clinical topic updates
Vaso-Occlusive Crisis and Other Complications of Sickle Cell Disease
Vaso-occlusive crisis (VOC) and other complications such as ischemic stroke can create a substantial burden in patients with sickle cell disease (SCD). Transfusion therapy for those with SCD at high risk for stroke is lifelong prophylaxis and is not only a pediatric practice.
Associate Professor, Division of Hematology and Oncology
“It is important to understand that, for most individuals at high risk for ischemic stroke, chronic transfusion therapy is lifelong prophylaxis, not just a pediatric practice.”
Ischemic stroke and VOC are 2 largely distinct manifestations of SCD that each can contribute profoundly to the overall burden of disease. The use of transcranial Doppler (TCD) screening of intracranial blood flow identifies children at high risk for stroke, where elevated time-averaged mean velocities are associated with increased risk. All children with SCD between the ages of 2 and 16 years should receive TCD screening annually, and chronic transfusion therapy should be initiated in those at high risk for stroke. This is consistent with data from the STOP 1 and 2 trials, in which chronic transfusion therapy significantly reduced the incidence of strokes in patients at high risk by TCD.
Hydroxyurea subsequently emerged as a disease-modifying treatment; it was originally used for the reduction of VOC and then later was found to have other properties as well. Although some evidence supports that hydroxyurea might reduce the risk of stroke in some patients, it is not the optimal first-line therapy for primary stroke prophylaxis. In the TWiTCH study, children who had an abnormal TCD but no evidence of ischemia or severe vascular disease on brain scan were transitioned to hydroxyurea after at least 1 year of transfusion therapy. Results of this study suggested that such patients who received hydroxyurea can maintain their normalized TCD velocities after stopping transfusion therapy, which should aid in primary stroke prevention. However, these data apply only to that subset; the majority of patients have to remain on chronic transfusion therapy for the rest of their lives to reduce the risk of an ischemic event. The STOP 2 trial investigated whether transfusion therapy could be safely stopped in patients who normalized their TCD velocities after 30 or more months of transfusions and who lacked severe vascular disease. This trial was stopped early because, among those whose transfusion therapy was halted, 14 participants reverted to abnormal TCD velocities and 2 children had overt strokes, suggesting that indefinite therapy for primary stroke prevention was required.
Newer treatments such as crizanlizumab and voxelotor have recently been approved by the US Food and Drug Administration for patients with SCD. At this time, we have not seen evidence that either of these therapies can be used for stroke prevention in SCD. For now, it is important to understand that, for most individuals at high risk for ischemic stroke, chronic transfusion therapy is lifelong prophylaxis, not just a pediatric practice. While both VOC and strokes are complications of SCD, there is not enough evidence to support the idea that decreasing VOC would decrease the risk of stroke. Further, merely increasing hemoglobin may not prevent strokes, and a therapy that decreases intracranial blood flow velocity among individuals with a conditional TCD does not necessarily prevent strokes either. At this time, having a conditional TCD result does not equate to any clinical outcomes.
Adams RJ, Brambilla D; Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) Trial Investigators. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. N Engl J Med. 2005;353(26):2769-2778.
Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med. 1998;339(1):5-11.
Carden MA, Little J. Emerging disease-modifying therapies for sickle cell disease. Haematologica. 2019;104(9):1710-1719.
Jacob S, Adcock A, Murray A, Kolodney J. More than meets the eye: cerebrovascular disease in sickle cell disease is about more than sickling. Stroke. 2018;49(6):e224-e227.
Kwiatkowski JL, Voeks JH, Kanter J, et al; Post-STOP Study Group. Ischemic stroke in children and young adults with sickle cell disease in the post-STOP era. Am J Hematol. 2019;94(12):1335-1343.
National Heart, Lung, and Blood Institute. Evidence-based management of sickle cell disease. Expert Panel Report, 2014. https://www.nhlbi.nih.gov/sites/default/files/media/docs/sickle-cell-disease-report%20020816_0.pdf. Accessed March 31, 2020.
Stotesbury H, Kawadler JM, Hales PW, Saunders DE, Clark CA, Kirkham FJ. Vascular instability and neurological morbidity in sickle cell disease: an integrative framework. Front Neurol. 2019;10:871.
Ware RE, Davis BR, Schultz WH, et al. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. Lancet. 2016;387(10019):661-670.
Ware RE, Helms RW; SWiTCH Investigators. Stroke with transfusions changing to hydroxyurea (SWiTCH). Blood. 2012;119(17):3925-3932.