Clinical outcomes of COVID-19 in patients with sickle cell disease and sickle cell trait: A critical appraisal of the literature.

Individuals with sickle cell disease (SCD) and sickle cell trait (SCT) have many risk factors that could make them more susceptible to COVID-19 critical illness and death compared to the general population. With a growing body of literature in this field, a comprehensive review is needed. We reviewed 71 COVID-19-related studies conducted in 15 countries and published between January 1, 2020, and October 15, 2021, including a combined total of over 2000 patients with SCD and nearly 2000 patients with SCT. Adults with SCD typically have a mild to moderate COVID-19 disease course, but also a 2- to 7-fold increased risk of COVID-19-related hospitalization and a 1.2-fold increased risk of COVID-19-related death as compared to adults without SCD, but not compared to controls with similar comorbidities and end-organ damage. There is some evidence that persons with SCT have increased risk of COVID-19-related hospitalization and death although more studies with risk-stratification and properly matched controls are needed to confirm these findings. While the literature suggests that most children with SCD and COVID-19 have mild disease and low risk of death, some children with SCD, especially those with SCD-related comorbidities, are more likely to be hospitalized and require escalated care than children without SCD. However, children with SCD are less likely to experience COVID-19-related severe illness and death compared to adults with or without SCD. SCD-directed therapies such as transfusion and hydroxyurea may be associated with better COVID-19 outcomes, but prospective studies are needed for confirmation. While some studies have reported favorable short-term outcomes for COVID-19 patients with SCD and SCT, the long-term effects of SARS-CoV-2 infection are unknown and may affect individuals with SCD and SCT differently from the general population. Important focus areas for future research should include multi-center studies with larger sample sizes, assessment of hemoglobin genotype and SCD-modifying therapies on COVID-19 outcomes, inclusion of case-matched controls that account for the unique sample characteristics of SCD and SCT populations, and longitudinal assessment of post-COVID-19 symptoms.

El dolor en la drepanocitosis / Pain in sickle cell disease

Introducción: La drepanocitosis incluye un grupo de desórdenes genéticamente heredados en los que a baja saturación de oxígeno ocurre la agregación de polímeros rígidos de hemoglobina S desoxigenada. El dolor es la principal característica clínica de la enfermedad drepanocítica, constituye la primera causa de hospitalización; es básicamente de tipo nociceptivo. Los pacientes con drepanocitosis pueden presentar varios tipos de dolor en dependencia de las estructuras lesionadas, el de tipo músculo-esquelético es el más frecuente. Objetivo: Analizar las principales modalidades terapéuticas para el manejo del dolor en la drepanocitosis. Métodos: Se realizó una revisión de la literatura, en inglés y español, a través del sitio web PubMed y el motor de búsqueda Google académico de artículos publicados en los últimos 5 años. Se hizo un análisis y resumen de la bibliografía revisada. Análisis y síntesis de la información: Actualmente existen varias opciones de tratamiento. La base del manejo del dolor es el reconocimiento y la evaluación de la gravedad, ya que de esta dependerá el tratamiento analgésico. Una vez instaurado el dolor, el manejo inicial debe enfocarse en proveer control rápido, garantizar las dosis terapéuticas de los fármacos y evitar la aparición de complicaciones. Conclusión: Se debe mantener un adecuado tratamiento y seguimiento de los pacientes con dolor en la drepanocitosis, pues esto permitirá disminuir en lo posible las complicaciones que pueden ocasionar la enfermedad en los pacientes desde el punto de vista orgánico y psicológico(AU)

Introduction: Sickle cell disease includes a group of genetically inherited disorders in which, at low oxygen saturation, aggregation of rigid polymers of deoxygenated hemoglobin S occurs. Pain is the main clinical characteristic of sickle cell disease. It is the first cause of hospitalization. It is basically of nociceptive type. Patients with sickle cell disease can present various types of pain depending on the injured structures; the musculoskeletal type is the most frequent. Objective: To analyze the main therapeutic modalities for pain management in sickle cell disease. Methods: A literature review was carried out, in English and in Spanish, through the PubMed website and the Google Scholar search engine, of articles published in the last five years. Analysis and summary of the revised bibliography was made. Information analysis and synthesis: Currently, there are several treatment options. The basis for pain management is the recognition and evaluation of severity, since analgesic treatment will depend on this. Once pain is established, initial management should focus on providing rapid control, guaranteeing therapeutic doses of drugs, and avoiding the onset of complications. Conclusion: Adequate treatment and follow-up of patients with pain in sickle cell disease should be maintained, as this will reduce, as much as possible, the complications that the disease can cause in patients from an organic and psychological point of view(AU)

5-(Hydroxymethyl)furfural restores low-oxygen rheology of sickle trait blood in vitro.

Sickle cell trait (SCT) is the benign heterozygous carrier state for the sickle variant of the HBB gene. Most of the ~300 million people with SCT worldwide will not experience any significant complications. However, accumulating evidence finds SCT associated with increased risk for the common conditions of chronic kidney disease and venous thromboembolism, and severe but rare renal medullary carcinoma and exercise-induced rhabdomyolysis. The mechanism is uncertain, but probably involves pathological rheology of SCT blood in regions of low oxygen tension, resulting from sickle haemoglobin polymerization in SCT red cells and leading to reduced blood flow and further tissue hypoxia and damage. Here, we used an in vitro microfluidic flow system to study the oxygen-dependent rheology of SCT blood and show that 5-(hydroxymethyl)furfural, a natural breakdown product of glucose and fructose-containing foods, such as fruit juices, can reduce the effects of hypoxia on SCT blood rheology in vitro, restoring near-normal flow velocities at very low oxygen. While opinions regarding the clinical significance of the risks associated with SCT are still evolving, these results suggest that a compound present in some food may provide a potential approach for managing risks that may be associated with SCT.

Red urine, updated for the nephrologist: a case report.

BACKGROUND: Sickle cell trait is not completely benign, and some renal complications can occur. The baseline rate of admission for gross hematuria in normal males carrying the sickle cell trait is 2%. CASE PRESENTATION: A 35-year-old non-smoking African man experienced a 2-week history of painless, profuse and persistent gross hematuria. Laboratory tests showed normal renal function, hematuria and mild proteinuria. Abdominal ultrasonography and computed tomography angiography revealed no renal abnormalities; the bladder appeared pristine under cystoscopy. The diagnosis of sickle cell trait associated with gross hematuria was made using hemoglobin electrophoresis; renal biopsy and its complications were avoided. Urine was clear after 2 weeks of oral hydration and gamma epsilon-aminocaproic acid. CONCLUSION: Hemoglobin electrophoresis should be performed in cases of gross hematuria. Coupled with other non-invasive evaluation, this could avoid renal biopsy and its associated complications.

Adverse events in cancer patients with sickle cell trait or disease: case reports.

PURPOSE: Given the relatively high prevalence of sickle cell trait and disease among African Americans and established racial disparities in cancer outcomes, we reviewed the literature regarding adverse events in cancer patients with these hematologic genotypes. Erythrocyte sickling can result from extreme hypoxia and other physiologic stressors, as might occur during cancer therapy. Further, tumoral hypoxia, a poor prognostic and predictive factor, could lead to a cycle of local sickling and increased hypoxia. METHODS: A search of PubMed produced 150 publications, most of which were excluded because of incidental relevance. Eleven case reports of patients diagnosed from 1993 to 2013 were reviewed. RESULTS: Two reports of patients with sickle cell trait describe an abundance of sickled erythrocytes within tumors, and a third report describes sickling-related events requiring multiday hospitalization. Eight reports of patients with sickle cell disease delineated multiorgan failure, vaso-occlusive crises, and rapid renal deterioration. Hypothesized triggers are delayed clearance of anticancer agents attributable to baseline kidney damage, activation of vasoadherent neutrophils from treatment to counter chemotherapy-induced neutropenia, hypoxia from general anesthesia, and intratumoral hypoxia. CONCLUSION: Clinical implications include pretreatment genotyping for prophylaxis, dose adjustment, and enhanced patient monitoring. With the current lack of high-quality evidence, however, the scope of poor outcomes remains unknown.

Dosis moderadas de hidroxiurea en niños con drepanocitosis y accidente vascular encefálico. Resultados preliminares / Moderate dose of hydroxyurea in children with sickle cell disease and stroke. Preliminary results

Se trataron 20 niños con anemia drepanocítica, dos ellos con hemoglobinopatía SC y uno con S/â0 talasemia con accidente vascular encefálico o Doppler transcraneal con velocidades del flujo sanguíneo mayor de 170 cm/s. La media de seguimiento fue de 41 ± 19 meses. En los pacientes con accidente vascular encefálico se administraron 25 mg/kg/día de hidroxiurea y se realizó régimen de transfusión crónica por un año. En los niños con Doppler transcraneal patológico se administró la hidroxiurea sola en igual dosis. Hubo una disminución significativa del número de accidentes vasculares encefálicos (p <0.02) y de la velocidad del flujo sanguíneo en la arteria cerebral media derecha (p <0.003). En tres niños con velocidades de flujo muy aumentadas en el Doppler transcraneal sin accidente vascular encefálico fue necesario asociar régimen de hipertransfusión por no respuesta al tratamiento. La asociación de hidroxiurea y transfusiones de glóbulos rojos durante un año pueden ser útiles en el tratamiento y prevención del accidente vascular encefálico

Twenty children with sickle cell anemia, two with SC hemoglobinopathy and one with S/â0 thalassemia were treated, with a previous stroke or abnormal ultrasound transcranial Doppler (TCD) flow velocities more than 170 cm/s. The mean follow-up was of 41 ± 19 months. Hydroxyurea (HU) at a dose of 25 mg/kg/day associated with chronic transfusion therapy, was administrated during one year to patients with stroke. Patients with abnormal TCD received only HU at the same dose. There was a significant decrease of stroke (p <0.02) and TCD flow velocities in the right middle cerebral artery (p <0.003). It was necessary to associate chronic transfusion therapy in three children with high velocities in TCD without stroke, due to the lack of response to the treatment with HU. The combination of HU and transfusions during one year can be useful for stroke therapy and prevention

Dosis moderadas de hidroxiurea en niños con drepanocitosis y accidente vascular encefálico. Resultados preliminares / Moderate dose of hydroxyurea in children with sickle cell disease and stroke. Preliminary results

Se trataron 20 niños con anemia drepanocítica, dos ellos con hemoglobinopatía SC y uno con S/â0 talasemia con accidente vascular encefálico o Doppler transcraneal con velocidades del flujo sanguíneo mayor de 170 cm/s. La media de seguimiento fue de 41 ± 19 meses. En los pacientes con accidente vascular encefálico se administraron 25 mg/kg/día de hidroxiurea y se realizó régimen de transfusión crónica por un año. En los niños con Doppler transcraneal patológico se administró la hidroxiurea sola en igual dosis. Hubo una disminución significativa del número de accidentes vasculares encefálicos (p <0.02) y de la velocidad del flujo sanguíneo en la arteria cerebral media derecha (p <0.003). En tres niños con velocidades de flujo muy aumentadas en el Doppler transcraneal sin accidente vascular encefálico fue necesario asociar régimen de hipertransfusión por no respuesta al tratamiento. La asociación de hidroxiurea y transfusiones de glóbulos rojos durante un año pueden ser útiles en el tratamiento y prevención del accidente vascular encefálico(AU)

Twenty children with sickle cell anemia, two with SC hemoglobinopathy and one with S/â0 thalassemia were treated, with a previous stroke or abnormal ultrasound transcranial Doppler (TCD) flow velocities more than 170 cm/s. The mean follow-up was of 41 ± 19 months. Hydroxyurea (HU) at a dose of 25 mg/kg/day associated with chronic transfusion therapy, was administrated during one year to patients with stroke. Patients with abnormal TCD received only HU at the same dose. There was a significant decrease of stroke (p <0.02) and TCD flow velocities in the right middle cerebral artery (p <0.003). It was necessary to associate chronic transfusion therapy in three children with high velocities in TCD without stroke, due to the lack of response to the treatment with HU. The combination of HU and transfusions during one year can be useful for stroke therapy and prevention(AU)

Cerebrovascular events in sickle cell-beta thalassemia treated with hydroxyurea: a single center prospective survey in adult Italians.

Stroke is a common cause of morbidity and mortality in sickle cell disease (SCD) and silent cerebral infarction is the most common form of neurologic injury. The frequency and risk factors for new silent cerebral infarction are incompletely understood. Moreover, no recommended treatment has been established. Although hydroxyurea (HU) is recommended for SCD, concerns remain regarding its role in the prevention of cerebrovascular events, including silent cerebral infarction. A single center population of 104 Italian patients with HbS-ß thalassemia treated with HU has been followed for a mean of 11 years. Clinical evaluation and brain imaging by Magnetic Resonance Imaging were done before and during HU treatment. During follow-up, the number of sickle cell crises (86%, 7.8 ± 6.9 vs. 1.2 ± 0.5 per year, P < 0.0001), hospitalizations (2.5 ± 2.9 vs. 0.3 ± 1.5 per year, P < 0.0001), and days in the hospital (22.4 ± 21.9 vs. 0.3±1.5 per year, P < 0.0001) decreased significantly and HbF increased from a mean of 8-20.8%. Cerebral infarcts occurred in 37.5% of patients. Among these, 6.7% had overt strokes, while 30% had new or progressive silent cerebral infarction. Stroke and silent cerebral infarction were not related to clinical hematologic or HbF response to HU. These findings suggest that in adults, HU treatment does not prevent new cerebrovascular events or the progression of existent silent cerebral infarcts in HbS-ß thalassemia. A major benefit of HU is the increase in HbF; the association of high HbF and reduced cerebrovascular disease has been weak. New treatment strategies should be developed for the prevention of sickle cerebrovascular disease.

A dose-escalation phase IIa study of 2,2-dimethylbutyrate (HQK-1001), an oral fetal globin inducer, in sickle cell disease.

2,2-Dimethylbutyrate (HQK-1001), an orally-bioavailable promoter-targeted fetal globin gene-inducing agent, was evaluated in an open-label, randomized dose-escalation study in 52 subjects with hemoglobin SS or S/ß(0) thalassemia. HQK-1001 was administered daily for 26 weeks at 30 mg/kg (n = 15), 40 mg/kg (n = 18) and 50 mg/kg (n = 19), either alone (n = 21) or with hydroxyurea (n = 31). The most common drug-related adverse events were usually mild or moderate and reversible. Gastritis was graded as severe in three subjects at 40 mg/kg and was considered the dose-limiting toxicity. Subsequently all subjects were switched to the maximum tolerated dose of 30 mg/kg. Due to early discontinuations for blood transfusions, adverse events or non-compliance, only 25 subjects (48%) completed the study. Drug plasma concentrations were sustained above targeted levels at 30 mg/kg. Increases in fetal hemoglobin (Hb F) were observed in 42 subjects (80%), and 12 (23%) had increases ≥4%. The mean increase in Hb F was 2% [95% confidence interval (CI), 0.8-3.2%] in 21 subjects receiving HQK-1001 alone and 2.7% (95% CI, 1.7-3.8%) in 31 subjects receiving HQK-1001 plus hydroxyurea. Total hemoglobin increased by a mean of 0.65 g/dL (95% CI, 0.5-1.0 g/dL), and 13 subjects (25%) had increases ≥1 g/dL. Future studies are warranted to evaluate the therapeutic potential of HQK-1001 in sickle cell disease. .

Antioxidant vitamins C and E supplementation increases markers of haemolysis in sickle cell anaemia patients: a randomized, double-blind, placebo-controlled trial.

Erythrocytes from sickle cell anaemia (SCA) patients continuously produce larger amounts of pro-oxidants than normal cells. Oxidative stress seems to primarily affect the membrane and results in haemolysis. The use of antioxidants in vitro reduces the generation of pro-oxidants. To evaluate the impact of vitamins C (VitC) and E (VitE) supplementation in SCA patients, patients over 18 years were randomly assigned to receive VitC 1400 mg + VitE 800 mg per day or placebo orally for 180 d. Eighty-three patients were enrolled (44 vitamins, 39 placebo), median age 27 (18-68) years, 64% female. There were no significant differences between the two groups regarding clinical complications or baseline laboratorial tests. Sixty percent of the patients were VitC deficient, 70% were VitE deficient. Supplementation significantly increased serum VitC and E. However, no significant changes in haemoglobin levels were observed, and, unexpectedly, there was a significant increase in haemolytic markers with vitamin supplementation. In conclusion, VitC + VitE supplementation did not improve anaemia and, surprisingly, increased markers of haemolysis in patients with SCA and S-ß(0) -thalassaemia. The exact mechanisms to explain this findings and their clinical significance remain to be determined.

Complete response to carboplatin, gemcitabine, and paclitaxel in a patient with advanced metastatic renal medullary carcinoma.

Renal medullary carcinoma (RMC) is a rare and aggressive malignancy seen primarily in patients with sickle-cell trait. We report a complete response to carboplatin, paclitaxel, and gemcitabine in a patient with advanced metastatic RMC.

Increased adhesive properties of neutrophils in sickle cell disease may be reversed by pharmacological nitric oxide donation.

Increased leukocyte adhesion to vascular endothelium contributes to vaso-occlusion in sickle cell disease. Since nitric oxide bioavailability is decreased in sickle cell disease and nitric oxide may inhibit leukocyte adhesion, we investigated whether stimulation of NO-signaling pathways can reduce the adhesive properties of neutrophils from sickle cell disease individuals (sickle cell diseaseneu). sickle cell diseaseneu presented greater adhesion in vitro to both fibronectin and ICAM-1 than control neutrophils. Co-incubation of sickle cell diseaseneu with the nitric oxide-donor agents, sodium nitroprusside and dietheylamine NONOate (DEANO), and the guanylate cyclase stimulator, BAY41-2272, all significantly reduced the increased adhesion to fibronectin/ICAM-1. Oxadiazolo[4,3-a]quinoxalin-1-one, a guanylate cyclase inhibitor, reversed sodium nitroprusside/DEANO-diminished adhesion to fibronectin, implicating cGMP-dependent signaling in this mechanism. Interestingly, intracellular cGMP was significantly higher in neutrophils from sickle cell disease individuals on hydroxyurea (sickle cell diseaseHUneu). Accordingly, sickle cell diseaseHUneu adhesion to fibronectin/ICAM-1 was significantly lower than that of sickle cell diseaseneu. Agents that stimulate the nitric oxide/cGMP-dependent pathway may have beneficial effects on leukocyte function if used in these subjects.

Tunable delocalization of unpaired electrons of nitroxide radicals for sickle-cell disease drug improvements.

Hydroxyurea is a drug recently approved to treat sickle cell diseases. Hydroxyurea benefits the patients by increasing the level of fetal hemoglobin via a nitroxide radical pathway. Here, we report an unpaired-electron-delocalization approach to tune the stability of nitroxide radicals. In this approach, the substitution by an unsaturated alkyl group containing conjugated C=C double bonds for the hydrogen on the nitrogen atom attached to the hydroxyl of hydroxyurea can significantly increase its ability to generate nitroxide radical. Furthermore, the increase can be remarkably enhanced by increasing the number of conjugated C=C double bonds. For a hydroxyurea derivative that contains two conjugated C=C double bonds, the reaction rate to generate its radical is 118 times faster than that of hydroxyurea, and for a hydroxyurea derivative containing 20 conjugated C=C double bonds, the reaction rate to form its radical is 238 times faster than that of hydroxyurea. For this reason, hydroxyurea derivatives with conjugated C=C double bonds may constitute new potential drugs for the treatment of sickle-cell diseases.

Prognostic significance of early vaso-occlusive complications in children with sickle cell anemia.

Sickle cell anemia (SS) is highly phenotypically variable, and early predictors of outcome could guide clinical care. To determine whether early vaso-occlusive complications predicted subsequent adverse outcomes in the Dallas Newborn Cohort, we studied all members with SS or sickle-beta0-thalassemia who presented in their first year of life and had 5 years or more of follow-up. We defined 3 potential early predictors: hospitalizations in the first 3 years of life for (1) painful events other than dactylitis, (2) dactylitis, and (3) acute chest syndrome (ACS). We studied the associations of these predictors with the following late adverse outcomes (occurring after the third birthday): death, first overt stroke, use of disease-modifying therapy, and hospitalizations for pain events and ACS. None of the early events predicted death or stroke. Early pain and ACS both predicted a modest, temporary increase in the number of later painful episodes, but early ACS strongly increased the odds of more frequent ACS throughout childhood. Dactylitis had limited utility as a predictor. Although we still lack a useful prognostic framework for young children with SS, those who experience early ACS might be candidates for higher risk interventions to mitigate or cure their disease.

The effect of hydroxyurea on the coagulation system in sickle cell anemia and beta-thalassemia intermedia patients: a preliminary study.

Hydroxyurea (HU) has been shown to reduce the frequency of vaso-occlusive manifestations in both adults and children with sickle cell disease (SCD), and the induction of hemoglobin F (HbF) is thought to be the underlying mechanism responsible for clinical improvement in some patients. However, there exists no good correlation between the amount of HbF increase and clinical response. Recent studies suggest that increased activity of the coagulation system may be important in the pathogenesis of vascular occlusion in sickle cell disease. To analyze the effect of HU on the coagulation system in children, the authors studied the levels of some coagulation factors and natural inhibitors. Eleven children who had been treated with HU because of SCD (5 patients), sickle-beta-thalassemia (3 patients), and beta-thalassemia intermedia (3 patients) were enrolled in the study. Levels of the coagulation factors II, V, VII, VIII, IX, X, XI, and XII, and of protein C and protein S, prothrombin times, activated partial thromboplastine times, thrombin times, and reptilase times were measured before the treatment and at the 5th or 6th months of HU therapy when the patients were in a steady-state condition. There was a decrease in all of the coagulation factors except for FIX and FXII and in inhibitors such as protein C and protein S. However, statistically significant decreases were observed only in factor VIII and protein C levels. The rates of decrease were 54.8 and 12.5% (p = .015 and p = .018) in FVIII and protein C, respectively. This result shows that HC has significant effects on the coagulation and natural inhibitory systems.

Optical tweezers for measuring red blood cell elasticity: application to the study of drug response in sickle cell disease.

The deformability of erythrocytes is a critical determinant of blood flow in microcirculation. By capturing red blood cells (RBC) with optical tweezers and dragging them through a viscous fluid we were able to measure their overall elasticity. We measured, and compared, the RBC deformability of 15 homozygous patients (HbSS) including five patients taking hydroxyurea (HU) for at least 6 months (HbSS/HU), 10 subjects with sickle cell trait (HbAS) and 35 normal controls. Our results showed that the RBC deformability was significantly lower in haemoglobin S (HbS) subjects (HbSS and HbAS), except for HbSS/HU cells, whose deformability was similar to the normal controls. Our data showed that the laser optical tweezers technique is able to detect differences in HbS RBC from subjects taking HU, and to differentiate RBC from normal controls and HbAS, indicating that this is a very sensitive method and can be applied for detection of drug-response in sickle cell disease.

Hydroxyurea promotes the reduction of spontaneous BFU-e to normal levels in SS and S/beta thalassemic patients.

We have studied the effects of hydroxyurea on growth and differentiation of early erythroid progenitor cells (BFU-e) from peripheral blood of sickle cell disease patients (five SS and two Hb S/beta-thalassemia) in the presence or absence of exogenous stimulating factors. When the mononuclear cells from the sickle cell disease patients were cultured at diagnosis (before hydroxyurea treatment), there was an increased number of BFU-e in relation to controls (p < 0.05, Wilcoxon test) when cells were grown in the presence or absence of 5637 conditioned medium and erythropoietin. Colonies that developed in the absence of added growth factors were considered "spontaneous". A significant difference was observed after hydroxyurea treatment in the number of BFU-e obtained in the presence and absence of stimulus, with a higher reduction in the spontaneous BFU-e number. As expected, there was an increased Hb F level in these patients when compared with their pretreatment levels. There was no correlation between spontaneous BFU-e and hemoglobin levels in all patients studied.