) was performed. The study was conducted at the Federal University of Minas Gerais, Belo Horizonte, Brazil. Of 1,597 articles initially identified, only seven cohort studies were included in the systematic review (five from the US and two from Brazil).

Of 1,597 articles initially identified, only seven cohort studies were included in the systematic review (five from the US and two from Brazil). The sample mean age ranged from 8.1 to 21 years. The mean dose of HU ranged from 19 to 27.1 +/- 4.3 mg/Kg, and the mean duration of treatment with HU ranged from 13.4 to 102 months.



The authors comment that "a complex regulation environment determines the HbF concentration in the blood as well as chromosome remodelling, transcription factors, erythropoiesis modulation, gene regulatory elements linked to the beta- globin gene cluster and the kinetics of erythroid cell differentiation and differential red cell survival. Consistent with this complex regulation apparatus, even with the restricted number of studies, our systematic review suggests that there is huge heterogeneity in genetic elements modulating the HbF levels in response to HU treatment". After extensive analysis, the authors concluded: "Changes in HbF levels in response to HU therapy are likely to be regulated by genetic variations on multiple loci, and there is evidence that the BCL11A gene affects HbF changes in patients with Sickle Cell Anaemia treated with Hydroxyurea". The induction of HbF is a powerful mechanism of action of HU; however, further research is needed to predict the success of treatment.

Tendo em conta que a resposta ao tratamento com HU é variável e parece ser uma caraterística hereditária, e que cerca de 25% dos doentes não respondem ao tratamento com HU ou são considerados metabolizadores pobres, estudos muito recentes que avaliam os determinantes genéticos da resposta à hidroxiureia, juntamente com a presença de variantes em genes responsáveis não só pelo metabolismo da HU, mas também pela regulação da expressão da HbF e pela proliferação de progenitores eritróides, podem ser a resposta para as diferenças nas respostas dos doentes à HU.

Ginette, C. et al. (2023) from Portugal have published that using HU in children with Sickle Cell Anaemia should be considered safe and beneficial. "Even in children considered non/poor responders, using HbF as the main criteria, significant changes were registered in almost the same parameters identified in responders, which also denotes clinical improvement in these patients".

Again, their conclusion was: "Several polymorphisms seem to be associated with response to Hydroxyurea treatment in Sickle Cell Anaemia patients as previously reported in other studies". On the other hand, apart from the co-inheritance of alfa-thalassaemia and phenotype elements determining HbF levels, environmental factors are undoubtedly crucial with socioeconomics and access to basic medical care explaining the considerable differences in outcomes between countries. In addition, studies indicate that the inflammatory profile can vary according to the genetic polymorphisms of the patient. The healthcare system should provide the necessary infrastructure to confirm new-borns’ diagnoses and provide appropriate counselling and treatment. The early diagnosis and treatment, as well as the follow-up with a multidisciplinary team, are fundamental to the survival rate and patients' quality of life.

As a final comment, the responsible healthcare provider should not withhold safe and effective therapy with Hydroxyurea from people with the disease while awaiting a better model to predict who will be the sickest of the sick. Every person with HbSS, as young as six to nine months of age, deserves disease-modifying therapy (Hydroxyurea); However, it can now be argued that every child with an HLA-matched sibling donor is a potential candidate for haematopoietic stem cell transplantation.

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Referências McDade,J. et.al. (2009). http://doi.org/10.1182/blood.V114.22.820.820 Habara,A. and Steinberg, MH.(2016). http://doi.org/10.1177/1535370216636726 Sales,RR. et.al. (2022). http://doi.org/10.3389/fphar.2021.779497 Ginete,C. et.al.(2023). http://doi.org/10.3390/ijms24108792 Written by: Enrique Blanco, MD. FCP.