Sickle Cell Disease
Vaso-Occlusive Crisis: Key Cellular Interactions
The understanding of the cellular processes involved in vaso-occlusive crises (VOCs) in sickle cell disease (SCD) has expanded greatly. Data from ongoing clinical trials and patient registries promise to further elucidate key interactions and therapeutic strategies.
Associate Professor, Division of Hematology and Oncology
“I think that recent successes do validate the thinking regarding the role of P-selectin and neutrophils, and it is likely that the cellular interactions involved will continue to be elucidated through investigations that are ongoing and/or planned."
We have known for some time that inflammation plays a role in SCD, and one of the things that we have come to understand is just how central the neutrophil is to the vaso-occlusive process. Individuals with SCD who have very extensive inflammation and high neutrophil counts have worse disease in terms of their frequency of VOCs. Consequently, understanding the role of the neutrophils and blocking their activity without causing an increase in infection remain important objectives.
The success of crizanlizumab in SCD is exciting from the perspective of efficacy, as well as conceptually and scientifically. I think that it does validate the thinking regarding the role of P-selectin and neutrophils, and it is likely that the cellular interactions involved will continue to be elucidated through investigations that are ongoing and/or planned. We know that thrombotic mechanisms may be important, and it might be interesting to see whether blocking 2 pathways by adding something like a direct oral anticoagulant or platelet inhibitor can help even more. There are ongoing studies of crizanlizumab, some of which include patients who are also receiving hydroxyurea, an agent with a different mechanism of action. Long-term studies will likely further our understanding of the inflammatory pathways involved and of the value of combination therapy.
Clinicians who treat SCD—including myself—have formed a community called the National Alliance of Sickle Cell Centers with the goal of improving the quality of care for this population. This organization is working to harness a longitudinal clinical registry, the Globin Research Network for Data and Discovery (GRNDaD), to ensure that the clinical centers work collaboratively to compile information and evaluate outcomes at participating treatment centers. This registry (in combination with evaluations of quality improvement) should greatly improve the understanding of SCD at the population and cellular levels. For example, data compiled in the registry will enable us to compare outcomes in patients with neutrophilia vs in patients with lower neutrophil counts. Such data should prove invaluable for answering some of the outstanding questions regarding the inflammatory processes at work in VOCs.
Ataga KI, Kutlar A, Kanter J, et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med. 2017;376(5):429-439. doi:10.1056/NEJMoa1611770
Barbu EA, Dominical VM, Mendelsohn L, Thein SL. Neutrophils remain detrimentally active in hydroxyurea-treated patients with sickle cell disease. PLoS One. 2019;14(12):e0226583. doi:10.1371/journal.pone.0226583
Barbu EA, Mendelsohn L, Samsel L, Thein SL. Pro-inflammatory cytokines associate with NETosis during sickle cell vaso-occlusive crises. Cytokine. 2020;127:154933. doi:10.1016/j.cyto.2019.154933
Darbari DS, Sheehan VA, Ballas SK. The vaso‐occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management. Eur J Haematol. 2020;105(3):237-246. doi:10.1111/ejh.13430
National Alliance of Sickle Cell Centers. Accessed June 23, 2021. http://www.sicklecellcenters.org