Sickle Cell Disease in Brazil: Current Management.

Sickle cell disease (SCD) comprises inherited red blood cell disorders due to a mutation in the ß-globin gene (c20A > T, pGlu6Val) and is characterized by the presence of abnormal hemoglobin, hemoglobin S, hemolysis, and vaso-occlusion. This mutation, either in a homozygous configuration or in compound states with other ß-globin mutations, leads to polymerization of hemoglobin S in deoxygenated conditions, causing modifications in red blood cell shape, particularly sickling. Vaso-occlusive crisis (VOC) is the hallmark of the disease, but other severe complications may arise from repeated bouts of VOCs. SCD is considered a global health problem, and its incidence has increased in some areas of the world, particularly the Americas and Africa. Management of the disease varies according to the region of the world, mainly due to local resources and socioeconomic status. This review aimed to describe more recent data on SCD regarding available treatment options, especially in Brazil. New treatment options are expected to be available to all patients, particularly crizanlizumab, which is already approved in the country.

Novel Insights into the Pathophysiology and Treatment of Sickle Cell Disease.

The polymerization of hemoglobin under deoxygenation is the main pathophysiological event in sickle cell diseases, described more than 70 years ago. The last two decades have seen a major increase in knowledge about the cascade of events that follow the polymerization of hemoglobin and the ensuing sickling of red blood cells. Several distinctive therapeutic targets have been discovered as a result, and a few drugs with innovative mechanisms of action are already on the market, while several others are the focus of ongoing trials. The aim of this narrative review is to describe some of the more recent data in the SCD literature regarding pathophysiology and novel treatments.

COVID-19 Infection in Sickle Cell Patients in a Developing Country: A Case Series.

Sickle cell disease is characterized by vaso-occlusive phenomena and haemolytic anaemia. There is a significant concern that the overlap of COVID-19 lung disease with acute chest syndrome that occurs in sickle cell patients may result in serious complications. Case reports of sickle cell patients with COVID-19 have been published. Here, we present a case series of COVID-19 infection in sickle cell patients in a developing country (Brazil). Only 10 patients tested positive so far for SARS-CoV-2 of 600 patients followed at our institution, of which 8 needed hospitalization (one in the intensive care unit), with no deaths. Even in a middle-income country, COVID-19 was reported to be relatively mild in sickle cell patients. In relation to risk factors, blood type O seems to confer some protection against developing severe COVID-19, a finding that could guide clinicians to adopt more clinical surveillance for patients with non-O blood type in sickle cell patients.

Molecular prevalence and genotypes of human pegivirus-1 (HPgV-1) and SENV-like viruses among multiply transfused patients with beta-thalassemia.

Due to the high number of transfusions which patients with hereditary hemoglobinopathies (thalassemia, sickle cell disease) receive, they represent high risk of acquiring parenterally transmitted infectious diseases. In this respect, non pathogenic human commensal viruses, which also demonstrate parenteral transmission routes might also be acquired. One of the most widely spread parenterally-transmitted human commensal viruses include the Human Pegivirus-1 (HPgV-1, GBV-C) and Torque teno viruses (TTV) including its SEN virus-like (SENV) forms. The objective of this study was to evaluate the prevalence of HPgV-1 RNA and SENV-like viruses, among a group of patients with beta-thalassemia from a Blood Transfusion Center in the São Paulo State, Brazil. The prevalence of HPgV-1 RNA was 14.3 % (n = 6/42) and all of the positive samples were characterized as belonging to genotype 2 (83.3 % were referred to subgenotype 2A and 16.7 % to 2B). The prevalence of SENV-like viruses was 28.6 % (n = 12/42). SENV-like viruses of the genotypes SENV-H and SENV-A were classified during the performed phylogenetic analysis. Our study came as a continuation of a viral metagenomic survey among multiple transfused patients with beta-thalassemia. The obtained results shed a light on the prevalence and genotype distribution of commensal parenterally transmitted viruses like HPgV-1 and SENV in this specific population. However, more studies are needed to evaluate the clinical impact of these apparently non-pathogenic viruses in patients with thalassemia and their significance for the hemotherapy.

Prevalence of hepatitis E virus infection in multiple transfused Brazilian patients with thalassemia and sickle cell disease.

Hepatitis E virus (HEV) is a leading cause of acute hepatitis worldwide. The virus is acquired by fecal-oral route; however, it can also be transmitted by blood transfusion. The objective of the study was to examine anti-HEV immunoglobulin G and HEV RNA prevalence in multiple transfused patients with thalassemia and sickle cell disease (SCD), and in blood donors. The HEV seroprevalence in the patients was 13% (20% in thalassemics; 7.7% in SCD), and 11% in blood donors. No positive result for HEV RNA was obtained. This is a pioneer study examining HEV circulation in Brazilian patients with hemoglobinopathies.

Altered erythropoiesis and iron metabolism in carriers of thalassemia.

The thalassemia syndromes (α- and ß-thalassemia) are the most common and frequent disorders associated with ineffective erythropoiesis. Imbalance of α- or ß-globin chain production results in impaired red blood cell synthesis, anemia, and more erythroid progenitors in the blood stream. While patients affected by these disorders show definitive altered parameters related to erythropoiesis, the relationship between the degree of anemia, altered erythropoiesis, and dysfunctional iron metabolism has not been investigated in both α-thalassemia carriers (ATC) and ß-thalassemia carriers (BTC). Here, we demonstrate that ATC have a significantly reduced hepcidin and increased soluble transferrin receptor levels but relatively normal hematological findings. In contrast, BTC have several hematological parameters significantly different from controls, including increased soluble transferrin receptor and erythropoietin levels. These changes in both groups suggest an altered balance between erythropoiesis and iron metabolism. The index sTfR/log ferritin and (hepcidin/ferritin)/sTfR are, respectively, increased and reduced relative to controls, proportional to the severity of each thalassemia group. In conclusion, we showed in this study, for the first time in the literature, that thalassemia carriers have altered iron metabolism and erythropoiesis.

Hydroxyurea increases plasma concentrations of microparticles and reduces coagulation activation and fibrinolysis in patients with sickle cell anemia.

Microparticles (MPs) are present in healthy subjects and their concentration increases in patients at high risk of thrombosis. We evaluated 10 patients with sickle cell anemia (SCA) treated with hydroxyurea (HU) and 13 SCA patients without this treatment. MP concentrations were determined by flow cytometry. Coagulation was evaluated using the thrombin-antithrombin complex (TAT) and D-dimers. Total MP concentrations were increased in the HU-treated group (265 × 10(6)/ml vs. 67.45 × 10(6)/ml; p = 0.0026), as well as MPs derived from RBC (67.83 × 10(6)/ml vs. 26.31 × 10(6)/ml; p = 0.05), monocytes (51.31 × 10(6)/ml vs. 9.03 × 10(6)/ml; p = 0.0084), monocytes with tissue factor (TF) expression (2.27 × 10(6)/ml vs. 0.27 × 10(6)/ml; p = 0.0058), endothelium (49.42 × 10(6)/ml vs. 7.23 × 10(6)/ml; p = 0.007) and endothelium with TF (1.42 × 10(6)/ml vs. 0.26 × 10(6)/ml; p = 0.0043). Furthermore, the concentrations of TAT (7.56 vs. 10.98 µg/l; p = 0.014) and D-dimers (0.65 vs. 1.29 µg/ml; p = 0.007) were reduced with HU. The MP elevation may suggest a direct cytotoxic effect of HU. Another explanation is a cell surface increase secondary to a megaloblastic process, resulting in increased vesicle release. In our opinion, the known benefits of HU on SCA patients, along with the reduction in coagulation activation, surpass its potential detrimental effect on MPs. Future studies should elucidate the role of MPs and demonstrate their significance in different contexts.

No evidence of xenotropic murine leukemia virus-related virus infection in Brazilian multiply transfused patients with sickle cell disease and beta-thalassemia major.

Although xenotropic murine leukemia virus-related virus (XMRV) has been regarded as a laboratory contaminant, it remains one of the most controversial viruses. The objective of the study was to determine if XMRV is present in 44 patients with beta-thalassemia major, 48 with sickle cell disease, and 89 volunteer blood donors. After RNA/ DNA extraction from plasma/buffy coat the samples were screened for XMRV sequences by conserved nested GAG primers. None of the RNA samples showed a positive result. Surprisingly, four DNA samples obtained from blood donors were positive for XMRV provirus. The subsequent phylogenetic analysis revealed that these sequences are identical to the positive control (murine leukemia retrovirus) and are probably consistent with laboratory contamination. XMRV infection (provirus and viral RNA) was absent in multiply transfused patients and volunteer blood donors. The positive result obtained from some blood donors probably reflects laboratory contamination. We believe that XMRV does not pose risk to blood transfusion.

Estimated mortality rates of individuals with sickle cell disease in Brazil: real-world evidence.

Sickle cell disease (SCD) is a group of hereditary chronic diseases with a substantial impact on quality of life and morbimortality. In Brazil, it is 1 of the most common hereditary diseases; however, there are sparse epidemiological data for the country. Using data from death certificates, we aimed to estimate the median age at death, years of life lost because of SCD, and the median survival. From 2015 to 2019, we identified 3320 records of deaths of individuals with SCD, from a total of 6 553 132 death records. Among individuals with SCD, the median age at death was 37 years less than that of the general population (SCD: aged 32.0 years at death, interquartile range [IQR], 19.0-46.0; general population: aged 69.0 years at death; IQR, 53.0-81.0). Results were consistent when stratified by sex or race. Over the 5 years evaluated, crude death rates varied from 0.30 to 0.34 per 100 000 inhabitants (mean 0.32 per 100 000 inhabitants). We estimated a prevalence of 60 017 individuals living with SCD (29.02 cases per 100 000) and an average incidence of 1362 cases yearly. The median estimated survival was 40 years for individuals with SCD and 80 years for the general population. SCD was associated with an increased risk of mortality in most age ranges. Among individuals with SCD aged between 1 and 9 years and between 10 and 39 years, the risk of death was 32 and 13 times higher, respectively. The most common causes of death were sepsis and respiratory failure. These results highlight the burden of SCD in Brazil and the necessity of improved care for this population.

Molecular and phylogenetic analyses of human Parvovirus B19 isolated from Brazilian patients with sickle cell disease and ß-thalassemia major and healthy blood donors.

Human Parvovirus B19 (B19V) is a recognized cause of life-threatening conditions among patients with hemoglobinopathies. This study investigates B19V infection in patients with sickle cell disease and ß-thalassemia using different experimental approaches. A total of 183 individuals (144 with sickle cell disease and 39 with ß-thalassemia major) and 100 healthy blood donors were examined for B19V using anti-B19V IgG enzyme immunoassay, quantitative PCR, DNA sequencing, and phylogenetic analysis. Viremia was documented in 18.6% of patients and 1% of donors, and was generally characterized by low viral load (VL); however, acute infections were also observed. Anti-B19V IgG was detected in 65.9% of patients with sickle cell disease and in 60% of donors, whereas the patients with thalassemia exhibited relatively low seroreactivity. The seroprevalence varied among the different age groups. In patients, it progressively increased with age, whereas in donors it reached a plateau. Based on partial NS1 fragments, all isolates detected were classified as subgenotype 1A with a tendency to elicit genetically complex infections. Interestingly, quasispecies occurred in the plasma of not only patients but also donors with even higher heterogeneity. The partial NS1 sequence examined did not exhibit positive selection. Quantitation of B19V with a conservative probe is a technically and practically useful approach. The extensive spread of B19V subgenotype 1A in patients and donors and its recent introduction into the countryside of the São Paulo State, Brazil were demonstrated; however, it is difficult to establish a relationship between viral sequences and the clinical outcomes of the infection.

Genotyping of Human parvovirus B19 among Brazilian patients with hemoglobinopathies.

Human parvovirus B19 (B19V) infection can be a life-threatening condition among patients with hereditary (chronic) hemolytic anemias. Our objective was to characterize the infection molecularly among patients with sickle cell disease and thalassemia. Forty-seven patients (37 with sickle cell disease, and 10 with ß-thalassemia major) as well as 47 healthy blood donors were examined for B19V infection by anti-B19V IgG enzyme immunoassay, quantitative PCR, which detects all B19V genotypes, and DNA sequencing. B19V viremia was documented in nine patients (19.1%) as two displayed acute infection and the rest had a low titre viremia (mean 3.4 × 10(4) copies/mL). All donors were negative for B19V DNA. Anti-B19V IgG was detected in 55.3% of the patients and 57.4% among the donors. Based on partial NS1 fragments, all patient isolates were classified as genotype 1 and subgenotype 1A. The evolutionary events of the examined partial NS1 gene sequence were associated with a lack of positive selection. The quantification of all B19V genotypes by a single hydrolytic probe is a technically useful method, but it is difficult to establish relationships between B19V sequence characteristics and infection outcome.

Stability and antioxidant activity of semi-synthetic derivatives of 4-nerolidylcatechol.

4-nerolidylcatechol (4-NC) is an unstable natural product that exhibits important antioxidant, anti-inflammatory and other properties. It is readily obtainable on a multi-gram scale through straightforward solvent extraction of the roots of cultivated Piper peltatum or P. umbellatum, followed by column chromatography on the resulting extract. Semi-synthetic derivatives of 4-NC with one or two substituent groups (methyl, acetyl, benzyl, benzoyl) on the O atoms have been introduced that have increased stability compared to 4-NC and significant in vitro inhibitory activity against the human malaria parasite Plasmodium falciparum. Antioxidant and anti-inflammatory properties may be important for the antiplasmodial mode of action of 4-NC derivatives. Thus, we decided to investigate the antioxidant properties, cytotoxicity and stability of 4-NC derivatives as a means to explore the potential utility of these compounds. 4-NC showed high antioxidant activity in the DPPH and ABTS assays and in 3T3-L1 cells (mouse embryonic fibroblast), however 4-NC was more cytotoxic (IC50 = 31.4 µM) and more unstable than its derivatives and lost more than 80% of its antioxidant activity upon storage in solution at -20 °C for 30 days. DMSO solutions of mono-O-substituted derivatives of 4-NC exhibited antioxidant activity and radical scavenging activity in the DPPH and ABTS assays that was comparable to that of BHA and BHT. In the cell-based antioxidant model, most DMSO solutions of derivatives of 4-NC were less active on day 1 than 4-NC, quercetin and BHA and more active antioxidants than BHT. After storage for 30 days at -20 °C, DMSO solutions of most of the derivatives of 4-NC were more stable and exhibited more antioxidant activity than 4-NC, quercetin and BHA and exhibited comparable antioxidant activity to BHT. These findings point to the potential of derivatives of 4-NC as antioxidant compounds.

Economic burden of sickle cell disease in Brazil.

BACKGROUND: Sickle cell disease (SCD) may cause several impacts to patients and the whole society. About 4% of the population has the sickle cell trait in Brazil, and 60,000 to 100,000 have SCD. However, despite recognizing the significant burden of disease, little is known about SCD costs. OBJECTIVE: To estimate SCD societal costs based on disease burden modelling, under Brazilian societal perspective. METHODS: A disease burden model was built considering the societal perspective and a one-year time horizon, including direct medical and indirect costs (morbidity and mortality). The sum of life lost and disability years was considered to estimate disability-adjusted life years (DALYs). Data from a public database (DATASUS) and the prevalence obtained from literature or medical experts were used to define complications prevalence and duration. Costs were defined using data from the Brazilian public healthcare system table of procedures and medications (SIGTAP) and the human capital method. RESULTS: Annual SCD cost was 413,639,180 USD. Indirect cost accounted for the majority of burden (70.1% of the total; 290,158,365 USD vs 123,480,816 USD). Standard of care and chronic complications were the main source of direct costs among adults, while acute conditions were the main source among children. Vaso-occlusive crisis represented the complication with the highest total cost per year in both populations, 11,400,410 USD among adults and 11,510,960 USD among children. CONCLUSIONS: SCD management may impose an important economic burden on Brazilian society that may reach more than 400 million USD per year.

Six-point DIXON and Magnetic Resonance Spectroscopy Techniques in Quantifying Bone Marrow Fat in Sickle Cell Disease.

RATIONALE AND OBJECTIVES: To compare bone marrow fat quantification using magnetic resonance spectroscopy (MRS) and six-point DIXON (6PD) techniques in patients with sickle cell disease (SCD) and healthy subjects. MATERIALS AND METHODS: Prospective study, with 43 SCD patients (24 homozygous [SS], 19 double heterozygous [SC), and 41 healthy subjects paired by age, weight and sex with SCD patients. All participants underwent magnetic resonance imaging with 6PD and single voxel MRS in the L3 vertebral body. Pearson's correlation, ROC curve, and bland-altman analysis were performed, p-values ​​≤0.05 were considered statistically significant for all tests. RESULTS: Significant linear correlation was found between fat fraction (FF) by 6PD and Total Lipids (TL) (r = 0.932; p < 0.001) and Saturated Lipids (SL) (r = 0.934; p < 0.001), in all subjects. Strong correlations were also identified considering subjects of the SS/SC subgroups. Despite high correlations, no significant difference was observed only between FF and SL in the SS subgroup (Bland-Altman analysis), indicating excellent agreement between the fat estimations in this specific situation. Significant differences were observed in all variables (FF, TL, SL) comparing the SCD and healthy subjects. The ROC curve between SCD and healthy subjects showed the following areas under the curve: FF(0.924) > TL(0.883) > SL(0.892). CONCLUSIONS: The comparison between fat quantification by the 6PD with MRS demonstrated an excellent correlation in SCD patients, especially in the SS subgroup, which usually has a higher degree of hemolysis. The diagnostic performance of 6PD and MRS is similar, with advantages of shorter imaging processing time and larger studied area with the 6PD.

Allogeneic haematopoietic stem cell transplantation resets T- and B-cell compartments in sickle cell disease patients.

Objectives: Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is the only currently available curative treatment for sickle cell disease (SCD). Here, we comprehensively evaluated the reconstitution of T- and B-cell compartments in 29 SCD patients treated with allo-HSCT and how it correlated with the development of acute graft-versus-host disease (aGvHD). Methods: T-cell neogenesis was assessed by quantification of signal-joint and ß-chain TCR excision circles. B-cell neogenesis was evaluated by quantification of signal-joint and coding-joint K-chain recombination excision circles. T- and B-cell peripheral subset numbers were assessed by flow cytometry. Results: Before allo-HSCT (baseline), T-cell neogenesis was normal in SCD patients compared with age-, gender- and ethnicity-matched healthy controls. Following allo-HSCT, T-cell neogenesis declined but was fully restored to healthy control levels at one year post-transplantation. Peripheral T-cell subset counts were fully restored only at 24 months post-transplantation. Occurrence of acute graft-versus-host disease (aGvHD) transiently affected T- and B-cell neogenesis and overall reconstitution of T- and B-cell peripheral subsets. B-cell neogenesis was significantly higher in SCD patients at baseline than in healthy controls, remaining high throughout the follow-up after allo-HSCT. Notably, after transplantation SCD patients showed increased frequencies of IL-10-producing B-regulatory cells and IgM+ memory B-cell subsets compared with baseline levels and with healthy controls. Conclusion: Our findings revealed that the T- and B-cell compartments were normally reconstituted in SCD patients after allo-HSCT. In addition, the increase of IL-10-producing B-regulatory cells may contribute to improve immune regulation and homeostasis after transplantation.

Pathophysiological insights in sickle cell disease.

The first coherent pathophysiological scheme for sickle cell disease (SCD) emerged in the sixties-seventies based on an extremely detailed description of the molecular mechanism by which HbS in its deoxy-form polymerises and forms long fibres within the red blood cell that deform it and make it fragile. This scheme explains the haemolytic anaemia, and the mechanistic aspects of the vaso-occlusive crises (VOCs), but, even though it constitutes the basic mechanism of the disease, it does not account for the processes that actually trigger VOCs. This paper reviews recent data which imply: red blood cell dehydration, its abnormal adhesion properties to the endothelium, the participation of inflammatory phenomenon and of a global activation of all the cells present in the vessel, and finally, abnormalities of the vascular tone and of nitric oxide metabolism. These data altogether have shed a new light on the pathophysiology of the first molecular disease i.e. sickle cell disease.

In vivo and in vitro antimalarial activity of 4-nerolidylcatechol.

4-Nerolidylcatechol (4-NC) isolated from Piper peltatum L. (Piperaceae) was evaluated for in vitro antiplasmodial activity against Plasmodium falciparum (cultures of both standard CQR (K1) and CQS (3D7) strains and two Amazonian field isolates) and for in vivo antimalarial activity using the Plasmodium berghei-murine model. 4-NC exhibits significant in vitro and moderate in vivo antiplasmodial activity. 4-NC administered orally and subcutaneously at doses of 200, 400 and 600 mg/kg/day suppressed the growth of P. berghei by up to 63% after four daily treatments (days 1-4). Also, 4-NC exhibited important in vitro antiplasmodial activity against both standard and field P. falciparum strains in which 50% inhibition of parasite growth (IC(50) ) was produced at concentrations of 0.05-2.11 µg/mL and depended upon the parasite strain. Interestingly, healthy (non-infected) mice that received 4-NC orally presented (denatured) blood plasma which exhibited significant in vitro activity against P. falciparum. This is evidence that mouse metabolism allows 4-NC or active metabolites to enter the blood. Further chemical and pharmacological studies are necessary to confirm the potential of 4-NC as a new antimalarial prototype.

Qualitative and quantitative magnetic resonance imaging evaluation of bone tissue vaso-occlusive events in patients with sickle cell disease.

OBJECTIVE: To evaluate the association between bone changes due to vaso-occlusive events in sickle cell disease (SCD) revealed by conventional MRI sequences and the fat fraction obtained using a 6-point DIXON technique (FFdix), in an attempt to use quantitative data as a biomarker for bone complications. METHODS: Cross-sectional study, with 48 SCD patients, 26-homozygous (HbSS), and 22-compound heterozygous (HbSC). Forty-eight healthy individuals paired by age, weight, and sex with SCD patients. All participants underwent lumbar spine and pelvis MRI. Conventional sequences: bone complications related to vaso-occlusive events-femoral head avascular necrosis, bone infarctions, "H"-shaped vertebrae, bone marrow necrosis. Six-point DIXON technique: quantitative evaluation of the bone marrow at pre-established sites (lumbar vertebrae, sacrum, iliacs, femoral heads, greater femoral trochanters, femoral necks). Pearson's correlation, ROC curve, and binary logistic regression analysis were performed. RESULTS: The most frequent findings in the SCD group included femoral head avascular necrosis (75%), bone infarctions (58.3%), "H"-shaped vertebrae (58.3%), and typical imaging findings of bone marrow necrosis (8.3%). Cortical bone thickness in the proximal femoral diaphysis in patients with SCD was moderately negatively correlated with FFdix in lumbar vertebrae, iliacs, femoral necks, and first sacral vertebrae. The ROC curves and odds ratios demonstrated excellent performance of FFdix in all the evaluated anatomical sites and identified patients having bone complications. CONCLUSIONS: FFdix could serve as a potential biomarker in SCD because of its association with bone complications secondary to vaso-occlusive events in patients with SCD, especially in femoral heads, femoral necks, and iliacs.

Deep sequencing applied to the analysis of viromes in patients with beta-thalassemia.

To date, blood banks apply routine diagnosis to a specific spectrum of transfusion-transmitted viruses. Even though this measure is considered highly efficient to control their transmission, the threat imposed by emerging viruses is increasing globally, which can impact transfusion safety, especially in the light of the accelerated viral discovery by novel sequencing technologies. One of the most important groups of patients, who may indicate the presence of emerging viruses in the field of blood transfusion, is the group of individuals who receive multiple transfusions due to hereditary hemoglobinopathies. It is possible that they harbor unknown or unsuspected parenterally-transmitted viruses. In order to elucidate this, nucleic acids from 30 patients with beta-thalassemia were analyzed by Illumina next-generation sequencing and bioinformatics analysis. Three major viral families: Anelloviridae, Flaviviridae and Hepadnaviridae were identified. Among them, anelloviruses were the most representative, being detected with high number of reads in all tested samples. Human Pegivirus 1 (HPgV-1, or GBV-C), Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) were also identified. HBV and HCV detection was expected due to the high seroprevalence in patients with beta thalassemia. Our results do not confirm the presence of emerging or unsuspected viruses threatening the transfusion safety at present, but can be used to actively search for viruses that threaten blood transfusion safety. We believe that the application of viral metagenomics in multiple-transfused patients is highly useful to monitor possible viral transfusion threats and for the annotation of their virome composition.

Polymorphisms in Inflammatory Genes Modulate Clinical Complications in Patients With Sickle Cell Disease.

Sickle cell disease (SCD), the most common monogenic disease worldwide, is marked by a phenotypic variability that is, to date, only partially understood. Because inflammation plays a major role in SCD pathophysiology, we hypothesized that single nucleotide polymorphisms (SNP) in genes encoding functionally important inflammatory proteins might modulate the occurrence of SCD complications. We assessed the association between 20 SNPs in genes encoding Toll-like receptors (TLR), NK cell receptors (NKG), histocompatibility leukocyte antigens (HLA), major histocompatibility complex class I polypeptide-related sequence A (MICA) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and the occurrence of six SCD clinical complications (stroke, acute chest syndrome (ACS), leg ulcers, cholelithiasis, osteonecrosis, or retinopathy). This study was performed in a cohort of 500 patients. We found that the TLR2 rs4696480 TA, TLR2 rs3804099 CC, and HLA-G, rs9380142 AA genotypes were more frequent in patients who had fewer complications. Also, in logistic regression, the HLA-G rs9380142 G allele increased the risk of cholelithiasis (AG vs. AA, OR 1.57, 95%CI 1.16-2.15; GG vs. AA, OR 2.47, 95%CI 1.34-4.64; P = 0.02). For SNPs located in the NKG2D loci, in logistic regression, the A allele in three SNPs was associated with a lower frequency of retinopathy, namely, rs2246809 (AA vs. GG: OR 0.22, 95%CI 0.09-0.50; AG vs. GG: OR 0.47, 95%CI 0.31-0.71; P = 0.004, for patients of same origin), rs2617160 (AT vs. TT: OR 0.67, 95%CI 0.48-0.92; AA vs. TT: OR 0.45, 95%CI 0.23-0.84; P = 0.04), and rs2617169 (AA vs. TT: OR 0.33, 95%CI 0.13-0.82; AT vs. TT: OR 0.58, 95%CI 0.36-0.91, P = 0.049, in patients of same SCD genotype). These results, by uncovering susceptibility to, or protection against SCD complications, might contribute to a better understanding of the inflammatory pathways involved in SCD manifestations and to pave the way for the discovery of biomarkers that predict disease severity, which would improve SCD management.