Sickle cell disease as a vascular disorder

ABSTRACT

Introduction

In sickle cell disease (SCD), hemoglobin S (HbS) red blood cells (RBCs) are characteristically deformed and inflexible. Often breaking down in the circulation, they exhibit increased adhesive properties with the endothelium and activated neutrophils and platelets, increasing the risk of occlusion of the microcirculation. SCD is categorized into two sub-phenotypes: hyperhemolytic, associated with priapism, leg ulcers, pulmonary hypertension, and stroke, and high hemoglobin/viscosity, which may promote vaso-occlusion-associated pain, acute chest syndrome, and osteonecrosis.

Areas covered

The sub-phenotypes are not completely distinct. Hemolysis may trigger vaso-occlusion, contributing to vascular complications. Targeting P-selectin, a key mediator of cross-talk between hyperhemolysis and vaso-occlusion, may be beneficial for vascular and vaso-occlusion-associated complications. English-language articles from PubMed on the topic of SCD and vaso-occlusive crises (VOCs) were reviewed from 1 January 2000 to 1 January 2019 using the search terms ‘sickle cell disease,’ ‘vaso-occlusive crises,’ and ‘selectin.’

Expert opinion

Besides targeting P-selectin, other strategies to counter VOCs and RBC sickling are being pursued. These include platelet inhibition to counter aggregation, intercellular adhesion, and thrombosis during VOCs; gene therapy to correct the homozygous missense mutation in the β-globin gene, causing polymerization of HbS; L-glutamine, possibly reducing oxidative stress in sickled RBCs; and fetal hemoglobin inducers.

KEYWORDS:

• Fetal hemoglobin
• P-selectin
• pain crisis
• sickle cell disease
• vascular cell adhesion molecules
• vascular disease
• vaso-occlusive crises

Article highlights box

• In sickle cell disease (SCD), multicellular adhesion between red blood cells (RBCs), white blood cells (WBCs), platelets, and endothelial cells can culminate in vaso-occlusive crises (VOCs), which are characterized by acute painful episodes, the hallmark of SCD.

• SCD may be categorized into two sub-phenotypes: a hyperhemolytic sub-phenotype associated with priapism, leg ulcers, chronic kidney disease, and stroke, and a high hemoglobin (Hb)/viscosity one, which may promote vaso-occlusion-associated pain, acute chest syndrome, osteonecrosis, and acute kidney injury.

• Vaso-occlusion may also contribute to vascular complications through cross-talk with hyperhemolysis and direct vascular damage. Hemolysis is a potential trigger of VOCs since the major byproduct heme alters the adhesive interactions between sickle RBCs, leukocytes, endothelial cells, and possibly platelets. Repeated vascular damage from vaso-occlusion may foster endothelial cell dysfunction, possibly through a mechanism resembling ischemia/reperfusion injury.

• Intravascular hemolysis is one of the mechanisms by which reactive oxygen species (ROS) are generated in SCD. Following hemolysis, iron and iron-containing molecules (eg, heme and Hb) are released into the plasma and can catalyze the formation of ROS, which are also produced in RBC, platelets, and neutrophils of patients with SCD at a higher level compared with healthy controls.

• Based on the key role of P-selectin in several processes involved in the relationship between vaso-occlusion and vascular disease in SCD, targeting P-selectin has the potential to have beneficial therapeutic effects on both vaso-occlusion-associated complications and vascular complications.

Acknowledgments

Editorial support in the preparation of this manuscript was provided by Phase Five Communications, supported by Novartis Pharmaceuticals Corporation.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Author is supported by a research grant from the NHLBI (U54HL141011).