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International Journal of Molecular Sciences, Volume 22; doi:10.3390/ijms22126408

Circulating hemopexin is the primary protein responsible for the clearance of heme; therefore, it is a systemic combatant against deleterious inflammation and oxidative stress induced by the presence of free heme. This role of hemopexin is critical in hemolytic pathophysiology. In this review, we outline the current research regarding how the dynamic activity of hemopexin is implicated in sickle cell disease, which is characterized by a pathological aggregation of red blood cells and excessive hemolysis. This pathophysiology leads to symptoms such as acute kidney injury, vaso-occlusion, ischemic stroke, pain crises, and pulmonary hypertension exacerbated by the presence of free heme and hemoglobin. This review includes in vivo studies in mouse, rat, and guinea pig models of sickle cell disease, as well as studies in human samples. In summary, the current research indicates that hemopexin is likely protective against these symptoms and that rectifying depleted hemopexin in patients with sickle cell disease could improve or prevent the symptoms. The data compiled in this review suggest that further preclinical and clinical research should be conducted to uncover pathways of hemopexin in pathological states to evaluate its potential clinical function as both a biomarker and therapy for sickle cell disease and related hemoglobinopathies.
Kyla Lief, Maggie Nyirenda
Published: 18 April 2021
by BMJ
Abstracts, Volume 5; doi:10.1136/bmjpo-2021-rcpch.65

Background The following case report highlights the difficulty in distinguishing Paediatric Multisystem Inflammatory Syndrome Temporally Associated with Sars- CoV- 2 (PIMS –TS) from sickle cell crisis. This is important in the context of a looming second wave of the Covid 19 pandemic, particularly in areas where there is a large population of children with sickle cell disease. This is the first case report discussing PIMS TS in a child with sickle cell disease and pulmonary emboli as a result of this. Objectives A 17 year old boy with sickle cell disease presented to the paediatric department of a district general hospital in South London with pleuritic chest pain and worsening shortness of breath in April 2020. He was tachypnoeic and tachycardic. Oxygen saturation was 95% in air and he was afebrile. He had quiet breath sounds and was tender in the right upper quadrant of his abdomen. A week prior to this he required intravenous (IV) antibiotics and two exchange transfusions via a femoral line. Blood tests showed a white cell count (WCC) of 11.4, a C-reactive protein (CRP) of 120, haemoglobin of 108, INR of 1.6 and deranged liver function tests. His D dimer was 8339, so a pulmonary Computed Tomography (CT) angiogram was performed. This demonstrated bilateral pulmonary emboli (PE). Results Differential diagnoses for the cause of the PE were sickle cell disease and PIMS-TS. Conclusions Both PIMS –TS and sickle cell crises are disorders involving exaggerated inflammation and risk of coagulopathy, with raised CRP, D Dimer, INR and WCC. The guidelines for investigations of PIMS TS include other markers such as LDH, troponin, BNP, ferritin and creatinine kinase. However, these blood tests are rarely performed in the general paediatric population or those with sickle cell disease, so they need to be specifically studied to determine whether they provide any significant distinction for a diagnosis of PIMS-TS. In terms of pathophysiology, a diagnosis of PE as a complication of sickle cell is not surprising; however in clinical practice it is rarely seen. This points towards PIMS-TS being the cause of this presentation, for which WHO definition requires evidence of SARSCOV2 infection or exposure. Indeed our patient is likely to have been exposed to Covid 19, given that he presented in the peak of the first wave, however PCR swabs were negative during admission. Three months after presentation, his anti Sars Cov 2 IgG was negative. The key take home message from this case is to consider other diagnoses in sickle cell patients during the time of Covid 19. There is a need for increased research into how to differentiate the two disorders. This is important because if the primary cause of illness is PIMS-TS rather than sickle cell disease, careful consideration needs to go into treatments as immunomodulation with IV Ig may increase viscosity and steroids can contribute to hypertension, thus worsening the progression of underlying sickle cell disease. Diagnosing PIMS –TS in those with sickle cell is particularly important as patients from a minority ethnic suffer worse outcomes.
Mazen Al-Qadi, Barbara LeVarge,
Published: 25 March 2021
Frontiers in Medicine, Volume 7; doi:10.3389/fmed.2020.616720

Pulmonary hypertension (PH) is recognized to be associated with a number of comorbid conditions. Based on these associations, PH is classified into 5 groups, considering common pathophysiologic drivers of disease, histopathologic features, clinical manifestations and course, and response to PH therapy. However, in some of these associated conditions, these characteristics are less well-understood. These include, among others, conditions commonly encountered in clinical practice such as sarcoidosis, sickle cell disease, myeloproliferative disorders, and chronic kidney disease/end stage renal disease. PH in these contexts presents a significant challenge to clinicians with respect to disease management. The most recent updated clinical classification schemata from the 6th World Symposium on PH classifies such entities in Group 5, highlighting the often unclear and/or multifactorial nature of PH. An in-depth review of the state of the science of Group 5 PH with respect to epidemiology, pathogenesis, and management is provided. Where applicable, future directions with respect to research needed to enhance understanding of the clinical course of these entities is also discussed.
, Alexandre Elabbadi, Grigorios Gerotziafas, François Lionnet, Guillaume Voiriot, Muriel Fartoukh
Published: 29 January 2021
BMC Pulmonary Medicine, Volume 21, pp 1-5; doi:10.1186/s12890-021-01412-x

Background Sickle-cell anaemia is a widespread genetic disease prevalent worldwide among African and African-American populations. The pathogenesis is most often revealed by pulmonary conditions, including acute thoracic syndrome, which is affecting the life expectancy of these populations. The global spread of CoV2-SARS infection with a respiratory tropism, endothelial damages and procoagulant status endangers the SCD population. However, with only a few case reports, consequences of the Covid-19 pandemic on SCD population remain poorly known. Case presentation We report a case of a 33-year-old man with a history of homozygous SS homozygous sickle cell anemia who consulted on March 24, 2020 for febrile dyspnea 11 days after the onset of symptoms. A nasopharyngeal swab was positive for SARS-CoV-2. His respiratory status worsened rapidly in the emergency room and then in ICU leading to severe ARDS requiring intubation, curarization, and venovenous ECMO. Hematologically, severe hemolysis associated with major thrombocytopenia without documented spinal cord injury was noted. Several transfusion exchanges are performed. The evolution was finally slowly favorable and led to discharge from the intensive care unit and then from the hospital. Conclusions This case recalls the importance of an increased prevention policy against COVID-19among the SCD population. In addition, from a therapeutic point of view, it advocates (1) a high preventive anticoagulation from the outset according to the level of D-dimers (2) the use of venovenous ECMO in this particular case, whereas this technique has had rather disappointing results in acute chest syndromes. (3) Unexpectedly, our patient did not develop pulmonary arterial hypertension (PAH) and acute cor pulmonale (ACP), whereas this is a common feature of ARDS during SCD. These last two observations suggest a different pathophysiology of pulmonary disorders in SCD patients in the case of SARS COv2. It could be associated with marked hypoxemia secondary to pulmonary vascular vasodilation.
Simrat Kaur Batth, Kim Bloom, Kenneth Scott Lloyd
Archives of Internal Medicine Research, Volume 04, pp 149-159; doi:10.26502/aimr.0066

The pathophysiology of pulmonary hypertension (PH) in sickle cell disease (SCD) is multifactorial: hemolysis, hypercoagulability, hypoxemia, oxidative stress, platelet activation, increased adhesiveness, inflammatory cell activation and genetic susceptibility, all contributing in varying degrees to endothelial dysfunction. Intravascular hemolysis is the main pathological process contributing to vasculopathy by releasing toxic red blood cell products that impair endothelial function, cause hypercoagulable state and drive oxidative and inflammatory stress. Hemolysis induced nitric oxide imbalance is one the most important contributors to high pulmonary artery pressures seen in SCD. Multi-faceted, targeted interventions, before irreversible vasculopathy develops, will allow for improved patient outcomes and life expectancy, stressing the need for a better understanding of the multiple pathophysiological mechanisms involved in the development of PH before considering those patients for targeted therapies. Hemolysis is still considered as the main contributor of PH in SCD but the mechanisms by which it causes PH are still not completely known. This review precisely presents the various pathophysiological mechanisms and factors that have been proposed till date to help the reader get an overview.
T D"humieres, J Inamo, S Deswarte, T Damy, G Loko, F Lionnet, M Humbert, G Derumeaux, L Savale, P Bartolucci
European Heart Journal - Cardiovascular Imaging, Volume 22; doi:10.1093/ehjci/jeaa356.023

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): PHRC Backgroung Echocardiography is the cornerstone in the diagnosis of cardiopulmonary involvement in sickle cell disease (SCD). However, given the unique pathophysiology of SCD associating high cardiac output, and various degrees of peripheral vasculopathy, differentiate the pathological from the physiological using echocardiography can be particularly challenging. Purpose This study sought to link cardiac phenotypes in homozygous SCD patients with clinical profiles and outcomes using cluster analysis. Methods We analyzed data of 379 patients with a sufficient echographic dataset included in the French Etendard Cohort, a prospective cohort initially designed to assess the prevalence of pulmonary hypertension. A cluster analysis was performed on echocardiographic variables, and the association between clusters and clinical profiles and outcomes was assessed. Results Three clusters were identified. Cluster 1 (N = 122) patients had the lowest cardiac output, only mild left cavities remodeling, diastolic dysfunction, and high tricuspid regurgitation velocity (TRV). They were predominantly female, as old as cluster 2, and displayed the most severe functional limitation. Cluster 2 (N = 103) patients had the highest cardiac output, left ventricular mass and a severely dilated left atrium. Diastolic function and TRV were similar to cluster 1. These patients had a higher blood pressure and a severe hemolytic anemia. Cluster 3 (N = 154) patients had mild left cavities remodeling, the best diastolic function and the lowest TRV. They were younger patients with the highest hemoglobin and lowest hemolytic markers. Right heart catheterization was performed in 94 patients. Cluster 1 gathered the majority of precapillary PH while cluster 2 gathered postcapillary PH and no PH was found in cluster 3. After a follow-up of 9.9 years (IQR: 9.3 to 10.5 years) death occurred in 38 patients (10%). Clusters 2 had the worst prognosis with 18% mortality rate vs. 12% in cluster 2 and 5% in cluster 1 (P log-rank = 0,02). Results are summarized in the central illustration. Conclusions Cluster analysis of echocardiographic variables identified 3 phenotypes among SCD patients, each associated with different clinical features and outcome. These findings underlines the necessity to rethink echocardiographic evaluation of SCD patients, with an integrative approach based on simultaneous evaluation of TRV along with left cavities remodeling and diastolic parameters. Abstract Figure.
Mbbs Nwabundo Anusim, Ruby Gupta, Md Mph Hycienth O Ahaneku, Do Candace Franklin, Savitha Balaraman, Do Marianne Terese Huben, Do Ishmael Jaiyesimi
Published: 5 November 2020
Blood, Volume 136, pp 29-30; doi:10.1182/blood-2020-138739

Background Sickle cell disease (SCD) is an inherited disorder of red blood cell (RBC) caused by a mutation in the beta-globin gene resulting in abnormal hemoglobin known as hemoglobin S (HbS) or the sickle hemoglobin. Several clinical variants of SCD have been elucidated, all driven by two fundamental pathophysiologic processes: RBC hemolysis and intermittent vaso-occlusive vasculopathy resulting in tissue ischemia/infarction. These two processes underscore the many complications and eventual multi-organ damage that may develop in patients with the most severe types of SCD. Cardiopulmonary complications including heart failure, pulmonary hypertension and acute chest syndrome (ACS) are major drivers of morbidity and mortality among patients with SCD. With regards to ACS, patients often present with fever, cough and shortness of breath caused by vaso-occlusive crisis affecting the lungs. This is particular concerning in view of its similar features to symptomatic COVID-19 infection. Methods We retrospectively identified SCD patients with COVID-19 infection admitted to Beaumont hospitals in Michigan between March 1st 2020 and July 1st 2020. Data was abstracted using the ICD 10 code of U07. 1 for COVID-19, ICD 9 and 10 codes of 282.60 and D57 for sickle cell disease. We excluded patients with sickle cell trait. Data regarding the demographics, presentation, management and outcomes were abstracted. Results A total of eleven patients with sickle cell disease were identified as having a positive SARS-Cov19 polymerase chain reaction test (Table I). All were African American and predominantly female (64%) with a mean age of 44 (22-60) years and mean BMI of 30.2 kg/m2. Genotypes identified were HbSS in 5 (45%) patients, HbSC in 4 (36%), HbS/beta-thalassemia in 1 (9%) and HbS/alpha-thalassemia in 1 (9%). All of the patients had seen a haematologist since their diagnosis but none of the patients were on hydroxyurea, voxeloter, L-glutamine or crizanlizumab at admission. The predominant clinical presentation was fever, chest pain, chills, exertional shortness of breath and cough but this was not consistent across all patients. All the patients were managed with intravenous hydration, pain management as well as hydroxychloroquine/azithromycin per institutional guideline at that time. Three patients (cases 1-3) had recurrent visits to the hospital for similar symptoms and new bone pain crises. Case 1 had a pulmonary embolus which was evident on re-admission. Two patients (cases 3 and 10) succumbed to COVID-19. Two patients (cases 5 and 7) presented with bone pain crisis and no respiratory symptoms, but chest imaging was suggestive of COVID-19 infection necessitating treatment with antibiotics, possibly indicating that the virus can trigger vaso-occlusive crises without respiratory symptoms. Case 8 had a high Charlson comorbidity index and age over 60, had the lengthiest hospital stay complicated by renal failure and polyneuropathy, and was discharged to a long-term acute care facility: an outcome which is consistent with current data showing that the elderly and unfit patients are more likely to have a higher morbidity and mortality with COVID-19. Conclusion To date, there no compelling evidence to provide guidelines for the management of SCD patients with COVID-19. However, following existing recommendations in managing acute chest syndrome and those for COVID-19 symptomatic infection, is a good place to start. We continue to seek to improve management of these patients as new evidence of successful treatment emerges, and also encourage patients to participate in clinical trials. Disclosures No relevant conflicts of interest to declare.
Jordan Milner, Deborah Friedman, Marise D'souza, Krishnan Sankaran, Liana Klejmont, Erin Morris, Harshini Mahanti, Neida Otero, Jessica C. Hochberg, Adele Brudnicki, et al.
Published: 5 November 2020
Blood, Volume 136, pp 8-9; doi:10.1182/blood-2020-139617

Background: Sickle cell disease (SCD) is a vasculopathy resulting in recurrent vaso-occlusive crises leading to endothelial dysfunction, chronic end-organ damage, poor quality of life, early mortality and the major curative therapy to date is allogeneic stem cell transplantation (AlloSCT) (Talano/Cairo, EJH, 2015). Acute chest syndrome (ACS) can result in pulmonary hypertension and is the leading cause of morbidity and mortality in patients with SCD (Gladwin et al, NEJM, 2008). ACS accounts for 25% of deaths (Vichinsky et al, Blood, 1997). Clinical definition of ACS is chest pain, fever, cough, dyspnea, and new pulmonary infiltrate on chest radiography. Defibrotide was approved in the US for the treatment of severe sinusoidal obstructive syndrome (SOS) with renal or pulmonary dysfunction following HSCT (Cairo et al, BJH, 2020). Defibrotide primarily targets endothelium in microvascular beds and has anti-inflammatory and anti-coagulant activity, which can treat the underlying pathophysiology of ACS (Falanga et al, Leukemia, 2003 and Scallia et al, Clin Pharm, 1996 and Pescador et al, Vasc Pharm, 2013). Objective: To determine the safety and toxicity of defibrotide in children, adolescents, and young adults with SCD-associated ACS. Design/Methods: Patients with SCD aged 2 to 40 years meeting ACS criteria (at least two of the following: fever, chest pain, cough, dyspnea, tachypnea, pulmonary infiltrate on chest imaging, decreased oxygen saturation with or without supplemental oxygen requirements) and eligibility were enrolled within 72 hours of diagnosis after consent was obtained (NCT03805581). Baseline studies comprised of chest radiograph, CT chest angiogram, echocardiography with TRJ velocity and brachial artery reactivity, pulmonary function tests, and biomarkers (IFN-a and -g, TNF-a, IL-6, 8, and 10, sCD163, TSP-1, secretory phospholipase A(2), sVCAM-1, sTNFR1, Ang2, sTei-2, PAI-1, sICAM-1, sP-and sE-selectin, sPECAM-1, VEGF-A, C, D and sVEGFR1 and 2). Defibrotide was administered at 6.25mg/kg IV q6 hours and continued for 7 days or until time of discharge, whichever occurred earlier and patients were followed until day +30 following defibrotide. Dose limiting toxicities include Grade III/IV infusion/allergic reaction or hemorrhage probably or directly related to defibrotide. Results: We have enrolled thirteen patients aged 3 to 18 years with a gender ratio (M/F) of 4/9. Patients' genotypes are as follows: hemoglobin SS disease in nine patients, hemoglobin SC disease in two patients, and hemoglobin Sb0/+ thalassemia in two patients. Presenting symptoms included fever, chest pain, cough, dyspnea, tachypnea, pulmonary infiltrate on imaging, and hypoxia.Eight patients completed seven days of treatment, one patient received 6 days of treatment, three patients were discharged after three days of treatment, and one patient withdrew due to recurrent fevers unrelated to defibrotide. All but one patient had resolution of fevers prior to end of treatment. Patients required an average of 1.15 days of oxygen support, with one patient requiring high flow nasal cannula, and no patients required mechanical ventilation. There were no adverse events possibly, probably, or directly related to defibrotide. There was no evidence of hemorrhage in any patient despite four patients receiving concomitant ketorolac or ibuprofen. Of the eleven patients who had pulmonary infiltrates on imaging, eight were evaluated on day +30, two had complete resolution of infiltrate, five had improvements, and one had no change. Seven patients did not follow-up for echocardiography or pulmonary function testing and two of those patients were unable to be evaluated at day +30 due to COVID-19. Discussion: The preliminary data suggest defibrotide is safe and well tolerated in patients with SCD-related ACS. All patients at diagnosis have had baseline studies, which included biomarkers; however, only eight of the thirteen patients have completed all required observations due to poor compliance. After four patients were enrolled and three failed to follow-up, changes to appointment schedules were made with detailed information on all follow-ups. Efforts at improving compliance post therapy are ongoing. Further accrual is needed to determine clinical significance of improvements in cardiac and/or pulmonary function. This study was funded in part by a grant from Jazz Pharmaceuticals. Disclosures Cooke: Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cairo:Nektar Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Technology Inc/Miltenyi Biotec: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Miltenyi: Research Funding. OffLabel Disclosure: Defibrotide is utilized in patients with acute chest syndrome to decrease the amount of time they are hospitalized and to assist in alleviating symptoms. Defibrotide is approved in the US for sinusoidal obstructive syndrome with renal or pulmonary dysfunction.
Daniel Adamkiewicz, Hongyan Xu, Rn Latanya Bowman, Msn Leigh Wells, Mbbs Niren Patel, PhD CEP Ryan Harris, Jennifer Pollock, David M. Pollock, Steffen E. Meiler, Abdullah Kutlar
Published: 5 November 2020
Blood, Volume 136, pp 25-26; doi:10.1182/blood-2020-142477

Endothelin-1 (ET1) is a potent vasoconstrictor, mitogen, proinflammatory mediator, and a mediator of nociception, whose synthesis is increased by hypoxia, ischemia, shear stress, oxidative stress and reduced nitric oxide (NO) bioavailability, all of which are well documented mechanisms in the pathophysiology of sickle cell disease (SCD). We earlier reported on our studies on the role of ET-1 in SCD, and in transgenic mouse models showed that ETA receptor blockade with ambrisentan provides renal protection by preventing the development of glomerular hyperfiltration and proteinuria (Kasztan et al, 2017, Taylor et al, 2019, Kasztan and Pollock, 2019). ETA receptor blockade was also shown to decrease pulmonary inflammation in response to hypoxia/reoxygenation and LPS (Meiler et al.). Additionally, Lutz et al (2018) showed that pharmacologic inhibition or neuron specific knockdown of ETA receptor in primary sensory neurons of dorsal root ganglia in Berk mice alleviated basal and post-hypoxia evoked pain sensitivity. More recently (Kutlar et al, Blood 2019, 617,130036) we reported the preliminary results of a placebo controlled, double-blind phase I trial of ambrisentan in 26 subjects with SCD (SS and S-ß0 thalassemia) and microalbuminuria, and showed that the drug was well tolerated without any dose limiting toxicities and patients on ambrisentan had a reduction in microalbuminuria, especially in the subgroup who had been on concomitant ACEi/ARB therapy at a stable dose for at least six months (n=6, 286.1 mg/g Cr at baseline to 197.7 mg/g on day 85, p=0.06). FMD measurements showed increased arterial diameter, and improved microvascular function. We analyzed data collected on secondary end points during the phase I study, including Tricuspid regurgitant jet velocity (TRV), Transcranial Doppler (TCD) velocities in distal internal carotid (dICA) and middle cerebral (MCA) arteries, and eGFR (calculated with CKD-Epi formula). Fig. 1a shows eGFRs in ambrisentan and placebo groups; Fig. 1b and Fig. 1c show a breakdown of ambrisentan and placebo groups based on concomitant ACEi/ARB usage. There is a reduction in glomerular hyperfiltration in the ambrisentan group compared to placebo, more pronounced in the subgroup who have not been on ACEi/ARBs. Fig. 1d depicts the change in flow velocity in MCA (TAMMV, Time Averaged Mean Maximal Velocity, cm/sec) between the ambrisentan and placebo groups; similarly, Fig. 1e and 1f show the breakdown of baseline and Day 85 TAMMVs in MCA according to ACEi/ARB usage. A similar trend is also observed in dICA flow (fig. 1g-1i), and suggests a synergistic effect of ETA receptor blockade with ACEi/ARBs in preventing an increase in blood flow velocities. TRV was available on 7 subjects, 6 of which were in the ambrisentan group. Fig. 1j shows the change in TRV in the ambrisentan group, and again is suggestive of a synergistic effect of ambrisentan and ACEi/ARBs in decreasing TRV. These data are clearly very preliminary, and are obtained on a small number of subjects, and as such, do not warrant any conclusions and or speculations. Nevertheless, an interesting observation is the apparent interaction of ETA receptor blockade and ACEi/ARBs in altering vascular flow/function in SCD patients. Decrease in microalbuminuria has been reported with ACEi and ARBs in SCD (Yee et al, 2018), without any effect on GFR. A reduction in hyperfiltration would likely have a significant renoprotective effect, at an earlier stage in the development of sickle nephropathy. ETA receptor antagonists are approved for the treatment of pulmonary arterial hypertension; thus, a decrease in TRV would have a beneficial effect. Increase in blood flow velocity in major intracranial vessels is a well established risk factor for ischemic stroke in children with SCD; however, much less is known in adults. In summary, the effect of ETA receptor blockade with or without ACEi/ARB, may have a significant effect on vascular function/blood flow in different organ systems, and should be explored in a large, multi-center phase II trial, with and without concomitant and or serial ACEi/ARBs, for a longer period of time, with a dose escalation, to further clarify the pleiotropic effects on multiple aspects of SCD pathology. Figure 1 Disclosures Kutlar: NIH/NHLBI (SCDIC): Research Funding; Global Blood Therapeutics: Research Funding, Speakers Bureau; Micelle Biopharma: Consultancy; Novartis Pharmaceuticals: Consultancy, Research Funding; Novo Nordisk: Research Funding; Forma Therapeutics: Research Funding; REACH: Other: DSMB Member; NOHARM: Other: DSMB Member; Bluebird Bio: Other: DSMB Member.
Published: 19 August 2020
Medicina, Volume 56; doi:10.3390/medicina56090420

Pulmonary hypertensive vascular disease (PHVD), and pulmonary hypertension (PH), which is a broader term, are severe conditions associated with high morbidity and mortality at all ages. Treatment guidelines in childhood are widely adopted from adult data and experience, though big differences may exist regarding aetiology, concomitant conditions and presentation. Over the past few years, paediatric aspects have been incorporated into the common guidelines, which currently address both children and adults with pulmonary hypertension (PH). There are multiple facets of PH in the context of cardiac conditions in childhood. Apart from Eisenmenger syndrome (ES), the broad spectrum of congenital heart disease (CHD) comprises PH in failing Fontan physiology, as well as segmental PH. In this review we provide current data and novel aspects on the pathophysiological background and individual management concepts of these conditions. Moreover, we focus on paediatric left heart failure with PH and its challenging issues, including end stage treatment options, such as mechanical support and paediatric transplantation. PH in the context of rare congenital disorders, such as Scimitar Syndrome and sickle cell disease is discussed. Based on current data, we provide an overview on multiple underlying mechanisms of PH involved in these conditions, and different management strategies in children and adulthood. In addition, we summarize the paediatric aspects and the pros and cons of the recently updated definitions of PH. This review provides deeper insights into some challenging conditions of paediatric PH in order to improve current knowledge and care for children and young adults.
European Respiratory Review, Volume 29; doi:10.1183/16000617.0054-2020

Sickle cell disease (SCD) is a life-threatening hereditary blood disorder that affects millions of people worldwide, especially in sub-Saharan Africa. This condition has a multi-organ involvement and highly vascularised organs, such as the lungs, are particularly affected. Chronic respiratory complications of SCD involve pulmonary vascular, parenchymal and airways alterations. A progressive decline of lung function often begins in childhood. Asthma, sleep-disordered breathing and chronic hypoxaemia are common and associated with increased morbidity. Pulmonary hypertension is a serious complication, more common in adults than in children. Although there is a growing attention towards respiratory care of patients with SCD, evidence regarding the prognostic meaning and optimal management of pulmonary issues in children with this condition is limited.This narrative review presents state-of-the-art evidence regarding the epidemiology, pathophysiology and therapeutic options for chronic respiratory complications commonly seen in paediatric patients with SCD. Furthermore, it highlights the gaps in the current knowledge and indicates future directions for studies that aim to improve our understanding of chronic respiratory complications in children with SCD.
Published: 1 March 2020
Progress in Pediatric Cardiology, Volume 56; doi:10.1016/j.ppedcard.2020.101194

Pulmonary hypertension (PH) is an insidious and potentially devastating complication in adults with hemolytic disorders, with pathophysiologic changes starting in childhood. Hemolysis predisposes to PH through nitric oxide depletion from extracellular release of hemoglobin and arginase, and through red blood cell membrane alterations and formation of microparticles, all promoting oxidative damage, vasoconstriction, inflammation, vascular remodeling, and thromboembolic state. PH is best diagnosed by right heart catheterization, though screening often utilizes Doppler echocardiographic measurement of tricuspid regurgitant velocity, and functional assessment by six minute walk test. Understanding the pathophysiology and clinical presentation of PH in sickle cell disease, thalassemias, paroxysmal nocturnal hemoglobinuria, and other hemolytic disorders can improve recognition, evaluation, and management of this condition.
, , Yuelong Guo, João Eduardo Ferreira, Carla Luana Dinardo, Anna Bárbara F. Carneiro-Proietti, Paula Loureiro, Rosimere Afonso Mota, , André Rolim Belisario, et al.
Published: 1 December 2019
The Journal of Sexual Medicine, Volume 16, pp 1988-1999; doi:10.1016/j.jsxm.2019.09.012

IntroductionPriapism is the persistent and painful erection of the penis and is a common sickle cell disease (SCD) complication.AimThe goal of this study was to characterize clinical and genetic factors associated with priapism within a large multi-center SCD cohort in Brazil.MethodsCases with priapism were compared to SCD type-matched controls within defined age strata to identify clinical outcomes associated with priapism. Whole blood single nucleotide polymorphism genotyping was performed using a customized array, and a genome-wide association study (GWAS) was conducted to identify single nucleotide polymorphisms associated with priapism.Main Outcome MeasureOf the 1,314 male patients in the cohort, 188 experienced priapism (14.3%).ResultsPriapism was more common among older patients (P = .006) and more severe SCD genotypes such as homozygous SS (P < .0001). In the genotype- and age-matched analyses, associations with priapism were found for pulmonary hypertension (P = .05) and avascular necrosis (P = .01). The GWAS suggested replication of a previously reported candidate gene association of priapism for the gene transforming growth factor beta receptor 3 (TGFBR3) (P = 2 × 10−4).Clinical ImplicationsOlder patients with more severe genotypes are at higher risk of priapism, and there is a lack of consensus on standard treatment strategies for priapism in SCD.Strengths & LimitationsThis study characterizes SCD patients with any history of priapism from a large multi-center cohort. Replication of the GWAS in an independent cohort is required to validate the results.ConclusionThese findings extend the understanding of risk factors associated with priapism in SCD and identify genetic markers to be investigated in future studies to further elucidate priapism pathophysiology.Ozahata M, Page GP, Guo Y, et al. Clinical and Genetic Predictors of Priapism in Sickle Cell Disease: Results from the Recipient Epidemiology and Donor Evaluation Study III Brazil Cohort Study. J Sex Med 2019;16:1988–1999.
Abdoul Karim Dembele, Claudine Lapoumeroulie, Mor Diaw, Oumar Tessougué, Lucile Offredo, Dapa Aly Diallo, Saliou Diop, Jacques Elion, Yves Colin Aronovicz, Pierre Louis Tharaux, et al.
Published: 13 November 2019
Blood, Volume 134, pp 3568-3568; doi:10.1182/blood-2019-121334

Introduction Although most individuals with sickle cell disease (SCD) live in sub-Saharan Africa, the history of the disease on this continent remains largely unknown. SCD is characterized by the association of chronic hemolytic anemia with episodes of acute vaso-occlusive events and progressive vascular organ damage. Several pathophysiological pathways in SCD result in the activation of circulating blood cells and the release of microparticles (MPs). In the present study, we investigated cell-derived MPs in patients with SCD living in Africa and analyzed their relationship with clinical complications. Patients and Methods This cross-sectional case-control study is nested in the CADRE cohort (clinical identifier NCTO3114137). We included 232 SS adults in two African centers: Bamako (Mali) and Dakar (Senegal). Patients were chosen depending on the absence or the presence of at least one of the following complications: tricuspid regurgitant jet velocity (TRJV) >3 m/s (which may indicate pulmonary hypertension), macroalbuminuria, leg ulcer, priapism, aseptic osteonecrosis, and retinopathy. Overall, 7 groups of 40 SS patients were constituted (20 in each center). Patients were investigated at steady state (i.e.,at least 15 days after a vaso-occlusive crisis, 8 days after fever or infectious disease, and 3 months after a transfusion). MPs were isolated in the African centers immediately after blood sampling by successive centrifugations at increasing speed: 2,500g x2 and 21,000g x2. MPs pellets were stored at -80 °C. The cellular origin of the MPs, erythrocyte, reticulocyte, endothelial, platelet, and leucocyte, was determined using antibodies directed against CD235a, CD71, CD106, CD41, and CD45, respectively, at the National Institute of Blood TransfusioninParis. To maintain the background at an acceptable level, events of 0.16 µm size were excluded (Fig 1A). Only MPs positive for Annexin V and the cell-type-specific labelling were retained. Potential associations between cell-derived MPs, hematological parameters, and vascular complications were assessed using logistic regression with adjustment for age, sex and country. Results The MP pellets of 106 SS patients from Bamako and 126 from Dakar were analyzed in Paris. In these patients, at a mean age of 29 years (+/- 11), high TRJV was present in 64, microalbuminuria in 84, leg ulcers in 33, priapism in 43, aseptic osteonecrosis in 45, and retinopathy in 31 patients whereas 28 patients had no complication at the time of sampling. As a typical result, Fig 1B shows erythrocyte-derived MPs labelled by Annexin V and CD235a (quarter Q2). The MPs distribution was as follows: erythroid 52% [reticulocytes (CD235a+CD71+) 14%, erythrocytes (CD235a+ CD71-) 38%], leukocyte 18%, platelet 21%, and endothelial 9%. Neither erythrocyte- nor reticulocyte-derived MPs significantly correlated with hemolysis markers (LDH, unconjugated bilirubin or reticulocytes) or hemoglobin levels. Erythrocyte- and...
Xu Zhang, Binal N. Shah, Roberto Machado, Santosh L. Saraf, Victor R Gordeuk
Published: 13 November 2019
Blood, Volume 134, pp 3574-3574; doi:10.1182/blood-2019-131813

Introduction In sickle cell disease (SCD), chronic anemia, hypoxia, and NO scavenging related to intravascular hemolysis contribute to diastolic dysfunction and pulmonary hypertension. Free hemoglobin and heme released during hemolysis cause oxidative stress and exacerbate vascular inflammation. Iron overload from frequent blood transfusions provokes reactive oxygen species and consequently cellular damage. We examined correlation of biomarkers reflecting major aspects of SCD patho-physiology (hemolysis, anemia, hypoxia, inflammation, and iron overload) with cardiopulmonary, renal, and liver dysfunction in an adult SCD cohort. The study provides observational evidence for etiologies of sickle cell organ damage by assessing the relative strength of outcome association for these biomarkers. Methods The study included 442 SCD patients with median age of 31 years, 77% with severe β hemoglobin mutation genotypes (HbSS, HbSβ0-thalassemia, HbSOarab) and 58% female. Biomarkers were identified for the SCD etiological conditions listed in Table 1. Primary cardiopulmonary outcomes were left heart enlargement (left atrial and ventricular diameter) and elevated systolic pulmonary artery pressure measured by tricuspid regurgitation peak velocity (TRV). The primary renal outcome was elevated urine albumin to creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. Primary hepatic outcomes were hepatocyte integrity estimated as the first principal component (PC) of alanine transaminase (ALT) and aspartate aminotransferase (AST), cholestasis estimated as the first PC of alkaline phosphatase (ALP) and direct bilirubin, and functioning liver mass measured by serum albumin1. Clinical associations between biomarkers and primary outcomes first applied single marker regression with covariates of age, gender, and severity of β hemoglobin genotype. Significant biomarkers representative of the major SCD etiological conditions were then analyzed by multi-marker regression and model selection. Results Left atrial diameter showed significant associations with biomarkers of hemolysis (LDH, percent reticulocytes, AST, total bilirubin), anemia (HCT, HGB), hypoxia (HCT, HGB, O2 saturation), and inflammation (WBC) (Table 1). Left ventricular diameter had a profile of biomarker associations similar to left atrial diameter. TRV showed significant associations with biomarkers of hemolysis (LDH, percent reticulocytes, AST), anemia (HCT, HGB), hypoxia (HCT, HGB, O2 saturation), inflammation (WBC), and iron overload (ferritin) (Table 1). In multi-marker analysis, anemia and hypoxia (low HCT, low O2 saturation) associated with greater left atrial diameter and with high TRV (Figure 1). Urine ACR significantly associated with biomarkers of hemolysis (LDH, AST, percent reticulocytes), anemia (HCT, HGB), hypoxia (HCT, HGB, O2 saturation), inflammation (WBC, serum albumin), and iron overload (ferritin) (Table 1). Impaired kidney function based on...
Annelies J. Van Vuren, Stephanie Van Straaten, Michal Mokry, Richard Van Wijk, Eduard J. Van Beers
Published: 13 November 2019
Blood, Volume 134, pp 980-980; doi:10.1182/blood-2019-124070

Introduction Sickle cell disease (SCD) is a hereditary hemolytic disease characterized by a complex pathophysiology including inflammation and oxidative stress. Intravascular hemolysis leads to release of heme, an erythrocyte-derived Danger Associated Molecular Pattern (e-DAMP) that augments Toll Like Receptor 4 (TLR4) signaling. TLR4 signaling is important in development of acute and chronic complications in SCD. We investigated gene expression profiles of TLR4+ cells (by positive selection of its co-receptor CD14) of patients with SCD and other hemolytic anemias to identify differential regulated pathophysiological pathways. Methods Analyses were performed in 60 adults with hereditary hemolytic anemia and 10 healthy controls included in the ZEbRA cohort (UMC Utrecht, [NL5189]). Patients treated with systemic anti-inflammatory drugs were excluded (n=1). Deferasirox (DFX)-treated SCD patients were analyzed separately as DFX ameliorated pro-inflammatory effects of heme. CD14+ cells were isolated using anti-CD14 microbeads. RNA sequencing was performed on a Nextseq500 platform (Illumina) using a single-end 75bp high-output run. Differentially expressed genes (DEGs) were identified using DESeq2 v1.24.0 in R. To correct for presence of reticulocytes and lymphocytes, data were corrected for expression of 4 hemoglobin (HBA1, HBB, HBG1, HBG2) and 4 T cell specific genes (CD3E, CD3D, CD3G, CD247). A list was constructed from all genes differentially expressed (adj. p<0.01; absolute log2fold change >1) in both the comparisons of SCD without DFX versus other hemolytic anemias and of SCD without DFX versus healthy controls. Pathway enrichment analysis (ReactomePA v1.28.0 in R) was performed with preselected DEGs (adj. p<0.1; absolute log2fold change >0.5). P-values were adjusted with the Benjamini-Hochberg procedure. Results Demographics and hematological values are provided in Table 1. Principal component analysis based on RNA sequencing data separated SCD patients without DFX from hemolytic anemia patients, healthy controls and SCD patients with DFX (Figure 1). Analysis of DEGs discriminating SCD patients from both patients with other hemolytic anemias and healthy controls rendered 29 genes (Figure 2). Heme oxygenase-1 (HMOX1) was one of these genes (versus healthy controls adj. p=5.6E-13; versus other hemolytic anemias adj. p=3.3E-15) and this is in line with the hypothesis that intravascular free heme is an important effector of gene regulation in monocytes. This sets SCD apart from the other studied hemolytic anemias. The other 28 genes included, PPARG, GUCY1A1, KLF5 and CXCR3 signaling (CXCL9 and CXCL11) which are associated with vascular remodeling and development of pulmonary hypertension. The list of 29 DEGs highlights interesting differences in gene expression of two processes related to immune signaling: CXCR3 signaling by CXCL9 and CXCL11, and lipid metabolism (STARD4, DLC1, SQLE, ME1). Pathway enrichment analysis showed enrichment of genes involved in IFN signaling (type I and II) in SCD versus healthy controls (adj. p=4.4E-16). And, in line with the list of 29 genes, enrichment of genes concerning chemokine signaling in SCD versus both healthy controls and other hemolytic anemias (respectively adj. p=0.06 and adj. p=0.01) and cholesterol biosynthesis in SCD versus other hemolytic anemias (adj. p=0.09). Conclusion Our data shows the unique inflammatory profile of SCD monocytes as opposed to other hemolytic anemias. Moreover, it suggests that lipid metabolism and IFN signaling are important differentiating immune signaling pathways. It is known that alterations in plasma lipid levels in SCD relate to hemolytic severity and vasculopathy. Our data suggests an important role for lipid biology in SCD monocytes. We hypothesize on an important contribution of cholesterol accumulation in enhancement of TLR4 signaling, as lipid rafts accelerated Nf-kB activation in macrophages. (Lee et al., Nat. Commun. 2017; Koseki et al., J. Lip. Res. 2007) The importance of type I and II IFN signaling in SCD suggests widespread involvement of the immune system. IFNg-inducible cytokines CXCL9 and CXCL11 are associated with Th1 polarization and activation. In summary, the data support the unique role of monocyte immune signaling in SCD. Furthermore, we identified pathways that seem to be relevant for immune regulation and thereby for development of disease complications. Disclosures van Wijk: Agios Pharmaceuticals: Consultancy, Research Funding; RR Mechatronics: Research Funding. van Beers:Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; RR Mechatronics: Research Funding; Novartis: Consultancy, Research Funding.
Ms Bukhari, M Mohd-Ghazaly, Qk Toe, Gj Quinlan, Sjw Wort
Genetic and cellular mechanisms of pulmonary hypertension, Volume 74; doi:10.1136/thorax-2019-btsabstracts2019.103

Background The link between pulmonary arterial hypertension (PAH) and haemolytic anaemias, such as sickle-cell disease and thalassaemia, is well established. Recent studies have implicated sub-clinical haemolysis and the release of cell free haemoglobin (CFH) in idiopathic PAH. The interaction between CFH and pulmonary artery endothelial cells (PAECs) could induce endothelial dysfunction, a key component of the pathophysiology of PAH. Objectives This study aims to investigate the role of CFH in PAEC dysfunction, defined in terms of intracellular and mitochondrial reactive oxygen species (ROS) generation, altered cell proliferation indices and changes in gene transcription of the ROS-generating enzyme NADPH oxidase-2 (Nox2). Methods Cultured human PAECs (hPAECs) were challenged with 10 μM haemoglobin (Hb) or no treatment (control) for 24 hours. Flow cytometry was used to measure total intracellular ROS (dihydroethidium assay), mitochondrial ROS (MitoSOX assay) and cell cycle profile using propidium iodide. Nox2 gene expression was measured using RT-qPCR. Cell proliferation was measured using the BrdU assay. Results Total intracellular and mitochondrial ROS production in HPAECs increased (∼3-fold) following Hb challenge compared to control. Additionally, Nox2 mRNA expression was greater in hPAECs treated with Hb for durations of 1 or 2 hours compared to control. Hb-treated hPAECs displayed a significant decrease (*p<0.05) in the percentage of cells in S and G2/M phases compared to control (see figure). In contrast, the BrdU results indicated a significant increase (∼1.8 fold) in proliferation in response to Hb treatment (**p<0.005). Conclusions These findings suggest that hPAECs exposed to Hb undergo an increase in intracellular and mitochondrial ROS production, which is also associated with an upregulation in Nox2 gene expression. Results from the cell cycle and BrdU assays suggest contrasting proliferative responses to Hb exposure, but warrant further investigation into possible changes in apoptotic or cell repair processes. Further studies are warranted to investigate the role of these processes in the PAH disease setting. Change in cell proliferation
Lynne D Neumayr, Carolyn C Hoppe,
Published: 1 November 2019
The American Journal of Managed Care, Volume 25

The publisher has not yet granted permission to display this abstract.
, Punam Malik
Blood Advances, Volume 3, pp 3170-3180; doi:10.1182/bloodadvances.2019000193

Sickle cell disease (SCD) is an inherited monogenic red blood cell disorder affecting millions worldwide. SCD causes vascular occlusions, chronic hemolytic anemia, and cumulative organ damage such as nephropathy, pulmonary hypertension, pathologic heart remodeling, and liver necrosis. Coagulation system activation, a conspicuous feature of SCD that causes chronic inflammation, is an important component of SCD pathophysiology. The key coagulation factor, thrombin (factor IIa [FIIa]), is both a central protease in hemostasis and thrombosis and a key modifier of inflammation. Pharmacologic or genetic reduction of circulating prothrombin in Berkeley sickle mice significantly improves survival, ameliorates vascular inflammation, and results in markedly reduced end-organ damage. Accordingly, factors both upstream and downstream of thrombin, such as the tissue factor–FX complex, fibrinogen, platelets, von Willebrand factor, FXII, high-molecular-weight kininogen, etc, also play important roles in SCD pathogenesis. In this review, we discuss the various aspects of coagulation system activation and their roles in the pathophysiology of SCD.
Nadjib Hammoudi, François Lionnet, Alban Redheuil, Gilles Montalescot
European Heart Journal, Volume 41, pp 1365-1373; doi:10.1093/eurheartj/ehz217

Sickle cell disease (SCD) is the most frequent genetic haemoglobinopathy worldwide. Early childhood mortality has dramatically decreased in high-income countries, and most patients now survive beyond the 5th decade. However, in the aging SCD population, the morbidity related to chronic organ damage, especially kidney and heart, has become a major concern. While pulmonary hypertension has attracted most attention, it appears that this condition is frequently linked to left heart failure (HF). Accordingly, SCD-associated cardiomyopathy is emerging as a major cause of reduced quality of life and early mortality in these patients. The diagnosis of this particular phenotype of high-output HF is challenging. Exercise intolerance and dyspnoea in SCD patients are linked to multiple causes including chronic anaemia. Moreover, echocardiographic features are unusual and can be misinterpreted. The classical diagnosis algorithm for HF is generally not suitable in SCD patients, and HF is poorly recognized and mostly diagnosed at a late congestive stage in routine practice. Such patients need to be identified at an earlier stage of myocardial dysfunction via improved phenotyping. This constitutes the first step towards further investigations in SCD needed to improve the prognosis and the quality of life. This article provides an updated review of the recent advances in the pathophysiology and diagnosis, and in addition, perspectives of new therapeutic approaches in SCD-related cardiac manifestations.
, Vijaya M. Joshi, Banu Aygun, Joseph Moen, , Devi Govindaswamy, Jola Dowdy, Alyssa Cotton, Guolian Kang, Russell E. Ware, et al.
Published: 12 February 2019
Pediatric Blood & Cancer, Volume 66; doi:10.1002/pbc.27717

Elevated tricuspid valve regurgitation jet velocity (TRV ≥ 2.5 m/s) is associated with mortality among adults with sickle cell disease (SCD), but correlative biomarkers are not studied according to treatment exposure or genotypes. To investigate the associations between biomarkers and TRV elevation, we examined the relationship between TRV and hemolytic, inflammatory, and cardiac biomarkers, stratified by disease‐modifying treatments and SCD genotype. In total, 294 participants with SCD (mean age, 11.0 ± 3.7 years) and 49 hereditary spherocytosis (HS; mean age, 22.9 ± 19.75 years) were included for comparison and enrolled. TRV was elevated in 30.7% of children with SCD overall: 18.8% in HbSC/HbSβ+‐thalassemia, 28.9% in untreated HbSS/HbSβ0‐thalassemia, 34.2% in HbSS/HbSβ0‐thalassemia hydroxyurea‐treated, and 57% in HbSS/HbSβ0‐thalassemia chronic transfusion treated. TRV was elevated in 10.7% and 27.8% in HS children and adults, respectively. In children with SCD, elevated TRV was correlated with hemoglobin (odds ratio [OR] = 0.78, P = 0.004), lactate dehydrogenase (LDH; OR = 2.52, P = 0.005), and N‐terminal pro‐brain natriuretic peptide (NT‐pro BNP; OR = 1.003, P = 0.004). In multivariable logistic regression, adjusting for genotype, sex, hemolytic index, and treatment, hemoglobin concentration remained the only significant variable associated with elevated TRV in untreated HbSS/HbSβ0‐thalassemia participants. TRV was not associated with inflammatory markers, other markers of hemolysis, or NT‐pro BNP in untreated HbSS/HbSβ0‐thalassemia. Neither hemoglobin nor LDH was associated with TRV in HbSC/HbSβ+‐thalassemia. These results suggest that elevated TRV is influenced by the degree of anemia, possibly reflecting sickling as part of the disease pathophysiology. Prospective studies should monitor hemoglobin concentration as children with SCD age into adulthood, prompting initiation of TRV screening and monitoring.
, Yasser Mohamad Sedky, Hesham Abd-Elkareem,
International Journal of Hematology-Oncology and Stem Cell Research, Volume 13, pp 35-41; doi:10.18502/ijhoscr.v13i1.323

Background: Sickle cell disease (SCD) is a hereditary disorder characterized by hemolytic anemia with different clinical manifestations. Patients with SCD exhibit a chronic inflammatory state and reduced length and quality of life. Interleukin-1 β (IL-1β) is important in acute and chronic diseases; and its single nucleotide polymorphisms (SNP) have been considered as predictors of prognosis in several inflammatory conditions. This study aimed at exploring IL-1β (+3954C/T) SNP as a potential genetic modifier and/or predictor of SCD clinical and laboratory phenotypes. Materials and Methods: This cross-sectional study involved 50 SCD patients and 50 age, sex and ethnicity-matched healthy individuals. IL-1β (+3954C/T) SNP was identified by PCR-RFLP. Associations between IL-1β (+3954 C/T) SNP and the clinical and laboratory profiles of patients with SCD were studied. Results: It was found that the homozygous mutant genotype TT was significantly higher in cases compared to controls [13(26%) vs. 3(6%) respectively; p=0.006, OR (95%CI): 5.505(1.460-20.756)]. The homozygous mutant genotype TT was associated with a higher mean pulmonary arterial pressure when compared to the CC and CT genotype (42.62 vs. 33.49 mmHg, p<0.001). Conclusion: There is an increased prevalence of the mutant genotype of IL-1β +3954 SNP in Egyptian SCD patients. Regarding disease complications, the mutant genotype was more prevalent in cases complicated by pulmonary hypertension. These findings point to the possible role of IL-1β +3954 SNP in the pathophysiology of SCD and its manifestations.
Tomasz Brzoska, Gregory J. Kato, Prithu Sundd
Published: 1 January 2019
Platelets pp 563-580; doi:10.1016/b978-0-12-813456-6.00031-x

Sickle cell disease is caused by the homozygous mutation in the beta globin gene that leads to erythrocyte sickling, rigidity, dehydration, impaired rheology and premature hemolysis. Growing evidence suggests that platelet activation in SCD contributes to the progression of major complications such as acute systemic painful vaso-occlusive crisis, chronic organ damage, acute chest syndrome and pulmonary hypertension. Erythrocyte- and tissue-derived damage associated molecular patterns molecules released in SCD promote platelet activation by regulating nitric oxide signaling, reactive oxygen species generation, toll-like-receptor-4-dependent innate immune signaling, purinergic signaling, and coagulation. Activated platelets adhere to leukocytes, sickle erythrocytes and endothelium to promote vaso-occlusion and/or vascular thrombosis. The knowledge of the platelet-dependent pathophysiology has led to the development of new therapies for SCD, by targeting different processes leading to platelet activation in SCD.
Elliott Vichinsky, Carolyn Hoppe, Jo Howard, Kenneth I. Ataga, Videlis Nduba, Amal El-Beshlawy, David L. Diuguid, Salam Al-Kindi, Clark Brown, Hoda Hassab, et al.
Published: 29 November 2018
Blood, Volume 132, pp 505-505; doi:10.1182/blood-2018-99-118508

Background: Sickle cell disease (SCD) is a genetic disorder in which deoxygenation results in polymerization of mutated hemoglobin S (HbS) and triggers the downstream effects of red blood cell (RBC) deformation (sickling), hemolytic anemia, vaso-occlusion, inflammation, predisposition to infection, and chronic organ damage. Two distinct pathophysiologic mechanisms of SCD-severe anemia and vasculopathy-overlap to cause severe morbidity. Chronic anemia and recurrent cycles of ischemia-reperfusion injury, often manifesting as fatigue and/or pain (vaso-occlusive crisis [VOC]), accumulate over the lifespan, resulting in end-organ parenchymal damage. The severity of steady-state anemia predicts CNS injury (including stroke and neurocognitive impairment), renal disease, and cardiopulmonary dysfunction (pulmonary hypertension). Long-term complications contribute to decreased quality of life and are associated with early death. Voxelotor (GBT440) is an oral once-daily therapy that modulates Hb affinity for oxygen, thereby inhibiting HbS polymerization and the resultant sickling of RBCs, potentially interrupting the molecular pathogenesis of the disease. The Hemoglobin Oxygen Affinity Modulation to Inhibit HbS PolymErization (HOPE) study (NCT03036813) is an ongoing, phase 3, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of voxelotor in patients with SCD aged 12 to 65 years. Methods: Part A of the HOPE study encompasses the first approximately 150 randomized patients, a group pre-specified in the protocol for analysis. Part A is a comparison of 2 doses of voxelotor (900 and 1500 mg/day) with placebo in patients treated for at least 12 weeks. The primary endpoint is an increase in Hb >1 g/dL from baseline (Hb responder). Secondary endpoints include SCD symptom assessment using a novel patient-reported outcome (PRO) measure, VOC during the treatment period, and change from baseline in measures of hemolysis (including % reticulocytes and unconjugated bilirubin). Eligible patients must have SCD (HbSS, HbSC, HbSβ0 thalassemia, or other variants), Hb ≥5.5 and ≤10.5 g/dL, and at least 1 VOC in the 12 months prior to study entry. Hydroxyurea is allowed if the dose has been stable for at least 90 days prior to study entry. Results: 154 patients with a median age of 28 years (range, 12-59), 42% male, have received treatment for a median of 21.9 weeks (voxelotor overall, range 1.7- 65.1) and 22.4 weeks (placebo, range 1.7-44.7). The majority have HbSS/HbSB0 genotype: 94% (900 mg), 92% (1500 mg), and 90% (placebo). Hydroxyurea use at study entry was 67% (900 mg), 62% (1500 mg), and 64% (placebo). Median Hb at study entry was 8.3 g/dL (900 mg; range, 6.3-10.8), 8.6 g/dL (1500 mg; range, 5.9-10.8), and 8.5 g/dL (placebo; range, 6.1-10.4). Data for Hb and measures of hemolysis at week 12 are available for 40 patients in the 900 and 1500 mg arms and 44 patients in the placebo arm. At week 12, the proportion of...
Ioannis Papassotiriou, Christos Poziopoulos, Georgia Avgerinou, Claudia R. Morris, Ersi Voskaridou
Published: 29 November 2018
Blood, Volume 132, pp 4912-4912; doi:10.1182/blood-2018-99-111445

Background: The complex pathophysiology of Sickle Cell Disease (SCD) makes unlikely that a single therapeutic agent will prevent or reverse all SCD complications. Metabolomic analysis might help in the characterization of the endogenous and exogenous effects of potential new treatments. Metabolites are small molecules that are chemically transformed during metabolism and provide a functional readout of cellular state. Metabolites serve as direct signatures of biochemical activity and are therefore easier to correlate with phenotype. The metabolome is typically defined as the collection of small molecules produced by cells and offers a window for investigating how mechanistic biochemistry relates to cellular phenotype. There are very few reports associated with SCD providing comprehensive measurements of metabolites present in blood. Low arginine bioavailability has been associated with a clinical phenotype of increased hemolytic rate, pulmonary hypertension risk and early mortality. Recently, the FDA approved the use of L-glutamine for the treatment of adults and children with SCD, on the basis of the results of randomized phase 3 clinical trials1, while L-arginine's involvement is under investigation2,3. In this context we aimed to quantify targeted metabolites' abnormalities in patients with Sickle Cell/beta thalassemia (HbS/βThal), to identify pathways that might be of interest to prevent disease complications. Patients and Methods: Thirty adult Caucasian patients with HbS/βThal aged 45.6±10.9y, (43% male), at steady-state were enrolled in the study, while 20 age-matched healthy individuals (45% male) served as controls. Along with measurements of hematologic and blood chemistry parameters, targeted metabolome analyses for 13 aminoacids and 2 aminoacid's derivatives were performed after extraction from dry blood spots (DBSs) on filter paper using LC/MS/MS, with derivatization (AB SCIEX 5500 triple quadrupole QTRAP® LC/MS/MS Systems, Framingham, MA, USA). Results: Multiple metabolite differences are identified in HbS/βThal vs. Controls (Figure1). From metabolites involved in the biosynthesis of glutathione, only L-glutamine's levels were lower in patients with HbS/βThal compared to controls, while 5-oxyproline levels, a catabolic product of glutathione metabolism, were markedly increased in patients with HbS/βThal compared to controls. Urea cycle amino acids, also involved in the production of nitric oxide, L-arginine and L-ornithine concentrations were significantly lower in patients with HbS/βThal compared to controls, with a trend towards lower L-citrulline in patients with HbS/βThal p=0.06). Finally, amino acids involved in catecholamines (dopamine, nor-epinephrine and epinephrine) biosynthesis, such as L-phenylalanine and L-tyrosine and its metabolite succinylacetone levels were significantly lower in patients with HbS/βThal compared to controls. No significant correlations were found between any metabolites and markers of...
I Astadicko, M F Dresse, M C Seghaye
Published: 1 November 2018
Revue medicale de Liege, Volume 73, pp 550-556

The publisher has not yet granted permission to display this abstract.
, Harold I. Palevsky
Published: 1 April 2018
Respiratory Medicine, Volume 137, pp 191-200; doi:10.1016/j.rmed.2018.02.020

Pulmonary hypertension has emerged as a major cause of morbidity and mortality in patients with hemoglobinopathies and chronic hemolytic anemias. These hematological diseases include – but are not limited to – sickle cell disease (SCD), thalassemia, paroxysmal nocturnal hematuria, and hereditary spherocytosis. Although most studies have been based on the use of echocardiography as a screening tool for pulmonary hypertension as opposed to the gold standard of right heart catheterization for definitive diagnosis, the association between chronic hemolytic anemia and pulmonary hypertension is evident. Studies have shown that patients with SCD and a tricuspid regurgitant velocity (TRV) ≥ 2.5 m/sec are at increased risk of pulmonary hypertension and are at increased mortality risk. Additional markers of risk of pulmonary hypertension and increased mortality include a pro-BNP >160 pg/mL combined with a 6-min walk distance of <333 m. There is currently a lack of concrete data to support the use of targeted oral pulmonary arterial hypertension therapy in chronic hemolytic anemia. As a result, management is generally targeted towards medical optimization of the underlying anemia. This literature review aims to discuss the pathophysiology, diagnostic and prognostic tools, recent studies and current protocols that are essential in guiding management of pulmonary hypertension in chronic hemolytic anemias.
Ashar Usmani,
Clinical Hemorheology and Microcirculation, Volume 68, pp 205-221; doi:10.3233/CH-189008

Sickle cell disease (SCD) is a monogenetic disorder caused by a mutation in the β-globin gene HBB leading to polymerization of red blood cells causing damage to cell membranes, increasing its rigidity and intravascular hemolysis. Multiple lines of evidence suggest that SCD can be viewed as pan-vasculopathy associated with multiple mechanisms but driven by hemoglobin S polymerization. Here we review the pathophysiology, clinical manifestations and management strategies for cerebrovascular disease, pulmonary hypertension and renal disease associated with SCD. These "vascular phenotypes" reflect the systemic nature of the complications of SCD and are a major threat to the well-being of patients with the disorder.
Clinical Hemorheology and Microcirculation, Volume 68, pp 263-299; doi:10.3233/CH-189012

The primary β-globin gene mutation that causes sickle cell disease (SCD) has significant pathophysiological consequences that result in hemolytic events and the induction of the inflammatory processes that ultimately lead to vaso-occlusion. In addition to their role in the initiation of the acute painful vaso-occlusive episodes that are characteristic of SCD, inflammatory processes are also key components of many of the complications of the disease including autosplenectomy, acute chest syndrome, pulmonary hypertension, leg ulcers, nephropathy and stroke. We, herein, discuss the events that trigger inflammation in the disease, as well as the mechanisms, inflammatory molecules and cells that propagate these inflammatory processes. Given the central role that inflammation plays in SCD pathophysiology, many of the therapeutic approaches currently under pre-clinical and clinical development for the treatment of SCD endeavor to counter aspects or specific molecules of these inflammatory processes and it is possible that, in the future, we will see anti-inflammatory drugs being used either together with, or in place of, hydroxyurea in those SCD patients for whom hematopoietic stem cell transplants and evolving gene therapies are not a viable option.
Natalie R. Shilo,
Published: 21 August 2017
Expert Review of Hematology, Volume 10, pp 875-890; doi:10.1080/17474086.2017.1364989

Pulmonary hypertension (PH) develops in a significant number of patients with sickle cell disease (SCD), resulting in increased morbidity and mortality. This review focuses on PH pathophysiology, risk stratification, and new recommendations for screening and treatment for patients with SCD. Areas covered: An extensive PubMed literature search was performed. While the pathophysiology of PH in SCD is yet to be fully deciphered, it is known that the etiology is multifactorial; hemolysis, hypercoagulability, hypoxemia, ischemic-reperfusion injury, oxidative stress, and genetic susceptibility all contribute in varying degrees to endothelial dysfunction. Hemolysis, in particular, seems to play a key role by inciting an imbalance in the regulatory axis of nitric oxide and arginine metabolism. Systematic risk stratification starting in childhood based on clinical features and biomarkers that enable early detection is necessary. Multi-faceted, targeted interventions, before irreversible vasculopathy develops, will allow for improved patient outcomes and life expectancy. Expert commentary: Despite progress in our understanding of PH in SCD, clinically proven therapies remain elusive and additional controlled clinical trials are needed. Prevention of disease starts in childhood, a critical window for intervention. Given the complex and multifactorial nature of SCD, patients will ultimately benefit from combination therapies that simultaneously targets multiple mechanisms.
Jun Ren, Xiuqing Ding, Marie Trudel, John J. Greer,
Published: 17 August 2017
Scientific Reports, Volume 7, pp 1-13; doi:10.1038/s41598-017-08860-8

The nature and development of cardiorespiratory impairments associated with sickle cell disease are poorly understood. Given that the mechanisms of these impairments cannot be addressed adequately in clinical studies, we characterized cardiorespiratory pathophysiology from birth to maturity in the sickle cell disease SAD mouse model. We identified two critical phases of respiratory dysfunction in SAD mice; the first prior to weaning and the second in adulthood. At postnatal day 3, 43% of SAD mice showed marked apneas, anemia, and pulmonary vascular congestion typical of acute chest syndrome; none of these mice survived to maturity. The remaining SAD mice had mild lung histological changes in room air with an altered respiratory pattern, seizures, and a high rate of death in response to hypoxia. Approximately half the SAD mice that survived to adulthood had an identifiable respiratory phenotype including baseline tachypnea at 7–8 months of age, restrictive lung disease, pulmonary hypertension, cardiac enlargement, lower total lung capacity, and pulmonary vascular congestion. All adult SAD mice demonstrated impairments in exercise capacity and response to hypoxia, with a more severe phenotype in the tachypneic mice. The model revealed distinguishable subgroups of SAD mice with cardiorespiratory pathophysiology mimicking the complications of human sickle cell disease.
Anton Lishmanov, Tara T. Bellamkonda,
Published: 1 June 2017
Chest, Volume 151; doi:10.1016/j.chest.2017.01.040

An African American female in her 20s with sickle cell disease, complicated by previous episodes of acute chest syndrome, was admitted for a planned termination of pregnancy at 18 weeks of gestation. One day post-procedure, in the setting of vaginal bleeding, the patient developed chest pain and hypoxia. Critical care consultation was requested for suspected acute chest syndrome.Initial evaluation of the patient was notable for significant distress, tachycardia, and severe chest pain, which worsened with respirations and exertion. Physical examination was limited because of her level of distress and pain. Vital signs were as follows: heart rate, 130 beats/min; blood pressure, 115/65 mm Hg; pulse oximetry, 89% on room air; and respiratory rate, 30 breaths/min. An electrocardiogram showed sinus tachycardia at 130 beats/min, with nonspecific T-wave changes in the anterior precordial leads. Laboratory results were significant for the following: hemoglobin level, 6 g/dL (baseline, 8-9 g/dL); leukocytosis (white blood cell count, 22,300/μL), troponin-T, 0.19 ng/mL; and N-terminal pro-B-type natriuretic peptide, 3,560 pg/mL. Chest radiography demonstrated mild cardiomegaly and a suggestion of a retrocardiac opacity (Fig 1Fig 1). Fluid resuscitation and red cell transfusion were initiated. The patient was transferred to the ICU for further treatment.Figure 1Chest radiography demonstrating mild cardiomegaly and a suggestion of retrocardiac opacity.View Large Image | View Hi-Res Image | Download PowerPoint SlideIn the ICU there was a rapid development of multiorgan failure that included a shock state, acute renal failure with hyperkalemia, coagulopathy, and severe lactic acidosis (13 mM). Arterial blood gas analysis was as follows: pH, 7.062; pCO2, 22.6 mm Hg; Pao2, 120 mm Hg on 100% nonrebreather mask. The patient required mechanical ventilation and vasopressor support. Despite aggressive support the patient continued to decompensate. The intensivist team performed point-of-care ultrasonography to further evaluate the cause of decompensation (Video 1Video 1).Question: Based on the clinical scenario and the findings of point-of-care ultrasonography, what is the most likely cause of cardiopulmonary failure in this patient?Answer: Acute right ventricular failureDiscussionJump to SectionDiscussionReverberationsAcknowledgmentsSupplementary DataReferencesWithout sonographic evidence (Video 2Video 2), acute right ventricular (RV) failure is difficult to diagnose. The clinical findings and organ failures that result from RV failure (circulatory collapse, renal failure, elevated lactate and liver test results, and coagulopathy) are often initially attributed to, or overlapping with, severe sepsis and septic shock. As a result, reflexive volume resuscitation is administered—ultimately worsening RV failure. Similarly, initial therapy for patients with sickle cell hemolytic crisis includes fluid resuscitation and red cell transfusion. When sickle cell crisis is complicated by acute chest syndrome, pulmonary vaso-occlusive disease, and resultant acute pulmonary hypertension/cor pulmonale, large-volume resuscitation is detrimental; it produces a downward spiral of RV failure and clinical deterioration.Goal-directed echocardiography is essential in determining the cause of cardiopulmonary failure and includes assessment of the right ventricular size and function. Echocardiographic guidelines used in the evaluation of right ventricular failure are complex.1,2 Simplified parameters are found in Table 1Table 1. Furthermore, in the majority of severe shock states, visual assessment of the RV alone is often adequate to determine RV function. Visual markers of failure include the following:•RV size comparable to or larger than left ventricular size in the apical four-chamber view•Paradoxical septal motion•“D-shaped” septumTable 1Simplified Echocardiographic Findings Used in the Evaluation of Right Ventricular Failure1. Right ventricular size > two-thirds of left ventricular size in the apical four-chamber view2. Paradoxical motion of the septum in the apical four-chamber and parasternal short-axis views3. “D-shaped” septum in short-axis view (leftward ventricular septal shift)4. Tricuspid annular plane systolic excursion in M-mode 2.1 cm with 2.5 m/s), and cor pulmonale occurred in 13% of patients.3 The pathophysiology of acute pulmonary hypertension and RV failure in acute chest syndrome is multifactorial and attributed to a combination of hypoxic pulmonary vasoconstriction, nitric oxide depletion due to hemolysis, and pulmonary vasculature occlusion.3The presence of RV dysfunction should alter shock management, and consideration should be given to fluid restriction, diuretics, inotropes and vasopressors, pulmonary vasodilators, and limiting tidal volume and positive end-expiratory pressure on mechanical ventilation.1 In the most severe cases, extracorporeal circulatory support and oxygenation may be implemented.In our case, veno-arterial extracorporeal membrane oxygenation (ECMO) via the femoral vasculature was implemented. Ultrasound guidance during percutaneous ECMO cannulation assisted with vascular identification, cannula sizing, and cannula deployment. Video 3Video 3 demonstrates the use of real-time ultrasound guidance, in accordance with Extracorporeal Life Support Organization (ELSO) guidelines, for the venous limb cannulation. After the guidewire was visualized ascending through the inferior vena cava and into the internal jugular vein, the cannula was deployed and positioned at the cavo-atrial junction (Discussion Video 4Video 4).4The signs and symptoms of RV failure mimic, and commonly overlap with, other causes of shock and acute respiratory failure—but the treatment can be markedly different. Without appropriate echocardiographic identification of shock states, empiric therapies can potentially result in further morbidity and mortality.ReverberationsJump to SectionDiscussionReverberationsAcknowledgmentsSupplementary DataReferences1.Point-of-care ultrasonography assists in differentiating shock states and can evaluate for possible causes of right ventricular failure.2.Pulmonary hypertension is prevalent among patients with sickle cell disease. Clinicians should be vigilant in identifying acute pulmonary hypertension with right ventricular failure in patients with acute chest syndrome.3.Real-time vascular ultrasound and echocardiography assist in percutaneous ECMO cannulation. Without sonographic evidence (Video 2Video 2), acute right ventricular (RV) failure is difficult to diagnose. The clinical findings and organ failures that result from RV failure (circulatory collapse, renal failure, elevated lactate and liver test results, and coagulopathy) are often initially attributed to, or overlapping with, severe sepsis and septic shock. As a result, reflexive volume resuscitation is administered—ultimately worsening RV failure. Similarly, initial therapy for patients with sickle cell hemolytic crisis includes fluid resuscitation and red cell transfusion. When sickle cell crisis is complicated by acute chest syndrome, pulmonary vaso-occlusive disease, and resultant acute pulmonary hypertension/cor pulmonale, large-volume resuscitation is detrimental; it produces a downward spiral of RV failure and clinical deterioration.Goal-directed echocardiography is essential in determining the cause of cardiopulmonary failure and includes assessment of the right ventricular size and function. Echocardiographic guidelines used in the evaluation of right ventricular failure are complex.1,2 Simplified parameters are found in Table 1Table 1. Furthermore, in the majority of severe shock states, visual assessment of the RV alone is often adequate to determine RV function. Visual markers of failure include the following:•RV size comparable to or l
, Nohair S. Mohamed, Rania S. Hamza, Rasha M. Ali, Mona K. El-Ghamrawy
Journal of Clinical Laboratory Analysis, Volume 32; doi:10.1002/jcla.22264

Sickle cell disease (SCD) is a monogenic disease associated with multisystem morbidity. Vasculopathy caused by delicate imbalance between coagulation and endothelial systems plays a pivotal role in disease course. As Protein Z and Endothelin-1 genetic polymorphisms may increase the thrombotic risk, the aim of the current work was to verify the possible impact of Protein Z (PROZ G79A) and Endothelin-1 (EDN1 G5665T) polymorphisms on the clinic-laboratory features of the SCD in a cohort of Egyptian pediatric patients. Genotyping of Protein Z G79A and Endothelin-1 G5665T was carried out by polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) assay for 100 SCD patients and 100 controls. Protein -Z G79A polymorphism was not associated with vascular complications in the studied SCD patients. Endothelin-1 G5665T polymorphism was associated with pulmonary dysfunction (pulmonary artery hypertension and acute chest syndrome) and severe vaso-occlusive crises (VOC). Endothelin-1 G5665T polymorphism could be considered as a molecular predictor for pulmonary dysfunction and severe VOC in SCD. Further researches with larger cohorts are recommended to understand the pathophysiology of SCD and to explain the inter-patients’ variability of disease severity.
Journal of Clinical Investigation, Volume 127, pp 750-760; doi:10.1172/jci89741

Hemolysis is a fundamental feature of sickle cell anemia that contributes to its pathophysiology and phenotypic variability. Decompartmentalized hemoglobin, arginase 1, asymmetric dimethylarginine, and adenine nucleotides are all products of hemolysis that promote vasomotor dysfunction, proliferative vasculopathy, and a multitude of clinical complications of pulmonary and systemic vasculopathy, including pulmonary hypertension, leg ulcers, priapism, chronic kidney disease, and large-artery ischemic stroke. Nitric oxide (NO) is inactivated by cell-free hemoglobin in a dioxygenation reaction that also oxidizes hemoglobin to methemoglobin, a non–oxygen-binding form of hemoglobin that readily loses heme. Circulating hemoglobin and heme represent erythrocytic danger-associated molecular pattern (eDAMP) molecules, which activate the innate immune system and endothelium to an inflammatory, proadhesive state that promotes sickle vaso-occlusion and acute lung injury in murine models of sickle cell disease. Intravascular hemolysis can impair NO bioavailability and cause oxidative stress, altering redox balance and amplifying physiological processes that govern blood flow, hemostasis, inflammation, and angiogenesis. These pathological responses promote regional vasoconstriction and subsequent blood vessel remodeling. Thus, intravascular hemolysis represents an intrinsic mechanism for human vascular disease that manifests clinical complications in sickle cell disease and other chronic hereditary or acquired hemolytic anemias.
, , John Lekakis, John Parissis
Published: 20 December 2016
European Journal of Heart Failure, Volume 19, pp 479-489; doi:10.1002/ejhf.708

Hereditary haemoglobinopathies, mainly beta-thalassemia and sickle cell disease, constitute the most common monogenic disorders in humans, and although once geographically confined, they are currently globally distributed. They are demanding clinical entities that require multidisciplinary medical management. Despite their genotypic and phenotypic heterogeneity, the haemoglobinopathies share several similarities in pathophysiology, clinical manifestations, therapeutic requirements, and complications, among which heart failure (HF) represents a leading cause of mortality and morbidity. However, haemoglobinopathies have generally been addressed in a rather fragmentary manner. A unifying approach focusing on the underlying similarities of HF attributes in the two main entities might contribute to their better understanding, characterization, and management. In the present review, we attempt such an approach to the pathophysiology, clinical phenotypes, and management of HF in haemoglobinopathies.
Nicolas V Currier, Gersham Dent, Paul S. Swerdlow, Willem Birkhoff, Jacobus Burggraaf, Jaspert De Vries, Jaladhar Neelavalli, Muhammad Shahid, Brijesh K Yadav, William E. Hobbs, et al.
Published: 2 December 2016
Blood, Volume 128, pp 4871-4871; doi:10.1182/blood.v128.22.4871.4871

Background: Vascular complications such as stroke and pulmonary hypertension are central features of sickle cell disease (SCD) pathophysiology and are associated with early mortality among patients with SCD. Better understanding of the abnormal blood flow patterns in sickle cell disease is critical to assessing the therapeutic benefit of emerging therapies. Previous studies have shown abnormal blood flow patterns in sickle cell patients using laser speckle contrast imaging (LSCI) (Ikeda et al. poster 1080 ASH annual meeting, December 8, 2012), however, no test re-test variability or changes in response to therapeutic intervention were assessed. As part of a larger study using multiple imaging technologies to concurrently evaluate blood flow and oxygenation in several organs of healthy subjects and subjects with SCD, the present study has analyzed skin blood flow by LSCI in these patients longitudinally using a multiple visit protocol. Furthermore, we analyzed the effect of Chronic Transfusion Protocol, the most effective intervention against vascular complications on skin blood flow. Methods: We enrolled 9 SCD patients (age 30.2 ± 8.6 years 5 men / 4 women) and 4 age and ethnically matched healthy controls (age 24.5 ± 4.5 years, 2 men / 2 women). 5 of the 9 SCD patients were on Chronic Transfusion Protocol. Following a screening visit where patients consented for the study, had basic labs, 12-lead EKG and physical exam, cutaneous blood flow was directly measured using LCSI at baseline, during and after a standard brachial artery occlusion-reperfusion maneuver (inflation of an occlusive pneumatic cuff for 3-5 min depending on patient tolerance). For assessment of test, re-test reliability this visit protocol was repeated within 1-10 days for patients not on transfusion protocols and healthy volunteers. Three visits occurred for transfusion patients, the first 2-4 days prior to transfusion, the second 1-2 days post transfusion and the third 6-14 days after the first post-transfusion imaging visit. Results: Baseline microvascular blood flow measured by LSCI was greater in patients with sickle cell disease compared to healthy controls (47 + 11 vs. 27 + 3 arbitrary units (AU); p=0.002) with sickle cell patients on chronic transfusion protocols exhibiting an intermediate blood flow phenotype (32 + 7 AU p= 0.001 vs. non-transfused patients and p= 0.039 vs. HV). Surprisingly, transfusion had no impact on baseline blood flow both 1-2 days and 6-14 days following transfusions (34 + 9 AU pre-transfusion, 32 + 7 AU first post-transfusion, 33 + 6 AU second post-transfusion). Maximal microvascular blood flow was similar across all groups (86 + 14 AU sickle cell patients vs. 82 + 12 AU healthy volunteers vs. 75 + 15 AU sickle cell patients on chronic transfusion). All measured values exhibited significant longitudinal stability across visits with r2= 0.865 for baseline blood flow measurements for non-transfusion sickle cell patients and healthy...
, Samir K. Ballas, Alicia Garcia, Haewon C Kim, Karen King, Bruce Sachais,
Published: 9 October 2016
Journal of Clinical Apheresis, Volume 32, pp 342-367; doi:10.1002/jca.21511

The American Society for Apheresis (ASFA) conducted a one-day consensus conference on red blood cell exchange (RBCx) in sickle cell disease (SCD) during its annual meeting in San Antonio, TX, on May 5, 2015. The authors of this article, a subcommittee of ASFA's Clinical Applications Committee, developed several questions with regard to pathophysiology of SCD and use of RBCx in the management of various complications. These questions were provided to the seven invited speakers who are the experts in the field of SCD. Two experts in the field moderated the proceedings of the conference, which was attended by more than 150 participants. After each presentation, there was a summary of the main points by the moderators and an open discussion with questions from the audience. A video recording of the proceedings, as well as each presentation, was made available to the authors. Each author's summary was reviewed and approved by the respective speaker before submission of this manuscript. The subcommittee also developed several key questions to generate a consensus amongst the speakers on key issues for using RBCx for patients with SCD.
, L. Calamy, Z. Germont, A. Lemoine, A.-A. Lopes, A. Massiot, J. Tencer, C. Thivent,
Published: 1 October 2016
Archives de Pédiatrie, Volume 23, pp 1094-1106; doi:10.1016/j.arcped.2016.06.014

Acute and chronic pulmonary complications are frequent in sickle cell disease (SCD), with different spectrum and characteristics in children and adults. Chronic hypoxia is frequent and plays a role in several respiratory complications in SCD. Furthermore, hypoxia has been associated with a higher risk of cerebral ischemia. Despite differing oxygen affinity between hemoglobin A and S, standard pulse oximetry was shown to be accurate in diagnosing hypoxia in SCD patients. Whereas acute hypoxia management is similar to non-SCD patients, chronic hypoxia treatment is mainly based on a transfusion program rather than long-term oxygen therapy. Acute chest syndrome (ACS) is the foremost reason for admission to the intensive care unit and the leading cause of premature death. Guidelines on its management have recently been published. Asthma appears to be a different comorbidity and may increase the risk of vaso-occlusive crisis, ACS, and early death. Its management is not specific in SCD, but systemic steroids must be used carefully. Pulmonary hypertension (PH) is a major risk factor of death in adult patients. In children, no association between PH and death has been shown. Elevated tricuspid regurgitant velocity was associated with lower performance on the 6-min walk test (6MWT) but its long-term consequences are still unknown. These differences could be due to different pathophysiology mechanisms. Systematic screening is recommended in children. Regarding lung functions, although obstructive syndrome appears to be rare, restrictive pattern prevalence increases with age in SCD patients. Adaptation to physical exercise is altered in SCD children: they have a lower walking distance at the 6MWT than controls and can experience desaturation during effort, but muscular blood flow regulation maintains normal muscular strength. Sleeping disorders are frequent in SCD children, notably Obstructive sleep apnea syndrome (OSAS). Because of the neurological burden of nocturnal hypoxia, OSAS care is primordial and mainly based on adenotonsillectomy, which has been shown to reduce ischemic events. The high morbidity and mortality related to pulmonary impairments in SCD require a careful pulmonary assessment and follow-up. Mainly based on clinical examination, follow-up aims to the diagnosis of SCD-related respiratory complications early in these children.
Published: 30 March 2016
Sickle Cell Anemia pp 285-318; doi:10.1007/978-3-319-06713-1_12

Despite being a disease that stems primarily from abnormalities in the erythrocytes, clinical manifestations and complications of sickle cell disease are known to affect virtually all organs and systems in the human body. Chronic hemolytic anemia and a systemic inflammatory state are the basic pathophysiological mechanisms that underlie the occurrence of both acute vaso-occlusive events (painful episodes, acute chest syndrome, priapism, stroke, etc.) and long-term end-organ damage (heart failure, chronic kidney disease, retinopathy, pulmonary hypertension, leg ulcers, osteoporosis, etc.). Adequate treatment for sickle cell disease in children with vaccination and prophylactic penicillin has allowed most of these patients to reach adulthood. Nevertheless, morbidity in the adult population is high, with many patients presenting with two or more vital organ complications by the age of 40. There is still room for improvement in the prevention, early diagnosis, and treatment of complications more frequently encountered by adult hematologists, and need for consultation with other subspecialties becomes a rule when caring for adult sickle cell patients. We review the clinical presentation, diagnosis, and management of the most relevant aspects of sickle cell disease in adults and summarize current treatment approaches, from supportive care with blood transfusions and hydroxyurea, to curative care with hematopoietic stem cell transplantation.
Sherif M. Yousry, , Gehan H. Shahin
Published: 4 March 2016
Hematology, Volume 21, pp 359-367; doi:10.1080/10245332.2016.1142710

Background: Sickle cell disease (SCD) is one of the major health problems in many parts of the world. SCD is characterized by multisystem complications with marked variability in its severity between patients, probably linked to nitric oxide (NO). Endothelial nitric oxide synthase (eNOS) enzyme which is responsible for NO synthesis may be implicated in SCD pathophysiology. Aim of the study: To explore the possible association between the eNOS gene polymorphisms and severity of SCD. Furthermore, we examined the genomic diversity of these polymorphisms in SCD patients. Methods: We genotyped 100 SCD patients and 80 controls were genotyped for eNOS 4a/b and eNOS 786T>C polymorphisms, using allele-specific polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism assay, respectively. Polymorphisms were analyzed in relation to severity of SCD manifestations. Results: The homozygous mutant eNOS-786T>T genotype was significantly associated with high risk of acute chest syndrome (ACS). The wild-type eNOS-4a/4b genotype was protective against vaso-occlusive crisis (VOC) and pulmonary hypertension (PHTN). The mutant homozygous haplotype (C –4a) was significantly associated with the risk of ACS, VOC, and PHTN. Conclusion: eNOS intron 4 and eNOS T>C gene polymorphisms may be used as a genetic marker of prognostic value in SCD, as they are associated with unfavorable clinical outcomes.
, , , Joshua Daily, Philip R. Khoury, Nihal Bakeer, Thomas R. Kimball, Jeffrey A. Towbin, Punam Malik, Michael D. Taylor
Published: 1 March 2016
JACC: Cardiovascular Imaging, Volume 9, pp 243-252; doi:10.1016/j.jcmg.2015.05.013

The aim of this study was to identify a unifying cardiac pathophysiology that explains the cardiac pathological features in sickle cell disease (SCD). 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. 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. 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. 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.
, Oswaldo L. Castro,
Published: 18 February 2016
Blood, Volume 127, pp 820-828; doi:10.1182/blood-2015-08-618561

Pulmonary hypertension affects ∼10% of adult patients with sickle cell disease (SCD), particularly those with the homozygous genotype. An increase in pulmonary artery systolic pressure, estimated noninvasively by echocardiography, helps identify SCD patients at risk for pulmonary hypertension, but definitive diagnosis requires right-heart catheterization. About half of SCD-related pulmonary hypertension patients have precapillary pulmonary hypertension with potential etiologies of (1) a nitric oxide deficiency state and vasculopathy consequent to intravascular hemolysis, (2) chronic pulmonary thromboembolism, or (3) upregulated hypoxic responses secondary to anemia, low O2 saturation, and microvascular obstruction. The remainder have postcapillary pulmonary hypertension secondary to left ventricular dysfunction. Although the pulmonary artery pressure in SCD patients with pulmonary hypertension is only moderately elevated, they have a markedly higher risk of death than patients without pulmonary hypertension. Guidelines for diagnosis and management of SCD-related pulmonary hypertension were published recently by the American Thoracic Society. Management of adults with sickle-related pulmonary hypertension is based on anticoagulation for those with thromboembolism; oxygen therapy for those with low oxygen saturation; treatment of left ventricular failure in those with postcapillary pulmonary hypertension; and hydroxyurea or transfusions to raise the hemoglobin concentration, reduce hemolysis, and prevent vaso-occlusive events that cause additional increases in pulmonary pressure. Randomized trials have not identified drugs to lower pulmonary pressure in SCD patients with precapillary pulmonary hypertension. Patients with hemodynamics of pulmonary arterial hypertension should be referred to specialized centers and considered for treatments known to be effective in other forms of pulmonary arterial hypertension. There have been reports that some of these treatments improve SCD-related pulmonary hypertension.
, Raymond E Kleinfelder, , William J Ennis, Caterina P Minniti
Published: 4 November 2015
International Wound Journal, Volume 13, pp 1315-1324; doi:10.1111/iwj.12522

Sickle cell leg ulcers (SCLUs) are a common complication of sickle cell disease (SCD). Patients who develop ulcers appear to have a more severe haemolysis-associated vasculopathy than individuals who do not develop them, and manifest other complications such as priapism and pulmonary hypertension. SCLUs are slow to heal and often recur, affecting both the emotional and physical well-being of patients. Here we summarise what is known about the pathophysiology of SCLUs, describe available treatment options and propose a treatment algorithm.
Guilherme Fonseca,
Current Opinion in Pulmonary Medicine, Volume 21, pp 432-437; doi:10.1097/mcp.0000000000000200

This review highlights the prevalence of pulmonary hypertension as a chronic complication of sickle cell disease (SCD) and its importance in the prognosis. In recent years, the limitations of echocardiogram for the appropriate diagnosis of SCD-associated pulmonary hypertension have been demonstrated, emphasizing the need of invasive hemodynamics assessment before any specific treatment for pulmonary hypertension is considered. The hemodynamic profile observed in this clinical situation is characterized by elevated cardiac output and low pulmonary vascular resistance that differs considerably from what is seen in pulmonary arterial hypertension. Furthermore, both hemodynamic profiles, precapillary and postcapillary, can be equally found in this setting stressing the need for a better understanding of the multiple pathophysiological mechanisms involved in the development of pulmonary hypertension before considering those patients for targeted therapies. Nevertheless, the presence of any form of pulmonary hypertension clearly denotes worse prognosis in SCD. Pulmonary hypertension is an important and prevalent complication of SCD with multiple associated mechanisms. A more aggressive approach of the baseline condition might be necessary, although the data supporting this assumption and also the use of targeted pulmonary arterial hypertension therapy are still lacking.
Fernando Manzur, Keyla Ángel, Hugo Corrales
Revista Colombiana de Cardiología, Volume 22, pp 187-196; doi:10.1016/j.rccar.2015.03.011

ResumenLa anemia de células falciformes es una hemoglobinopatía hereditaria producida por la presencia de hemoglobinaS, que disminuye la solubilidad y a través del proceso de polimerización da lugar a hematíes en forma de hoz que obstruyen la red microvascular. Se caracteriza por episodios de daño por isquemia-reperfusión que contribuyen a la disfunción de órganos vitales. El advenimiento de la terapia inductora de hemoglobina fetal, asociada a la profilaxis antibiótica, ha permitido prolongar la supervivencia. Sin embargo, al incrementar la longevidad, las complicaciones cardiovasculares se hacen evidentes con el desarrollo de vasculopatía sistémica, infarto agudo de miocardio, hipertensión arterial pulmonar y disfunción ventricular. El objetivo de este artículo es revisar la fisiopatología y el tratamiento de las principales manifestaciones cardiovasculares en pacientes con anemia de células falciformes.AbstractSickle cell anemia is an inherited hemoglobinopathy caused by the presence of hemoglobinS, which lowers the solubility and through the process of polymerization results in sickle erythrocytes obstructing the microvascular network. This entity is characterized by episodes of ischemia-reperfusion injury to vital organs, contributing to its dysfunction. The advent of inducing fetal hemoglobin therapy associated with antibiotic prophylaxis has allowed prolonged survival. However, by increasing longevity, cardiovascular complications are evident, with the development of systemic vascular disease, acute myocardial infarction, pulmonary arterial hypertension and left ventricular dysfunction. The aim of this paper is to review the pathophysiology and treatment of major cardiovascular events in patients with sickle cell anemia
Kerry A. Morrone, Xue Xiaonan, Suzette O. Oyeku, Jane A. Little, Catherine Driscoll, Jacob Rand, Deepa Manwani
Published: 6 December 2014
Blood, Volume 124, pp 1394-1394; doi:10.1182/blood.v124.21.1394.1394

Background: In sickle cell disease (SCD) abnormally shaped RBCs interact with white blood cells and the endothelium, leading to a vasculopathy and thrombotic/ prothrombotic complications such as stroke and pulmonary hypertension. About 10 % of patients with a thrombotic event in the general population will have the presence of an antiphospholipid (aPL) antibody (Andreoli et al. 2013). One proposed mechanism for the thrombophilic nature of aPL antibodies is the disruption of annexin A5. Annexin A5 is a potent anticoagulant protein that has an affinity to phospholipids. In the presence of aPL antibodies, annexin A5 is unable to form its crystallized anticoagulant shield (annexin A5 resistance). There is a paucity of data which assesses the association of aPL antibodies with vasculopathic complications of SCD, and there have been no studies investigating the annexin A5 resistance assay (A5R). We designed a pilot study assessing aPL antibody levels and A5R in a pediatric sickle cell population. Methods: Patients with a history of stroke, abnormal transcranial doppler (TCD) and elevated TR gradient by echocardiography (>25mm of Hg) were eligible. A5R, lupus anticoagulant- DRRVT, anti β2GP1, anti phosphatidylserine and anti cardiolipin antibody (IgG, IgA, IgM) assays were performed on samples obtained prospectively when patients were at a steady state (at least 4 weeks after an acute event). A5R measures coagulation times in the presence and absence of annexin A5. Resistance to the anticoagulant effects of annexin is expressed as a reduction in this ratio (Rand et al. 2004). Statistical analysis assessed multiple variables including age, gender, hemoglobin, reticulocyte count, LDH, hydroxyurea therapy, transfusion therapy, elevated TR gradient, stroke and silent stroke. Univariate analysis and multivariate logistic regression was performed with abnormal annexin A5 as the outcome variable. Results:There were a total of 39 patients: 12 patients with a history of stroke, 6 with an elevated TCD velocity and 15 patients with an elevated TR gradient. Of the 27 patients that did not have a stroke, 25 had a screening MRI in the prior year, and 9 of these patients had silent infarcts. Only 1 of 39 patients had elevated anticardiolipin IgG antibodies and 1 had an abnormal lupus coagulant (DRVVT). In contrast, 5/39 patients (12.8%) had low or abnormal annexin A5 resistance, 7/39 (18%) were in the borderline range and 27/39 (69%) were normal. This frequency of abnormality was unexpected in the antiphospolipid antibody and lupus anticoagulant negative population. None of the patients, except the one with the positive lupus anticoagulant, developed any thrombotic events in 3.5 years of follow up. None of the patients with overt stroke or abnormal TCDs had an abnormal A5R. Multivariate logistic regression analyses showed statistically significant association of hemoglobin (p= 0.037, OR 0.25, CI 0.07-0.92)), age (p =0.047, OR 1.43, CI 1.01-2.04) and silent infarct (p =0.015, OR 28.5, CI 1.9-420.5) with abnormal annexin A5 resistance. A multivariate analysis using linear regression with annexin A5 resistance as a continuous outcome variable (Table 1), showed persistence of the significant association of silent infarcts (p =0.037). Conclusion: We report an association between annexin A5 resistance and low hemoglobin, older age and presence of silent infarct in a subgroup of SCD patients. Prevalence of abnormal aPL antibody assays and lupus anticoagulant was strikingly low in this cohort. A potential role for perturbed annexin A5 resistance in the pathophysiology of silent infarction in SCD will need to be evaluated further in carefully designed prospective studies and may be a novel therapeutic target. Table 1. Hemoglobin, Age and Silent Stroke are Associated with Abnormal Annexin A5 Resistance Characteristic Odds Ratio Odds Ratio Confidence Interval p-value Hemoglobin* 0.25 0.07-0.92 0.037 Reticulocyte count 0.77 0.54-1.08 0.13 LDH 1.00 0.99-1.00 0.51 Age* 1.43 1.01-2.04 0.047 Monocyte count 1.00 1.00-1.00 0.34 Silent infarct* 28.5 1.9-420.5 0.015 Stroke 0.47 0.05-4.88 0.53 Elevated TR gradient 0.34 0.03-3.49 0.36 Gender 0.47 0.05-4.88 0.53 Allosensitization 0.56 0.05-5.86 0.63 HU vs no treatment 0.46 0.03-6.93 0.58 Transfusion vs no treatment 0.18 0.01-4.26 0.29 Disclosures No relevant conflicts of interest to declare.
, Amira Abdel Moneam Adly, Eman Abdel Rahman Ismail, Yasser Wagih Darwish, Marwa Ali Zedan
Published: 1 December 2014
Blood Cells, Molecules, and Diseases, Volume 53, pp 189-193; doi:10.1016/j.bcmd.2014.07.003

High expression of growth differentiation factor-15 (GDF-15) contributes to pathological iron overload in thalassemia. Sickle cell syndromes are characterized by increased levels of erythropoiesis, although the primary defect involves the destruction of mature erythrocytes. To determine serum GDF-15 in 35 children and adolescents with sickle cell disease (SCD) compared to 35 healthy controls and assess its relation to markers of hemolysis, iron overload and vascular complications. GDF-15 was measured and correlated to genotype, frequency of sickling crises, hydroxyurea therapy and serum ferritin. GDF-15 levels were increased in SCD patients whether sickle cell anemia or sickle β° thalassemia compared with controls (p<0.001) with no significant difference between patients' groups. GDF-15 was significantly higher in patients who had serum ferritin ≥2500 μg/L, previous cerebral stroke, and splenectomy. GDF-15 was not significantly related to frequency of sickling crises, pulmonary hypertension, or hydroxyurea therapy. On regression analysis, transfusion index, lactate dehydrogenase and serum ferritin were independently related to GDF-15. Increased GDF-15 in SCD reflects the importance of ineffective erythropoiesis in the pathophysiology and severity of anemia in SCD. GDF-15 levels are related to hemolysis and iron overload and may provide utility for identifying patients at increased risk of thrombotic events.
, François Lionnet
Published: 1 October 2014
La Revue du praticien, Volume 64

The publisher has not yet granted permission to display this abstract.
, Gert Victor D. Pretorius, Kim M. Kerr, Gerard R. Manecke
Seminars in Cardiothoracic and Vascular Anesthesia, Volume 18, pp 331-340; doi:10.1177/1089253214537688

Chronic thromboembolic pulmonary hypertension (CTEPH) results from recurrent or incomplete resolution of pulmonary embolism. CTEPH is much more common than generally appreciated. Although pulmonary embolism (PE) affects a large number of Americans, chronic pulmonary thromboembolic hypertension remains underdiagnosed. It is imperative that all patients with pulmonary hypertension (PH) be screened for the presence of CTEPH since this form of PH is potentially curable with pulmonary endarterectomy (PEA) surgery. The success of this procedure depends greatly on the collaboration of a multidisciplinary team approach that includes pulmonary medicine, cardiothoracic surgery, and cardiac anesthesiology. This review, based on the experience of more than 3000 pulmonary endarterectomy surgeries, is divided into 2 parts. Part I focuses on the clinical history and pathophysiology, diagnostic workup, and intraoperative echocardiography. Part II focuses on the surgical approach, anesthetic management, postoperative care, and complications.
Published: 1 January 2014
Annals of Thoracic Medicine, Volume 9, pp 67-73; doi:10.4103/1817-1737.134039

Hereditary hemoglobin disorders affecting the globin chain synthesis namely thalassemia syndromes and sickle cell disease (SCD) are the most common genetic disorders in human. Around 7% of the world population carries genes for these disorders, mainly the Mediterranean Basin, Middle and Far East, and Sub-Saharan Africa. An estimated 30 million people worldwide are living with sickle cell disease, while 60-80 million carry beta thalassemia trait. About 400,000 children are born with severe hemoglobinopathies each year.Cardiovascular complications of hemoglobinopathies include left and right ventricular (RV) dysfunction, arrhythmias, pericarditis, myocarditis, valvular heart disease, myocardial ischemia, and notably pulmonary hypertension (PH).Because of a unique pathophysiology, pulmonary hypertension associated with hemolytic disorders was moved from WHO group I to group V PH diseases. Treatment strategies are also unique and include blood transfusion, iron chelation, hydroxyurea, and oxygen therapy. The role of PH-specific agents has not been established.
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