Recent studies have recognised the importance of pulmonary hypertension (PH) in sickle cell disease (SCD). The aim of this study was to determine the prevalence and prognostic impact of PH and its ...features in patients with SCD. 80 patients with SCD underwent baseline clinical evaluation, laboratory testing, 6-min walk tests (6MWTs) and echocardiography. Patients with a peak tricuspid regurgitant jet velocity (TRV) of ≥ 2.5 m·s(-1) were further evaluated through right heart catheterisation (RHC) to assure the diagnosis of PH. Our study evidenced a 40% prevalence of patients with elevated TRV at echocardiography. RHC (performed in 25 out of 32 patients) confirmed PH in 10% (95% CI 3.4-16.5%) of all patients, with a prevalence of post-capillary PH of 6.25% (95% CI 0.95-11.55%) and pre-capillary PH of 3.75% (95% CI -0.4-7.9%). Patients with PH were older, had worse performance in 6MWTs, and more pronounced anaemia, haemolysis and renal dysfunction. Survival was shorter in patients with PH. Our study reinforced the use of echocardiography as a screening tool for PH in SCD and the mandatory role of RHC for proper diagnosis. Our findings confirmed the prognostic significance of PH in SCD as its association to pronounced haemolytic profile.
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
4696480
3804099
, and HLA-G,
9380142
genotypes were more frequent in patients who had fewer complications. Also, in logistic regression, the HLA-G
9380142
allele increased the risk of cholelithiasis (
vs.
, OR 1.57, 95%CI 1.16-2.15;
vs.
, OR 2.47, 95%CI 1.34-4.64;
= 0.02). For SNPs located in the
loci, in logistic regression, the A allele in three SNPs was associated with a lower frequency of retinopathy, namely,
2246809 (
vs.
: OR 0.22, 95%CI 0.09-0.50;
vs.
: OR 0.47, 95%CI 0.31-0.71;
= 0.004, for patients of same origin),
2617160 (
vs.
: OR 0.67, 95%CI 0.48-0.92;
vs.
: OR 0.45, 95%CI 0.23-0.84;
= 0.04), and
2617169 (
vs.
: OR 0.33, 95%CI 0.13-0.82;
vs.
: OR 0.58, 95%CI 0.36-0.91,
= 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.
Patients' inflammatory history is an important factor underlying red blood cell (RBC) alloimmunization, which is a frequent transfusion complication among individuals with sickle cell disease (SCD). ...HLA-G has been associated with different inflammatory and auto - immune diseases. Our goal was to verify whether the HLA-G + 3142 C>G and 14-bp Ins/Del variations are associated with RBC antibody development among SCD patients.
This was a single-center case-control study. SCD patients were randomly selected for the study and divided into two groups: ‘Alloimmunized’ and ‘Nonalloimmunized’ depending on the presence of irregular antibodies. The ‘Alloimmunized’group was further divided into two subgroups according to the presence of only antibodies against the Rh and Kell blood group systems or the existence of antibodies to antigens of the other blood group systems.
A total of 213 patients were included in the study (110 alloimmunized and 103 non-alloimmunized). The ‘Alloimmunized’ and ‘Non-alloimmunized’ groups did not differ statistically regarding the HLA-G + 14 bp Ins/Del ( p = 0.494) and + 3142 C>G ( p = 0.334). Individuals who had only antibodies against the Rh and Kell antigens had a frequency of HLA-G + 3142GG genotype almost twice as high compared to the groupwith antibodies against less immunogenic antigens ( p = 0.043).
The genotype frequency of HLA-G + 3142 C>G differs among alloimmunized SCD patients, depending on the presence of antibodies against low immunogenic RBC antigens. This highlights a possible role played by the HLA-G molecule in the RBC alloimmunization process.
The complexity of Rh genetic variation among sickle cell disease (SCD) patients is high. Conventional molecular assays cannot identify all genetic variants already described for the RH locus as well ...as foresee novel alleles. Sequencing RHD and RHCE is indicated to broaden the search for Rh genetic variants.
To standardize the Next Generation Sequencing (NGS) strategy to assertively identify Rh genetic variants among SCD patients with serologic suspicion of Rh variants and evaluate if it can improve the transfusion support.
Thirty-five SCD patients with unexplained Rh antibodies were enrolled. A NGS-based strategy was developed to genotype RHD and RHCE using gene-specific primers. Genotype and serological data were compared.
Data obtained from the NGS-based assay were gene-specific. Ten and 25 variant RHD and RHCE alleles were identified, respectively. Among all cases of unexplained Rh antibodies, 62% had been inaccurately classified by serological analysis and, of these, 73.1% were considered as relevant, as were associated with increased risk of hemolytic reactions and shortage of units suitable for transfusion.
The NGS assay designed to genotype RH coding regions was effective and accurate in identifying variants. The proposed strategy clarified the Rh phenotype of most patients, improving transfusion support.
Summary
Despite adequate immunization and penicillin prophylaxis, bacterial infections remain a leading cause of morbidity and mortality in patients with sickle cell disease (SCD). Besides ...hyposplenism, inflammatory and genetic factors might modulate their susceptibility to bacterial infections. We performed a candidate gene association of single nucleotide polymorphisms (SNPs) located in Toll‐like receptor (TLR) genes, encoding prominent molecules for innate immune responses, with the occurrence of bacterial infections in patients with SCD. A cohort followed in centres in Brazil, France and Senegal (n = 430) was divided in two groups: patients who presented at least one episode of bacterial infection (n = 235) and patients who never had bacterial infections (n = 195). There were no differences in gender or age distribution among the groups. The frequency of the TLR2 rs4696480 TA genotype was significantly lower in the infected group (50% vs. 67%, odds ratio OR = 0·50, 95% confidence interval CI 0·34–0·75, P < 0·001), and the TT genotype was significantly higher in the infected group (15% vs. 5%, OR = 3·18, 95% CI 1·53–6·61, P < 0·001). Previous reports demonstrated higher secretion of inflammatory factors in cells from AA individuals, lower occurrence and severity of immune diseases in T carriers. The rs4696480 TA genotype might stand between deleterious effects of over inflammatory response (AA genotype) and inefficient responses (TT genotype) to infectious agents in SCD settings.
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