Effect of hydroxyurea therapy on intravascular hemolysis and endothelial dysfunction markers in sickle cell anemia patients

Chenou, Francine; Hounkpe, Bidossessi Wilfried; Domingos, Igor de Farias; Tonassé, Wouitchékpo Vincent; Batista, Thais Helena Chaves; Santana, Rodrigo Marcionilo; Arcanjo, Gabriela da Silva; Alagbe, Adekunle Emmanuel; Araújo, Aderson da Silva; Lucena-Araújo, Antonio R.; Bezerra, Marcos André Cavalcanti; Costa, Fernando Ferreira; Sonati, María de Fátima; Paula, Erich Vinícius De; Santos, Magnun Nueldo Nunes

doi:10.1007/s00277-021-04636-3

Cited by 6 publications

(5 citation statements)

References 29 publications

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“…Discontinuing the HU treatment may activate the bone marrow. However, our unexpected findings regarding this group are either suggestive of a possible hemolysis rise, showing the beneficial effects of HU on intravascular hemolysis markers in SCA patients, 34,35 or it resulted from our small number of non‐adherent cases. Furthermore, Black and Pardo children presented higher HbA2 and HbSS, and lower MCV, MCH and RET‐He.…”

Section: Discussionmentioning

confidence: 79%

Advanced clinical parameters: A complementary hydroxyurea adherence evaluation in sickle cell anemia treatment

Moreira

Lessa

Rocha

et al. 2022

European J of Haematology

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Objectives Given the complex pathology of sickle cell anemia (SCA) and low adherence to hydroxyurea (HU) treatment, there is a need to seek parameters that identify recent changes in patient status. The advanced clinical parameters (ACPs) allow an early analysis of hematopoiesis. We aimed to draw the demographic profile of non‐adherent SCA patients and to verify the use of ACPs as a measure of HU treatment adherence. Method In a cross‐sectional study, we divided 83 SCA subjects treated with HU into Children (<12 years old) and adolescents/adults (≥12 years old). Their hemogram with the ACPs, electronic medical charts and pharmacy claim data were analyzed. Results Non‐adherent ≥12 years old patients had significantly increased WBC, absolute neutrophil, lymphocyte, monocyte, and basophil counts, RBC, RET, RDW, and PLT, and significantly decreased MCV and MCH. Subjects in the adolescent/adult group with IG† ≥0.035 cells/mm3 had the RR for non‐adherence increased by 4.6 times (p = .014), and the systemic immune inflammation index (SII) of non‐adherent patients was also significantly higher (p = .042). Conclusion IG† presents clinical utility in early identification of non‐adherence to HU, especially when combined with other parameters, suggesting the evaluation of ACPs in laboratory routine, as they can be easily implemented.

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Section: Discussionmentioning

confidence: 79%

Advanced clinical parameters: A complementary hydroxyurea adherence evaluation in sickle cell anemia treatment

Moreira

Lessa

Rocha

et al. 2022

European J of Haematology

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“…Gender is therefore a valuable factor in the risk stratification of SCD at diagnosis, with the possibility to guide therapeutic decisions [45]. HU has many characteristics of an ideal drug for SCD [10, [50][51][52][53][54][55][56][57][58][59][60], but concerns regarding adverse effects on fertility have persisted [25,31,35,[39][40][41][42][43][44][61][62][63][64]. In this systematic review and meta-analysis, the impact of HU on fertility was comparable in male and female SCD patients.…”

Section: Discussionmentioning

confidence: 81%

Effects of hydroxyurea on fertility in male and female sickle cell disease patients. A systemic review and meta-analysis

Sewaralthahab,

Alsubki,

Alhrabi

et al. 2024

PLoS ONE

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Background Evidence supports the benefits of hydroxyurea (HU) in adults with sickle cell disease (SCD), but reservations remain due to long-term concerns of fertility. Retrospective analysis of clinical records of SCD patients (haemoglobin SS genotype) have identified gender-related differences in disease progression. This could inform risk stratification during SCD at diagnosis with the possibility to guide therapeutic decisions. Methods This systemic review and meta-analysis evaluated fertility parameters in both children (aged ≥ 6 years) and adults with SCD receiving HU therapy. Studies were sourced from PubMed and EMBASE from inception to July 2023. A total of 160 potentially relevant articles were identified. Results Four studies were included that evaluated the effects of HU on sperm parameters in males. A further 4 studies assessed anti-mullerian hormone (AMH) levels and ovarian reserves in females. Differences from baseline values were used to identify compromised fertility. Amongst males, HU treatment negatively impacted the concentration of spermatozoa (MD = -15.48 million/mL; 95% CI: [-20.69, -10.26]; p< 0.001), which continued following treatment cessation (MD = -20.09 million/mL; 95% CI: [-38.78, -1.40]; P = 0.04). HU treatment also led to lower total sperm counts (MD = -105.87 million; 95% CI: [-140.61, -71.13]; P< 0.001) which persisted after treatment (MD = -53.05 million; 95% CI: [-104.96, -1.14]; P = 0.05). Sperm volume, initial forward motility and morphology were unaffected by HU treatment. In females, HU treatment decreased the mean AMH levels 1.83 (95% CI [1.42, 2.56]. A total of 18.2.% patients treated with HU showed reduced ovarian reserves. Interpretation & conclusions This systemic review and meta-analysis suggest that the use of HU for SCD impacts seminal fluid parameters in males and can diminish AMH levels and ovarian reserves in females.

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“…25 Despite this recycling mechanism, it has been demonstrated that upregulation of endogenous HPX is not sufficient to provide enough levels to cope with massive amounts of heme released in conditions associated with intravascular hemolysis, in which HPX levels are markedly decreased. [26][27][28][29] Given the deleterious effects of heme in these conditions, demonstrated mainly in animal models, 16,17 but also in human studies, 30 a strategy capable of enhancing the efficiency of endogenous heme-sequestering mechanisms could be attractive, particularly for patients with congenital conditions.…”

Section: Discussionmentioning

confidence: 99%

Safety and feasibility of the gene transfer of hemopexin for conditions with increased free heme

Lima

Hounkpe

Moraes

et al. 2023

Exp Biol Med (Maywood)

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Heme is a fundamental molecule for several biological processes, but when released in the extracellular space such as in hemolytic diseases, it can be toxic to cells and tissues. Hemopexin (HPX) is a circulating protein responsible for removing free heme from the circulation, whose levels can be severely depleted in conditions such as sickle cell diseases. Accordingly, increasing HPX levels represents an attractive strategy to mitigate the deleterious effects of heme in these conditions. Gene transfer of liver-produced proteins with adeno-associated virus (AAV) has been shown to be an effective and safety strategy in animal and human studies mainly in hemophilia. Here, we report the feasibility of increasing HPX levels using an AAV8 vector expressing human HPX (hHPX). C57Bl mice were injected with escalating doses of our vector, and expression was assessed by enzyme immunoassay (ELISA), Western blot, and quantitative polymerase chain reaction (qPCR). In addition, the biological activity of transgenic hHPX was confirmed using two different models of heme challenge consisting of serial heme injections or phenylhydrazine-induced hemolysis. Sustained expression of hHPX was confirmed for up to 26 weeks in plasma. Expression was dose-dependent and not associated with clinical signs of toxicity. hHPX levels were significantly reduced by heme infusions and phenylhydrazine-induced hemolysis. No clinical toxicity or laboratory signs of liver damage were observed in preliminary short-term heme challenge studies. Our results confirm that long-term expression of hHPX is feasible and safe in mice, even in the presence of heme overload. Additional studies are needed to explore the effect of transgenic HPX protein in animal models of chronic hemolysis.

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Effect of hydroxyurea therapy on intravascular hemolysis and endothelial dysfunction markers in sickle cell anemia patients

Cited by 6 publications

References 29 publications

Advanced clinical parameters: A complementary hydroxyurea adherence evaluation in sickle cell anemia treatment

Advanced clinical parameters: A complementary hydroxyurea adherence evaluation in sickle cell anemia treatment

Effects of hydroxyurea on fertility in male and female sickle cell disease patients. A systemic review and meta-analysis

Safety and feasibility of the gene transfer of hemopexin for conditions with increased free heme

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