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Crizanlizumab for the prevention of painful crises in sickle cell disease

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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)


  • 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

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