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Overview

Repetitive vaso-occlusive episodes (VOEs) are the most common clinical manifestation of sickle cell disease (SCD). A VOE occurs when the microcirculation is temporarily or permanently obstructed by cellular aggregates, causing ischemic injury to the supplied organs and inducing pain. Acute pain and chronic organ damage provoked by the vascular occlusion may require emergency department visits or hospitalization for affected patients. Clinical presentations induced by VOE are variable and summarized in Table 3-1.1,2 Although acute pain is a major reason for hospital admission and permanent organ damage is a frequent cause of mortality in SCD patients,3,4 whether these 2 manifestations are linked remains unclear. VOE-associated ischemia in local tissue can indeed lead to organ dysfunction, but the etiology of these injuries is very complicated and not yet fully understood. For instance, the primary cause of acute chest syndrome is still debated, although it is thought to be a combination of infection, fat embolism, hypoventilation, and occlusion of the pulmonary vasculature.5 VOE can be triggered by multiple circumstances such as dehydration, infection and/or fever, cold, stress, acidosis, hypoxia, and pain itself.4 In addition, environmental factors, such as geographic altitude, weather, and air pollution, are likely to play an important role in triggering VOE.2,6 Changes in these factors may promote red blood cell (RBC) sickling and initiate an inflammatory response with a cascade of cellular interactions among endothelial cells, leukocytes, and platelets and lead to vaso-occlusion in SCD patients. In this chapter, we will review the pathophysiology of VOE and discuss the implications for the development of suitable biomarkers of disease activity and therapeutic targets to prevent, treat, or cure the disease.

TABLE 3-1Organ manifestations of vaso-occlusive events

Fundamental Science Background

Endothelial Cells in Hemostasis

Endothelial cells form the lining of blood and lymphatic vessels and create a single-layered interface between circulating blood cells and the vessel wall. In addition to acting as conduit for blood transportation, endothelial cells regulate vessel permeability for fluid filtration and immune cell recruitment at the site of inflammation, while maintaining the vessel tone.7,8 At steady state, endothelial cells repel platelet binding by the presence of negatively charged heparin sulphate proteoglycans on their surface9,10 and can restrict platelet activation by secreting prostaglandin I2 (PGI2; also known as prostacyclin)....

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