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Definition, Etiology, PathogenesisTop
Sickle hemoglobin (HbS) was the first hemoglobin (Hb) variant to be discovered. The beta-globin gene mutation that gives rise to HbS is a single nucleotide substitution in the sixth codon of the beta-globin gene that converts glutamic acid, which is relatively hydrophilic, to valine, which is hydrophobic. This single amino acid substitution results in an Hb molecule that polymerizes when deoxygenated, resulting in formation of sickle cells. Sickling of red blood cells (RBCs) causes shortened RBC life-span due to destruction (hemolysis) and blockage of blood flow (vaso-occlusion), resulting in diverse acute and chronic disease manifestations.
The inheritance of a single sickle cell gene (heterozygous HbS) is known as “sickle cell trait” and occurs in >20% of the population of equatorial Africa, 20% of the eastern provinces of Saudi Arabia and central India, and 5% of people living in various regions of the Mediterranean, Middle East, and North Africa. Owing to the autosomal recessive pattern of inheritance of the HbS gene, sickle cell trait is typically a silent carrier state.
The term sickle cell disease (SCD) encompasses all genotypes resulting in a combination of hemolysis and vaso-occlusive complications, which are hallmarks of the condition. Genotypes include homozygous HbS (HbSS) or compound heterozygous states, including HbS and another beta-globin gene mutation (eg, sickle cell-HbC [HbSC], sickle cell–beta0-thalassemia, sickle cell–beta+-thalassemia, and less commonly, sickle cell-OArab [HbSOArab] or sickle cell-DPunjab [HbSDPunjab]).
Clinical features of SCD are the result of 2 main pathophysiologic processes: hemolysis and vaso-occlusion.
The average RBC life-span in SCD is shortened from the typical 120 days to anywhere from 10 to 25 days, resulting in chronic hemolytic anemia, with Hb concentrations in patients with HbSS genotype typically ranging from 60 to 90 g/L.
Sickled RBCs also result in microvascular obstruction, leading to local tissue hypoxia, ischemia, and even infarction. Disease manifestations in SCD are highly varied and can be divided broadly into acute and chronic complications.
1. Acute complications:
1) Pain crisis (also referred to as vaso-occlusive crisis): The most common complication of SCD. It is caused by local obstruction of the bone marrow microcirculation by sickled RBCs and other reactive cells, leading to local tissue hypoxia and infarction. It may occur in the long bones, sternum, ribs, and spine. Pain crisis may be precipitated by physiologic stress, including hypoxia, fever, dehydration, cold temperatures, or pregnancy. Many episodes occur with no clear trigger.
2) Acute chest syndrome: Defined by (1) respiratory symptoms (cough, dyspnea, chest pain, tachypnea, hypoxia) and/or fever with (2) a new infiltrate on chest radiography. It is a leading cause of hospitalization in patients with SCD and a major risk factor for early mortality. Causes include infection (viral, bacterial, mixed), pulmonary vaso-occlusion, and fat embolism. Pulmonary embolism is an important alternative cause that should be considered as part of differential diagnosis.
3) Stroke and cerebrovascular diseases: SCD places individuals at risk of stroke (hemorrhagic and ischemic), transient ischemic attacks, cerebral vasculopathy, and moyamoya syndrome. Moyamoya (Japanese for “hazy puff of smoke”) refers to a unique pattern on cerebral angiography characterized by large-vessel occlusion affecting the circle of Willis and corresponding formation of collateral vessels. Moyamoya syndrome is a rare complication of SCD that results from progressive damage to the intimal layers of large cerebral vessels and significantly predisposes to ischemic stroke.
4) Priapism: A prolonged painful erection of the penis due to sickle cell vaso-occlusion. It occurs in 30% to 45% of male patients with SCD. Minor episodes can last from minutes to hours and are often self-limited, while major episodes can last up to several days and compromise tissue viability.
5) Hypercoagulability: SCD is recognized as a prothrombotic state due to endothelial dysfunction, chronic inflammation leading to white blood cell (WBC) activation, increased platelet activity, and oxidative damage from free Hb. Thrombosis in SCD ranges from microvascular and small-vessel arterial thrombosis to venous thromboembolism.
6) Aplastic crisis: A transient arrest of RBC production in patients with SCD can cause a sudden decrease in their reticulocyte count and Hb level. It is most commonly provoked by parvovirus B19 infection, which directly infects RBC precursors in the bone marrow.
7) Hepatic and splenic sequestration: Trapping of blood cells in the spleen, liver, or both. There is typically increase in size of the liver or spleen, depending on the organ involved, and accompanying severe decrease in Hb concentration and platelet counts; reticulocyte counts are often increased. This represents an acute and potentially life-threatening complication of SCD.
8) Infection: Worldwide, infection is the most common cause of mortality among patients with SCD. Patient predisposition towards infection in SCD is multifactorial. Patients develop functional asplenia early in life due to splenic infarction, typically by the age of 5 years, and thus become predisposed to infection by encapsulated microorganisms. Abnormal clearance of viral and bacterial pathogens is caused by dysfunctional complement activity in patients with SCD.
9) Acute cholecystitis and other biliary tract diseases: Chronic hemolysis and associated increased bilirubin turnover can result in the formation of pigment gallstones and biliary sludge, which can predispose to acute and chronic cholecystitis.
2. Chronic complications:
1) Leg ulcers: These can be chronic and disabling, tending to form over the medial and lateral malleoli of the ankles, and less commonly over the anterior tibial areas and dorsal aspects of the feet.
2) Avascular necrosis (AVN): Bone pain is common in SCD. If it is present chronically in the hips or shoulders, AVN should be considered. Magnetic resonance imaging (MRI) is the most sensitive diagnostic imaging modality.
3) Chronic pain: Most commonly arises from chronic tissue injury (eg, AVN of bone, skin ulcers). Additionally, following recurrent pain crises, SCD patients are at risk of developing central hypersensitivity to pain. Patients who have been treated with high doses of opioids or received prolonged opioid therapy can develop a combination of opioid dependence and opioid-induced hyperalgesia. A detailed assessment by a care team with expertise in SCD and chronic pain is essential to individualized optimization of chronic pain management.
4) Osteoporosis: Reduced bone mineral density is common in children and adults with SCD. Associated factors include low vitamin D levels, low body weight, low Hb concentration, male sex, elevated ferritin, and low zinc concentration.
5) Retinopathy: Proliferative retinal vascular disease is the most common ocular manifestation of SCD. Patients may be asymptomatic or describe floaters or visual field loss. Eye examinations should be performed as part of routine screening in patients with SCD.
6) Pulmonary complications: Patients with SCD are at increased risk of developing multiple pulmonary complications, such as pulmonary hypertension, asthma, restrictive lung defects, and sleep-disordered breathing. While the pathophysiology of specific SCD-associated lung diseases remains poorly understood, recurrent episodes of acute lung inflammation, as seen in acute chest syndrome, and chronic subclinical inflammation from sickle cell–related vasculopathy can predispose to airway inflammation and intraparenchymal scarring.
7) Renal complications: RBC sickling and vaso-occlusion primarily affect the kidneys at the level of the medulla and glomeruli. Over time, this results in renal tubular damage, hematuria, and inability to form concentrated urine (hyposthenuria). When sickle vasculopathy affects the glomeruli, this is known as sickle glomerulopathy, which manifests as proteinuria and sometimes even nephrotic syndrome.
1. Complete blood count (CBC): Varying degrees of anemia along with elevated reticulocyte counts. Review of the peripheral blood smear reveals sickled RBCs and Howell-Jolly bodies.
2. Hemolytic markers: Elevated indirect bilirubin and lactate dehydrogenase, reduced haptoglobin levels.
3. Hb separation techniques: Automated methods using high-performance liquid chromatography (HPLC) or capillary electrophoresis (CE) separate and quantify the various fractions of Hb that are present. Normal Hbs in adults are hemoglobin A (HbA) and hemoglobin A2 (HbA2), with a possible small quantity of hemoglobin F, also known as fetal hemoglobin (HbF). In most SCD genotypes HbA is absent and HbS is present, with or without other variant Hbs that comprise compound heterozygous SCD (eg, HbC in HbSC genotype).
4. Molecular studies and DNA analysis: These can be further pursued to confirm positive characterization of the Hb variant(s).
Strategies to treat SCD are generally divided into 4 categories: curative treatment, disease-modifying therapy, preventive measures, and management of acute complications.
1. Curative treatment:
1) Hematopoietic stem cell transplantation (HSCT) is the only curative treatment currently available for patients with SCD. The decision to proceed to HSCT is challenging due to the significant potential risks of HSCT, including acute and chronic graft-versus-host disease (GVHD), infertility, and transplant-related death. HSCT has been more extensively studied in children than with adult patients with SCD and has better outcomes in children, particularly with human leukocyte antigen (HLA)-matched related donors. HSCT in older SCD patients is primarily considered with progressive vaso-occlusive complications or organ dysfunction despite optimal use of disease-modifying therapies.Evidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of the study. Gluckman E, Cappelli B, Bernaudin F, et al; Eurocord, the Pediatric Working Party of the European Society for Blood and Marrow Transplantation, and the Center for International Blood and Marrow Transplant Research. Sickle cell disease: an international survey of results of HLA-identical sibling hematopoietic stem cell transplantation. Blood. 2017 Mar 16;129(11):1548-1556. doi: 10.1182/blood-2016-10-745711. Epub 2016 Dec 13. PubMed PMID: 27965196; PubMed Central PMCID: PMC5356458.
2) Gene therapy is a curative therapy under active study.
2. Disease-modifying therapy:
1) Hydroxyurea has been shown to reduce the incidence of painful vaso-occlusive crises, hospitalization, and need for RBC transfusion in adults and children with SCD. Mechanisms of action of hydroxyurea in SCD are multifactorial and include promoting the production of HbF, reducing WBC count, and improving RBC hydration. Hydroxyurea is recommended for adults with SCD and ≥3 painful episodes in a year.Evidence 2Strong recommendations (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med. 1995 May 18;332(20):1317-22. PubMed PMID: 7715639. Hydroxyurea can also reduce the incidence of acute chest syndrome and improve mortality in SCD patients.Evidence 3Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of the study. Voskaridou E, Christoulas D, Bilalis A, et al. The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS). Blood. 2010 Mar 25;115(12):2354-63. doi: 10.1182/blood-2009-05-221333. Epub 2009 Nov 10. PubMed PMID: 19903897. CBC with WBC differential count should be measured at least every 4 weeks during periods of dose adjustments to monitor for peripheral blood cytopenias. If the absolute neutrophil count decreases <2000 × 106/L and/or platelet count decreases <80,000 × 106/L, hydroxyurea should be withheld until the counts recover and subsequently reinstituted at a dose 5 mg/kg/d lower than the previous dose. Once a stable dose is established, monitoring can be performed every 2 to 3 months.
2) RBC transfusions can be used either prophylactically, to reduce the incidence of SCD-related complications (eg, preoperatively), or for the treatment of acute complications, such as aplastic crisis and acute chest syndrome. The target Hb concentration with simple transfusion depends on the indication. RBC exchange transfusion involves removal of the patient’s RBCs and replacement with donor RBCs, targeting an HbS level <30%. The advantage of RBC exchange over simple RBC transfusion is the avoidance of hyperviscosity and volume overload.
a) Prophylactic RBC transfusion: Simple RBC transfusion targeting an Hb concentration of 100 g/L is recommended for patients requiring surgery under general or regional anesthesia, with consideration of exchange transfusion in high-risk patients (eg, previous history of stroke, recurrent acute chest syndrome).Evidence 4Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered as the majority of meta-analysis studies are observational with a high risk of bias. Alotaibi GS, Alsaleh K, Bolster L, McMurtry MS, Wu C. Preoperative transfusion in patients with sickle cell disease to prevent perioperative complications: a systematic review and meta-analysis. Hematology. 2014 Dec;19(8):463-71. doi: 10.1179/1607845414Y.0000000158. Epub 2014 Mar 11. Review. PubMed PMID: 24611757.
b) Chronic RBC transfusion: This is recommended for children with silent cerebral infarction or 2 transcranial Doppler (TCD) ultrasonography velocity measurements ≥200 cm/s within a 1- to 2-week period.Evidence 5Strong recommendations (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med. 1998 Jul 2;339(1):5-11. PubMed PMID: 9647873. DeBaun MR, Gordon M, McKinstry RC, et al. Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia. N Engl J Med. 2014 Aug 21;371(8):699-710. doi: 10.1056/NEJMoa1401731. PubMed PMID: 25140956; PubMed Central PMCID: PMC4195437. Despite the absence of high-quality evidence, chronic transfusion therapy may be indicated for patients with recurrent acute chest syndrome, priapism, and refractory painful vaso-occlusive episodes.
c) Blood transfusion as acute treatment: Simple RBC transfusion may be indicated for patients with symptomatic anemia due to decreased oxygen delivery. The target Hb should not exceed 100 g/L to avoid the risks of hyperviscosity. Exchange transfusion is usually reserved for SCD patients with multiorgan failure, respiratory compromise, or severe acute chest syndrome.Evidence 6Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of data. Hassell KL, Eckman JR, Lane PA. Acute multiorgan failure syndrome: a potentially catastrophic complication of severe sickle cell pain episodes. Am J Med. 1994 Feb;96(2):155-62. PubMed PMID: 8109600.
3. Preventive measures:
1) Penicillin prophylaxis is advised for all children with SCD up to the age of 5 years for the prevention of pneumococcal infections.Evidence 7Strong recommendations (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Hirst C, Owusu-Ofori S. Prophylactic antibiotics for preventing pneumococcal infection in children with sickle cell disease. Cochrane Database Syst Rev. 2012 Sep 12;(9):CD003427. doi: 10.1002/14651858.CD003427.pub2. Review. Update in: Cochrane Database Syst Rev. 2014;(11):CD003427. PubMed PMID: 22972063.
2) Age-appropriate vaccinations, including those against encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenza, and Neisseria meningitides), seasonal influenza virus, and hepatitis B virus.
3) Screening TCD ultrasonography should be performed in children to identify those at high risk of stroke who would benefit from chronic RBC transfusions.
4. Management of SCD-related acute complications:
1) Acute painful crisis: Patients should have a clear management plan and regular follow-up regarding the effectiveness of their home analgesic therapy with guidance on alarming signs of serious SCD complications. Home medications usually include short-acting opioids, long-acting opioids, and nonopioid adjuncts such as nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (INN paracetamol). If pain is intense or unresponsive to oral analgesics, hospital admission with the administration of IV opioids is warranted. IV morphine or hydromorphone are commonly used to treat painful crises in the emergency department. It is important to review the previous effective dose used for prior pain episodes. Constant assessment of pain should be performed, as many patients will not have relief following their initial dose of analgesic. Adequate IV hydration is recommended but consider further monitoring for patients with acute chest syndrome as volume overload may worsen hypoxemia.
2) Acute chest syndrome: Empiric broad-spectrum IV antibiotics, supplemental oxygen, and fluids to target euvolemia are the cornerstones of treatment. Simple transfusion is recommended for mild acute chest syndrome, targeting an Hb concentration of 95 to 100 g/L, while exchange transfusion is recommended for moderate to severe acute chest syndrome, targeting an Hb concentration of 95 to 100 g/L and HbS concentration <30%.
3) Stroke: Suspicion for an acute neurologic event in patients with SCD requires urgent neuroimaging with computed tomography (CT) to identify intracranial hemorrhage followed by MRI to identify ischemia if the CT result is normal. Ischemic and hemorrhagic strokes are acutely managed by RBC exchange transfusion, targeting an HbS percentage <30%.
SCD is associated with a decreased life expectancy, previously estimated at 48 years of age in women and 42 years of age in men with HbSS genotype in North America. However, novel therapeutic strategies are changing clinical expectations and outcomes in SCD, and newer studies are needed to better understand life expectancy in SCD in the current therapeutic landscape.