Primary Prophylaxis in Sickle Cell Disease: Is It Feasible? Is It Effective?

Hematology ◽  
2011 ◽  
Vol 2011 (1) ◽  
pp. 434-439 ◽  
Author(s):  
Alexis A. Thompson
Keyword(s):  
Clinical Trials ◽  
Sickle Cell Disease ◽  
Disease Progression ◽  
Organ Dysfunction ◽  
Sickle Cell ◽  
Primary Prophylaxis ◽  
Organ Injury ◽  
Clear Understanding ◽  
Cell Disease ◽  
Laboratory Tool

Abstract Consideration of primary prophylaxis to prevent complications of sickle cell disease (SCD) requires a clear understanding of the earliest manifestations of SCD-related organ injury, a reliable clinical or laboratory tool to detect organ dysfunction, and evidence that an intervention instituted in the presymptomatic state can mitigate disease progression. This review examines the pathophysiology of SCD in organs that may be potential targets for intervention, our current capacity to evaluate early SCD manifestations, results of clinical trials, and opportunities for future interventions.

scholarly journals A case of severe multi-system disease in a sickle cell SC patient caused by parvovirus B19 infection

2021 ◽  
Vol 2 (5) ◽  
Author(s):  
Mohamed Almuqamam ◽  
◽  
Swetha Madhavarapu ◽  
Nataly Apollonsky ◽  
◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Parvovirus B19 ◽  
Acute Infection ◽  
Organ Injury ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Splenic Sequestration ◽  
Increased Risk ◽  
Parvovirus B19 Infection

Sickle Cell Disease (SCD) is an inherited hemoglobinopathy, which results in production of abnormal hemoglobin S. HbSC disease is a variant of SCD, which shares a similar clinical complication profile to HbSS disease, but often thought to be a milder condition. In patients with SCD, Hb S in deoxygenated state undergoes polymerization, leading to hemolysis, vaso-occlusive events, and eventually end-organ damage. Among other complications in patients with SCD is increased risk of complications caused by parvovirus B19. We present a case of a 14-year-old female with HbSC disease who presented to the emergency room with complaint of abdominal pain and found to have splenic sequestration. Splenic sequestration progressed rapidly, Hemoglobin (hb) dropped to 4.6 g/dl and acute chest syndrome (ACS) developed. She was treated following the ACS protocol, received 4 units of Packed Red Blood Cells (PRBC) and subsequently underwent a single volume PRBC exchange transfusion. Considering her unusual presentation, with severe ARDS from alveolar hemorrhage requiring mechanical ventilation and multi-organ injury, several autoimmune and infectious conditions with a cytokine storm component including COVID-19 disease, were considered. Results of viral testing revealed parvovirus B19 IgM antibodies signifying an acute infection. She fully recovered with supportive care and was discharged home. Multisystem involvement simulating connective tissue disorders or malignancies with acute parvovirus B19 infection has been reported and is considered extremely rare. To our knowledge, there were no reports of pediatric patients with SC disease presenting with splenic sequestration and ACS in the setting of parvovirus B19 multisystem disease. Keywords: sickle cell disease; acute respiratory distress syndrome; acute chest syndrome; parvovirus B19.

scholarly journals End points for sickle cell disease clinical trials: patient-reported outcomes, pain, and the brain

2019 ◽  
Vol 3 (23) ◽  
pp. 3982-4001 ◽  
Author(s):  
Ann T. Farrell ◽  
Julie Panepinto ◽  
C. Patrick Carroll ◽  
Deepika S. Darbari ◽  
Ankit A. Desai ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Patient Reported Outcomes ◽  
Cell Disease ◽  
End Points ◽  
Additional Clinical Trial ◽  
Patient Reported ◽  
The Brain

Abstract To address the global burden of sickle cell disease (SCD) and the need for novel therapies, the American Society of Hematology partnered with the US Food and Drug Administration to engage the work of 7 panels of clinicians, investigators, and patients to develop consensus recommendations for clinical trial end points. The panels conducted their work through literature reviews, assessment of available evidence, and expert judgment focusing on end points related to: patient-reported outcomes (PROs), pain (non-PROs), the brain, end-organ considerations, biomarkers, measurement of cure, and low-resource settings. This article presents the findings and recommendations of the PROs, pain, and brain panels, as well as relevant findings and recommendations from the biomarkers panel. The panels identify end points, where there were supporting data, to use in clinical trials of SCD. In addition, the panels discuss where further research is needed to support the development and validation of additional clinical trial end points.

scholarly journals Metabolomic and molecular insights into sickle cell disease and innovative therapies

2019 ◽  
Vol 3 (8) ◽  
pp. 1347-1355 ◽  
Author(s):  
Morayo G. Adebiyi ◽  
Jeanne M. Manalo ◽  
Yang Xia
Keyword(s):  
Sickle Cell Disease ◽  
Disease Progression ◽  
Sickle Cell ◽  
Intracellular Signaling ◽  
Metabolic Reprogramming ◽  
Flux Analysis ◽  
High Morbidity ◽  
Cell Disease ◽  
Sickle Hemoglobin

Abstract Sickle cell disease (SCD) is an autosomal-recessive hemolytic disorder with high morbidity and mortality. The pathophysiology of SCD is characterized by the polymerization of deoxygenated intracellular sickle hemoglobin, which causes the sickling of erythrocytes. The recent development of metabolomics, the newest member of the “omics” family, has provided a powerful new research strategy to accurately measure functional phenotypes that are the net result of genomic, transcriptomic, and proteomic changes. Metabolomics changes respond faster to external stimuli than any other “ome” and are especially appropriate for surveilling the metabolic profile of erythrocytes. In this review, we summarize recent pioneering research that exploited cutting-edge metabolomics and state-of-the-art isotopically labeled nutrient flux analysis to monitor and trace intracellular metabolism in SCD mice and humans. Genetic, structural, biochemical, and molecular studies in mice and humans demonstrate unrecognized intracellular signaling pathways, including purinergic and sphingolipid signaling networks that promote hypoxic metabolic reprogramming by channeling glucose metabolism to glycolysis via the pentose phosphate pathway. In turn, this hypoxic metabolic reprogramming induces 2,3-bisphosphoglycerate production, deoxygenation of sickle hemoglobin, polymerization, and sickling. Additionally, we review the detrimental role of an impaired Lands’ cycle, which contributes to sickling, inflammation, and disease progression. Thus, metabolomic profiling allows us to identify the pathological role of adenosine signaling and S1P-mediated erythrocyte hypoxic metabolic reprogramming and hypoxia-induced impaired Lands' cycle in SCD. These findings further reveal that the inhibition of adenosine and S1P signaling cascade and the restoration of an imbalanced Lands' cycle have potent preclinical efficacy in counteracting sickling, inflammation, and disease progression.

scholarly journals Biologic Complexity in Sickle Cell Disease: Implications for Developing Targeted Therapeutics

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Beatrice E. Gee
Keyword(s):  
Clinical Trials ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Vascular Occlusion ◽  
Current Therapy ◽  
Cell Disease ◽  
Primary Defect ◽  
Relative Contribution ◽  
Hb S

Current therapy for sickle cell disease (SCD) is limited to supportive treatment of complications, red blood cell transfusions, hydroxyurea, and stem cell transplantation. Difficulty in the translation of mechanistically based therapies may be the result of a reductionist approach focused on individual pathways, without having demonstrated their relative contribution to SCD complications. Many pathophysiologic processes in SCD are likely to interact simultaneously to contribute to acute vaso-occlusion or chronic vasculopathy. Applying concepts of systems biology and network medicine, models were developed to show relationships between the primary defect of sickle hemoglobin (Hb S) polymerization and the outcomes of acute pain and chronic vasculopathy. Pathophysiologic processes such as inflammation and oxidative stress are downstream by-products of Hb S polymerization, transduced through secondary pathways of hemolysis and vaso-occlusion. Pain, a common clinical trials endpoint, is also complex and may be influenced by factors outside of sickle cell polymerization and vascular occlusion. Future sickle cell research needs to better address the biologic complexity of both sickle cell disease and pain. The relevance of individual pathways to important sickle cell outcomes needs to be demonstratedin vivobefore investing in expensive and labor-intensive clinical trials.

scholarly journals Machine learning predicts early-onset acute organ failure in critically ill patients with sickle cell disease

2019 ◽  
Author(s):  
Akram Mohammed ◽  
Pradeep S. B. Podila ◽  
Robert L. Davis ◽  
Kenneth I. Ataga ◽  
Jane S. Hankins ◽  
...  
Keyword(s):  
Machine Learning ◽  
Intensive Care ◽  
Sickle Cell Disease ◽  
Kidney Disease ◽  
Organ Failure ◽  
Organ Dysfunction ◽  
Sickle Cell ◽  
Machine Learning Techniques ◽  
Cell Disease ◽  
Learning Techniques

AbstractBackgroundSickle cell disease (SCD) is a genetic disorder of the red blood cells, resulting in multiple acute and chronic complications including pain episodes, stroke, and kidney disease. Patients with SCD develop chronic organ dysfunction, which may progress to organ failure during disease exacerbations. Early detection of acute physiological deterioration leading to organ failure is not always attainable. Machine learning techniques that allow for prediction of organ failure may enable earlier identification and treatment, and potentially reduce mortality. We tested the hypothesis that machine learning physiomarkers could predict the development of organ dysfunction in an adult sample of patients with SCD admitted to intensive care units.Methods and FindingsWe studied 63 sequential SCD patients with 163 patient encounters, mean age 33.0±11.0 years, admitted to intensive care units, some of whom (6.7%) had pre-existing cardiovascular or kidney disease. A subset of these patient encounters (37; 23%) met sequential organ failure assessment (SOFA) criteria. The site of organ failure included: central nervous system (32), cardiovascular (11), renal (10), liver (7), respiratory (5) and coagulation (2) systems. Most (81.5%) of the patient encounters who experienced organ failure had single organ failure. The other 126 SCD patient encounters served as controls. A set of signal processing features (such as fast fourier transform, energy, continuous wavelet transform, etc.) derived from heart rate, blood pressure, and respiratory rate were identified to distinguish patients with SCD who developed acute physiological deterioration leading to organ failure, from SCD patients who did not meet the criteria. A random forest model accurately predicted organ failure up to six hours prior to onset, with a five-fold cross-validation accuracy of 94.57% (average sensitivity and specificity of 90.24% and 98.9% respectively).ConclusionsThis study demonstrates the viability of using machine learning to predict acute physiological deterioration heralded organ failure among hospitalized adults with SCD. The discovery of salient physiomarkers through machine learning techniques has the potential to further accelerate the development and implementation of innovative care delivery protocols and strategies for medically vulnerable patients.

scholarly journals Elevated sphingosine-1-phosphate promotes sickling and sickle cell disease progression

2014 ◽  
Vol 124 (7) ◽  
pp. 3274-3274
Author(s):  
Yujin Zhang ◽  
Vladimir Berka ◽  
Anren Song ◽  
Kaiqi Sun ◽  
Wei Wang ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Disease Progression ◽  
Sickle Cell ◽  
Cell Disease ◽  
Sphingosine 1 Phosphate

Two Sides of a Coin: Case Report of Unilateral Synangiosis and Contralateral Stroke Highlighting Consequences of Disease Progression and Efficacy of Revascularization in Sickle Cell Disease Associated Moyamoya Syndrome

2021 ◽  
Author(s):  
Anna L. Slingerland ◽  
Madeline B. Karsten ◽  
Edward R. Smith ◽  
Amy E. Sobota ◽  
Alfred P. See
Keyword(s):  
Sickle Cell Disease ◽  
Disease Progression ◽  
Sickle Cell ◽  
Heart Association ◽  
Standard Of Care ◽  
Collaborative Management ◽  
Moyamoya Syndrome ◽  
Cell Disease ◽  
Revascularization Surgery ◽  
Consequences Of Disease

Moyamoya syndrome increases the risk of stroke in sickle cell disease, but revascularization surgery can modify this risk. Collaborative management between hematology and neurosurgery offers effective strategies to reduce stroke risk in these patients. We describe a challenging case where a patient with sickle cell disease undergoing standard of care management as prescribed by the Stroke Prevention Trial in Sickle Cell Anemia (STOP) and revascularization with pial synangiosis subsequently developed rapidly progressive disease in other cerebral vessels and suffered ischemic hemispheric stroke. This case demonstrates the success of management in accordance with American Heart Association (AHA) and American Stroke Association (ASA) guidelines, but also demonstrates critical areas where we lack understanding of disease progression.

Progression of Organ Dysfunction in Iron Overloaded Patients with β Thalassemia and Sickle Cell Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1683-1683 ◽  
Author(s):  
Ellen B. Fung ◽  
Paul Harmatz ◽  
Jacqueline Madden ◽  
Elliott Vichinsky ◽  
Keyword(s):  
Sickle Cell Disease ◽  
Longitudinal Data ◽  
Organ Dysfunction ◽  
Sickle Cell ◽  
Thyroid Dysfunction ◽  
Chelation Therapy ◽  
Baseline Assessment ◽  
Cell Disease ◽  
Patient Interview

Abstract Iron overload occurs equally in transfused patients with thalassemia (Thal) and sickle cell disease (SCD). However, organ dysfunction that occurs frequently in patients with Thal has not been reported in SCD. A 5-year, prospective, multi-center study is being conducted to assess the incidence and rate of development of iron related organ dysfunction in tranfused Thal and SCD subjects compared to a group of non-transfused subjects with SCD. Data are collected annually by patient interview and medical record review. Differences between the groups at baseline were analyzed by t-test or χ2. ANCOVA was used to analyze longitudinal data to control for differences at baseline. 204 subjects with SCD (44% Male, 24.7 ±0.9 yrs: Mean ± SEM), 144 subjects with Thal (52% M; 25.6±0.7 yrs) and 54 non-transfused subjects with SCD (Control: 50% M, 22.2 ±1.3 yrs) were eligible and have completed baseline assessment. To date, 70% of the sample has completed 1 year of follow-up, 31% have completed 2 years. Since baseline assessment, 3% have been lost to follow-up and 16 case subjects (4%) have died. At baseline, LIC (Thal: 19.6±1.1 vs. SCD: 20.0±1.2 mg/g dry wt) did not differ between the two case groups, however, serum ferritin was significantly higher in the SCD group (p=0.006). Ferritin increased significantly at year 1 (p=0.02) in SCD compared to Thal, with a similar trend towards a 4 mg/g dry wt increase in LIC (p=0.07). Thal subjects were more likely to be receiving chelation therapy at all timepoints (p<0.001); 16% of SCD cases never received chelation therapy despite significant iron burden. Thal subjects were 5x more likely than SCD and 2x more likely than controls to be taking antioxidant supplements (p<0.001). Overall, Thal subjects were more likely to have gonadal failure (p<0.001), thyroid dysfunction (p=0.002), have sustained a fracture (p=0.003) and be taking bisphosphonates (p=0.007) and hormone replacements (p<0.001) compared to subjects with SCD or Controls. Only 15% of adult females with Thal had successful pregnancies compared to SCD (34%) and Controls (27%, p=0.02). Each of these differences remained significant at one year of follow-up, and all variables with the exception of thyroid dysfunction were independent of years of transfusion or LIC. Surprisingly, there were no differences in cardiac dysfunction or heart medication usage between the 2 case groups at any timepoint. At baseline, roughly 10% of SCD and Thal subjects vs. 0% of controls had abnormal echocardiograms (LVEF<55%). In contrast, the general health of subjects with SCD was worse than Thal. SCD subjects were more likely to have kidney disease (p<0.001), hypertension (p=0.001) and were hospitalized more frequently (p<0.001). Iron overloaded SCD subjects were 5x more likely than SCD Controls and 3x more likely than Thal to have died (p=0.02). Subjects who died were more likely to be hyptertensive (p=0.007), on heart medications (p<0.001), or have had an abnormal ECHO (p=0.01). These data suggest that despite a trend towards an increase in iron stores in SCD, subjects with Thal continue to have significantly more endocrine dysfunction than those with SCD. What is surprising is the similar incidence and progression of cardiac disease in the 2 iron overloaded groups. Further collection of longitudinal data may provide clarification of these findings. Supported in part by NIH grants: R01DK05777801 and M01 RR01271

Serum Ferritin in Children with Sickle Cell Disease on Chronic Transfusion: Measure of Iron Overload or End Organ Injury? STOP/STOP II Liver Iron Ancillary Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 791-791 ◽  
Author(s):  
Tom Adamkiewicz ◽  
Miguel R. Abboud ◽  
Julio C. Barredo ◽  
Melanie Kirby-Allen ◽  
Ofelia A. Alvarez ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Serum Ferritin ◽  
Iron Removal ◽  
Organ Injury ◽  
Cell Disease ◽  
Liver Iron ◽  
Flow Measurements ◽  
Transfusion Therapy

Abstract Between 1995 and 2004, two NIH-sponsored studies (STOP/STOP II) showed that children with sickle cell disease (SCD) and abnormal transcranial Doppler blood flow measurements (high stroke risk) are protected from stroke with regular blood transfusions. Iron overload, which may lead to complications and requires iron removal therapy, was monitored by serum ferritin (SF). Liver iron concentration (LIC) measurement was not mandated by protocol and was performed at investigator discretion. Biopsy dates and lab values were captured during STOP/STOP II, providing an opportunity to validate SF against LIC. 75 LICs on 36 patients (19 female, 17 male) at 8 centers were obtained. No liver biopsy complications were reported. LICs were correlated with STOP/STOP II core laboratory SF and alanine aminotransferase (ALT) obtained within 180 days of LICs. Median age at first biopsy was 11.1 years (range, 4.5–17.8), median time from start of transfusion was 36 months (range, 2–100). Iron removal treatment was initiated a median 23 months (range, 4–108) from start of transfusion, with deferoxamine (n=27), and/or exchange transfusion (n=9). 21 pts (58%) had multiple LIC measures: 2 (n=9), 3 (n=8), 4 (n=2), 5 (n=2). Last LICs on iron removal therapy were obtained a median 72 months (range, 35–124) from start of transfusion. Correlation between SFs and LICs were r=-0.06 (n=18) for first LICs obtained prior to iron removal therapy, r=0.50 (n=17) for last LICs obtained on iron removal therapy, and r=0.51 for all LICs (n=60). Pts with single/last LIC &gt;=15 mg/gram dry liver were significantly more likely to have ALTs &gt;=45 IU/L compared to those with LICs &lt;15 mg/gram (5/12 vs. 1/18; odds ratio 12.1; 95% CI 1.2–123.6; p=0.03). Pts with LIC &gt;=15 mg/gram and ALT &gt;=45 IU/L tended to have higher SFs then those with normal ALT (mean SF 4927 ng/ml, 95% CI 1739–8115 vs. mean SF 2255 ng/ml, 95% CI 1599–2912). 37% (7/19) of pts with LIC &gt;=15 mg/gram had SFs &lt;2000 ng/ml. 55% (11/20) of pts with repeated LICs, had last LICs &lt;15 mg/gram after initiation of iron removal therapy. SF did not correlate with LICs after initiation of blood transfusion therapy and correlated weakly after initiation of iron removal therapy. Over 1/3 of children with evidence of significant iron overload, as measured by LICs, had low serum SFs (&lt;2000 ng/ml), leading to a potentially erroneous interpretation of low iron stores. A significant portion of pts with elevated LICs had evidence of liver injury (ALT elevation). SF elevation observed in some pts may be due in part to end organ injury. Sustained iron overload control was achieved in over 1/2 of pts examined with repeated LICs.

Bone Marrow Transplantation Arrests Cerebrovascular Disease Progression and Improves Psychometric Outcomes in Children with Sickle Cell Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 11-11
Author(s):  
Neha Bhatnagar ◽  
Ruth Erskine ◽  
Farah O'Boyle ◽  
Subarna Chakravorty ◽  
Irene Roberts ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Magnetic Resonance ◽  
Sickle Cell Disease ◽  
Cerebrovascular Disease ◽  
Disease Progression ◽  
Sickle Cell ◽  
Graft Failure ◽  
Psychometric Testing ◽  
Cell Disease ◽  
Moya Moya Disease

Abstract Abstract 11 Stem cell transplantation (SCT) is currently the only curative option for sickle cell disease. Cerebrovascular disease (CVD) is one of the main indications to undertake this procedure as even with best conventional approaches there is a significant risk of recurrence or progression and there is evidence that SCT arrests disease progression, though more detailed study of outcomes is awaited. Early studies of SCT in sickle cell disease showed a high rate of neurological complications that led to the optimization of protocols. We conducted a retrospective analysis of related SCT in children with severe SCD between 2001 and 2010 at our institution to study the effect of transplantation. 20 patients (11 male, 9 female) received a BMT for sickle CVD (n=11) or recurrent vaso-occlusive crises (n=9). One patient with CVD was a second procedure following primary graft failure in a previous sibling transplant. CVD was investigated with clinical history and examination, transcranial Doppler ultrasound, magnetic resonance imaging/magnetic resonance angiography and psychometric testing using WISC-IV: 7 patients had no evidence of CVD, 5 had silent infarcts, 6 ischaemic stroke and 2 Moya-Moya disease. The median age at transplantation was 136 months (range 34 – 210 months). Donor source was HLA-matched siblings in 18 patients, one 9/10 mismatched sibling and HLA-matched relative in another. Bone marrow was used in all (n=19) but one patient who received combined bone marrow and umbilical cord. All patients (n=18) but two received conditioning with oral busulfan 14 mg/kg, cyclophosphamide 200 mg/kg and alemtuzumab 0.3 mg/kg; 1 patient received fludarabine 160 mg/m2, treosulfan 42 mg/m2, thiotepa 10mg/kg and ATG (Thymoglobulin) 11.25 mg/kg and 1 patient received oral busulfan 16mg/kg, cyclophosphamide 200 mg/kg and antilymphocyte globulin (45 mg/kg). GvHD prophylaxis was provided with ciclosporin and short course methotrexate (n=18), ciclosporin and MMF (n=1) and ciclosporin alone (n=1). Mean cell dose was 3.70 × 108 TNC/kg (range 1.45 – 6.16 × 108 TNC/kg). Neutrophil engrafment (>0.5 × 109/L) occurred at a median of 19.5 days (range 12 – 28 days) and platelet engrafment (>50 × 109/L) at median of 26 days (range 21 – 52 days). The median follow up is 974 days (range 270 – 3622 days). 18 patients achieved stable donor haemopoiesis, one patient suffered secondary graft failure due to Parvovirus B19 infection and one patient died on day +21 post-transplant due to sepsis and multi-organ failure. No significant sickle related neurological events occurred during these transplants. All 18 patients with long-term engraftment achieved radiological stabilization of the underlying CVD. Imaging performed at least 12 months post SCT showed no further changes from pre-transplant images. There were no clinical neurological events after SCT. Psychometric testing demonstrated improvements in all areas in patients transplanted for silent infarcts, particularly those affecting processing speed. In summary, SCT appears safe even in patients with severe CVD, arrests further progression and shows functional improvement. Disclosures: No relevant conflicts of interest to declare.

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