American Society of Hematology 2020 guidelines for sickle cell disease: prevention, diagnosis, and treatment of cerebrovascular disease in children and adults

Abstract

Background: Central nervous system (CNS) complications are among the most common, devastating sequelae of sickle cell disease (SCD) occurring throughout the lifespan.

Objective: These evidence-based guidelines of the American Society of Hematology are intended to support the SCD community in decisions about prevention, diagnosis, and treatment of the most common neurological morbidities in SCD.

Methods: The Mayo Evidence-Based Practice Research Program supported the guideline development process, including updating or performing systematic evidence reviews. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE evidence-to-decision frameworks, to assess evidence and make recommendations.

Results: The panel placed a higher value on maintaining cognitive function than on being alive with significantly less than baseline cognitive function. The panel developed 19 recommendations with evidence-based strategies to prevent, diagnose, and treat CNS complications of SCD in low-middle- and high-income settings.

Conclusions: Three of 19 recommendations immediately impact clinical care. These recommendations include: use of transcranial Doppler ultrasound screening and hydroxyurea for primary stroke prevention in children with hemoglobin SS (HbSS) and hemoglobin Sβ0 (HbSβ0) thalassemia living in low-middle-income settings; surveillance for developmental delay, cognitive impairments, and neurodevelopmental disorders in children; and use of magnetic resonance imaging of the brain without sedation to detect silent cerebral infarcts at least once in early-school-age children and once in adults with HbSS or HbSβ0 thalassemia. Individuals with SCD, their family members, and clinicians should become aware of and implement these recommendations to reduce the burden of CNS complications in children and adults with SCD.

Keywords: Anemia-Clinical: Sickle cell anemia; RED CELLS.

Figure 1.

High incidence of cerebrovascular accidents in children and adults with SCD prior to the onset of primary stroke prevention with transcranial Doppler (TCD) and regular blood transfusion or hydroxyurea. Data from the 3647 children and adults with SCD followed prospectively from 1978 to 1988 in the Cooperative Study for Sickle Cell Disease cohort. The incidence rates of cerebrovascular accidents (CVA) were used to determine CVA-free survival curves. The estimated age at first CVA was significantly different for individuals with HbSS (SS) and HbSC (SC; P < .001). Chances of having a first CVA by 20 years of age, 30 years of age, and 45 years of age were estimated at 11%, 15%, and 24%, respectively, for HbSS patients and 2%, 4%, and 10%, respectively, for those with HbSC. Reprinted from Ohene-Frempong et al with permission.

Figure 2.

Prevalence of SCIs in unselected children and adults with HbSS or HbSβ⁰thalassemia. Silent cerebral infarcts (SCI) were detected with MRI of the brain in children and adults with HbSS or HbSβ⁰ thalassemia and no history of focal neurological deficits or strokes. Each point represents distinct cross-sectional studies in children and adults with HbSS or HbSβ⁰ thalassemia. Reprinted from Kassim et al with permission.

Figure 3.

STOP trial results. Results of the STOP trial and STOP 2.^, TCD screening coupled with regular blood transfusion therapy for those with an abnormal TCD measurement (TAMMV > 200 cm/s) was associated with a 92% reduction in stroke incidence compared with observation alone. The threshold for treatment is 2 nonimaging TCD measurements >200 cm/s, TAMMV of ≥200 cm/s, or a single measurement >220 cm/s. Reprinted from Adams et al with permission.

Figure 4.

Pooled analysis of the 10 studies documenting TCD measurement before and after hydroxyurea therapy in children with HbSS or HbSβ⁰thalassemia. This meta-analysis demonstrates the average drop in TCD measurement after starting hydroxyurea therapy of 21 cm/s (95% confidence interval [CI], 14.8-29.0). The plot also suggests that the decrease in TCD measurements can be seen as early as 3 months after the start of hydroxyurea therapy with a sustained impact of hydroxyurea therapy on decreasing TCD measurements for at least 36 months. The analysis is updated from a previous one by DeBaun and Kirkham, plus additional references.^-,,, ♦ represents the pooled estimate from a random-effect model, the edges of the diamonds represent the 95% CI; ▪ represents individual studies. MTD, maximum tolerated dose.

Figure 5.

Relationship between hemoglobin level and oxygen delivery in individuals with SCD. The maximal hemoglobin (Hb_max) to deliver oxygen transport in sickle cell patients is 10 to 11 g/dL because SCD alters red cell viscosity and decreases oxygen transport. However, when the HbS level is low (∼20%), this impairment of oxygen transport is improved, and a higher hemoglobin level (such as 13 g/dL) may be beneficial. Red cell apheresis can rapidly lower the HbS to levels that maximize oxygen delivery, in contrast to the risks of simple transfusion resulting in increased viscosity and decreased oxygen delivery.^, Professional illustration by Patrick Lane, ScEYEnce Studios. Adapted from Swerdlow with permission.

Figure 6.

Algorithm of management of acute suspected ischemic stroke in children with SCD. The goal is prompt transfusion beginning within 2 hours of presentation to medical care to achieve hemoglobin of 10 g/dL and an HbS level of 15% to 20%. *See text for PICO question 4 or established inclusion and exclusion criteria. Professional illustration by Patrick Lane, ScEYEnce Studios.

Figure 7.

Algorithm of management of acute suspected ischemic stroke in adults with SCD. The goal is prompt transfusion beginning within 2 hours of presentation to medical care to achieve hemoglobin of 10 g/dL and an HbS level of 15% to 20%. *See PICO questions 4 and 7 or established inclusion and exclusion criteria. Professional illustration by Patrick Lane, ScEYEnce Studios.

Figure 8.

SCI and mimics in SCD. (A) Axial (left) and coronal fluid-attenuated inversion recovery (FLAIR) images illustrate a qualifying silent cerebral infarct in the left parietal lobe (white arrows). An infarct-like lesion was defined as an MRI signal abnormality that was at least 3 mm in 1 dimension and that was visible in 2 planes on FLAIR images or similar image with 3D FLAIR sequence (not shown) and documented neurological examination performed by a neurologist demonstrating that the participant has a normal neurologic examination or an abnormality on examination that could not be explained by the location of the brain lesion(s). (B) Axial FLAIR (left), T₂-weighted (middle), and T₁-weighted (right) images of the same lesion demonstrate that the FLAIR sequence is better for the identification of SCIs (green circles). (C) Axial FLAIR images show that higher magnet strength (3.0 Tesla) improves image quality and identification of subtle lesions only seen at 3.0 Tesla (arrowhead). More obvious lesions are visible at 1.5 Tesla and 3.0 Tesla (arrows). (D) Linear and punctate T₂ hyperintensities that suppress on FLAIR are consistent with prominent perivascular spaces (Virchow-Robin spaces). (E) Terminal zones of myelination on T₂-weighted images. Axial FLAIR and T₂-weighted images show ill-defined symmetrical T₂-weighted hyperintensity in the deep parietal white matter. The T₂-weighted image on the right illustrates that there are well-defined linear perivascular spaces extending throughout the area of subtle hyperintensity (green arrows). (F) Axial FLAIR images demonstrate a case of white matter injury in a premature infant (periventricular leukomalacia) that can mimic a SCI because of the increased signal on FLAIR (white arrows).

Figure 9.

Preexisting SCIs. (A) Preexisting SCIs associated with subsequent neurological events in children with HbSS or HbSβ⁰ thalassemia. Time to first neurological event-stroke, seizure, TIA for children with normal or conditional TCD measurements (time averaged mean maximum velocity of <200 cm/s, nonimaging, or <185 cm/s imaging technique) and with (n = 68) and without SCIs on MRI (n = 353). (B) Associated with recurrent SCIs in adults with sickle cell anemia. A total of 54 adults with HbSS or HbSβ⁰ thalassemia had a minimum time of 6 months between at least 2 MRIs of the brain; in this group of adults, 43% (n = 23) had SCI at baseline and 57% (n = 31) had no SCI at baseline; individuals with overt stroke were excluded based on history and examination by a neurologist. Reprinted from Jordan et al (A) and Jordan et al (B) with permission.