Vaso-occlusive crisis in sickle cell disease: a vicious cycle of secondary events

Abstract

Painful vaso-occlusive crisis (VOC) remains the most common reason for presenting to the Emergency Department and hospitalization in patients with sickle cell disease (SCD). Although two new agents have been approved by the Food and Drug Administration for treating SCD, they both target to reduce the frequency of VOC. Results from studies investigating various approaches to treat and shorten VOC have so far been generally disappointing. In this paper, we will summarize the complex pathophysiology and downstream events of VOC and discuss the likely reasons for the disappointing results using monotherapy. We will put forward the rationale for exploring some of the currently available agents to either protect erythrocytes un-involved in the hemoglobin polymerization process from sickling induced by the secondary events, or a multipronged combination approach that targets the complex downstream pathways of VOC.

Keywords: Downstream events; Secondary vaso-occlusive crisis; Sickle cell disease; Treatment strategies.

Conflict of interest statement

All authors declare no competing interests.

© 2021. The Author(s).

Figures

Fig. 1

Origins of ongoing inflammatory processes in SCD patients. Endogenous stimuli arise due to erythrocyte membrane damage induced by a combination of background HbS polymerization and auto-oxidation. Exogenous stimuli contributing to the ongoing inflammatory process are due to increased intestinal permeability and enhanced translocation of bacteria/bacterial products into the systemic circulation to stimulate leukocytes and aged neutrophils. The inflammatory processes are compensated by various host adaptive mechanisms that prevent the progress of the process to VOC. Events such as infection/inflammation, stress, dehydration, increased hemolysis, and hypoxemia tilt the equilibrium and result in a decompensation state that precipitates the development of VOC. Cytokine reactions associated with ischemia/reperfusion injury induced by VOC may further feed into increasing the intestinal permeability (represented by dashed lines) and form part of the vicious cycle of vaso-occlusion

Fig. 2

The complex downstream events induced by VOC. Among the many downstream events are the following five pathways, all of which result in a positive-feedback into the VOC process to induce secondary VOC: (1). Increased hemolysis produces more free heme and overwhelms heme scavenging mechanisms, precipitating the development of neutrophil extracellular traps that promotes a local prothrombotic condition. (2). Local hypoxemia caused by vaso-occlusion induces sickling of erythrocytes in the vicinity. (3). Cytokine release due to VOC activates leukocytes and platelets and increases their recruitment to the site of local tissue damage. (4). Increased enterocyte damage due to VOC further increases the gut permeability and worsens the translocation of luminal bacteria/bacterial products into the systemic circulation. (5). Stress induced by painful VOC leads to increased production of epinephrine and glucocorticoid response. The former enhances the expression of adhesion molecules on the erythrocytes and the latter worsens the translocation of luminal bacteria/bacterial products into the systemic circulation

Fig. 3

A proposed multipronged approach to treating VOC. Instead of just using intravenous fluid, oxygen, and pain management and wait for the VOC process to resolve spontaneously, a more proactive approach is proposed using a combination of the listed agents to target as many of the downstream processes as possible. Acute use of antisickling agents such as voxelotor may protect the un-involved erythrocytes from sickling induced by the many downstream events of VOC. On the other hand, approaches that target the downstream events will more likely be successful if used in combination to overcome as many of the downstream pathways as possible