The use of antithrombin as a predictive tool in determining the development of stroke in patients with sickle cell anemia based on transcranial doppler ultrasound risk group

Silent cerebral infarcts and arteriopathy are common and progressive in individuals with sickle cell anemia. However, most data describing brain lesions in sickle cell anemia are cross-sectional or derive from pediatric cohorts with short follow-up. We investigated the progression of silent cerebral infarct and cerebral vessel stenosis on brain MRI and MRA, respectively, by describing the incidence of new or worsening lesions over a period of up to 25 years among young adults with sickle cell anemia and explored risk factors for progression. Forty-four adults with sickle cell anemia (HbSS or HbSβ0thalassemia), exposed to chronic transfusions ( n = 12) or hydroxyurea ( n = 32), median age 19.2 years (range 18.0–31.5), received a screening brain MRI/MRA and their results were compared with a clinical exam performed during childhood and adolescence. We used exact log-rank test to compare MRI and MRA progression among any two groups. The hazard ratio (HR) and 95% confidence interval (CI) were calculated from Cox regression analyses. Progression of MRI and MRA occurred in 12 (27%) and 4 (9%) young adults, respectively, relative to their pediatric exams. MRI progression risk was high among participants with abnormal pediatric exams (HR: 11.6, 95% CI: 2.5–54.7) and conditional or abnormal transcranial Doppler ultrasound velocities (HR: 3.9, 95% CI: 1.0–15.1). Among individuals treated with hydroxyurea, high fetal hemoglobin measured in childhood was associated with lower hazard of MRI progression (HR: 0.86, 95% CI: 0.76–0.98). MRA progression occurred more frequently among those with prior stroke (HR: 8.6, 95% CI: 1.2–64), abnormal pediatric exam ( P = 0.00084), and elevated transcranial Doppler ultrasound velocities ( P = 0.004). Brain MRI/MRA imaging in pediatrics can identify high-risk patients for CNS disease progression in young adulthood, prompting consideration for early aggressive treatments.

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Use of a Electronic Sickle Cell Dashboard to Improve Annual Transcranial Doppler Ultrasound (TCD) Completion Rates

Blood ◽

10.1182/blood-2019-128846 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3384-3384

Author(s):

Joanna L. Gendreau ◽

Kelli Fischbeck ◽

Brooke Cook ◽

Steve McCalley ◽

Lori Wagner ◽

...

Keyword(s):

Real Time ◽

Doppler Ultrasound ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Transcranial Doppler ◽

Transcranial Doppler Ultrasound ◽

Cell Phenotype ◽

Completion Rates ◽

Transfusion Therapy ◽

Annual Screening

Background: Stroke, a feared and common complication of sickle cell anemia can be prevented by early recognition of at-risk individuals using annual screening transcranial Doppler ultrasound (TCD) and subsequent treatment with chronic transfusion therapy. The landmark STOP trial established annual screening TCD from 2 to 16 years of age as a standard of care for children with sickle cell anemia. Compliance with this recommendation remains challenging in a majority of sickle cell centers due to various reasons. Methods: An analysis of the institutional process of obtaining TCD revealed several opportunities for improvement. Provider attention was diverted from TCD screening towards management of acute complications such as fever and pain, hydroxyurea management, vaccine administration and psychosocial issues. Other factors contributing to poor TCD completion rates included high no-show rates for annual comprehensive visits, routine preventive visits, and hospital follow-ups. In addition, there were barriers to scheduling and completion of TCD studies after order placement. We hypothesized that by utilizing information technology (IT) tools we could improve TCD ordering and completion rates. Our IT team, in collaboration with our hematology team, designed and optimized the electronic clinic note specific to sickle cell disease in order to capture data such as age, sickle cell phenotype, eligibility for TCD, and last completed TCD date. Utilizing these data an innovative, real-time, sickle-cell dashboard was created and made available to all clinicians. In a single screen view, the dashboard displayed data regarding TCD eligible patients that needed an order for TCD, had a TCD scheduled, or were over-due or near-due for TCD. Amongst these, those who had upcoming appointments were especially highlighted in order to coordinate their clinic and TCD visits on the same day. The dashboard also highlighted patients who were overdue for TCD with no scheduled clinic appointments This data was reviewed by sickle cell nurse coordinator, a physician champion and an IT representative at least weekly. Inaccuracies in data were identified and corrected. The action items were then presented at the weekly sickle cell team meeting and acted upon. We then measured TCD order and completion rates before and after the January 2019 implementation of the dashboard. Results: In 2018 thirty-six orders for TCD were placed with eighteen completed studies (50%) versus 47 orders placed with 42 completed TCD in the first 7 months of 2019 (89%). These results were clinically significant (p=0.0001, Two-sided Fisher's exact test). As of July 31, 2019 out of 68 eligible patients, all but 2 had TCD orders placed (97%). Fifty-one patients were current on their TCD (75%) and the majority of those patients with missing TCD were noncompliant with clinic and radiology appointments. For the first 6 months of the year, an average of 93% of patients were compliant with annual TCD at the time of their clinic visit Conclusion: An IT dashboard created using real-time data; collaboration and communication between clinical, IT and radiology teams; and action during regularly scheduled sickle cell team meetings resulted in marked improvement in TCD ordering and completion rates within a few months. The process was sustainable by training nursing and ancillary staff to utilize data. In the future, this sickle cell dashboard could be utilized to also improve other areas of sickle cell care such as immunizations and medication compliance. Disclosures Gomez: Alnylam: Consultancy; Novo Nordisk, Novartis, Pfizer, Sanofi, Takeda, UniQure: Research Funding.

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Transcranial Doppler Ultrasound (TCD) Outcomes for Children with Prior Normal TCD: Post-STOP Study Results

Blood ◽

10.1182/blood.v124.21.562.562 ◽

2014 ◽

Vol 124 (21) ◽

pp. 562-562

Author(s):

Janet L. Kwiatkowski ◽

Heather Fullerton ◽

Jennifer Voeks ◽

Lynette Brown ◽

Ellen Debenham ◽

...

Keyword(s):

Clinical Practice ◽

Doppler Ultrasound ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Transcranial Doppler ◽

Stroke Prevention ◽

Transcranial Doppler Ultrasound ◽

The Mean ◽

Outcomes For Children

Abstract Background: The Stroke Prevention Trial in Sickle Cell Anemia (STOP) and Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) study established routine transcranial Doppler ultrasound (TCD) screening with indefinite transfusions for children with abnormal TCD as standard of care. Children with normal TCD studies have the lowest risk of stroke of ~0.5-1% per year (y). Annual TCD screening is usually recommended for these children to detect possible subsequent conversion to high risk. We sought to determine the frequency of TCD screening utilized in “real world” clinical practice and the TCD outcomes for children with prior normal TCD. Subjects and Methods: During STOP and STOP2 (STOP/2), 3,837 children, ages 2 to 16 y with sickle cell disease type SS or S-Beta-0-thalassemia underwent screening TCD. The Post-STOP study was designed to follow-up the outcomes of children who were screened for or participated in one or both of these randomized trials. 19 of the 26 original study sites participated in Post-STOP, contributing a total of 3,541 (92%) of the STOP/2 subjects. After exit from STOP/2, these children received TCD screening and treatment according to local practices. Data abstractors visited each clinical site and obtained retrospective data from STOP/2 study exit to 2012-2014 (depending on site) on follow-up TCD results and clinical information using standard data collection forms. The rates of TCD re-screening and the proportion of children who converted to abnormal TCD were calculated. Factors associated with conversion to abnormal TCD were assessed. Results: Of the 3,541 subjects, follow-up data were available for 2,838 (80%). The mean age at the last TCD study obtained in STOP/2 was 9.5 y and the mean age at last follow-up in Post-STOP was 19.6 y. The mean duration of follow-up after exiting STOP/2 was 9.2 y. Subjects were classified by their worst TCD in STOP/2: the TCD was normal in 1,814 (64%), conditional in 479 (17%), abnormal in 357 (13%) and inadequate 188 (7%). Among the 1,814 children with only normal studies in STOP/2, follow-up TCD screening was obtained in the Post-STOP era on 842 (46%) at a median rate of 0.28 TCD studies/y (range, 0.05-3.04/y). Among these children, 26 (3.1%) developed an abnormal TCD at a median of 11.5 y (2.2-18.2 y) from the last STOP/2 study, while 77.5% still had normal TCD at a median of 10.7 y (0.7-18.3 y) from last STOP/2 study. The worst follow-up TCD classification for this group with prior normal TCD was conditional in 9.7% and inadequate in 9.6%. Among those that converted from prior normal to abnormal TCD, 12 had an interval conditional study (at median 2.8 y, 0.98-9.2 y) while 14 children converted from normal to abnormal at a median of 4.2 y (1.4-12.7 y) without documented interval conditional study. Children who developed abnormal TCD were younger at STOP/2 study exit (4.9 vs. 7.8 y, p<0.001) and had higher TCD velocity at their last STOP/2 TCD study (154 vs. 136 cm/s, p<0.001) than children whose TCD remained normal. There was no significant difference between the time interval from the last STOP/2 TCD and the first Post-STOP TCD in these 2 groups. Conclusions: In clinical practice, follow-up TCD for children with prior normal TCD was performed less frequently than the generally recommended annual basis. Among children re-screened, the risk of conversion to abnormal TCD was relatively low, but re-screening with TCD identified a subset of at-risk children who could benefit from transfusions to prevent a potentially devastating outcome. Predictors of conversion to abnormal TCD included younger age and prior TCD velocity in the high normal range. Disclosures Adams: Novartis: Consultancy.

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Transcranial Doppler Ultrasound in Peninsular Arab Patients With Sickle Cell Disease

Journal of Ultrasound in Medicine ◽

10.1002/jum.14680 ◽

2018 ◽

Vol 38 (1) ◽

pp. 165-172 ◽

Cited By ~ 3

Author(s):

Adekunle Adekile ◽

Meaad Hassan ◽

Akram Asbeutah ◽

Mohamed Al‐Hinai ◽

Omar Trad ◽

...

Keyword(s):

Sickle Cell Disease ◽

Doppler Ultrasound ◽

Sickle Cell ◽

Transcranial Doppler ◽

Transcranial Doppler Ultrasound ◽

Cell Disease

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Transcranial Doppler Ultrasound Velocity, Cerebral Vasculopathy, and Silent Infarcts In Sickle Cell Disease

Blood ◽

10.1182/blood.v116.21.269.269 ◽

2010 ◽

Vol 116 (21) ◽

pp. 269-269

Author(s):

Peter M.K. de Blank ◽

Daniel M Hayward ◽

Robert Zimmerman, MD ◽

Avrum Pollock ◽

Janet L Kwiatkowski

Keyword(s):

Magnetic Resonance ◽

Sickle Cell Disease ◽

Doppler Ultrasound ◽

Sickle Cell ◽

Cerebral Artery ◽

Transcranial Doppler ◽

Transcranial Doppler Ultrasound ◽

Cell Disease ◽

Increased Risk ◽

The Mean

Abstract Abstract 269 Background: Approximately one-fourth of children with sickle cell disease (SCD), type SS, show evidence of cerebral ischemia on magnetic resonance imaging (MRI) without overt neurologic symptoms. Children with these silent infarcts have an increased risk of neuropsychological abnormalities and overt stroke. The pathophysiology of silent infarcts is unclear. Elevated transcranial Doppler ultrasound (TCD) velocities in the internal cerebral artery (ICA) and middle cerebral artery (MCA) are associated with an increased risk of overt stroke, but have not been associated previously with silent infarct. However, prior studies of silent infarcts failed to examine the association with anterior cerebral artery (ACA) vessel abnormalities, despite a predominantly frontal distribution of these infarcts. In addition, the relationship of magnetic resonance angiography (MRA) abnormalities to silent infarcts has not been extensively studied, although children with abnormal TCD velocity who also have stenosis or occlusion of vessels by MRA have the highest risk of overt stroke. We hypothesized that elevated ACA velocity and/or significant vasculopathy of the cerebral vessels demonstrated by MRA would be associated with a higher risk of silent stroke. Methods: A retrospective analysis of children followed at our Sickle Cell Center with SCD, type SS or Sb0-thalassemia was performed. Children with TCD (with ACA velocity) and brain MRI/A performed within a year of each other were included. TCD studies performed while on chronic transfusions were excluded. The last eligible MRI/TCD combination was used for patients who had multiple studies. Laboratory values obtained within a year of the MRI also were analyzed. Results: Of the 254 eligible subjects, 54% were male and the mean age was 10.6 ± 5.2 years. Silent infarcts were present in 78/254 (30.7%); the location was frontoparietal in 68%. The mean time-averaged mean of the maximal velocity (TAMMvel) of qualifying STOP vessels (MCA, bifurcation, and ICA) was 139±35cm/s, while the mean TAMMvel of the ACA was 117±34cm/s, which is 84% of the velocity of the other anterior vessels. As previously reported, TAMMvel inversely correlated with age (r=-0.40, p<0.0001) and hemoglobin concentration (r=-0.30, p<0.0001). There was no significant difference in TAMMvel in STOP qualifying vessels (MCA, bifurcation, DICA; 137cm/s vs. 145cm/s, p=0.08) among those with and without silent infarct. However, silent infarcts were associated with abnormal TAMMvel (≥200cm/s, 69/239 with normal/conditional vs. 9/15 with abnormal TAMMvel p=0.01) in these vessels. TAMMvel in the ACA was significantly higher (125 cm/s vs. 113 cm/s, p=0.004) in children with silent infarcts, and elevated ACA TAMMvel (≥170cm/s) was associated with silent infarcts (70/242 with normal vs. 8/12 with elevated velocity, p=0.006). No other single vessel velocity was significantly associated with silent infarct. Abnormal ICA/MCA TAMMvel was associated with stenosis of these vessels by MRA (p<0.001), and abnormal ACA velocities were associated with ACA stenosis by MRA (p<0.001). Further, stenosis by MRA in the ICA/MCA was associated with silent infarct (p<0.006) as were abnormalities of the ACA vessels (p=0.001). Conclusions: Unlike prior studies, we demonstrate a significant association between abnormal ICA/MCA velocity and silent infarcts. We also show an association between ACA velocity and silent infarct, which may in part be due to the predominantly frontoparietal distribution of these lesions. This, together with the association of MRA abnormalities of all three anterior vessels (ICA, MCA, ACA) with silent infarcts suggests a possible role of larger cerebral vessel vasculopathy in the pathophysiology of silent infarcts. This could be due to decreased distal blood flow related to the larger vessel narrowing, embolization of thrombus in larger vessels, or small vessel vasculopathy associated with larger vessel disease. However, mechanisms other than larger vessel vasculopathy are also likely to be involved given that silent infarcts occur in a substantial number of children without elevated TCD velocity or vasculopathy by MRA. Nonetheless, assessment of TCD velocity and MRA abnormalities may help provide information on risk assessment for CNS disease in children with SCD. Disclosures: No relevant conflicts of interest to declare.

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PO12-TU-02 Transcranial Doppler ultrasound in sickle cell disease: an experience from Oman

Journal of the Neurological Sciences ◽

10.1016/s0022-510x(09)70849-4 ◽

2009 ◽

Vol 285 ◽

pp. S222-S223

Author(s):

G.R. Gujjar ◽

Z. Lamki ◽

Y. Wali ◽

A. AlAsmi ◽

A. Pathare ◽

...

Keyword(s):

Sickle Cell Disease ◽

Doppler Ultrasound ◽

Sickle Cell ◽

Transcranial Doppler ◽

Transcranial Doppler Ultrasound ◽

Cell Disease

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An Educational Study Promoting the Delivery of Transcranial Doppler Ultrasound Screening in Paediatric Sickle Cell Disease: A European Multi-Centre Perspective

Journal of Clinical Medicine ◽

10.3390/jcm9010044 ◽

2019 ◽

Vol 9 (1) ◽

pp. 44

Author(s):

Baba P. D. Inusa ◽

Laura Sainati ◽

Corrina MacMahon ◽

Raffaella Colombatti ◽

Maddalena Casale ◽

...

Keyword(s):

Sickle Cell Disease ◽

Doppler Ultrasound ◽

Sickle Cell ◽

Transcranial Doppler ◽

Stroke Risk ◽

Transcranial Doppler Ultrasound ◽

Ultrasound Screening ◽

Cell Disease ◽

Risk Distribution ◽

The Impact

Background: Effective stroke prevention in sickle cell disease (SCD) is recommended for children with sickle cell anaemia. Effective implementation relies on the correct stratification of stroke risk using Transcranial Doppler Ultrasound (TCD), prior to committing children to long-term treatment with transfusion. Nevertheless, less than 50% of children with SCD in Europe receive annual TCD—one of the reasons being a lack of trained personnel. The present European multi-centre study was designed to promote the standardisation and delivery of effective screening. Methods: Fifty-five practitioners from differing professional backgrounds were recruited to the TCD training program. The impact of the training programme was evaluated in three European haematology clinics by comparing stroke risk classification and middle cerebral artery time-averaged maximum velocity (TAMMV) obtained from a cohort of 555 patients, before and after training. Results: 42% (23/55) of trainees successfully completed the program. The TAMMV, used to predict stroke risk at each Centre, demonstrated the highest values in Centre 3 (p < 0.0001) before training. The imaging-TCD TAMMV was also higher in Centre 3 (p < 0.001). Following training, the TAMMV showed closer agreement between centres for both imaging-TCD and non-imaging TCD. The stroke risk distribution of children at each centre varied significantly before training (p < 0.001), but improved after training (Fisher’s Exact: no treatment = 5.6, p = 0.41, treatment = 13.8, p < 0.01). The same consistency in stroke risk distribution following training was demonstrated with both non-imaging and imaging-TCD data. Conclusion: The attainment of competency in stroke screening using transcranial Doppler scanning (TCD) in sickle cell disease is more feasible for professionals with an ultrasound imaging background. A quality assurance (QA) system is required to ensure that standards are maintained. Further work is in progress to develop an achievable and reproducible QA program.

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