Key Information
Source
Year
2026
summary/abstract
Abstract
Sickle cell disease (SCD) is the most common inherited clinically relevant blood disorder. Although a deceptively simple monogenetic disorder, the associated complications have multiple downstream effects. In this review, we explore the many facets of SCD, with a particular focus on its impact on the vascular system. Despite progress in understanding the underlying mechanisms of SCD, including Hemoglobin S polymerization, microvascular occlusion, and inflammation, there are still many questions surrounding the condition, especially predicting which affected individuals will acquire specific complications in order to personalize treatments. While current standard of care treatments, including hydroxyurea and chronic red blood cell transfusions, have been proven to be disease-modifying, newer therapies like crizanlizumab and voxelotor have only proven to manage symptoms. Newer gene therapies have been approved; however, it is not clear what impact these will have long-term on the end-organ complications of SCD. There is still a significant need to understand how we optimize and personalize therapies to improve outcomes for patients. This review highlights the importance of recognizing SCD as a vascular disease to understand its multi-organ complications and heterogeneity of effects.
1. Introduction
Sickle cell disease (SCD) was first identified in 1910 [1,2]. However, despite over one-hundred years of knowledge and discovery, there are still many questions related to outcomes and complications. SCD refers to a group of inherited hemoglobin disorders that render red blood cells RBC more adherent, more fragile, and less able to contain oxygen molecules. When de-oxygenated, the hemoglobin in the RBC polymerizes, resulting in the classic “sickle” shape, leading to the name. Until the 1970s, SCD was mainly a pediatric disease, resulting in death at a median age of 10 years [3] due to infection, stroke, and splenic sequestration. As a result of multiple improvements in early screening and diagnosis, as well as new treatment options, most affected individuals can reach adulthood in high-resource countries. As individuals age, the persistent endothelial dysfunction and anemia result in widespread vasculopathy and end-organ complications in most affected individuals regardless of genotype [4].
The Centers for Disease Control and Prevention (CDC) reports that SCD affects approximately 300,000 births worldwide each year, with at least 100,000 individuals living in the United States [5]. Africa has the greatest frequency worldwide, ranging from 5% to 40% [6], mostly in the sub-Saharan region. In recent years, large populations of affected individuals have also been identified in India and the Middle East, as well as throughout Europe and the United Kingdom. Globally, SCD is the most common, clinically relevant inherited blood disorder affecting approximately 30 million people worldwide.
While originally considered an isolated “blood disorder,” evidence now highlights multiple concomitant pathobiological processes (HbS polymerization, vaso-occlusion, hemolysis-mediated endothelial dysfunction, and inflammation) causing widespread vascular damage and the resulting clinical manifestations of SCD [7]. It is important to understand the vasculopathy caused by SCD to fully appreciate, assess, and treat the breadth of complications. Much of the early understanding of the clinical findings in SCD is the result of the Cooperative Study of Sickle Cell Disease (CSSCD), a large pediatric and young adult registry study. Unfortunately, this study was completed before the widespread implementation of hydroxyurea or the use of prophylactic transfusions for primary stroke prevention and included few people beyond the 5th decade of life [8]. Despite these imperfections, this study remains highly influential in how we consider SCD today, but imparts little information on the current population of aging children and adults who now have the potential to live well into the 7th decade. Further, the CSSCD highlights the complications of homozygous SCD (HbSS), especially in childhood, while downplaying the severity of other types of SCD, which often do not manifest their severity until the 3rd decade of life. More recent data have highlighted these findings and are discussed below.