crizanlizumab for the prevention of painful crises in sickle cell disease

Last edited 10/2021 and last reviewed 10/2021

Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease

• Sickle cell disease
  • is characterized by the presence of sickle hemoglobin (HbS), chronic hemolysis, recurrent pain episodes, multiorgan dysfunction, and early death

Recurrent pain episodes (called sickle cell-related pain crises or vaso-occlusive crises)

• are the primary cause of health care encounters in patients with sickle cell disease
• are thought to be caused by vascular occlusion in the microcirculation, increased inflammation, and alterations in nociception
• polymerization of deoxygenated HbS distorts the shape of erythrocytes, and leads to the "sickle" appearance associated with
• vaso-occlusion
  • is caused by the adhesion of sickle erythrocytes and leukocytes to the endothelium, which results in vascular obstruction and tissue ischemia
  • degree of sickle erythrocyte adhesion correlates with vaso-occlusion and increased severity of disease
    • activated and adherent leukocytes are the likely drivers of vaso-occlusion in collecting venules, whereas sickle erythrocytes may contribute to the occlusion of smaller vessels
    • also, platelets can bind to erythrocytes, monocytes, and neutrophils to form aggregates, which contribute to abnormalities of blood flow in patients with sickle cell disease
  • cell adhesion molecule P-selectin plays a key role in the pathogenesis of a vaso-occlusive crisis in patients with sickle cell disease
    • initiation of a vaso-occlusion is a complex event involving a multitude of molecules
      • one of the molecules involved is P-selectin, a cell adherence molecule that is rapidly and chronically expressed on the surface of endothelial cells and platelets when activated
    • process is initiated by P-selectin
      • found in storage granules of resting endothelial cells and platelets and is rapidly transferred to the cell membrane on activation of the cell during processes such as inflammation
      • is expressed on the surface of the endothelium mediates abnormal rolling and static adhesion of sickle erythrocytes to the vessel surface in vitro
        • translocation of endothelial P-selectin to the cell surface results in the prompt adhesion of sickle erythrocytes to vessels and the development of vascular occlusion in transgenic mice with sickle cell disease
        • activated platelets bind to neutrophils to form aggregates in a P-selectin-dependent manner in mice and humans with sickle cell disease
          • leukocytes are initially captured on the endothelium via P-selectin and its ligand P-selectin glycoprotein ligand 1 (PSGL-1)
          • expression of PSGL-1 by leukocytes also causes activated platelets to adhere to the leukocyte, leading to aggregate formation

Crizanlizumab is a humanized monoclonal antibody that binds to P-selectin and blocks its interaction with P-selectin glycoprotein ligand 1 (PSGL-1)

• with sickle cell disease, crizanlizumab therapy resulted in a significantly lower rate of sickle cell-related pain crises than placebo and was associated with a low incidence of adverse events (1,2)

Reference:

• 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
• Kutlar A, Kanter J, Liles DK, Alvarez OA, Cançado RD, Friedrisch JR, Knight-Madden JM, Bruederle A, Shi M, Zhu Z, Ataga KI. Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: A SUSTAIN study analysis. Am J Hematol. 2019 Jan;94(1):55-61. doi: 10.1002/ajh.25308. Epub 2018 Nov 25. PMID: 30295335