May 24, · INTRODUCTION TO SICKLE CELL DISEASE, INFLAMMATION, AND PAIN PATHWAYS. Defining Sickle Cell Disease. Sickle cell disease (SCD) is the consequence of homozygosity for a single amino acid change in the beta-globin chain that results in structurally abnormal hemoglobin S, or by compound heterozygosity for hemoglobin S and another β-globin chain Jun 02, · Converting a pathogenic hemoglobin gene to a benign variant enables healthy blood cell production in an animal model of sickle cell disease. Sickle cell disease (SCD) is the most common deadly genetic disorder, affecting more than , newborns worldwide each year Annual Sickle Cell Disease Clinical Research Meetings. Each year, we bring together researchers and health professionals to discuss clinical trials, research, and clinical care for sickle cell disease. Explore resources from the annual meeting. Global Leadership in Sickle Cell Disease Research and Care
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Sickle cell disease SCD is the consequence of homozygosity for a single amino acid change in the beta-globin chain that results in structurally abnormal hemoglobin S, or sickle cell research paper compound heterozygosity for hemoglobin S and another β-globin chain abnormality, typically hemoglobin C or beta-0 thalassemia, sickle cell research paper.
Hemoglobin SS HbSS and HbS beta-0 thalassemia present in a similar clinical manner and are commonly referred to together as sickle cell anemia SCAwhich is the most severe subtype of SCD. The sickling process causes secondary changes in cell shape, size, cation and water content, and membrane structure that contribute to the impairment of intrinsic cell deformability.
Whole sickle cell research paper viscosity is dependent on the number and volume of erythrocytes in the blood, and is thus linearly related to hematocrit. Sickle cell patients with high blood viscosity usually have more frequent vaso-occlusive crises and impaired oxygen delivery than those with low blood viscosity. Abnormal sickle-shaped red blood cells disrupt blood flow in capillaries, with the vaso-occlusion leading to distal tissue ischemia and ischemia-reperfusion injury,defined as tissue damage that occurs as the sickle cell research paper of the interruption of the blood supply causing hypoxia, followed by resolution and consequent reperfusion of the tissue.
These DAMPs can promote multiple inflammatory pathways, including neutrophil extracellular trap NET formation and inflammasome assembly. When blood flow is restored following disruption of vaso-occlusion, the tissue is then reperfused and the damaged tissues are reoxygenated, paradoxically causing further damage, due to the production of reactive oxygen species ROS and calcium overload.
An effect of ischemia-reperfusion injury may be the activation of invariant natural killer T iNKT cells, which can induce pulmonary inflammation by triggering IFN-γ and INF-γ-inducible chemokines.
Pain, hemolysis, acute chest syndrome, bone or joint necrosis, sepsis, stroke, acute cholecystitis, pulmonary hypertension, pulmonary embolus, bone marrow fat embolism, priapism, as well as renal failure, with increased morbidity and mortality can occur with sickle cell inflammatory processes and crises. Image: iStock. Cell-free heme also induces microvascular endothelial barrier dysfunction in the lung by inducing necrotic death.
Once activated, sickle cell research paper, the endothelium produces and releases a number of potent inflammatory molecules, including IL-1β, IL-8, IL-6, IL-1α, GM-CSF, plasminogen activator inhibitor PAI -1, MCP-1, and RANTES Regulated on Activation, Normal T Cell Expressed and Secretedwhich contribute to the inflammatory milieu in SCD.
Activated endothelium also expresses adhesion molecules such as VCAM-1, ICAM-1, E-selectin, and P-selectin, which are important for red cell, leukocyte, and platelet tethering and adhesion.
Endothelin-B receptor-mediated signaling in leukocyte adhesion to the endothelium has also been shown in SCD. Surrogate markers of endothelial dysfunction and inflammation, including pro-inflammatory cytokines eg, interleukin [IL]1β, IL6, IL8, tumor necrosis factor [TNF]-α.
and interferon [INF]-γ and markers of endothelial activation eg, endothelin [ET]-1, adhesion molecules, and selectinsare elevated at baseline and during complications.
In addition to the inflammatory molecules known to be elevated during steady-state in SCD, some of these are further elevated during acute vaso-occlusive episodes VOEsincluding the cytokines CD40L, IL-6, and IL, and chemokine IL-8 CXCL8. The acute phase proteins, substance P, C-reactive protein, sickle cell research paper pentraxin-3, and the lipid chemoattractant, leukotriene B4 LTB4are also further increased during VOE.
In the initiation of the acute painful vaso-occlusive episodes that sickle cell research paper characteristic of SCD, sickle cell research paper, inflammatory processes act as key components. Complications of the disease including autosplenectomy, acute chest syndrome, pulmonary hypertension, leg ulcers, nephropathy, and stroke.
Median IL-6 level in sputum is dramatically elevated during acute chest syndrome ACS compared with non-ACS patients. Thus massive production of IL-6 in the lungs by activated endothelial cells or other inflammatory cells is involved in ACS pathophysiology, by inducing local inflammation independently of systemic inflammation.
Acute chest syndrome may show elevated IL6 levels and may be sickle cell research paper with Sickle cell research paper receptor antibodies such as tocilizumab. Dramatic improvement has been reported after tocilizumab administration in a child and an adult patient with SCD and ACS related to SARS-CoV The Sickle Cell Crisis may include: excruciating pain, hemolysis, acute chest syndrome, bone or joint necrosis, sepsis, stroke, acute cholecystitis, pulmonary hypertension, pulmonary embolus, bone marrow fat embolism, priapism, as well as renal failure, with increased morbidity and mortality.
Further, hemolysis plays a central role in the pathophysiology, contributing significantly to anemia, jaundice, vasculopathy, sickle cell research paper, nitric oxide deficiency, and inflammation. Vasculopathy of SCD has been implicated in the development of pulmonary hypertension, stroke, leg ulceration, and priapism, particularly associated with hemolytic severity. In children, sickle cell research paper, splenic sequestration of the sickle-shaped red blood cells may result in splenic enlargement, sickle cell research paper, profound anemia, infection due to lack of splenic function, and death before age 7 years.
Among those with sickle cell-hemoglobin C disease, the median age at death was 60 years for sickle cell research paper and 68 years for females. In patients with SCA, acute chest syndrome, renal failure, seizures, a baseline white cell count above 15, cells per cubic millimeter, and a low level of fetal hemoglobin were associated with an increased risk of early death. In sickle cell crisis, vaso-occlusion leads to distal tissue ischemia as well as ischemia-reperfusion injury.
A variety of inflammatory mediators are generated by tissue and organ injury. These include substances produced by damaged tissue, substances of vascular origin as well as substances released by nerve fibers themselves, sickle cell research paper, sympathetic fibers, and various immune cells.
The inflammatory mediators activate local pain receptors and nerve terminals and produce hypersensitivity in the area of injury. Activity of the mediators results in the excitation of pain receptors in the skin, ligaments, muscle, nerves, and joints.
Excitation of these pain receptors stimulates the specialized nerves eg, C fibers and A-delta fibers that carry pain impulses to the spinal cord and brain. Subsequent to tissue injury, the expression of sodium channels in nerve fibers is altered significantly, thus leading to abnormal excitability in the sensory neurons.
Nerve impulses arriving in the spinal cord stimulate the release of inflammatory protein Substance P. The presence of Substance P and other inflammatory proteins such as calcitonin gene-related peptide CGRPneurokinin A, and vasoactive intestinal peptide removes magnesium-induced inhibition and enables excitatory inflammatory proteins such as glutamate and aspartate to activate specialized spinal cord NMDA receptors.
This results in magnification of all nerve traffic and pain stimuli that arrive in the spinal cord from the periphery. Constant C-fiber nerve stimulation to transmission pathways in the spinal cord results in even more release of inflammatory mediators, but this time within the spinal cord. Inflammation causes increased production of the enzyme cyclooxygenase-2 Cox-2 and 5-lipoxygenase 5-LOXleading to the release of chemical mediators both in the area of injury and in the spinal cord.
Widespread induction of Cox-2 expression in spinal cord neurons and in other regions of the central nervous sickle cell research paper elevates inflammatory mediator prostaglandin E2 PGE2 levels in the cerebrospinal fluid. The major inducer of central Cox-2 upregulation is inflammatory mediator interleukin-1 in the CNS.
Abnormal development of sensory-sympathetic connections follows nerve sickle cell research paper and contributes to the hyperalgesia abnormally severe pain and allodynia pain due to normally innocuous stimuli. These abnormal connections between sympathetic and sensory neurons arise in part due to sprouting of sympathetic axons. The CNS response to pain can keep increasing even though the painful stimulus from the injured tissue remains steady.
Local tissue inflammation can also result in pain hypersensitivity in neighboring uninjured tissue secondary hyperalgesia by spread and diffusion of the excess inflammatory mediators that have been produced as well as by an increase in nerve excitability in the spinal cord central sensitization. This can result in a chronic pain syndrome comprising diffuse muscle pain and spasm, joint pain, fever, lethargy, and anorexia.
Thus, persistent afferent neuronal barrage due to failure to timely and adequately treat multiple acute pain crises can result in chronic pain in patients with SCD. In the US, SCDoccurs among about 1 out of every black or African American births, and about 1 out of every 16, Hispanic American births. About 1 in 13 black or African American babies is born with sickle cell trait SCT.
Population estimates range fromtobased on birth-cohort disease prevalence, sickle cell research paper, but from 72, to 98, when corrected for early mortality.
Several global agencies, including the UN and World Health Organization, have recognized SCD as a public health issue. Looking at the total cost of care for a population of both children and adults with SCD, nationwide hospitalization costs are substantial, at about a half billion dollars per year. It is likely that these calculations are a marked underestimate.
Extensive emergency room and non-hospitalization-based treatment, as well as other social costs, must also be considered, making the actual financial burden to society much greater.
Similarly, in the United States, the medical costs do not begin to capture the economic burden. Many adults with sickle cell disease are disabled to some degree, and many have varying organ damage, making it difficult for them to work. Family members often wind up as caregivers, sickle cell research paper, with a rippling outward of the economic burden.
Pathophysiological triggers that may contribute to VOC include hypoxia, daytime exertion, waking up earlier with a shortened duration of sleep, stress, fatigue, exercise, exposure to cold, ingestion of alcohol, airline travel, altitude that exceeds 2, feet, infection, sickle cell research paper, malaria, or pregnancy. In patients with SCD, VOC tends to occur most often at night, due to the relative hypoxia as a result of varying degrees of sleep apnea, or due sickle cell research paper a trigger the patient may have been exposed to during the day.
During sleep, minimum oxygen saturation is significantly lower. Castele, et al, 27 performed 5 full-night and 7 daytime studies to examine this further. According to the findings:. In all patients a fall in oxygen saturation was associated with a decrease in respiratory depth without a change in respiratory frequency. This nocturnal hypoxemia is a prelude to VOC. Exposure to cold results in vasoconstriction and delayed transit time, which can trigger a crisis, sickle cell research paper.
Subsequent to commercial airline flights, sickle cell research paper, patients with SCD are known to experience complications such as bone pain, splenic infarction, 30,31 osteonecrosis avascular necrosis of the hip, and, in some cases, prolonged crisis resulting in death anecdotal report. In a sickle cell pain crisis, pain is initially localized and frequently affects a single joint or the spine.
This is the golden moment to interrupt the pain and abort the crisis at home. As pain increases in severity, chest splinting leads to regional hypoventilation, hypoxemia, and increased sickling of the red blood cells. There is a release of adhesion molecules, causing interaction of this rigid, polymerized sickled RBC to the endothelium.
The increased adhesion of erythrocytes followed by the formation of heterocellular aggregates physically causes small vessel occlusion and resultant local hypoxia.
This process triggers a vicious cycle of increased HbS formation and the release of inflammatory mediators and free radicals that contribute to reperfusion injury, increased pain, increased hypoventilation, and increased sickling. Ischemic injury progresses with every passing minute, generating more inflammatory mediators. The pain crisis begins to spread over multiple bones and joints as well as the spine, becoming a full-blown crisis, well before the patient arrives at the emergency room.
Intravascular in situ sickling in the pulmonary capillaries results in lung infarction and acute chest syndrome. A study by Needleman found that patients with VOC and chest pain have more shallow, rapid breathing than patients with pain elsewhere. Adequate opiate analgesia reduces these differences. The authors stated that pain-associated shallow breathing and maldistribution of ventilation may contribute to the pathogenesis of acute chest syndrome, and these results support the need for adequate pain relief and monitoring of ventilatory patterns during the treatment of VOC.
The major acute pulmonary complication of SCD is ACS, and it sickle cell research paper a major cause of morbidity and mortality. The National Acute Chest Syndrome Study Group reported on episodes of ACS that were treated sickle cell research paper 30 centers.
Half of the patients were admitted to the hospital for a reason other than ACS, mostly VOC. Clinical findings of patients with ACS developed in a mean of 2.
Fat emboli, with or without infection, were present in 8. Bilobar involvement was typical. Pain was determined to be a prodrome of the ACS, indicating the need to monitor for and try to prevent its development in those admitted to the hospital for VOC.
Termination of a sickle cell pain crisis may be achieved with immediate administration of oxygen, intramuscular injection of anti-inflammatory medications such as ketorolac or diclofenac in the absence of any contraindicationsand treatment of pain using a unit dose of a parenteral opioid such as hydromorphone, morphine, pethidine meperidineor fentanyl by intramuscular IM or subcutaneous SQ injection.
Of note, meperidine is generally not recommended as an analgesic in any condition by US or NICE guidelines due to increased accumulation of active metabolite normeperidine, high levels of which can induce CNS excitation including tremor, myoclonus, and seizures. However, there may be situations where no other opioid is available or where patients cannot tolerate any other opioid.
In one study, intravenous patient-controlled analgesia IV PCA meperidine hydrochloride was used for post-operative pain relief.
The sole use of partial opioid agonists such as pentazocine not available in the US, but still used in Africanalbuphine, or buprenorphine is strongly discouraged as these classes of drugs have a ceiling effect and are not indicated in severe pain.
However, partial agonists sickle cell research paper be combined with full agonists such as hydromorphone or morphine to provide better analgesia with reduced side effects.
Oral opioid medications are ineffective in aborting a pain crisis and will result in exacerbation and prolongation of the crisis with subsequent multi-organ damage. The American Society of Hematology guidelines panel for management of acute and chronic pain in sickle cell disease, noted two theoretical concerns of rapid treatment and tailored dosing of opioids: rapid pain treatment and higher doses could increase euphoria and the risk of opioid tolerance, and higher opioid dosing could increase perceptions of opioid misuse.
However, the panel determined that both theoretical concerns had no supporting evidence sickle cell research paper that sickle cell research paper concerns should not affect the decision to improve SCD analgesia in the ED. The panel noted that rapid treatment of all medical conditions is a general goal of acute care, which is so self-evident that additional evidence may not be needed to support rapid treatment of SCD pain, and that conducting an RCT to further support this recommendation would be unethical.
The History of the Sickle-Shaped Cell - Sickle Cell Disease: A Lethal Advantage (1/5)
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Abstract Background Sickle cell disease is characterized by hemolytic anemia, pain, and progressive organ damage. A high level of erythrocyte fetal hemoglobin (HbF) comprising α- and γ-globins Jun 02, · Converting a pathogenic hemoglobin gene to a benign variant enables healthy blood cell production in an animal model of sickle cell disease. Sickle cell disease (SCD) is the most common deadly genetic disorder, affecting more than , newborns worldwide each year Annual Sickle Cell Disease Clinical Research Meetings. Each year, we bring together researchers and health professionals to discuss clinical trials, research, and clinical care for sickle cell disease. Explore resources from the annual meeting. Global Leadership in Sickle Cell Disease Research and Care
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