Sickle cell disease: a malady beyond a hemoglobin defect in cerebrovascular disease

Abstract

Introduction Sickle cell disease (SCD) is a devastating monogenic disorder that presents as a multisystem illness and affects approximately 100,000 individuals in the United States alone. SCD management largely focuses on primary prevention, symptomatic treatment and targeting of hemoglobin polymerization and red blood cell sickling. Areas covered This review will discuss the progress of SCD over the last few decades, highlighting some of the clinical (mainly cerebrovascular) and psychosocial challenges of SCD in the United States. In addition, focus will also be made on the evolving science and management of this inherited disease. Expert Commentary Until recently hydroxyurea (HU) has been the only FDA approved therapy for SCD. However, advancing understanding of SCD pathophysiology has led to multiple clinical trials targeting SCD related thrombo-inflammation, abnormal endothelial biology, increased oxidant stress and sickle cell mutation. Yet, despite advancing understanding, available therapies are limited. SCD also imposes great psychosocial challenges for the individual and the affected community, which has previously been under-recognized. This has created a pressing need for complementary adjuvant therapies with repurposed and novel drugs, in addition to the establishment of comprehensive clinics focusing on both the medical treatment and the psychosocial issues associated with SCD.

Ischemia-Reperfusion Injury in Sickle Cell Disease

“…31 Neutrophilia has long been considered a risk factor in SCD and positively correlates with early death, SCIs, hemorrhagic strokes, and ACS. 3 Reduction of neutrophil count with the use of hydroxyurea markedly decreases the frequency of painful crisis and ACS in moderate and severe SCD. 4 Neutrophils in SCD also have an activated phenotype with lower levels of Lselectin (CD62L) and higher levels of CD64.…”

“…Clinical hallmarks of SCD, which include hemolytic anemia, VOC, and vascular endothelial dysfunction, all contribute to the increased risk of cerebral ischemic injury in SCD, 3 which constitutes 54% of all cerebrovascular accidents 48 and is one of the most devastating complications of SCD. The risk of overt stroke for children with SCD is >333 times higher than that for the general population, and this burden continues well into adulthood, with approximately 11% of patients with SCD having clinically apparent strokes before the age of 20 years, increasing to 24% by the age of 45 years.…”

“…This inherited disease is found in 1 of every 365 African Americans and is responsible for approximately 113,000 hospitalizations and $488 million in costs annually. 3 The clinical hallmark of SCD is episodes of acute pain and other common manifestations, including cerebrovascular events, such as transient ischemic attacks, ischemic strokes [including silent cerebral infarcts (SCIs)], intracerebral hemorrhages, acute chest syndrome (ACS), pulmonary hypertension (PH), bacterial infections, splenic infarcts, and progressive multiorgan dysfunction syndrome. 3 This review focuses on ischemia-reperfusion injury (I/RI) in SCD with the main emphasis on the immunopathology (neutrophils and platelets) and discusses various I/RI-associated SCD clinical outcomes and therapeutic interventions.…”

Spatio-Temporal Epidemiological Analyses of Sickle Cell Disorder of a Tribal Region in Odisha, India

“…As SCD is a haematological disorder related to haemoglobin (Ansari et al,2018). The concentration of haemoglobin of normal male individual is about 14 mg/dL and female individual is about 12 mg/dL.…”

A dose‐ranging study of ticagrelor in children aged 3‐17 years with sickle cell disease: A 2‐part phase 2 study

“…Current understanding of sickle cell disease (SCD) includes pathophysiology beyond the red blood cell, for example, inflammation, oxidant stress, vasoregulation, endothelial dysfunction, and thrombosis . Platelet activation is at the cross‐roads of most of these pathophysiologic pathways, both acute and chronic.…”