Rethinking Sickle Cell Disease as a Systemic Vasculopathy

TL;DR

This paper argues that sickle cell disease should be viewed as a systemic vascular disorder, not just a blood disorder, to better understand and treat its complications.

Contribution

The paper redefines sickle cell disease as a systemic vasculopathy, emphasizing the need for vascular-focused therapies and biomarkers.

Findings

Sickle cell disease causes progressive vascular-mediated organ damage through vaso-occlusion and inflammation.

End-organ complications are best understood as manifestations of a systemic vasculopathy.

Current therapies manage symptoms but do not fully address vascular complications or long-term outcomes.

Abstract

What are the main findings?
Sickle cell disease is a multi-system disorder in which vaso-occlusion, endothelial dysfunction, and chronic inflammation drive progressive vascular-mediated organ damage.With increasing age, end-organ complications in sickle cell disease are best understood as manifestations of a systemic vasculopathy in addition to a hematologic disorder.

Sickle cell disease is a multi-system disorder in which vaso-occlusion, endothelial dysfunction, and chronic inflammation drive progressive vascular-mediated organ damage.

With increasing age, end-organ complications in sickle cell disease are best understood as manifestations of a systemic vasculopathy in addition to a hematologic disorder.

What are the implications of the main findings?
Advancing outcomes in sickle cell disease will require therapies that address vascular complications in addition to the use of red blood cell-specific therapeutics.In sickle cell disease, the development of biomarkers that enable real-time detection of end-organ injury and longitudinal monitoring of organ damage is essential to rigorously assess clinically meaningful outcomes of novel pharmaceutical therapies.

Advancing outcomes in sickle cell disease will require therapies that address vascular complications in addition to the use of red blood cell-specific therapeutics.

In sickle cell disease, the development of biomarkers that enable real-time detection of end-organ injury and longitudinal monitoring of organ damage is essential to rigorously assess clinically meaningful outcomes of novel pharmaceutical therapies.

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.

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