Managing the Cerebrovascular Complications of Sickle Cell Disease: Current Perspectives

Abstract

The importance of protecting brain function for people with sickle cell disease (SCD) cannot be overstated. SCD is associated with multiple cerebrovascular complications that threaten neurocognitive function and life. Without screening and preventive management, 11% of children at 24% of adults with SCD have ischemic or hemorrhagic strokes. Stroke screening in children with SCD is well-established using transcranial Doppler ultrasound (TCD). TCD velocities above 200 cm/s significantly increase the risk of stroke, which can be prevented using chronic red blood cell (RBC) transfusion. RBC transfusion is also the cornerstone of acute stroke management and secondary stroke prevention. Chronic transfusion requires long-term management of complications like iron overload. Hydroxyurea can replace chronic transfusions for primary stroke prevention in a select group of patients or in populations where chronic transfusions are not feasible. Silent cerebral infarction (SCI) is even more common than stroke, affecting 39% of children and more than 50% of adults with SCD; management of SCI is individualized and includes careful neurocognitive evaluation. Hematopoietic stem cell transplant prevents cerebrovascular complications, despite the short- and long-term risks. Newer disease-modifying agents like voxelotor and crizanlizumab, as well as gene therapy, may treat cerebrovascular complications, but these approaches are investigational.

From Stress to Sick(le) and Back Again–Oxidative/Antioxidant Mechanisms, Genetic Modulation, and Cerebrovascular Disease in Children with Sickle Cell Anemia

“…Finally, the genetically modified progenitor cells are reinfused after high-dose chemotherapy conditioning. Despite the advantages of not requiring donors, thus reducing the risk of graft-vs-host disease [159], these strategies are highly dependent on several key issues. These include: quality of viral delivery systems; quality and quantity of HSC harvested; optimization of the gene modification system in HSC; choice of recombination pathway (homologous vs. non-homologous); identification of the best gene targets; cell manufacturing; preparation regimens to allow the bone marrow to receive genetically modified cells with minimized toxicity; issues related to off-target effects; optimization of preclinical models for testing of developing gene therapy strategies; and parameters that should be used to define a cure [160].…”

“…Levels of hemolysis markers (namely bilirubin, but also reticulocyte and LDH) were also decreased. The HOPE study did not measure stroke incidence, despite initial concerns that increasing oxygen affinity would reduce oxygen extraction in sensitive tissues like the brain [159,172].…”

Overview of the Association Between the Pathophysiology, Types, and Management of Sickle Cell Disease and Stroke

“…The pathophysiological alterations that result in a stroke in a patient with SCD diverge from those in other stroke patients, necessitating distinct treatment approaches (particularly for IS). In SCD cases, the primary objective is to reduce hemoglobin S levels, a goal achievable through methods such as exchange transfusion or, albeit challenging to execute rapidly, simple blood transfusion [85,90,99,100].…”

Role of Traditional Stroke Risk Factors Aiding in Prediction of Infarcts in Adult Patients With Sickle Cell Disease

“…The characteristic sickle‐shaped RBCs are lodged in small blood vessels causing blockages and reduction of blood flow to different organs. 3 , 4 , 5 In that condition, bone fragility, avascular necrosis, and bone infarction can occur, particularly in the hip joint, leading to pain and limited joint mobility. 6 , 7 This is also commonly observed in spleen, which is vulnerable to infarction due to trapping of the sickle‐shaped RBCs in the splenic microvessels.…”