Additional Material

What Is Sickle Cell Disease (SCD)?

An inherited disease which causes the red blood cells to assume a sickled shape

Sickled cells can obstruct flow in small blood vessels, creating a blockage, and impairing oxygen delivery causing pain episodes called vaso-occlusive crisis (VOC) pain

Types include:

βS/βS, (SCD-SS) found in approximately 65% of US patients with SCD

βS/βC, (SCD-SC) found in approximately 25% of US patients with SCD

βS/β+ -thalassemia (SCD-Sβ+-thal) found in approximately 8% of US patients with SCD

βS/β°-thalassemia, (SCD-Sβ°-thal), found in approximately 2% of US patients with SCD

SCD-SS is the most common genotype, and typically associated with the most complications


Sickle Cell Disease. Available at Accessed February 20, 2019

Sickle Cell Disease in the US

  • Sickle cell disease (SCD) is present in
    • 1:365 African Americans
    • 1:1,000-1,400 Hispanic Americans
  • The most common genetic disease in the US
  • All newborn babies are tested at birth for SCD or sickle cell trait, allowing early identification and referral
    • Newborns with a positive screen for SCD or trait are referred to a pediatric hematologist for confirmatory blood tests
    • Once confirmed, preventative care and education about disease management begins


Sickle Cell Disease. Available at Accessed February 20, 2019

Pain with Sickle Cell Disease

In addition to everyday pain, children with SCD may have pain from:

  • Postoperative pain due to increased frequency of surgical procedures
  • Acute Chest Syndrome (ACS) (chest pain, infiltrates, hypoxia) with respiratory infections or after surgery
  • Splenic sequestration: sickled cells get trapped in the spleen, causing tenderness to the touch and acute, severe decrease in hemoglobin

Tylee Talking About His Pain

Tylee talks about his pain from a 2018 interview.

What is the Pathophysiology of Sickle Cell Disease (SCD)?

  • Earlier pathophysiology of Vaso-Occlusive Crisis (VOC):
    • Focused on sickling of red blood cells due to low blood flow and low oxygen content in small blood vessels causing sickled cells to stick to vessel walls and obstruct blood flow
  • Recent pathophysiology of Vaso-Occlusive Crisis (VOC):
    • Emphasizes the role of inflammation and endothelial cells and mediators (e.g., P-selectin) as well as leucocytes in the process of vascular obstruction
  • These inflammatory mediators are thought to be involved in the development of increased and chronic pain through altered nociception and central sensitization


Manwani D Frenette PS: Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies. Blood 122 24:3892, 2013

Vaso-Occlusive Crisis (VOC)

  • VOC occurs when:
    • Sickled red blood cells adhere to one another and to the walls of the blood vessels
    • Blocks vessels, impairing oxygen delivery to tissues
    • Ischemia leads to release of inflammatory mediators which trigger nociceptive afferent nerve impulses to the dorsal horn (spinal cord) and somatosensory cortext (brain)
  • Precipitating factors that lead to pain episodes:
    • Change in temperature
    • Dehydration
    • Stress
    • Being tired
    • Second hand smoke exposure
  • Causes of VOC pain episodes are not always evident
  • VOC negatively affects the health-related quality of life of children:
    • Decreased physical and social functioning
    • Increased fatigue
    • Issues with school performance

The cycle of vaso-occlusion continually promotes future vaso-occlusion and VOCs.

  1. Inflammation and cell activation
  2. Multicellular adhesion
  3. Vaso-occlusion and VOCs
  4. Tissue and organ damage


Anie KA Green J., 2012; Brandow AM, et al., 2004; Dampier C, et al.,. 2004; Edwards LY Edwards CL., 2010; Ely B, et al., 2002; Stuart MJ Nagel RL., 2004; Wright J Ahmedzai SH., 2010

New Treatment Options

Opioid Alternatives for Vaso-Occlusive Crisis (VOC) Pain


  • NMDA receptor antagonist with strong analgesic properties
  • NMDA receptor effects may modulate central sensitization and hyperalgesia that are associated with recurrent VOC and therefore reduce opioid requirements
  • Low dose infusion associated with lower pain scores and reduced opioid usage
  • Trial of intranasal ketamine is underway
  • Oral ketamine may also be effective
  • Only given in the hospital (IV administered)

Hagedorn JM Monico EC., 2019; Manwani D Frenette PS., 2013; Young JR, et al., 2017; Jennings CA, Bobb BT, Noreika DM Coyne PJ., 2013


  • Dexmedetomidine: a specific α2-adrenoreceptor agonist with analgesic and mild sedative properties without respiratory depression
  • Dexmedetomidine infusion associated with reduced pain scores, decreased opioid requirement in patients with pain unresponsive to escalating opioid dosage and ketamine
  • Only given in the hospital (IV administered)

Sheehy KA., 2015

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