OBJECTIVES: The aim of this study was to identify a unifying cardiac pathophysiology that explains the cardiac pathological features in sickle cell disease (SCD). BACKGROUND: Cardiopulmonary complications, the leading cause of adult death in SCD, are associated with heart chamber dilation, diastolic dysfunction, elevated tricuspid regurgitant jet velocity (TRV), and pulmonary hypertension. However, no unifying cardiac pathophysiology has been identified to explain these findings. METHODS: In a 2-part study, we first examined patients with SCD who underwent screening echocardiography during steady state at our institution. We then conducted a meta-analysis of cardiac studies in SCD. RESULTS: In the 134 patients with SCD studied (median age 11 years), significant enlargement of the left atrial volume was present (z-score 3.1, p = 0.002), shortening fraction was normal (37.6 ± 4.7%), and lateral and septal ratios of mitral velocity to early diastolic velocity of the mitral annulus (E/e') were severely abnormal in 8% and 14% of patients, respectively, indicating impaired diastolic function. Both TRV and lateral E/e' correlated with enlarged left atrial volume in SCD (p = 0.003 and p = 0.006, respectively). Meta-analysis of 68 studies confirmed significant left atrial diameter enlargement in patients with SCD compared with controls, evidence of diastolic dysfunction and enlarged left ventricular end-diastolic dimension with normal shortening fraction. The majority of patients with catheter-confirmed pulmonary hypertension had mild pulmonary venous hypertension consistent with restrictive cardiac physiology. CONCLUSIONS: Patients with SCD have a unique form of cardiomyopathy with restrictive physiology that is superimposed on hyperdynamic physiology and is characterized by diastolic dysfunction, left atrial dilation, and normal systolic function. This combination results in mild, secondary, pulmonary venous hypertension and elevated TRV. Sudden death is common in other forms of restrictive cardiomyopathy. Our finding of this unique restrictive cardiomyopathy may explain the increased mortality rates and sudden death seen in patients with SCD with mildly elevated TRV. Abstract source Full text Full text (PMC)

BACKGROUND: Data regarding pregnancy outcomes in sickle cell disease are conflicting. Previous studies are limited by small sample size, narrow geographic area, and a wide range of resource availability. OBJECTIVE: The purpose of this study was to examine the association between maternal sickle cell disease and adverse pregnancy outcomes in a contemporary North American cohort. STUDY DESIGN: We performed a retrospective cohort study of 2,027,323 women with singleton pregnancies delivered in California from 2005-2008. Deliveries at 42 6/7 weeks of gestation were excluded. Women with sickle cell disease were compared with control subjects. Maternal outcomes of interest included preeclampsia, preterm delivery, placental abruption, oligohydramnios, and cesarean delivery; neonatal outcomes included small for gestational age, anomalies, stillbirth, neonatal death, and infant death. RESULTS: The prevalence of sickle cell disease was 0.017%. Compared with control subjects, women with sickle cell disease were more likely to have limited prenatal care (7.4 vs 3.8%; P=.001), underlying chronic hypertension (2.3% vs 1.1%; P=.038), and fetal anomalies (14.0 vs 6.4%; P<.001). The increased odds of fetal anomalies persisted after adjustment for multiple confounders (odds ratio, 1.73; 95% confidence interval, 1.26-2.38). Women with sickle cell disease also had higher odds of severe preeclampsia (odds ratio, 3.75; 95% confidence interval, 2.21-6.38), preterm delivery (odds ratio, 2.50; 95% confidence interval, 1.93-3.21), small for gestational age (odds ratio, 1.96; 95% confidence interval, 1.18-3.25), and cesarean delivery (odds ratio, 1.93; 95% confidence interval, 1.40-2.67). CONCLUSION: Women with sickle cell disease are at high risk of maternal and neonatal morbidity. Low rates of fetal and neonatal death may reflect improved antenatal surveillance and management as compared with previous studies. The association between sickle cell disease and fetal anomalies warrants further investigation. Abstract source Full text

PURPOSE: To determine alterations in bulbar conjunctival microvascular haemodynamics in sickle cell retinopathy (SCR) subjects with focal macular thinning (FMT). METHODS: Conjunctival microcirculation imaging and spectral domain optical coherence tomography (SD-OCT) were performed in 22 subjects (eyes) diagnosed with SCR. Based on evaluation of SD-OCT retinal thickness maps, eyes were assigned to one of the two groups: with or without FMT. Conjunctival venular diameter and axial blood velocity were measured in multiple venules in each eye by customized image analysis algorithms. Measurements were then categorized into two vessel size groups (vessel size 1 and 2) and compared between FMT groups. A Pearson correlation coefficient was computed to assess the relationship between retinal thickness and axial blood velocity. RESULTS: Mean age, haematocrit, sickle cell haemoglobin type and median retinopathy score were not significantly different between the two groups (p ≥ 0.1). Retinal thickness in parafoveal and perifoveal temporal subfields was significantly lower in eyes with FMT as compared to eyes without FMT (p ≤ 0.04). There was a significant effect of FMT on axial blood velocity (p = 0.04), while the effect of vessel size was not significant (p = 0.4). In vessel size 1, axial blood velocity was lower in eyes with FMT than in eyes without FMT (p = 0.03), while in vessel size 2, there was no statistically significant difference between FMT groups (p = 0.1). In vessel size 1, there was a significant positive correlation between axial blood velocity and retinal thickness in the perifoveal (r = 0.48, p = 0.02) and parafoveal (r = 0.43, p = 0.04) temporal subfields. CONCLUSION: Conjunctival axial blood velocity in small venules is reduced in SCR subjects with focal macular thinning. Abstract source Full text Full text (PMC)

Community health workers are increasingly recognized as useful for improving health care and health outcomes for a variety of chronic conditions. Community health workers can provide social support, navigation of health systems and resources, and lay counseling. Social and cultural alignment of community health workers with the population they serve is an important aspect of community health worker intervention. Although community health worker interventions have been shown to improve patient-centered outcomes in underserved communities, these interventions have not been evaluated with sickle cell disease. Evidence from other disease areas suggests that community health worker intervention also would be effective for these patients. Sickle cell disease is complex, with a range of barriers to multifaceted care needs at the individual, family/friend, clinical organization, and community levels. Care delivery is complicated by disparities in health care: access, delivery, services, and cultural mismatches between providers and families. Current practices inadequately address or provide incomplete control of symptoms, especially pain, resulting in decreased quality of life and high medical expense. The authors propose that care and care outcomes for people with sickle cell disease could be improved through community health worker case management, social support, and health system navigation. This paper outlines implementation strategies in current use to test community health workers for sickle cell disease management in a variety of settings. National medical and advocacy efforts to develop the community health workforce for sickle cell disease management may enhance the progress and development of "best practices" for this area of community-based care. Abstract source Full text Full text (PMC)

BACKGROUND AND PURPOSE: The recommended treatment for ischemic stroke is tPA (tissue-type plasminogen activator). Although sickle cell disease (SCD) represents no known contraindication to tPA, National Heart Lung and Blood Institute of the National Institutes of Health recommended acute exchange transfusion for stroke in SCD, not tPA. Data on safety and outcomes of tPA in patients are needed to guide tPA use in SCD. METHODS: We matched patients from the American Heart Association and American Stroke Association Get With The Guidelines-Stroke registry with SCD to patients without SCD and compared usage, complications, and discharge outcomes after tPA. Multivariable logistic regression models using generalized estimating equations were used to assess outcomes. RESULTS: From 2 016 652 stroke patients admitted to Get With The Guidelines-Stroke sites in the United States, 832 SCD and 3328 non-SCD controls with no differences in admission National Institutes of Health Stroke Scale or blood pressure were identified. Neither the fraction receiving thrombolytic therapy (8.2% for SCD versus 9.4% non-SCD) nor symptomatic intracranial hemorrhage (4.9% of SCD versus 3.2% non-SCD; P=0.4502) was different. There was no difference in a prespecified set of outcome measures for those with SCD compared with controls. CONCLUSIONS: Coexistent SCD had no significant impact on the safety or outcome of thrombolytic therapy in acute ischemic stroke. Although the sample size is relatively small, these data suggest that adults with SCD and acute ischemic stroke should be treated with thrombolysis, if they otherwise qualify. Addition studies, however, should track the intracranial hemorrhage rate and provide information on other SCD-related care such as transfusion. Abstract source Full text

Sickle cell disease (SCD) is a hypercoagulable state. Patients exhibit increased platelet activation, high plasma levels of markers of thrombin generation, depletion of natural anticoagulant proteins, abnormal activation of the fibrinolytic system, and increased tissue factor expression, even in the non-crisis "steady state." Furthermore, SCD is characterized by an increased risk of thrombotic complications. The pathogenesis of coagulation activation in SCD appears to be multi-factorial, with contributions from ischemia-reperfusion injury and inflammation, hemolysis and nitric oxide deficiency, and increased sickle RBC phosphatidylserine expression. Recent studies in animal models suggest that activation of coagulation may contribute to the pathogenesis of SCD, but the data on the contribution of coagulation and platelet activation to SCD-related complications in humans are limited. Clinical trials of new generations of anticoagulants and antiplatelet agents, using a variety of clinical endpoints are warranted. Abstract source Full text Full text (PMC)

Children with sickle cell disease (SCD) have a significant vascular morbidity, especially cerebral macrovasculopathy (CV), detectable by transcranial Doppler. This study aimed to identify risk factors for CV using longitudinal biological and clinical data in a SCD newborn cohort followed at the Robert Debre Reference centre (n = 375 SS/Sβ(0) ). Median follow-up was 6·8 years (2677 patient-years). Among the 59 children presenting with CV, seven had a stroke. Overall, the incidence of CV was 2·20/100 patient-years [95% confidence interval (95% CI): 1·64-2·76] and the incidence of stroke was 0·26/100 patient-years (95% CI: 0·07-0·46). The cumulative risk of CV by age 14 years was 26·0% (95% CI: 20·0-33·3%). Risk factors for CV were assessed by a Cox model encompassing linear multivariate modelling of longitudinal quantitative variables. Years per upper-airway obstruction [Hazard ratio (HR) = 1·47; 95% CI: 1·05-2·06] or bronchial obstruction (HR = 1·76; 95% CI: 1·49-2·08) and reticulocyte count (HR = 1·82 per 50 × 10(9) /l increase; 95% CI: 1·10-3·01) were independent risk factors whereas fetal haemoglobin level (HR = 0·68 per 5% increase; 95% CI: 0·48-0·96) was protective. Alpha-thalassaemia was not protective in multivariate analysis (ancillary analysis n = 209). Specific treatment for upper or lower-airway obstruction and indirect targeting of fetal haemoglobin and reticulocyte count by hydroxycarbamide could potentially reduce the risk of CV. Abstract source Full text

Sickle cell disease (SCD), the most common genetic hemolytic anemia worldwide, affects 250,000 births annually. In the United States, SCD affects approximately 100,000 individuals, most of African descent. Hemoglobin S (HbS) results from a glutamate-to-valine mutation of the sixth codon of the β-hemoglobin allele; the homozygous genotype (HbSS) is associated with the most prevalent and severe form of the disease. Other SCD genotypes include HbSC, composed of one HbS allele and one HbC (glutamate-to-lysine mutation) allele; and HbS-β-thalassemia(0) or HbS-β-thalassemia(+), composed of one HbS allele and one β-thalassemia allele with absent or reduced β-chain production, respectively. Despite advances in care, median survival remains in the fifth decade, due in large part to chronic complications of the disease. Chronic pulmonary complications in SCD are major contributors to this early mortality. Although our understanding of these conditions has improved much over the past 10 to 15 years, there remains no specific treatment for pulmonary complications of SCD. It is unclear whether conventional treatment regimens directed at non-SCD populations have equivalent efficacy in patients with SCD. This represents a critical research need. In this review, the authors review the state-of-the-art understanding of the following pulmonary complications of SCD: (1) pulmonary hypertension; (2) venous thromboembolic disease; (3) sleep-disordered breathing; (4) asthma and recurrent wheezing; and (5) pulmonary function abnormalities. This review highlights the advances as well as the knowledge gaps in this field to update clinicians and other health care providers and to garner research interest from the medical community. Abstract source Full text

Chronic opioid therapy (COT) for chronic non-cancer pain is frequently debated, and its effectiveness is unproven in sickle cell disease (SCD). The authors conducted a descriptive study among 83 adult SCD patients and compared the severity of disease and pain symptoms among those who were prescribed COT (n=29) with those who were not using COT. All patients completed baseline laboratory pain assessment and questionnaires between January 2010 and June 2014. Thereafter, participants recorded daily pain, crises, function, and healthcare utilization for 90 days using electronic diaries. Analyses were conducted shortly after the final diary data collection period. Patients on COT did not differ on age, sex, or measures of disease severity. However, patients on COT exhibited greater levels of clinical pain (particularly non-crisis); central sensitization; and depression and increased diary measures of pain severity, function, and healthcare utilization on crisis and non-crisis diary days, as well as a greater proportion of days in crisis. Including depressive symptoms in multivariate models did not change the associations between COT and pain, interference, central sensitization, or utilization. Additionally, participants not on COT displayed the expected positive relationship between central sensitization and clinical pain, whereas those on COT demonstrated no such relationship, despite having both higher central sensitization and higher clinical pain. Overall, the results point out a high symptom burden in SCD patients on COT, including those on high-dose COT, and suggest that nociceptive processing in SCD patients on COT differs from those who are not. Abstract source Full text Full text (PMC)

Early transcranial Doppler (TCD) screening of the Créteil sickle cell anemia (SCA)-newborn cohort, and rapid initiation of transfusion programs, resulted in successful prevention of overt strokes, but a high cumulative risk of silent cerebral infarcts (SCI) remained, suggesting that TCD screening does not identify all patients with SCA at risk for SCI. We hypothesized that episodes of hypoperfusion/hypoxia, as observed during acute chest syndromes or acute anemic events (AAE), and extracranial internal carotid artery (eICA) stenoses, detectable via submandibular Doppler sonography and cervical magnetic resonance angiography (MRA), could also be risk factors for SCI. This study includes 189 stroke-free patients with SCA from the Créteil newborn cohort (1992-2010) followed longitudinally by magnetic resonance imaging/MRA, including cervical MRA at the last assessment. All patients with abnormal TCD and/or intracranial stenoses were placed on a transfusion program. Mean follow-up was 9.9 years (range, 2.2-19.9 years; 1844 patient-years). Annual rates of clinical events were calculated. The cumulative risk for SCI was 39.1% (95% confidence interval [CI], 23.5%-54.7%) by age 18 years, with no plateau. We confirm that baseline hemoglobin level lower than 7 g/dL before age 3 years is a highly significant predictive risk factor for SCI (hazard ratio, 2.97; 95% CI, 1.43-6.17; P = .004). Furthermore, we show that AAE rate (odds ratio, 2.64 per unit increase; 95% CI, 1.09-6.38; P = .031) and isolated eICA stenosis (odds ratio, 3.19; 95% CI, 1.18-8.70; P = .023) are significant and independent risk factors for SCI. Abstract source Full text