Sickle Cell disease New Insights into Pathophysiology and Treatment
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New Insights into Pathophysiology and Treatment Pediatric Annals, Volume 37, Issue 5, May 2008: 311-21 Sickle Cell Disease Adlette Inati, MD Ali Taher, MD Suzan Koussa, MD Susan Perrine, MD Ivana Dabaj, MD
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Introduction Sickle cell disease, the most common monogenetic disorder worldwide affecting an estimated 30 million people, represents a major public health concern because of its associated significant morbidity and mortality Sickle cell disease denotes all genotypes including at least one sickle gene in which hemoglobin S (HbS) makes up at least half of the hemoglobin present
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Sickle cell trait, or the carrier state Is the heterozygous form characterized by the presence of about 40% HbS, absence of anemia, inability to produce concentrated urine, and hematuria Under conditions leading to hypoxia, may become a pathologic risk factor
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Major sickle genotypes described so far HbSC disease: double heterozygote for HbS and HbC, characterized by moderate clinical severity HbS/hereditary persistence of fetal Hb (S/HPHP): very mild or asymptomatic phenotype HbS/HbE syndrome: very rare with a phenotype usually similar to HbS/beta- thalassemia Rare combinations of HbS with other abnormal hemoglobins such as HbD Los Angeles, G-Philadelphia, HbO Arab, and others 1. HbSS disease or sickle cell anemia (the most common form): homozygous for S hemoglobin usually with a severe or moderately severe phenotype and the shortest survival 2. HbS/beta-thalassemia: double heterozygote for HbS and beta-thalassemia and clinically indistinguishable from sickle cell anemia 3. HbS/beta-thalassemia: mild to moderate severity with variability in different ethnicities
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Diagnosis The diagnosis of sickle cell disease is usually straightforward and based on gel electrophoresis showing more than 50% HbS and on blood smear demonstrating sickle forms With modern DNA diagnostics, prenatal diagnosis is now possible in the first few weeks of pregnancy through chorionic villous sampling
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Pathophysiology A single nucleotide substitution (GTG for GAG) in the sixth codon of the beta-globin gene results in a single amino acid substitution of valine for glutamic acid leading to HbS formation Upon deoxygenation, HbS, which is less soluble than normal HbA, undergoes polymerization, leading to the characteristic sickle red cell The polymerization of deoxygenated HbS is the primary indispensable event in the molecular pathogenesis of sickle cell disease but is an insufficient determinant of phenotype. HbS polymerization is dependent on intracellular HbS and HbF concentrations, the extent of cell deoxygenation, and pH.
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Pathophysiology (c’td) HbS polymerization is associated with a reduction of red cell ion and water content (cell dehydration), transient increase in free intracellular calcium, and increased red cell density (dense erythrocytes). HbS is also associated with red cell membrane damage favoring the generation of distorted rigid sickle cells, thus contributing to vaso-occlusion and premature red cell destruction (hemolytic anemia).
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Pathophysiology of SCD
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I. Vaso-occlusion Involves a complex interaction of sickle and nonsickle erythrocytes, reticulocytes, leukocytes, platelets, plasma factors, and endothelial cells driven by inflammatory mediators through the upregulation of adhesion molecules Hb polymers disrupt the red cell membrane leading to extracellular exposure of protein epitopes and glycolipids. Exposure of negatively charged glycolipids increases anemia due to enhanced phagocytic recognition and removal, increased adhesion to endothelium and extracellular matrix components, and the development of a proinflammatory and prothrombotic state of sickle cell blood.
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I. Vaso-occlusion (c’td) Sickle cells stimulate vascular endothelium through induction of inflammatory and coagulation mediators and directly through adhesion. The stimulated endothelial cells recruit rolling and adherent leukocytes in venules. Leukocyte adhesion offers an attractive therapeutic target for sickle cell disease and is consistent with studies in which high leukocyte counts correlated with mortality, acute chest syndrome, stroke, and poor prognosis.
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Leukocyte adhesion in small post capillary venules as a contributing factor to vaso-occlusion
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II.Hemolysis, an underrecognized entity in SCD In SCD, red cell survival of is 10 to 20 days. It is estimated that around 30 g of Hb are released daily by the hemolyzed red cell mass. 1/3 of hemolysis occur intravascularly, releasing into plasma free hemoglobin (PFH), and arginase. PFH is maintained in the ferrous oxyHb state, which reacts with nitric oxide (NO) to form nitrate, leading to severe reduction in NO bioavailability. PFH has been associated with endothelial injury, hallmark of which is the development of pulmonary arterial hypertension in adulthood. Loss of NO signaling results in hemostasis, including vasoconstriction, endothelial adhesiveness and thrombosis.
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CLINICAL PRESENTATION Some individuals have very severe disease with frequent vaso-occlusive complications and early morbidity and death at a very young age, whereas others can go unnoticed until adulthood. Two major subphenotypes described: Vaso-occlusive subphenotype Hemolytic subphenotype The most common causes of disease-related morbidity are pain and acute chest syndrome episodes
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1.Vaso-occlusive Subphenotype Manifested clinically by: self-limited pain episodes acute chest syndrome joint necrosis stroke acute splenic sequestration hepatic sequestration organ failure functional asplenia
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2.Hemolytic Subphenotype Manifested clinically by Chronic anemia Gallstones Pulmonary arterial hypertension Priapism Leg ulceration Sudden death Possibly stroke
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Clinical PresentationPain Clinical hallmark of SCD and leading cause of emergency department visits and hospitalizations Sometimes triggered by infection, temperature extremes, or physical or emotional stress, but often spontaneous. Three major types of sickle cell pain: acute, chronic, and neuropathic Chronic sickle cell pain may be due to disease complications like avascular necrosis and leg ulcers Intractable chronic pain may be due to central sensitization
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Clinical Presentation Acute Chest Syndrome Defined as a new infiltrate on chest xray associated with fever and/or respiratory symptoms. Affects about 40% of all people with SCD and has become the most common reason for early mortality.
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Clinical Presentation Acute Chest Syndrome Often develops after acute infections, painful episodes, rib or bone marrow or pulmonary infarction, and surgery. Causes : pulmonary embolism and infection. Secretory phospholipase A2 (sPLA2), an enzyme that cleaves fatty acids from triglycerides, is an accurate marker for identifying present or incipient acute chest syndrome in young patients with sickle cell pain crises. Serum concentration of sPLA2 increases before acute chest syndrome becomes clinically apparent, peaks at its clinical onset, and declines during its resolution.
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Clinical Presentation Infection Recurrent vaso-occlusion-induces splenic infarctions and consequent autosplenectomy ? predisposition to severe infections with encapsulated organisms ( pneumococcus, Haemophilus influenza type B,Neisseria meningitidis, GBS, Salmonella Typhi). Defective activation of the alternate pathway of the complement system ? increase in the risk of encapsulated bacterial infection and failure to eliminate antigens, predisposing affected patients to autoimmune diseases. HLAE*0101/E*0101 genotype was recently shown to be more frequent among sickle cell anemia patients with infections than those without infections. Pneumococcal sepsis continues to be a major cause of death Parvovirus B19 infection causes aplastic crises.
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Clinical Presentation Stroke One of the most devastating complications of SCD Leading cause of morbidity and mortality among affected children. Affects 30% of children and 11% of patients by 20 years. Ischemic in children and hemorrhagic in adults. Transcranial doppler can detect children at risk of developing stroke months to years before the stroke and/or before changes are found on magnetic resonance angiography (MRA).
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Clinical Presentation Silent Cerebral Infarcts (SCI) Defined as an abnormal magnetic resonance image (MRI) of the brain with evidence of ischemia but no clinical signs and symptoms Seen in about 20% of SS children Can be associated with poor performance on neuropsychological tests and high risk of developing stroke Single nucleotide polymorphisms in 12 genes that interact with Hb F to modulate the risk of stroke recently described
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Clinical Presentation Pulmonary Arterial Hypertension (PAH) An emergent complication seen in 32% of adult SCD patients and associated with high mortality. A complication of chronic intravascular hemolysis which leads to NO scavenging and arginine degradation, thereby limiting NO bioavailability ? endothelial and vasomotor dysfunction, coagulopathy, and pro-oxidant and proinflammatory stress ? proliferative pulmonary vasculature changes Contributing factors: Chronic lung disease Older age Renal insufficiency Cardiovascular disease Cholestatic hepatopathy Systolic hypertension High hemolytic markers Iron overload History of priapism
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Clinical Presentation Pulmonary Arterial Hypertension Up to 75% of sickle cell disease patients have histologic evidence of PAH on autopsy. SCD patients with PAH have both pulmonary arterial hypertension and venous hypertension Associated with severe reduction in exercise capacity and herald a poor prognosis. The 6-minute walk test is a noninvasive measure of severity of PAH
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Clinical Presentation Pulmonary Arterial Hypertension 5. Both PAH and cardiac sequalae such as diastolic dysfunction are associated with mortality in the SCD population 6. Survival among patients with a tricuspid regurgitant jet velocity of < 2.5 m/sec (indicating normal pulmonary artery pressure) is significantly higher than among those with a tricuspid regurgitant jet velocity of >2.5 m/sec 7. Some patients with SCD develop parenchymal lung disease and are at increased risk for pulmonary thromboembolic disease and potentially chronic thromboembolic PAH
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Clinical PresentationAcute Splenic Sequestration Defined as sudden enlargement of the spleen with a decrease in Hb concentrations (2.0 g/L at least) and substantial reticulocytosis. A life threatening complication seen in the first few years of life and resulting in death from anemia and hypovolemic shock
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Clinical Presentation Aplastic Crises Severe anemia due to temporary cessation of erythropoiesis Parvovirus B19 infection is responsible for most cases
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Clinical Presentation Priapism Painful failure of detumescence presenting as either scattered episodes or a stuttering pattern (an undesirable prolonged painful erection). Leads to impotence and difficult to manage. Associated Lab findings: Lower levels of Hb Higher reticulocyte, leucocyte and platelet counts LDH, bilirubin, and aspartate aminotransferase levels than control subjects Likely to be associated with increased hemolysis which decreases circulating NO availability and leads to erectile dysfunction Linked to polymorphisms of the Klotho gene
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Clinical Presentation Chronic Organ Damage
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Clinical Presentation Chronic Organ Damage
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SURVIVAL The Cooperative Study of Sickle Cell Disease estimated that the median survival for individuals with SS was 48 years for women and 42 years for men with sickle-cell disease-related childhood mortality contributing significantly to this shortened survival In the Dallas newborn cohort, estimated survival at 18 years was 94%. In a recent neonatal U.K. cohort followed in a hospital and community-based program, survival of HbSS children at 16 years was 99.0% Increase in life expectancy and survival attributed to: Neonatal screening Penicillin prophylaxis Pneumococcal immunization Red cell transfusion/chelation for selected patients Hydroxyurea therapy Stem Cell Transplant
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PREDICTORS OF DISEASE SEVERITY
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Disease Ameliorating Factors coinheritance of alpha-thalassemia beta thalassemia and beta-C gene interaction specific beta-globin haplotypes genetic determinants outside the beta-globin gene cluster cMYB gene on chromosome 6p23 responsible for the variability in HbF levels
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TREATMENT Aimed at Preventing and treating complications: Prevention and reversal of polymerization Augmenting the level of fetal hemoglobin For seriously affected children, three therapeutic options currently validated: Hydroxyurea transfusion/chelation therapy hematopoetic stem cell transplant New therapeutic targets based on the new pathophysiologic model of sickle cell disease defined during the past two decades
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Hydroxyurea HbF inducer and inhibitor of ribonucleotide reductase, is considered the most successful drug therapy for severe SCD. Involved in the regulation of arginase activity and increased production of NO, in vivo. Increases Hb, MCV, and HbF levels and decreases reticulocyte, leucocyte, and platelet counts as well as bilirubin levels. Decreases: endothelial adhesion VCAM-1 expression number of adherent leukocytes
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Hydroxyurea Clinically, reduces : the frequency of painful episodes and acute chest syndrome transfusion requirements and hospitalizations improves well-being and survival and may attenuate mortality. May preserve splenic and brain function in children with sickle cell anemia. Significantly decreases elevated TCD flow velocities, often into the normal range? stroke prevention. Interferes with rapidly multiplying cells, particularly young blood cells leading to cytopenias and can cause decreased sperm production, dryness of skin and hyperpigmentation
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Transfusion Blood transfusion therapy, aimed at increasing total Hb while keeping HbS at less than 30%, is now considered standard care for primary and secondary stroke prevention in children with sickle cell disease The Stroke Prevention Trial in Sickle Cell Anemia (STOP) showed that regular blood transfusions produced a marked (90%) reduction in first stroke in asymptomatic high-risk children who had 2 abnormal TCD studies with velocities of 200 cm/s or greater During the transfusion period, most of the TCD studies reverted to or toward normal, but once transfusion was stopped, there was an unacceptably high rate of TCD reversion to high risk, as well as to actual strokes
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Transfusion Required for sudden severe anemia and on an urgent basis Helpful in acute chest syndrome, perioperatively and during pregnancy Acute red cell exchange transfusion indicated in acute infarctive strokes, severe acute chest syndrome, multi-organ failure syndromes, right upper quadrant syndrome, and possibly priapism Transfusion not needed for the usual anemia or episodes of pain associated with sickle cell disease Transfusion (simple or exchange) unlikely to speed up resolution of acute pain
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Chelation A long term effect of transfusion is “Iron overload” Iron overload is managed with the parenteral desferrioxamine, which is efficacious but associated with a high noncompliance rate. The introduction of an oral iron chelator is likely to improve compliance
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Stem-cell Transplantation The only curative treatment for sickle cell disease. Associated with Risk of transplant-related mortality and morbidity Very high survival rate, with few transplant-related complications and with elimination of sickle related complications Donor availability possible for only 20% to 30% of patients.
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New and Developing Therapeutic Agents: Induction of HbF
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New and Developing Therapeutic Agents Other potential therapeutic targets are currently undergoing clinical investigations for their potential role in preventing RBC dehydration and sickling Nitric oxide inhalation effective in acute chest syndrome and in diminishing opioid use in pain episodes Oral L-arginine improves endothelial function, inhibits Gardos channel, and seems to modify SCD related PH
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Treatment of Specific ComplicationsPain Failure to treat acute pain aggressively and promptly may lead to chronic pain syndrome Pain management should include four stages: Assessment Treatment Reassessment Adjustment Pain treatment is primarily pharmacologic in nature
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Treatment of Specific ComplicationsPain Fentanyl patches Acetaminophen with codeine or an NSAID ? for mild to moderate pain Severe pain should be given a parenteral opiate at fixed intervals until pain diminishes, at which time the opiate is tapered, then stopped, and oral analgesic therapy is instituted. If more frequent doses are needed, patient-controlled analgesia can be used. For all types of pain, incentive spirometry is recommended Long-term hydroxyurea ? for frequent and severe pain. Chronic transfusion for a limited period ? for hydroxyurea non-responders
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Treatment of Specific ComplicationsAcute chest syndrome Consists of: Oxygen Antibiotics Incentive spirometry Bronchodilators Simple transfusion Exchange transfusion may be indicated for severe cases. Over hydration must be avoided Hematopoietic stem cell transplantation is an option for severely affected young patients Early and effective anti asthma therapy might reduce acute chest syndrome-associated morbidity
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Exchange transfusion Oxygen selective pulmonary vasodilator therapy Oral arginine and l-carnitine alone or in combination with other agents are additional treatments. Phosphodiesterase inhibitor sildenafil has a potential role Treatment of Specific Complications Pulmonary arterial hypertension
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Treatment of Specific Complications Acute splenic sequestration ? immediate transfusion has reduced the number of deaths attributed to this life-threatening medical emergency. For children older than 2 to 3 years and for older patients with chronic hypersplenism, splenectomy is recommended. Priapism? early exchange transfusion ? Epidural neuraxial blockade offers superior analgesia to the often painful conservative treatments ?Surgical intervention is the last therapeutic option
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Conclusion Natural history studies on sickle cell disease cohorts have yielded important information on clinical manifestations, predictors of disease severity, and treatment modalities Current research has led to improved understanding of pathogenesis and prevention of complications and has opened the way to novel innovative treatments Therapeutic advances will have a very limited impact on the natural history of the disease unless they are widely accepted by patients and parents and are applied in developing countries with high disease prevalence
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Conclusion Early detection is crucial for control of a disease that is associated with significant morbidity and mortality The major challenge facing the scientific community is to develop safe, easily administered, and effective treatments and, most importantly, render these treatments available to all affected patients worldwide
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