The SickKids Caribbean Initiative to improve care for children with cancer and blood disorders.

To improve pediatric hematology and oncology outcomes, there is a recognized potential for partnerships between low- and high-resource institutions within health care systems. The SickKids Caribbean Initiative is a partnership between health care professionals at the Hospital for Sick Children in Toronto, Canada, and seven Caribbean institutions across six countries (Bahamas, Barbados, Jamaica, Saint Lucia, Saint Vincent and the Grenadines, and Trinidad and Tobago). The primary aim of the SickKids Caribbean Initiative has been to improve the outcomes and the quality of life of children in the Caribbean aged <18 years who have cancer and blood disorders. This article describes five key activities undertaken within the SickKids Caribbean Initiative, including providing education and training, assisting with case consultations and diagnostic services, developing local oncology databases, engaging in advocacy and ensuring stakeholder engagement, and coordinating administration and project management.

Las colaboraciones de instituciones de recursos bajos y altos dentro de los sistemas de atención de salud tienen un potencial reconocido para mejorar las respuestas a los tratamientos hematológicos y oncológicos pediátricos. La iniciativa SickKids para el Caribe es una asociación entre profesionales de la salud del Hospital for Sick Children de Toronto (Canadá) y siete instituciones de seis países del Caribe (Bahamas, Barbados, Jamaica, Santa Lucía, San Vicente y las Granadinas y Trinidad y Tabago). El objetivo principal de la iniciativa SickKids para el Caribe ha sido mejorar la respuesta a los tratamientos y la calidad de vida de los menores de 18 años del Caribe con cáncer o trastornos hematológicos. En este artículo se describen cinco actividades clave emprendidas en el marco de la iniciativa SickKids para el Caribe, consistentes en impartir formación y capacitación, prestar asistencia en materia de consultas de pacientes y servicios de diagnóstico, crear bases de datos locales en el área de la oncología, participar en actividades de promoción y garantizar la participación de las partes interesadas, y coordinar la administración y gestión de proyectos.

Há um potencial reconhecido para parcerias entre instituições com poucos e muitos recursos dentro dos sistemas de saúde para melhorar os resultados de hematologia e oncologia pediátricas. A iniciativa SickKids no Caribe é uma parceria entre profissionais de saúde do Hospital for Sick Children em Toronto, Canadá, e sete instituições em seis países do Caribe (Bahamas, Barbados, Jamaica, Santa Lúcia, São Vicente e Granadinas e Trinidad e Tobago). O objetivo principal da iniciativa SickKids no Caribe tem sido melhorar os desfechos e a qualidade de vida das crianças caribenhas com menos de 18 anos que têm câncer e doenças hematológicas. Este artigo descreve cinco atividades principais realizadas no âmbito da iniciativa SickKids no Caribe: oferecimento de educação e capacitação; assistência em consultas de casos e serviços diagnósticos; desenvolvimento de bancos de dados locais em oncologia; promoção da causa, assegurando o envolvimento das partes interessadas; e coordenação da administração e da gestão de projetos.

Evolution of Extracranial Internal Carotid Artery Disease in Children With Sickle Cell Anemia.

BACKGROUND: Cerebral arteriopathy in patients with sickle cell anemia mainly affects the intracranial anterior circulation. However, the extracranial internal carotid artery (eICA) can also be stenosed and responsible for ischemic lesions. In children with sickle cell anemia, we perform routine annual Doppler ultrasound assessment of the eICA and magnetic resonance imaging with 3-dimensional time-of-flight magnetic resonance angiography of the Willis circle and neck arteries in those with abnormal velocity. Our aim was to report the evolution of eICA stenoses from 2011 to the present as a function of therapy in a retrospective case-series study. We hypothesized that chronic transfusion (CTT) would be more effective than hydroxyurea and simple observation on the evolution of eICA stenosis. METHODS: Eligibility criteria were a history of eICA velocity ≥160 cm/s with a minimum Doppler and magnetic resonance imaging follow-up of 1 year. eICAs were graded for stenosis according to NASCET (The North American Symptomatic Carotid Endarterectomy Trial). Magnetic resonance imaging was investigated for ischemic lesions. Treatment with hydroxyurea and CTT were obtained from the chart review. RESULTS: Fifty-four patients were included. Eight patients had a stroke history. The median (range) follow-up was 4.7 years (1.1-9.2 years). On the first neck magnetic resonance angiography, stenosis was present in 48/54 (89%) patients. Kinking was found in 39/54 (72%) patients. On the last neck magnetic resonance angiography, the proportion of patients with eICA stenosis decreased to 39/54 (72%). ICA occlusion occurred in 5 patients despite CTT. Three patients had carotid webs without intracranial stenosis. The proportion of patients with improvement in stenosis score was 8% with no treatment intensification, 20% with hydroxyurea, and 48% with CTT (P=0.016). The mean (SD) change per year in stenosis score was 0.40 (0.60) without intensification, 0.20 (0.53) with hydroxyurea, and -0.18 (0.55) with CTT (P=0.006). Ischemic lesions were present initially in 46% of patients, and the incidence of progressive ischemic lesions was 2.5 events/100 patient-years. Cox regression analysis showed that the initial score for eICA stenosis was a significant predictive factor for the risk of new silent cerebral infarct events. CONCLUSIONS: Our study reinforces the need to assess cervical arteries for better prevention of cerebral ischemia and encourage initiation of CTT in sickle cell anemia children with eICA stenosis.

Anticoagulation strategies and recurrence of venous thromboembolic events in patients with sickle cell disease: a systematic review and meta-analysis.

Sickle cell disease (SCD) results in many complications including an increased risk of developing venous thromboembolic events (VTEs) and an increased risk of mortality as a result. We conducted a systematic review using multiple databases to compare the efficacy of different anticoagulation in preventing recurrence, development of bleeding, progression of thrombus, and mortality in patients with SCD and a venous thrombotic event. Eight hundred seventy-one studies were screened and six studies were included. Among patients with SCD who experienced a VTE and were anticoagulated, the overall recurrence of VTE was 27.6% (95%CI 23.5-31.9). The overall progression to pulmonary embolism (PE) was 11.7% (95%CI 4.3-22.1). The overall bleeding rate was 14.1% (95%CI 7.8-21.9) and the overall mortality was 3.7% (95%CI 0.8-8.5). Based on observational studies, there did not appear to be differences between anticoagulant classes for the above adverse outcomes. Significant heterogeneity in the patient population and outcome measures limited the interpretation of the results. More studies, specifically randomized trials, are needed to help direct appropriate management of VTE's in patients with sickle cell disease (PROSPERO ID: 236,208).

Xanthine Oxidase Drives Hemolysis and Vascular Malfunction in Sickle Cell Disease.

OBJECTIVE: Chronic hemolysis is a hallmark of sickle cell disease (SCD) and a driver of vasculopathy; however, the mechanisms contributing to hemolysis remain incompletely understood. Although XO (xanthine oxidase) activity has been shown to be elevated in SCD, its role remains unknown. XO binds endothelium and generates oxidants as a byproduct of hypoxanthine and xanthine catabolism. We hypothesized that XO inhibition decreases oxidant production leading to less hemolysis. Approach and Results: Wild-type mice were bone marrow transplanted with control (AA) or sickle (SS) Townes bone marrow. After 12 weeks, mice were treated with 10 mg/kg per day of febuxostat (Uloric), Food and Drug Administration-approved XO inhibitor, for 10 weeks. Hematologic analysis demonstrated increased hematocrit, cellular hemoglobin, and red blood cells, with no change in reticulocyte percentage. Significant decreases in cell-free hemoglobin and increases in haptoglobin suggest XO inhibition decreased hemolysis. Myographic studies demonstrated improved pulmonary vascular dilation and blunted constriction, indicating improved pulmonary vasoreactivity, whereas pulmonary pressure and cardiac function were unaffected. The role of hepatic XO in SCD was evaluated by bone marrow transplanting hepatocyte-specific XO knockout mice with SS Townes bone marrow. However, hepatocyte-specific XO knockout, which results in >50% diminution in circulating XO, did not affect hemolysis levels or vascular function, suggesting hepatocyte-derived elevation of circulating XO is not the driver of hemolysis in SCD. CONCLUSIONS: Ten weeks of febuxostat treatment significantly decreased hemolysis and improved pulmonary vasoreactivity in a mouse model of SCD. Although hepatic XO accounts for >50% of circulating XO, it is not the source of XO driving hemolysis in SCD.

Physical Impairment and Function in Children and Adolescents With Sickle Cell Disease: A Systematic Review.

OBJECTIVE: To examine physical impairments and physical function in children and adolescents with sickle cell disease (SCD). DATA SOURCES: PubMed, Embase (embase.com), Cumulative Index to Nursing and Allied Health (EBSCO), Cochrane Central Register of Controlled Trials (Wiley), and Dissertations and Theses (ProQuest) were searched from January 1, 1990, to September 25, 2020. References retrieved were required to include a term for SCD and a term for physical impairments or physical function. Results were limited to articles with children and adolescents and in the English language. STUDY SELECTION: A total of 3054 nonduplicate articles were independently screened by 2 reviewers, resulting in 240 articles for full-text review. The full-text review, performed by 2 independent reviewers, resulted in 67 articles. DATA EXTRACTION: Data were extracted from each full text to a custom Excel document by a single reviewer and were verified by a secondary reviewer. DATA SYNTHESIS: The studies identified in this systematic review offer evidence that children and adolescents with SCD demonstrate physical impairments and physical function limitations compared with control participants as noted by varying percentages in deficits up to 19%-58% in muscle and bone composition and/or symptoms, muscle strength, cardiopulmonary function, motor performance, physical activity, and physical function domains of quality of life questionnaires. CONCLUSIONS: Children and adolescents with SCD present with physical impairments and physical function limitations. Scientists and clinicians should consider developing collaborative standards to define and objectively measure physical impairment and function in this population to comprehensively examine the underlying factors that contribute to physical impairments and function.

Pilot assessment of omega-3 fatty acids and potassium thiocyanate in sickle cell anemia patients with conditional peak systolic cerebral artery blood velocity.

OBJECTIVE: The purpose of this pilot study was to explore the effect of omega-3 fatty acids and potassium thiocyanate on conditional peak systolic cerebral artery blood velocity in children with sickle cell anemia (SCA). METHODS: Transcranial doppler ultrasonography (TCD) was done on 232 SCA children, and 21 found with conditional peak systolic blood velocity (PSV) of 200-249 cm/s in internal carotid, middle or anterior cerebral arteries. These were randomized to receive omega-3 fatty acids and potassium thiocyanate with standard treatment of SCA (test group, N = 14), or standard treatment only (control group, N = 7). After 3 months of treatment, PSV was measured again. RESULTS: Right middle cerebral artery PSV was significantly reduced in the test relative to the control groups (p = 0.04). PSV returned to normal in 79% of the test versus 43% of the control group; and increased to abnormal in one member of the control group, but none of the test group. CONCLUSIONS: The pilot data suggest that in SCA, omega-3 fatty acids and potassium thiocyanate might reduce conditional blood velocity to normal, or prevent progression to abnormal values. A larger, randomized, clinical trial is required to further address the current gap in management of conditional TCD blood velocity.

Non-invasive urinary biomarkers of renal function in sickle cell disease: an overview.

Sickle cell disease (SCD) is a hereditary condition characterized by homozygosis of the hemoglobin S (HbS) gene. Marked morbimortality is observed due to chronic hemolysis, endothelial injury, and episodes of vaso-occlusion, which leads to multi-organ damage. Renal impairment is common and may have different presentations, such as deficiency in urinary acidification or concentration, glomerulopathies, proteinuria, and hematuria, frequently resulting in end-stage renal disease (ESRD). Novel biomarkers of renal function, such as kidney injury molecule 1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) and monocyte chemoattractant protein 1 (MCP-1) are being studied in order to enable early diagnosis of kidney damage in SCD.

Patient-Centered eHealth Interventions for Children, Adolescents, and Adults With Sickle Cell Disease: Systematic Review.

BACKGROUND: Sickle cell disease is an inherited blood disorder that affects over 100,000 Americans. Sickle cell disease-related complications lead to significant morbidity and early death. Evidence supporting the feasibility, acceptability, and efficacy of self-management electronic health (eHealth) interventions in chronic diseases is growing; however, the evidence is unclear in sickle cell disease. OBJECTIVE: We systematically evaluated the most recent evidence in the literature to (1) review the different types of technological tools used for self-management of sickle cell disease, (2) discover and describe what self-management activities these tools were used for, and (3) assess the efficacy of these technologies in self-management. METHODS: We reviewed literature published between 1995 and 2016 with no language limits. We searched MEDLINE, EMBASE, CINAHL, PsycINFO, and other sources. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two independent reviewers screened titles and abstracts, assessed full-text articles, and extracted data from articles that met inclusion criteria. Eligible studies were original research articles that included texting, mobile phone-based apps, or other eHealth interventions designed to improve self-management in pediatric and adult patients with sickle cell disease. RESULTS: Of 1680 citations, 16 articles met all predefined criteria with a total of 747 study participants. Interventions were text messaging (4/16, 25%), native mobile apps (3/16, 19%), Web-based apps (5/16, 31%), mobile directly observed therapy (2/16, 13%), internet-delivered cognitive behavioral therapy (2/16, 13%), electronic pill bottle (1/16, 6%), or interactive gamification (2/16, 13%). Interventions targeted monitoring or improvement of medication adherence (5/16, 31%); self-management, pain reporting, and symptom reporting (7/16, 44%); stress, coping, sleep, and daily activities reporting (4/16, 25%); cognitive training for memory (1/16, 6%); sickle cell disease and reproductive health knowledge (5/16, 31%); cognitive behavioral therapy (2/16, 13%); and guided relaxation interventions (1/16, 6%). Most studies (11/16, 69%) included older children or adolescents (mean or median age 10-17 years; 11/16, 69%) and 5 included young adults (≥18 years old) (5/16, 31%). Sample size ranged from 11 to 236, with a median of 21 per study: <20 in 6 (38%), ≥20 to <50 in 6 (38%), and >50 participants in 4 studies (25%). Most reported improvement in self-management-related outcomes (15/16, 94%), as well as high satisfaction and acceptability of different study interventions (10/16, 63%). CONCLUSIONS: Our systematic review identified eHealth interventions measuring a variety of outcomes, which showed improvement in multiple components of self-management of sickle cell disease. Despite the promising feasibility and acceptability of eHealth interventions in improving self-management of sickle cell disease, the evidence overall is modest. Future eHealth intervention studies are needed to evaluate their efficacy, effectiveness, and cost effectiveness in promoting self-management in patients with sickle cell disease using rigorous methods and theoretical frameworks with clearly defined clinical outcomes.

[Rare diseases recognizable from blood smears]. / Seltene Erkrankungen am Blutbild erkennen.

The examination of peripheral blood smears is not only essential for the differential diagnostics of hematological diseases but can also provide important indications for general internal diseases, infections, hereditary diseases and poisoning. By the systematic analysis of a blood smear for alterations to thrombocytes, erythrocytes and leukocytes, a blood smear investigation can make a decisive contribution to the formulation of a diagnosis. In this way evidence of rare diseases can also be gained when taking the corresponding clinical findings into consideration.

Arterial Stiffness Impairment in Sickle Cell Disease Associated With Chronic Vascular Complications: The Multinational African CADRE Study.

BACKGROUND: Although a blood genetic disease, sickle cell disease (SCD) leads to a chronic vasculopathy with multiple organ involvement. We assessed arterial stiffness in SCD patients and looked for associations between arterial stiffness and SCD-related vascular complications. METHODS: The CADRE (Coeur Artères et Drepanocytose, ie, Heart Arteries and Sickle Cell Disease) study prospectively recruited pediatric and adult SCD patients and healthy controls in Cameroon, Ivory Coast, Gabon, Mali, and Senegal. Patients underwent clinical examination, routine laboratory tests (complete blood count, serum creatinine level), urine albumin/creatinine ratio measure, and a measure of carotid-femoral pulse wave velocity (cf-PWV) and augmentation index (AI) at a steady state. The clinical and biological correlates of cf-PWV and AI were investigated by using a multivariable multilevel linear regression analysis with individuals nested in families further nested in countries. RESULTS: Included were 3627 patients with SCD and 943 controls. Mean cf-PWV was lower in SCD patients (7.5±2.0 m/s) than in controls (9.1±2.4 m/s, P<0.0001), and lower in SS-Sß(0) than in SC-Sß(+) phenotypes. AI, corrected for heart rate, increased more rapidly with age in SCD patients and was higher in SCD than in control adults. cf-PWV and AI were independently associated with age, sex, height, heart rate, mean blood pressure, hemoglobin level, country, and hemoglobin phenotype. After adjustment for these correlates, cf-PWV and AI were associated with the glomerular filtration rate and osteonecrosis. AI was also associated with stroke, pulmonary hypertension, and priapism, and cf-PWV was associated with microalbuminuria. CONCLUSIONS: PWV and AI are deeply modified in SCD patients in comparison with healthy controls. These changes are independently associated with a lower blood pressure and a higher heart rate but also with the hemoglobin phenotype. Moreover, PWV and AI are associated with several SCD clinical complications. Their prognostic value will be assessed at follow-up of the patients.

Sickle Mice Are Sensitive to Hypoxia/Ischemia-Induced Stroke but Respond to Tissue-Type Plasminogen Activator Treatment.

BACKGROUND AND PURPOSE: The effects of lytic stroke therapy in patients with sickle cell anemia are unknown, although a recent study suggested that coexistent sickle cell anemia does not increase the risk of cerebral hemorrhage. This finding calls for systemic analysis of the effects of thrombolytic stroke therapy, first in humanized sickle mice, and then in patients. There is also a need for additional predictive markers of sickle cell anemia-associated vasculopathy. METHODS: We used Doppler ultrasound to examine the carotid artery of Townes sickle mice tested their responses to repetitive mild hypoxia-ischemia- and transient hypoxia-ischemia-induced stroke at 3 or 6 months of age, respectively. We also examined the effects of tPA (tissue-type plasminogen activator) treatment in transient hypoxia-ischemia-injured sickle mice. RESULTS: Three-month-old sickle cell (SS) mice showed elevated resistive index in the carotid artery and higher sensitivity to repetitive mild hypoxia-ischemia-induced cerebral infarct. Six-month-old SS mice showed greater resistive index and increased flow velocity without obstructive vasculopathy in the carotid artery. Instead, the cerebral vascular wall in SS mice showed ectopic expression of PAI-1 (plasminogen activator inhibitor-1) and P-selectin, suggesting a proadhesive and prothrombotic propensity. Indeed, SS mice showed enhanced leukocyte and platelet adherence to the cerebral vascular wall, broader fibrin deposition, and higher mortality after transient hypoxia-ischemia. Yet, post-transient hypoxia-ischemia treatment with tPA reduced thrombosis and mortality in SS mice. CONCLUSIONS: Sickle mice are sensitive to hypoxia/ischemia-induced cerebral infarct but benefit from thrombolytic treatment. An increased resistive index in carotid arteries may be an early marker of sickle cell vasculopathy.

Hepatobiliary Ultrasonographic Abnormalities in Adult Patients with Sickle Cell Anaemia in Steady State in Ile-Ife, Nigeria.

BACKGROUND: Sickle cell anaemia (SCA) is associated with structural manifestations in the hepatobiliary axis. This study aimed to investigate the hepatobiliary ultrasonographic abnormalities in adult patients with sickle cell anaemia in steady state attending the Haematology clinic of a federal tertiary health institution in Ile-Ife, Nigeria. MATERIAL/METHODS: Basic demographic data as well as right upper abdominal quadrant ultrasonography of 50 consecutive sickle cell anaemia patients were compared with those of 50 age- and sex-matched subjects with HbAA as controls. RESULTS: Each of the study groups (patients and controls) comprised of 21 (42%) males and 29 (58%) females. The age range of the patients was 18-45 years with a mean (±SD) of 27.6±7.607 years, while that of the controls was 21-43 years with a mean (±SD) of 28.0±5.079 years (p=0.746). Amongst the patients, 32 (64%) had hepatomegaly, 15 (30%) cholelithiasis and 3 (6%) biliary sludge. Fourteen (28%) of the patients had normal hepatobiliary ultrasound findings. In the control group, one (2%) person had cholelithiasis, one (2%) biliary sludge, one (2%) fatty liver and none hepatomegaly. Forty-seven (94%) of the controls had normal hepatobiliary ultrasound findings. There was a statistically significant difference in the prevalence of hepatomegaly and cholelithiasis between the patients and controls (p value <0.001 for both comparisons). CONCLUSIONS: In this study, hepatomegaly, cholelithiasis and biliary sludge were the most common hepatobiliary ultrasound findings in patients with sickle cell anaemia. Ultrasonography is a useful tool for assessing hepatobiliary abnormalities in patients with sickle cell anaemia.

Intracranial Aneurysms in Sickle-Cell Disease Are Associated With the Hemoglobin SS Genotype But Not With Moyamoya Syndrome.

BACKGROUND AND PURPOSE: Intracranial aneurysms and aneurysmal subarachnoid hemorrhage may occur more frequently in sickle-cell disease (SCD), and this could be related to the sickle genotype and moyamoya syndrome seen in SCD. METHODS: Records from a total of 1002 patients with SCD attending 2 specialized adult hematologic services were retrospectively reviewed. We analyzed data of a cohort of 767 patients attending 1 SCD clinic between 2002 and 2013 and of 235 patients from the other clinic who have had neurovascular imaging between 2007 and 2014. RESULTS: We identified 4 patients in the cohort who had an aneurysmal subarachnoid hemorrhage during 9063 patient-years. The highest incidence rate was seen among women in the age group 30 to 39 years with the hemoglobin SS (HbSS) genotype (440 per 100 000 patient-years). Unruptured intracranial aneurysms were found in 20 of the 324 patients, who had imaging data; the prevalence was significantly higher in patients with HbSS genotype compared with other sickle genotypes with the highest prevalence (15%) observed in women in the age group 30 to 39 years. Fifty-one HbSS patients had a moyamoya vasculopathy, but only 3 of these had concomitant intracranial aneurysms. CONCLUSIONS: Intracranial aneurysms are common in HbSS SCD. There was also a trend toward more common occurrence of aneurysmal subarachnoid hemorrhage in HbSS; women in the age group 30 to 39 years were most at risk. There was no correlation between the occurrence of intracranial aneurysms and moyamoya syndrome.

[Increase in genetically determined anemia as a result of migration in Germany]. / Zunahme genetisch determinierter Anämien durch Migration in Deutschland.

BACKGROUND: Due to the increasing numbers of migrants and asylum seekers, hemoglobinopathies and glucose-6-phosphate dehydrogenase deficiency are no longer rare diseases in Germany. As a result of the current migration movements these genetically determined diseases will gain in importance. METHODS: Following a literature search the prevalence of the original endemic regions was compiled and compared to the population composition based on statistical data on migrants, foreign residents and asylum seekers in Germany. RESULTS: In the endemic regions a prevalence of 40 % and sometimes higher have been found for glucose-6-phosphate dehydrogenase deficiency and hemoglobinopathies. The number of people arriving in Germany from these endemic regions is rapidly increasing. CONCLUSION: Due to the high number of asylum seekers arriving from Asian and African regions, genetic erythrocyte defects will gain importance in the differential diagnosis of anemia; therefore, medical education and training must incorporate heightened awareness of risks, diagnostics and therapy of these disease patterns.

Hypoxic response contributes to altered gene expression and precapillary pulmonary hypertension in patients with sickle cell disease.

BACKGROUND: We postulated that the hypoxic response in sickle cell disease (SCD) contributes to altered gene expression and pulmonary hypertension, a complication associated with early mortality. METHODS AND RESULTS: To identify genes regulated by the hypoxic response and not other effects of chronic anemia, we compared expression variation in peripheral blood mononuclear cells from 13 subjects with SCD with hemoglobin SS genotype and 15 subjects with Chuvash polycythemia (VHL(R200W) homozygotes with constitutive upregulation of hypoxia-inducible factors in the absence of anemia or hypoxia). At a 5% false discovery rate, 1040 genes exhibited >1.15-fold change in both conditions; 297 were upregulated and 743 downregulated including MAPK8 encoding a mitogen-activated protein kinase important for apoptosis, T-cell differentiation, and inflammatory responses. Association mapping with a focus on local regulatory polymorphisms in 61 patients with SCD identified expression quantitative trait loci for 103 of these hypoxia response genes. In a University of Illinois SCD cohort, the A allele of a MAPK8 expression quantitative trait locus, rs10857560, was associated with precapillary pulmonary hypertension defined as mean pulmonary artery pressure ≥25 mm Hg and pulmonary capillary wedge pressure ≤15 mm Hg at right heart catheterization (allele frequency, 0.66; odds ratio, 13.8; n=238). This association was confirmed in an independent Walk-Treatment of Pulmonary Hypertension and Sickle Cell Disease With Sildenafil Therapy cohort (allele frequency, 0.65; odds ratio, 11.3; n=519). The homozygous AA genotype of rs10857560 was associated with decreased MAPK8 expression and present in all 14 of the identified precapillary pulmonary hypertension cases among the combined 757 patients. CONCLUSIONS: Our study demonstrates a prominent hypoxic transcription component in SCD and a MAPK8 expression quantitative trait locus associated with precapillary pulmonary hypertension.

First Ischemic Stroke in Sickle-Cell Disease: Are There Any Adult Specificities?

BACKGROUND AND PURPOSE: There is little evidence about characteristics of ischemic stroke (IS) occurring in adults with sickle-cell disease (SCD). The objective of this study was to assess characteristics of first-ever IS in adults with SCD and to assess whether they differ from those occurring in child patients with SCD. METHODS: Adult and child individuals with SCD who had a first-ever IS were identified from cohorts of patients followed up in an adult and a child sickle cell referral center. Mechanisms of IS were determined by consensus meeting from all available explorations using the following predefined classification: Vasculopathy, cardioembolism, other defined cause, and undetermined. Treatment and stroke recurrences were recorded from prospective follow-up performed in the referral centers. RESULTS: Twenty-nine adults and 26 children had a first-ever IS; mean age (SD) was 7.1 (4.3) and 32.3 (11.6), respectively. With regard to IS mechanism, vasculopathy was less often the cause of IS in adults (12/29, 41%) than in children (24/26, 92%; P<0.001). Other causes of IS in adults were cardioembolism in 7, antiphospholipid syndrome in 1, toxic (cocaine) in 1, and undetermined in 8. Adults with SCD had a higher risk of recurrent stroke (23.1% [7.0-39.2] at 5 years) compared with children (1 recurrence only; P log rank=0.046) despite exchange-blood transfusion in patients with vasculopathy. CONCLUSIONS: First-ever IS occurring in adults with SCD has specificities that justify further studies conducted in adults with SCD to improve understanding and management.

Impact of Hydroxyurea to Treat Haematological Disorders on Male Fertility: Two Case Reports and a Systematic Review.

PURPOSE: Hydroxyurea (HU) is a cytoreductive agent used as standard treatment option for sickle cell anaemia/disease (SCD), essential thrombocythemia (ET), and polycythaemia vera (PV). Despite its overall good safety profile, its use also in relatively young patients raises an interest on its potential impact on spermatogenesis. To perform a systematic review of all published articles investigating fertility in male patients affected by SCD, ET, and PV and treated with HU. Two paradigmatic case reports of patients affected by PV and ET, respectively, have been also reported. MATERIALS AND METHODS: PubMed, EMBASE, and Cochrane databases were queried for all the published studies indexed up to November 15th, 2022. A combination of the following keywords was used: "hydroxyurea," "fertility," "male," "sperm," "sickle cell anaemia," "sickle cell disease," "essential thrombocythemia," "polycythaemia vera." RESULTS: Of 48 articles identified, 8 studies, involving 161 patients, were eligible for inclusion. Overall, the number of spermatogonia per round cross section of seminiferous tubule were decreased in patients with SCD compared to healthy males. HU treatment was always associated with a worsening of semen parameters, even up to azoospermia. Notably, treatment discontinuation was associated with an improvement of semen parameters and a trend toward normalization in the case of PV and ET, with a less clear amelioration in men with SCD. In both our patients with either PV or ET, HU discontinuation was associated with a significant improvement of spermatogenesis with successful spontaneous pregnancies. CONCLUSIONS: Published evidence do not consistently report normalization of spermatogenesis after HU discontinuation in SCD cases. Conversely, the literature almost consistently reported an improvement of semen parameters at the discontinuation of HU therapy in PV and ET cases. Our real-life two cases confirmed those findings. The willing of fatherhood and the need for effective fertility treatment warrant further research to improve work-up management in men with hematological disorders.

[Management of acute complications of sickle cell disease]. / Prise en charge des complications aiguës de la drépanocytose.

MANAGEMENT OF ACUTE COMPLICATIONS OF SICKLE CELL DISEASE. Acute complications are the most frequent causes of hospitalization and morbidity in patients with sickle cell disease. Vaso-occlusive crisis are responsible of more than 90% of hospitalization, but numerous acute complications can affect multiples organ or function, that may be life-threatening. Thus, a single reason for hospitalization may include many complications such as worsening of an anemia, vascular disease (stroke, thrombosis, priapism), acute chest syndrome, liver or spleen sequestration. Evaluation of acute complications includes the understanding of chronic complications, particularities related to patient's age, the search for a triggering factor and a differential diagnosis. Analgesia and venous access difficulties, post transfusion immunization, medical history of the patient can make the management of acute complication particularly complex.

PRISE EN CHARGE DES COMPLICATIONS AIGUËS DE LA DRÉPANOCYTOSE. Les complications aiguës représentent la cause la plus fréquente de recours au système de soins et de morbi-mortalité des patients porteurs de drépanocytose. Quoique dominées par les crises vaso-occlusives osseuses qui constituent plus de 90 % des hospitalisations, les complications aiguës peuvent toucher de nombreux organes ou fonctions et menacer le pronostic vital du patient. Ainsi, un même motif d'hospitalisation peut être l'occasion d'une décompensation d'une anémie, d'une atteinte vasculaire (AVC, thrombose, priapisme), d'un syndrome thoracique aigu, d'une séquestration splénique ou hépatique. L'évaluation d'une complication aiguë doit prendre en compte l'histoire médicale du patient, les particularités liées à l'âge, la recherche d'un facteur déclenchant et d'un diagnostic différentiel. Les difficultés d'abord veineux, d'antalgie, les particularités transfusionnelles liées à la maladie et le parcours de soins de certains patients peuvent rendre la prise en charge particulièrement complexe.