CO‐CBS‐H2S Axis: From Vascular Mediator to Cancer Regulator

CO is a gaseous mediator generated by HO. Our previous studies revealed that CO generated from inducible HO‐1 or from constitutive HO‐2 modulates function of different heme proteins or enzymes through binding to their prosthetic ferrous heme to alter their structures, regulating biological function of cells and organs. Such CO‐directed target macromolecules include sGC and CBS. In the liver, CO serves as a sinusoidal dilator through its action on sGC in hepatic stellate cells, while the same gas accounts for vasoconstrictor that inhibits H₂S generated by CO‐sensitive CBS in astrocytes. Since molecular O₂ is a substrate for HO, the latter mechanism contributes to hypoxic vasodilation in neurovascular units. We have recently uncovered that stress‐inducible CO in and around cancer cells suppresses CBS to result in decreased methylation of PFKFB3, the enzyme regulating PFK‐1, leading to a shift of glucose biotransformation from glycolysis toward pentose phosphate pathway; such a metabolic remodeling causes chemoresistance through increasing NADPH and reduced glutathione under stress conditions for cancer cells. This article reviews the intriguing networks of CO‐sensitive metabolic regulatory mechanisms in microcirculation and cancer.     

Red blood cell adhesion to heme‐activated endothelial cells reflects clinical phenotype in sickle cell disease

In sickle cell disease (SCD), ‘disease severity’ associates with increased RBC adhesion to quiescent endothelium, but the impact on activated endothelium is not known. Increased concentrations of free heme result from intravascular hemolysis in SCD. Heme is essential for aerobic metabolism and plays an important role in numerous biological processes. Excess free heme induces reactive oxygen species generation and endothelial activation, which are associated with cardiovascular disorders including atherosclerosis, hypertension, and thrombosis. Here, we utilized an endothelialized microfluidic platform (Endothelium‐on‐a‐chip) to assess adhesion of sickle hemoglobin‐containing red blood cells (HbS RBCs), from adults with homozygous SCD, to heme‐activated human endothelial cells (EC) in vitro. Confluent EC monolayers in microchannels were treated with pathophysiologically relevant levels of heme in order to simulate the highly hemolytic intravascular milieu seen in SCD. RBC adhesion to heme‐activated ECs varied from subject to subject, and was associated with plasma markers of hemolysis (LDH) and reticulocytosis, thereby linking those RBCs that are most likely to adhere with those that are most likely to hemolyze. These results re‐emphasize the critical contribution made by heterogeneous adhesive HbS RBCs to the pathophysiology of SCD. We found that adhesion of HbS RBCs to heme‐activated ECs varied amongst individuals in the study population, and associated with biomarkers of hemolysis and inflammation, age, and a recent history of transfusion. Importantly, the microfluidic approach described herein holds promise as a clinically feasible Endothelium‐on‐a‐chip platform with which to study complex heterocellular adhesive interactions in SCD.     

Resveratrol and liver disease: from bench to bedside and community

Liver diseases incorporate several maladies, which can range from benign histological changes to serious life‐threatening conditions. These may include inborn metabolic disease, primary and metastatic cancers, alcoholic cirrhosis, viral hepatitis and drug‐induced hepatotoxicity. Liver disease remains a major cause of morbidity and mortality with significant economic and social costs. Several novel approaches are currently being studied which may provide a better therapeutic outcome. The use of naturally occurring phytochemicals, some of them obtained from dietary sources, in the amelioration of illness have recently gained considerable popularity. These agents, having anti‐oxidant and anti‐inflammatory properties, provide a safe and effective means of ameliorating chronic disease. Resveratrol, a grape polyphenol, has shown considerable promise as a therapeutic agent in the treatment of the aforementioned liver ailments. Several studies have highlighted the hepatoprotective properties of resveratrol. Resveratrol has been shown to prevent hepatic damage because of free radicals and inflammatory cytokines, induce anti‐oxidant enzymes and elevate glutathione content. Resveratrol has also been shown to modulate varied signal transduction pathways implicated in liver diseases. This review critically examines the current preclinical in vitro and in vivo studies on the preventive and therapeutic effects of resveratrol in liver diseases. The review highlights the pharmacological mechanisms involved in mediating the aforementioned effects. Toxicity, pharmacokinetics and clinical bioavailability of resveratrol are also reviewed in this article. The challenges involved, future directions and novel approaches such as site‐specific drug delivery in the use of resveratrol for the prevention and treatment of liver disease are also discussed.     

Stem cell transplantation after reduced‐intensity conditioning for sickle cell disease

Sickle cell disease (SCD) is still associated with substantial morbidity and reduced life expectancy. Disease‐related mortality rises to 14% in adolescents and young adults. Overall and disease‐free survival following haematopoietic stem cell transplantation (HSCT) is 90% and 95%, respectively. To reduce transplant‐associated late effects, the feasibility of a highly immunosuppressive reduced‐intensity conditioning (RIC) regimen was explored in children with SCD and a matched sibling donor. Eight patients (median age, 9 yr) and symptomatic SCD were included. The conditioning regimen consisted of fludarabine, melphalan and either thiotepa or total lymphoid irradiation plus antithymocyte globuline or alemtuzumab. The graft was bone marrow in seven and cord blood in one case. The conditioning regimen was well tolerated and no severe infectious complications occurred. All patients displayed mixed chimaerism on day +28. After a median follow‐up of 4 yr, 3/8 patients have mixed leucocyte chimaerism and 8/8 patients have 100% donor erythropoiesis. HSCT from matched sibling donors following a RIC regimen was well tolerated and resulted in cure in all patients studied. If confirmed in larger patient cohorts, these observations will have important implications for the indications of HSCT in children with SCD.     

Increased levels of the inflammatory biomarker C‐reactive protein at baseline are associated with childhood sickle cell vasocclusive crises

Several lines of evidence suggest that sickle cell disease (SCD) is associated with a chronic inflammatory state. In this study of 70 children with SCD at steady state evaluated by a broad panel of biomarkers representing previously examined mechanisms of pathogenicity in SCD, high sensitivity C‐reactive protein (hs‐CRP), a marker of low‐grade, systemic inflammation, emerged as the most significant laboratory correlate of hospitalizations for pain or vaso‐occlusive (VOC) events. While markers of increased haemolytic status, endothelial activation and coagulation activation all correlated positively with VOC events by univariate analysis, baseline hs‐CRP levels provided the most significant contribution to the association in multiple regression models (22%), and, hs‐CRP, along with age, provided the best fit in negative binomial models. These data highlight the clinical relevance of the role of inflammation in paediatric VOC, providing both a rationale for future therapeutic strategies targeting inflammation in microvessel occlusive complications of SCD, and the potential clinical use of hs‐CRP as a biomarker in childhood SCD.     

Sevuparin binds to multiple adhesive ligands and reduces sickle red blood cell‐induced vaso‐occlusion

Sevuparin is a novel drug candidate in phase II development as a treatment for vaso‐occlusive crises (VOC) in patients with sickle cell disease (SCD). As a heparin‐derived polysaccharide, sevuparin has been designed to retain anti‐adhesive properties, while the antithrombin‐binding domains have been eliminated, substantially diminishing its anticoagulant activity. Here, we demonstrate that sevuparin inhibits the adhesion of human sickle red blood cells (SS‐RBCs) to stimulated cultured endothelial cells in vitro. Importantly, sevuparin prevents vaso‐occlusion and normalizes blood flow in an in vivo mouse model of SCD vaso‐occlusion. Analyses by surface plasmon resonance (SPR) and fluorescence correlation spectroscopy (FCS) demonstrate that sevuparin binds to P‐ and L‐selectins, thrombospondin, fibronectin and von Willebrand factor, all of which are thought to contribute to vaso‐occlusion in SCD. Despite low anticoagulation activity, sevuparin has anti‐adhesive efficacy similar to the low molecular weight heparin tinzaparin both in vitro and in vivo. These results suggest that the anti‐adhesive properties rather than the anticoagulant effects of heparinoids are critical for the treatment of vaso‐occlusion in SCD. Therefore, sevuparin is now being evaluated in SCD patients hospitalized for treatment of VOC.     

Potential involvement of ubiquitin‐proteasome system dysfunction associated with oxidative stress in the pathogenesis of sickle cell disease

The ubiquitin‐proteasome system (UPS) is an important intracellular proteolytic pathway responsible for the degradation of proteins and oxidative damage; hence it plays a central role in maintaining homeostasis of red blood cells (RBCs). The present study investigated the levels of polyubiquitination, the function of proteasomes and effect of hydroxycarbamide (HC) therapy in RBCs from sickle cell disease (SCD) patients. Polyubiquitinated proteins were found to be elevated in untreated SCD (UT‐SCD) patients compared to those in HC‐treated SCD patients (HC‐SCD) and controls. Activities of β1 and β2 subunits were a little higher in UT‐SCD patients, and much higher proteolytic activities were observed in all three subunits (β1, β2 and β5) of RBCs in HC‐SCD patients compared to those of UT‐SCD patients and controls, although the protein levels of these subunits remained approximately the same. It is notable that, despite HC therapy, some patients showed persistent complications and accumulation of polyubiquitinated proteins. The enhanced proteasomal activity among HC‐treated patients might remove the polyubiquitinated protein and could be one of the important mechanisms of therapeutic action. These findings could be useful to understand the pathophysiology of SCD and its clinical heterogeneity and identify a suitable therapeutic target for the better management of these patients.     

Gene editing for sickle cell disease and transfusion dependent thalassemias- A cure within reach

Sickle cell disease (SCD) is associated with significant morbidity and shortened life expectancy. Similarly, patients with transfusion dependent beta thalassemia (TdT) require life-long transfusion therapy, chelation therapy and significant organ dysfunction. Allogeneic transplantation from a matched family donor provided the only curative option for patients with SCD and TdT. Unfortunately, less than 20% of patients have a fully matched related donor and results using unrelated donor transplant were associated with high rate of complications. Ex vivo gene therapy through globin gene addition has been investigated extensively and recent encouraging preliminary data resulted in regulatory approval in patients with TdT. Recent improvements in our understanding of the molecular pathways controlling erythropoiesis and globin switching from fetal hemoglobin to adult hemoglobin offer a new and exciting therapeutic options. Rapid and substantial advances in genome editing tools using CRISPR/Cas9, have raised the possibility of genetic editing and correction in patient derived hematopoietic stem and progenitor cells. We will review results of gene editing approach that can induce fetal hemoglobin production in patients with SCD and TdT.     

Exercise capacity and haemodynamics in patients with sickle cell disease with pulmonary hypertension treated with bosentan: results of the ASSET studies

Doppler‐defined pulmonary hypertension (PH) in sickle cell disease (SCD) is associated with 40% mortality at 40 months. To assess the effect of bosentan in SCD‐PH, two randomized, double‐blind, placebo‐controlled, 16‐week studies were initiated. Safety concerns are particularly relevant in SCD due to comorbid conditions. ASSET‐1 and ‐2 enrolled patients with pulmonary arterial hypertension (PAH) and pulmonary venous hypertension (PH), respectively. Haemodynamics and 6‐min walk distance (6MWD) were obtained at baseline and week 16. The studies were terminated due to slow site initiation and patient enrolment (n = 26). Bosentan appeared to be well tolerated. Although sample sizes were limited, in ASSET‐1 at baseline, 6MWD correlated with cardiac output (CO; P = 0·006) with non‐significant inverse correlations between 6MWD and pulmonary vascular resistance (PVR; P = 0·07) and between 6MWD and right atrial pressure (P = 0·08). In ASSET‐2 at baseline, there was a non‐significant correlation between 6MWD and CO (P = 0·06). Due to limited sample sizes, efficacy endpoints were not analysed. However, in both studies, non‐significant increases in CO were observed with bosentan compared to placebo. Similarly, non‐significant decreases in PVR were observed with bosentan. Limited data in SCD‐PH suggest that a low 6MWD predicts a low CO. Standard‐dose bosentan appears to be well tolerated. Further investigation is warranted. Clinicaltrials.gov registration numbers NCT00310830, NCT00313196, NCT00360087.     

Haemoglobin disorders in Australia: where are we now and where will we be in the future?

Inherited disorders of haemoglobin (Hb), such as thalassaemia and sickle cell disease (SCD) are common and responsible for significant morbidity and mortality on a global scale. As Australia becomes increasingly ethnically diverse, their prevalence will increase. However, we lack important demographic and epidemiological data to manage these disorders and their consequences and to support affected individuals and communities. Thalassaemia and SCD are lifelong conditions. Affected individuals have reduced life expectancies, poorer quality of life and complex healthcare needs. Treatment strategies currently focus on prenatal diagnosis, red blood cell transfusion, iron chelation, management of iron‐related complications, haemopoietic stem cell transplantation (HSCT) and hydroxyurea. Currently, the only curative therapy is HSCT; however, gene therapy offers the possibility of cure and trials are currently underway. These therapies are associated with significant complications and substantial costs; there is also evidence of variation in approaches to diagnosis and care. Optimal strategies for many aspects of management are not yet defined and more research is necessary to inform clinical care and health service delivery.     

New insights provided by a comparison of impaired deformability with erythrocyte oxidative stress for sickle cell disease

Sickle cell disease (SCD) is associated with increase in oxidative stress and irreversible membrane changes that originates from the instability and polymerization of deoxygenated hemoglobin S (HbS). The relationship between erythrocyte membrane changes as assessed by a decrease in deformability and oxidative stress as assessed by an increase in heme degradation was investigated. The erythrocyte deformability and heme degradation for 27 subjects with SCD and 7 with sickle trait were compared with normal healthy adults. Changes in both deformability and heme degradation increased in the order of control to trait to non-crisis SCD to crisis SCD resulting in a very significantly negative correlation between deformability and heme degradation. However, a quantitative analysis of the changes in deformability and heme degradation for these different groups of subjects indicated that sickle trait had a much smaller effect on deformability than on heme degradation, while crisis affects deformability to a greater extent than heme degradation. These findings provide insights into the relative contributions of erythrocyte oxidative stress and membrane damage during the progression of SCD providing a better understanding of the pathophysiology of SCD.     

The glomerulopathy of sickle cell disease

Sickle cell disease (SCD) produces many structural and functional abnormalities in the kidney, including glomerular abnormalities. Albuminuria is the most common manifestation of glomerular damage, with a prevalence between 26 and 68% in adult patients. The pathophysiology of albuminuria in SCD is likely multifactorial, with contributions from hyperfiltration, glomerular hypertension, ischemia‐reperfusion injury, oxidative stress, decreased nitric oxide (NO) bioavailability, and endothelial dysfunction. Although its natural history in SCD remains inadequately defined, albuminuria is associated with increased echocardiography‐derived tricuspid regurgitant jet velocity, systemic blood pressure, and hypertension, as well as history of stroke, suggesting a shared vasculopathic pathophysiology. While most patients with albuminuria are treated with angiotensin converting enzyme inhibitors/angiotensin receptor blockers, there are no published long‐term data on the efficacy of these agents. With the improved patient survival following kidney transplantation, SCD patients with end‐stage renal disease should be considered for this treatment modality. Given the high prevalence of albuminuria and its association with multiple SCD‐related clinical complications, additional studies are needed to answer several clinically important questions in a bid to adequately elucidate its pathophysiology, natural history, and treatment. Am. J. Hematol. 89:907–914, 2014. © 2014 The Authors American Journal of Hematology Published by Wiley Periodicals, Inc.     

Totally implantable intravenous catheters in the management of sickle cell anemia

Totally implantable catheters (TICs) have recently been employed for long-term central venous access in patients with sickle cell disease (SCD). We have reviewed our experience with 10 TICs inserted in patients with SCD. These were compared to 33 TICs inserted in patients without SCD (controls). The primary diagnosis was malignancy in most of the controls. The SCD patients experienced a marked increase in total complications (70 vs. 24%), as well as in complications requiring catheter removal (50 vs. 3%). No variable explained these differences except the presence of SCD. The complications requiring catheter removal from SCD patients were infections, catheter thrombosis, and venous thrombosis. The increased risk of these complications must be considered before a catheter is inserted; however, the average useful life of these catheters exceeded 12 months. They remained useful in the care of patients with poor venous access and multiple complications of SCD.     

The severity of anaemia depletes cerebrovascular dilatory reserve in children with sickle cell disease: a quantitative magnetic resonance imaging study

Overt ischaemic stroke is one of the most devastating complications in children with sickle cell disease (SCD ). The compensatory response to anaemia in SCD includes an increase in cerebral blood flow (CBF ) by accessing cerebrovascular dilatory reserve. Exhaustion of dilatory reserve secondary to anaemic stress may lead to cerebral ischaemia. The purpose of this study was to investigate CBF and cerebrovascular reactivity (CVR ) using magnetic resonance imaging (MRI ) in children with SCD and to correlate these with haematological markers of anaemia. Baseline CBF was measured using arterial spin labelling. Blood‐oxygen level‐dependent MRI in response to a CO ₂ stimulus was used to acquire CVR . In total, 28 children with SCD (23 not on any disease‐modifying treatment, 5 on chronic transfusion) and 22 healthy controls were imaged using MRI . Transfusion patients were imaged at two time points to assess the effect of changes in haematocrit after a transfusion cycle. In children with SCD , CBF was significantly elevated compared to healthy controls, while CVR was significantly reduced. Both measures were significantly correlated with haematocrit. For transfusion patients, CBF decreased and CVR increased following a transfusion cycle. Lastly, a significant correlation was observed between CBF and CVR in both children with SCD and healthy controls.     

2015 Clinical trials update in sickle cell anemia

Polymerization of HbS and cell sickling are the prime pathophysiological events in sickle cell disease (SCD). Over the last 30 years, a substantial understanding at the molecular level has been acquired on how a single amino acid change in the structure of the beta chain of hemoglobin leads to the explosive growth of the HbS polymer and the associated changes in red cell morphology. O₂ tension and intracellular HbS concentration are the primary molecular drivers of this process, and are obvious targets for developing new therapies. However, polymerization and sickling are driving a complex network of associated cellular changes inside and outside of the erythrocyte, which become essential components of the inflammatory vasculopathy and result in a large range of potential acute and chronic organ damages. In these areas, a multitude of new targets for therapeutic developments have emerged, with several ongoing or planned new therapeutic interventions. This review outlines the key points of SCD pathophysiology as they relate to the development of new therapies, both at the pre‐clinical and clinical levels. Am. J. Hematol. 90:934–950, 2015. © 2015 Wiley Periodicals, Inc.     

Carbon Monoxide as a Guardian against Hepatobiliary Dysfunction

Abstract : Carbon monoxide (CO) generated through the reaction of heme oxygenase (HO) has attracted great interest in regulation of hepatobiliary homeostasis. The gas generated by HO‐2 in the hepatic parenchyma can modestly activate soluble guanylate cyclase (sGC) expressed in hepatic stellate cells in a paracrine manner and thereby constitutively relax sinusoids. Kupffer cells express HO‐1, the inducible isozyme, even under normal unstimulated conditions and constitutes approximately 30% of the total HO activity in this organ. Upon exposure to a variety of stressors such as cytokines, endotoxin, hypoxia and oxidative stress, the liver induces HO‐1 and overproduces CO. The stress‐inducible CO has been shown to guarantee ample blood supply during detoxification of heme and thus to play a protective role in the liver. However, molecular mechanisms by which CO serves as a protectant for hepatocytes, the cells expressing little sGC, remain to be solved. Previous observation suggested that CO modulates intracellular calcium mobilization through inhibiting cytochrome P‐450 activities and thereby maintain stroke volume of bile canalicular contraction in cultured hepatocytes. CO also stimulates mrp2‐dependent excretion of bilirubin‐IXα and helps heme catabolism. Although a direct molecular target responsible for the latter event remains unknown, such properties of CO could support xenobiotic metabolism through its actions on sinusoidal hemodynamics and hepatobiliary systems.     

Asthma management: Reinventing the wheel in sickle cell disease

Asthma is a common comorbidity in sickle cell disease (SCD) with a reported prevalence of 30–70%. The high frequency of asthma in this population cannot be attributed to genetic predisposition alone, and likely reflects in part, the contribution of overlapping mechanisms shared between these otherwise distinct disorders. There is accumulating evidence that dysregulated arginine metabolism and in particular, elevated arginase activity contributes to pulmonary complications in SCD. Derangements of arginine metabolism are also emerging as newly appreciated mechanism in both asthma and pulmonary hypertension independent of SCD. Patients with SCD may potentially be at risk for an asthma‐like condition triggered or worsened by hemolysis‐driven release of erythrocyte arginase and low nitric oxide bioavailability, in addition to classic familial asthma. Mechanisms that contributed to asthma are complex and multifactorial, influenced by genetic polymorphisms as well as environmental and infectious triggers. Given the association of asthma with inflammation, oxidative stress and hypoxemia, factors known to contribute to a vasculopathy in SCD, and the consequences of these factors on sickle erythrocytes, comorbid asthma would likely contribute to a vicious cycle of sickling and subsequent complications of SCD. Indeed a growing body of evidence documents what should come as no surprise: Asthma in SCD is associated with acute chest syndrome, stroke, pulmonary hypertension, and early mortality, and should therefore be aggressively managed based on established National Institutes of Health Guidelines for asthma management. Barriers to appropriate asthma management in SCD are discussed as well as strategies to overcome these obstacles in order to provide optimal care. Am. J. Hematol., 2009. © 2008 Wiley‐Liss, Inc.     

Resiniferatoxin lowers TNF‐α, NO and PGE2 in the intestinal phase and the parasite burden in the muscular phase of Trichinella spiralis infection

During the course of infection with Trichinella spiralis, an inflammatory response is triggered at the intestinal level in the host, playing a crucial role in the expulsion and elimination of the parasite. However, several studies have demonstrated that this inflammatory response is harmful to the host; hence, the importance of studying molecules with therapeutic potential like resiniferatoxin, which is known to have an anti‐inflammatory effect both in vitro and in vivo. In this article, we evaluated the anti‐inflammatory activity of resiniferatoxin during the intestinal phase of T. spiralis infection by quantitatively determining the levels of TNF‐α, NO and PGE₂ as well as the percentage of eosinophils in the blood and intestinal pathology. In addition, parasite burden was determined during the muscle infection. Our results show that resiniferatoxin lowered the serum levels of TNF‐α, NO and PGE₂, as well as the percentage of eosinophils in the blood and intestinal pathology during the intestinal infection. Moreover, resiniferatoxin also lowered the parasite burden in muscle, resulting in a reduction of the humoral response (IgG) associated to treatment with resiniferatoxin. These findings suggest a potential therapeutic use of the anti‐inflammatory effect of resiniferatoxin, which also contributes to host defence against the challenge of T. spiralis infection.     

Mouse models of severe asthma: Understanding the mechanisms of steroid resistance,tissue remodelling and disease exacerbation

Severe asthma has significant disease burden and results in high healthcare costs. While existing therapies are effective for the majority of asthma patients, treatments for individuals with severe asthma are often ineffective. Mouse models are useful to identify mechanisms underlying disease pathogenesis and for the preclinical assessment of new therapies. In fact, existing mouse models have contributed significantly to our understanding of allergic/eosinophilic phenotypes of asthma and facilitated the development of novel targeted therapies (e.g. anti‐IL‐5 and anti‐IgE). These therapies are effective in relevant subsets of severe asthma patients. Unfortunately, non‐allergic/non‐eosinophilic asthma, steroid resistance and disease exacerbation remain areas of unmet clinical need. No mouse model encompasses all features of severe asthma. However, mouse models can provide insight into pathogenic pathways that are relevant to severe asthma. In this review, as examples, we highlight models relevant to understanding steroid resistance, chronic tissue remodelling and disease exacerbation. Although these models highlight the complexity of the immune pathways that may underlie severe asthma, they also provide insight into new potential therapeutic approaches.     

Arterio‐venous fistula for automated red blood cells exchange in patients with sickle cell disease: Complications and outcomes

Erythrocytapheresis (ER) can improve outcome in patients with sickle cell disease (SCD). A good vascular access is required but frequently it can be difficult to obtain for sickle cell patients. Arterio‐venous fistulas (AVFs) have been suggested for ER in SCD supported by limited evidence. We report the largest cohort of ER performed with AVFs from three French SCD reference centers. Data of SCD patients undergoing ER with AVFs in the French SCD reference center were retrospectively collected. The inclusion criteria were: SS or Sβ‐Thalassemia and AVF surgery for ER. SCD‐related complications, transfusion history, details about AVF surgical procedure, echocardiographic data before and after AVF, AVF‐related surgical and hemodynamical complications were collected. Twenty‐six patients (mean age 20.5 years, mean follow‐up 68 months [11–279]) were included. Twenty‐three patients (88.5%) required central vascular access before AVF. Fifteen AVFs (58%) were created on the forearm and 11 (42%) on the arm. Nineteen patients (73%) had stenotic, thrombotic or infectious AVF complications. A total of 0.36 stenosis per 1,000 AVF days, 0.37 thrombosis per 1,000 AVF days and 0.078 infections per 1.000 AVF days were observed. The mean AVF lifespan was 51 months [13–218]. One patient with severe pulmonary hypertension worsened after AVF creation and died. We report the first series of SCD patients with AVF for ER, demonstrating that AVFs could be considered as a potential vascular access for ER. Patients with increased risk for hemodynamic intolerance of AVFs must be carefully identified, so that alternative vascular accesses can be considered. Am. J. Hematol. 92:136–140, 2017. © 2016 Wiley Periodicals, Inc.