First systemic evidence for safety of tPA in stroke patients with sickle cell disease

Adult patients with sickle cell disease (SCD) who experience a stroke caused by a clot (i.e., ischemic strokes or IS) can be treated safely with tissue plasminogen activator (tPA) if they qualify, report investigators at the Medical University of South Carolina (MUSC) and elsewhere in the March 2017 issue of Stroke.

Tissue plasminogen activator (tPA), which has been the established therapy for treating IS since 1996, speeds up the body’s ability to dissolve clots, thus improving blood flow to the brain. When administered in the requisite time window, tPA can help prevent some of the disability associated with IS.

The use of tPA in SCD patients is not well established, although it has never been contraindicated. Stroke has a different pathophysiology in those with SCD—it is caused by the enhanced adhesion of the red blood cells to the endothelium. People with SCD also have an increased risk of intracranial hemorrhage, an uncommon but potentially fatal complication of tPA.

For the study reported in Stroke, researchers at MUSC, including lead author Robert J. Adams, M.D., Distinguished Professor of Neurology and Director of the South Carolina Center for Economic Excellence in Stroke, Julie Kanter, M.D., a hematologist specializing in the care of patients with SCD who also serves as Director of Sickle Cell Research, and Shelly D. Ozark, M.D., Assistant Professor of Neurology, teamed up with researchers at other universities to analyze in-hospital data compiled by the quality improvement program Get With The Guidelines – Stroke on 2,016,652 stroke patients seen at 1952 participating US hospitals between January 2008 and March 2015.

They identified 832 patients with SCD and 3325 age-, sex- and race-matched controls and found no statistically significant differences between the two cohorts in the rate of tPA use (8.2 percent for SCD patients vs 9.4 percent for non-SCD patients), the timeliness of its administration (door-to-needle time, 73 minutes for SCD patients vs. 79 minutes for non-SCD patients) or the rate of in-hospital complications. Of patients receiving tPA, 4.9 percent of those with SCD experienced intracerebral hemorrhage vs. 3.2 percent of those without SCD, a difference that was not statistically significant but still bears watching. The overall rate of complications (6.6 percent for SCD patients and 6.0 percent for non-SCD patients), in-hospital mortality (odds ratio of 1.21 for SCD patients 1.21) and length of stay above four days (odds ratio of 1.15 for SCD patients) also did not differ significantly between the two cohorts.

“Having sickle cell disease did not adversely affect any of the indicators we measured,” says Adams.

“People with sickle cell disease and an acute stroke who would otherwise qualify for tPA did not have worse outcomes than stroke patients who did not have sickle cell disease.”

Although additional studies are needed to track the intracranial hemorrhage rate, these findings suggest that tPA is safe in patients with SCD and could potentially be used as a complementary therapy to rapid and complete red blood cell exchange, the current guideline-recommended frontline therapy for IS in patients with SCD. These patients would be best served by a care team including both a hematologist and a neurologist.

“These findings suggest that a future randomized trial that compares using red-blood cell exchange alone versus combination therapy with tPA and red-blood cell exchange should be undertaken to evaluate the outcomes of IS in patients with sickle cell disease,” says Kanter.

“This is a great example of the power of the large Get With The Guidelines – Stroke database, which allows us to better understand the best care for relatively small, unique populations that are difficult to study individually,” says Edward C. Jauch, M.D., Director of the Division of Emergency Medicine at MUSC and lead author on the 2013 AHA/ASA Acute Ischemic Stroke Guidelines.


Register Now: April 19 Webinar – Evaluating and Addressing Challenges to Optimal Sickle Cell Disease Care, Within the Health Literate Care Model

The California Rare Disease Surveillance Program invites you to attend a webinar, “Evaluating and Addressing Challenges to Optimal Sickle Cell Disease Care within the Health Literate Care Model,” presented by Dr. Marsha Treadwell, Clinical Scientist at the UCSF Benioff Children’s Hospital Oakland on Wednesday, April 19, 2017, from 10-11 am PDT (1-2 pm EDT).

Dr. Treadwell’s research integrates physical, behavioral and psychological processes, allowing for the identification of risk and resiliency factors and the development of more effective interventions for vulnerable populations in both high and low resource settings. She directs the Sickle Cell Care Coordination Initiative, which uses implementation science to improve outcomes for youth and adults with sickle cell disease in Northern California by improving understanding of barriers to care and utilization of evidence based guidelines.

Register here:

The agenda will include a brief update on the Sickle Cell Data Collection Program (the host of the webinar).

This webinar is part of a series of quarterly webinars featuring experts in sickle cell disease and updates on this project. Previous webinars are available at This work is funded by the CDC Foundation, Pfizer Inc., and Biogen Inc., and is a partnership with CDC’s Division of Blood Disorders.


Articles in the Medical Literature

  1. Pain. 2017 Apr 5. doi: 10.1097/j.pain.0000000000000914. [Epub ahead of print]

Development and validation of the self-reported PROMIS pediatric pain behavior item bank and short form scale.

Cunningham NR1, Kashikar-Zuck S, Mara C, Goldschneider KR, Revicki DA, Dampier C, Sherry DD, Crosby L, Carle A, Cook KF, Morgan EM.


Pain behaviors are important indicators of functioning in chronic pain; however, no self-reported pain behavior instrument has been developed for pediatric populations. The purpose of this study was to create a brief pediatric measure of patient-reported pain behaviors as part of the Patient- Reported Outcome Measurement Information System (PROMIS). A pool of 47 candidate items for this measure had been previously developed through qualitative research. In this study, youth with chronic pain associated with juvenile fibromyalgia (JFM), juvenile idiopathic arthritis (JIA), or sickle cell disease (SCD) (ages 8 to 18 years) from three pediatric centers completed all 47 candidate items for development of the pain behavior item bank along with established measures of pain interference, depressive symptoms, fatigue, average pain intensity, and pain catastrophizing. Caregivers reported on socio-demographic information and health history. Psychometric properties of the pain behavior items were examined using an item response theory (IRT) framework with confirmatory factor analysis and examination of differential item functioning, internal consistency, and test information curves. Results were used, along with expert consensus and alignment with the adult PROMIS pain behavior items to arrive at an 8- item pediatric pain behavior short form, and all 47 items were retained in a calibrated item bank. Confirmatory factor analysis and correlations with validated measures of pain, pain interference, and psychosocial functioning provided support for the short form’s reliability and validity. The new PROMIS pediatric pain behavior scale provides a reliable, precise, and valid measure for future research on pain behavior in school-age children with chronic pain.

PMID: 28394851

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  1. Cytokine. 2017 Apr 5;96:87-93. doi: 10.1016/j.cyto.2017.03.010. [Epub ahead of print]

Relationship between serum 25-hydroxyvitamin D and inflammatory cytokines in paediatric sickle cell disease.

Adegoke SA1, Smith OS2, Adekile AD3, Figueiredo MS4.



Alteration in the concentration of inflammatory cytokines may contribute to pathogenesis in sickle cell anaemia (SCA). Vitamin D may suppress pro-inflammatory cytokines and enhance anti-inflammatory cytokines.


To compare steady state levels of pro-and anti-inflammatory cytokines of Nigerian SCA children with age- and sex-matched healthy controls, and determine the relationship with 25-hydroxyvitamin-D (25-OHD). Effects of three months of vitamin D supplementation on cytokines of SCA children with suboptimal 25-OHD were also evaluated.


Serum 25-OHD, IL-1β, 2, 6, 8, 11, 12, 13, 17, 18 of 95 SCA children and 75 matched controls were determined using HPLC. The 12 SCA children with suboptimal 25-OHD received 2000IU of vitamin D daily for 3months, and their post supplementation cytokines and 25-OHD levels were compared with the baseline values.


IL-2, 6, 8, 12, 17 and 18 were higher in SCA children than the controls (p≤0.001), but no significant variation in IL-11 and 13 (p=0.131 and 0.057 respectively). Patients with suboptimal serum 25-OHD had higher IL-6, 8 and 18 (p=0.003, 0.010 and 0.002 respectively) and lower levels of IL-11 (p=0.005). Significant positive treatment effects were observed: post-supplementation, serum 25-OHD increased by 23.3ng/mL, p<0.001; proinflammatory cytokines IL-2, 6, 8, 17 and 18 (p<0.001) were reduced and anti-inflammatory cytokine IL-11 was increased, p<0.001.


Suboptimal 25OHD is associated with enhanced levels of pro-inflammatory markers in children with SCA. Three months of daily vitamin D supplementation reversed the trend. Hence; Vitamin D supplementation may reduce the inflammatory milieu and serve as an anti-inflammatory agent in the management of SCA.

Copyright © 2017 Elsevier Ltd. All rights reserved.

PMID: 28390266

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  1. Blood. 2017 Apr 6. pii: blood-2017-02-765891. doi: 10.1182/blood-2017-02-765891. [Epub ahead of print]

Treating sickle cell disease by targeting HbS polymerization.

Eaton WA1, Bunn HF2.


Although the root cause of sickle cell disease is the polymerization of HbS to form fibers that make red cells less flexible, most drugs currently in clinical trials are targeting the downstream sequelae of this primary event. Less attention has been devoted toward investigation of the multiple ways in which fiber formation can be inhibited. In this Perspective, we describe the molecular rationale for 5 distinct approaches to inhibit polymerization and also discuss progress with the few anti-polymerization drugs currently in clinical trials.

Copyright © 2017 American Society of Hematology.

PMID: 28385699

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  1. Pediatr Nephrol. 2017 Apr 5. doi: 10.1007/s00467-017-3658-8. [Epub ahead of print]

Evaluating risk factors for chronic kidney disease in pediatric patients with sickle cell anemia.

Lebensburger JD1, Cutter GR2, Howard TH3, Muntner P4, Feig DI5.



Patients with sickle cell anemia (SCA) have an increased prevalence of nephropathy and mortality from chronic kidney disease (CKD).


We evaluated the association of hyperuricemia and nocturnal hypertension with lower estimated glomerular filtration rate (eGFR) using cystatin-C in patients aged 10-21 years with the HbSS or HbSB0 form of the disease during a non-acute clinic visit. eGFR and uric acid measurements were obtained in 83 and 81 participants, respectively, and 24-h ambulatory blood pressure monitoring (ABPM) was performed in 44 participants. Annual testing included vital signs, complete blood count, comprehensive metabolic panel, medications, urine microalbumin/creatinine, and lactate dehydrogenase measurements. Hyperuricemia was defined as a uric acid level of ≥5.5 mg/dL. Nocturnal hypertension was defined as >25% of nocturnal readings at >95th percentile according to norms established by the American Heart Association Statement on ABPM in children and adolescents.


The mean eGFR was statistically significantly lower in patients with hyperuricemia than in those with normal uric acid levels (143 vs. 161 mL/min/1.73 m2, respectively). Of the 44 participants for whom ABPM data were available, 14 (32%) had systolic nocturnal hypertension and 12 (27%) had diastolic nocturnal hypertension. The mean eGFR was statistically significantly lower in participants with nocturnal systolic and diastolic hypertension than in those with normal nocturnal blood pressure. In a regression model, nocturnal hypertension and hyperuricemia were associated with a lower eGFR.


Two risk factors for CKD, i.e., nocturnal hypertension and hyperuricemia, were associated with lower eGFR in older children and adolescent patients with SCA. Long-term studies on their association with progression to CKD in this population are warranted.


Nocturnal hypertension and hyperuricemia are established risk factors for nephropathy in other diseases and may play a role in SCA nephropathy.

PMID: 28382567

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  1. Mol Ther. 2017 Apr 1. pii: S1525-0016(17)30123-5. doi: 10.1016/j.ymthe.2017.03.024. [Epub ahead of print]

Gene Therapy for β-Hemoglobinopathies.

Cavazzana M1, Antoniani C2, Miccio A3.

2 Paris Descartes, Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France; INSERM UMR 1163, Laboratory of Chromatin and Gene Regulation, 75015 Paris, France.

3 Paris Descartes, Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France; INSERM UMR 1163, Laboratory of Chromatin and Gene Regulation, 75015 Paris, France. Electronic address:


β-Thalassemia and sickle cell disease (SCD) are the world’s two most widely disseminated hereditary hemoglobinopathies. β-Thalassemia originated in the Mediterranean, Middle Eastern, and Asian regions, and SCD originated in central Africa. However, subsequent population migration means that these two diseases are now global and thus constitute a growing health problem in many countries. Despite remarkable improvements in medical care for patients with β-hemoglobinopathies, there is still only one definitive treatment option: allogeneic hematopoietic stem cell (HSC) transplantation. The development of gene therapy for β-hemoglobinopathies has been justified by (1) the limited availability of human leukocyte antigen (HLA)-identical donors, (2) the narrow window of application of HSC transplantation to the youngest patients, and (3) recent advances in HSC-based gene therapy. The huge ongoing efforts in translational medicine and the high number of related publications show that gene therapy has the potential to become the treatment of choice for patients who lack either an HLA genoidentical sibling or an alternative, medically acceptable donor. In this dynamic scientific context, we first summarize the main steps toward clinical translation of this therapeutic approach and then discuss novel lentiviral- and genome editing-based treatment strategies for β-hemoglobinopathies.

Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

PMID: 28377044

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  1. Qual Manag Health Care. 2017 Apr/Jun;26(2):108-115. doi: 10.1097/QMH.0000000000000135.

Evidence-Based Practice Standard Care for Acute Pain Management in Adults With Sickle Cell Disease in an Urgent Care Center.

Kim S1, Brathwaite R, Kim O.



Vaso-occlusive episodes (VOEs) with sickle cell disease (SCD) require opioid treatment. Despite evidence to support rapid pain management within 30 minutes, care for these patients does not consistently meet this benchmark. This quality improvement study sought to decrease the first analgesic administration time, increase patient satisfaction, and expedite patient flow.


A prospective pre-/postevaluation design was used to evaluate outcomes with patients 18 years or older with VOEs in an urgent care (UC) center after implementation of evidence-based practice standard care (EBPSC). A pre- and postevaluation survey of SCD patients’ satisfaction with care and analogous surveys of the UC team to assess awareness of EBPSC were used. A retrospective review of the electronic medical records of patients with VOEs compared mean waiting time from triage to the first analgesic administration and the mean length of stay (LOS) over 6 months.


Implementing EBPSC decreased the mean time of the first analgesic administration (P = .001), significantly increased patient satisfaction (P = .002), and decreased the mean LOS (P = .010).


Implementing EBPSC is a crucial step for improving the management of VOEs and creating a positive patient experience. The intervention enhances the quality of care for the SCD population in a UC center.

PMID: 28375958

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  1. Br J Haematol. 2017 Apr 3. doi: 10.1111/bjh.14655. [Epub ahead of print]

Increased incidence of VTE in sickle cell disease patients: risk factors, recurrence and impact on mortality.

Brunson A1, Lei A1, Rosenberg AS1, White RH2, Keegan T1, Wun T1,3,4.


Previous reports show increased incidence of venous thromboembolism [VTE, deep-vein thrombosis (DVT) and pulmonary embolus (PE)] in sickle cell disease (SCD) patients but did not account for frequency of hospitalization. We determined the incidence of VTE in a SCD cohort versus matched controls. For SCD patients, risk factors for incident VTE, recurrence and the impact on mortality were also determined. Among 6237 patients with SCD, 696 patients (11·2%) developed incident-VTE: 358 (51·6%) had PE (±DVT); 179 (25·7%) had lower-extremity DVT only and 158 (22·7%) had upper-extremity DVT. By 40 years of age, the cumulative incidence of VTE was 17·1% for severe SCD patients (hospitalized ≥3 times a year) versus 8·0% for the matched asthma controls. Amongst SCD patients, women (Hazard ratio [HR] = 1·22; 95% confidence interval [CI]: 1·05-1·43) and those with severe disease (HR = 2·86; 95% CI: 2·42-3·37) had an increased risk of VTE. Five-year recurrence was 36·8% in patients with severe SCD. VTE was associated with increased risk of death (HR = 2·88, 95% CI: 2·35-3·52). In this population-based study, the incidence of VTE was higher in SCD patients than matched controls and was associated with increased mortality. The high incidence of recurrent VTE in patients with severe SCD suggests that extended anticoagulation may be indicated.

© 2017 John Wiley & Sons Ltd.

PMID: 28369826

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  1. Br J Haematol. 2017 Mar 28. doi: 10.1111/bjh.14580. [Epub ahead of print]

Simvastatin reduces vaso-occlusive pain in sickle cell anaemia: a pilot efficacy trial.

Hoppe C1, Jacob E2, Styles L3, Kuypers F4, Larkin S4, Vichinsky E1.


Sickle cell anaemia (SCA) is a progressive vascular disease characterized by episodic vaso-occlusive pain. Despite the broad impact of inflammation on acute and chronic clinical manifestations of SCA, no directed anti-inflammatory therapies currently exist. Statins are cholesterol-lowering agents shown to confer protection from vascular injury by suppressing inflammation. We previously documented a reduction in soluble biomarkers of inflammation in patients with sickle cell disease treated with simvastatin. To determine the potential clinical efficacy of simvastatin, we treated 19 SCA patients with single daily dose simvastatin for 3 months and assessed changes from baseline in the frequency and intensity of diary-reported pain and levels of circulating nitric oxide metabolites (NOx), high sensitivity C-reactive protein (hs-CRP), vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), ICAM-3, E-selectin, and vascular endothelial growth factor (VEGF). Treatment with simvastatin resulted in a significant reduction in the frequency of pain (P = 0·0003), oral analgesic use (P = 0·003) and circulating hs-CRP (P = 0·003), soluble (s)E-selectin (P = 0·01), sICAM-1 (P = 0·02), sICAM-3 (P = 0·02) and sVEGF (P = 0·01). Simvastatin had no effect on pain intensity or levels of NOx, sP-selectin and sVCAM-1. The observed reductions in pain rate and markers of inflammation were greatest in subjects receiving hydroxycarbamide (HC), suggesting a synergistic effect of simvastatin. These results provide preliminary clinical data to support a larger trial of simvastatin in SCA.

© 2017 John Wiley & Sons Ltd.

PMID: 28369718

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  1. Sci Rep. 2017 Apr 3;7:45488. doi: 10.1038/srep45488.

A Paper-Based Test for Screening Newborns for Sickle Cell Disease.

Piety NZ1, George A2, Serrano S3, Lanzi MR3, Patel PR4, Noli MP4, Kahan S4, Nirenberg D2,4, Camanda JF5, Airewele G2, Shevkoplyas SS1,2.


The high cost, complexity and reliance on electricity, specialized equipment and supplies associated with conventional diagnostic methods limit the scope and sustainability of newborn screening for sickle cell disease (SCD) in sub-Saharan Africa and other resource-limited areas worldwide. Here we describe the development of a simple, low-cost, rapid, equipment- and electricity-free paper-based test capable of detecting sickle hemoglobin (HbS) in newborn blood samples with a limit of detection of 2% HbS. We validated this newborn paper-based test in a cohort of 159 newborns at an obstetric hospital in Cabinda, Angola. Newborn screening results using the paper-based test were compared to conventional isoelectric focusing (IEF). The test detected the presence of HbS with 81.8% sensitivity and 83.3% specificity, and identified SCD newborns with 100.0% sensitivity and 70.7% specificity. The use of the paper-based test in a two-stage newborn screening process could have excluded about 70% of all newborns from expensive confirmatory testing by IEF, without missing any of the SCD newborns in the studied cohort. This study demonstrates the potential utility of the newborn paper-based test for reducing the overall cost of screening newborns for SCD and thus increasing the practicality of universal newborn SCD screening programs in resource-limited settings.

Free PMC Article

PMID: 28367971

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  1. Cochrane Database Syst Rev. 2016 Oct;2016(10). pii: CD012389. doi: 10.1002/14651858.CD012389.

Interventions for preventing silent cerebral infarcts in people with sickle cell disease.

Estcourt LJ1, Fortin PM2, Hopewell S3, Trivella M4, Doree C2, Abboud MR5.


This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the effectiveness of red blood transfusions and hydroxyurea alone or in combination and HSCT to reduce or prevent SCI in people with SCD.

PMCID: PMC5360228 Free PMC Article

PMID: 28344510

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Conflict of interest statement

Declarations of Interest Lise Estcourt: partly funded by the NIHR Cochrane Programme Grant – Safe and Appropriate Use of Blood Components.Patricia Fortin: funded by the NIHR Cochrane Programme Grant – Safe and Appropriate Use of Blood Components.Sally Hopewell: partly funded by the NIHR Cochrane Programme Grant – Safe and Appropriate Use of Blood Components.Marialena Trivella: partly funded by the NIHR Cochrane Programme Grant – Safe and Appropriate Use of Blood Components.Miguel Abboud: has received research funding from Mast Therapeutics, Eli Lilly, Shire, Dilaforette, he also serves on advisory boards and steering committees for Eli Lilly, Pfizer, Astra Zeneca and Novo. These activities had no relationship to the management of neurologic complications in sickle cell disease.


  1. Cochrane Database Syst Rev. 2016 Oct;2016(10). pii: CD012380. doi: 10.1002/14651858.CD012380.

Interventions for chronic kidney disease in people with sickle cell disease.

Roy NB1, Fortin PM2, Bull KR3, Doree C2, Trivella M4, Hopewell S5, Estcourt LJ6.


This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the effectiveness of any intervention in preventing or reducing kidney complications or CKD in people with SCD (including red blood cell transfusions, hydroxyurea and ACEI (either alone or in combination with each other)).

PMCID: PMC5360229 Free PMC Article

PMID: 28344511

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Sickle Cell Conferences and Events

Foundation for Sickle Cell Disease Research Annual meeting

April 28-30, 2017

Fort Lauderdale FL

SCDAA is pleased to announce the 45th Annual National Convention on Sickle Cell Disease. With over

447 researchers, physicians, nurses, socials workers, individuals living with SCD & SCT and more we are excited to reunite with you again on October 23-28, 2017!

The SCDAA Annual Convention is a four-day conference designed to address the multi-factorial aspects of Sickle Cell Disease. This year the event will be held in Atlanta, Georgia, a city near and dear to the sickle cell community!


The 11th Sickle Cell in Focus Conference 26-27, October 2017 Kingston, Jamaica

We are pleased to announce that Sickle Cell in Focus (SCiF) will be held for the first time in Kingston, Jamaica on October 26-27, 2017. This year, SCiF will be co-hosted by the National Heart, Lung, and Blood Institute and the University of West Indies, Jamaica. SCiF is a two-day, intensive, educational update on sickle cell disease. This year’s conference will focus on the latest clinical trials, the science and mechanisms for new therapeutic targets, and curative therapies. This two-day intensive educational conferences includes both clinical and scientific lectures, aimed at clinicians, academics, and other healthcare professionals involved in sickle cell disease around the world.

Contact Rusinel Amarante|