Sickle Cell Disease

Sickle cell disease (SCD) is a group of genetic disorders in which an abnormal Hb molecule (HbS) transforms RBCs into sickle-shaped cells, resulting in chronic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview, vasoocclusive episodes, pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, and organ damage. Sickle cell trait, which is the heterozygous condition, is the only 1 of the group that is generally benign and rarely associated with serious SCD-like complications. Triggers such as stress and hypoxia can induce or worsen the sickling of RBCs. Individuals with SCD are susceptible to infection, infarction of various organs, and bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow aplasia; lung involvement in acute chest syndrome can be rapidly fatal. Sickle cells can usually be seen on the peripheral blood smear, but Hb electrophoresis is needed for diagnosis. The management of painful episodes consists of IV fluids IV fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids and analgesics, and in severe episodes, exchange transfusions may be required. Survival is improved by vaccination Vaccination Vaccination is the administration of a substance to induce the immune system to develop protection against a disease. Unlike passive immunization, which involves the administration of pre-performed antibodies, active immunization constitutes the administration of a vaccine to stimulate the body to produce its own antibodies. Vaccination against bacterial infections, prophylactic antibiotics, and aggressive treatment of infections.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Sickle cell disease (SCD) is a group of genetic disorders that cause an abnormal Hb molecule (HbS) that transforms RBCs into sickle-shaped cells, resulting in chronic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview, vasoocclusive episodes, pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, and organ damage.

Epidemiology

  • Most common form of intrinsic hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia worldwide
  • Occurs in individuals whose ancestors came from sub-Saharan Africa, India, Saudi Arabia, or Mediterranean countries
  • Prevalence of sickle cell trait (heterozygous benign carrier): 
    • 300 million people worldwide
    • 2.5 million people in the United States
  • Incidence of sickle cell trait:
    • 30% of individuals in sub-Saharan Africa 
    • 7.3% of African Americans
  • Equally present in men and women

Etiology

  • Sickle cell disease is any syndrome with a sickle mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations that alters normal beta globin:
    • Determined by specific allelic pairings
    • Autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritanceinheritance 
  • Homozygous genotype = HbSS; causes sickle cell anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview
  • Heterozygous condition = HbSA; benign carrier condition called “sickle cell trait”:
    • Only 1 allele has the HbS mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations.
    • Important for counseling about risk of having a child with SCD 
  • Hemoglobinopathies with another globin gene mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations:
    • Occur as compound heterozygotes with HbS from 1 parent
    • Variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables clinical severity as compared with homozygous sickle mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations (HbSS)
    • Affect the alpha-, beta-, or gamma-globin genes:
      • Sickle-beta thalassemia Thalassemia Thalassemia is a hereditary cause of microcytic hypochromic anemia and results from a deficiency in either the α or β globin chains, resulting in hemoglobinopathy. The presentation of thalassemia depends on the number of defective chains present and can range from being asymptomatic to rendering the more severely affected patients to be transfusion dependent. Thalassemia: less severe if HbS compounded with beta-plus thalassemia Thalassemia Thalassemia is a hereditary cause of microcytic hypochromic anemia and results from a deficiency in either the α or β globin chains, resulting in hemoglobinopathy. The presentation of thalassemia depends on the number of defective chains present and can range from being asymptomatic to rendering the more severely affected patients to be transfusion dependent. Thalassemia (some beta globin is produced) than with beta-zero thalassemia Thalassemia Thalassemia is a hereditary cause of microcytic hypochromic anemia and results from a deficiency in either the α or β globin chains, resulting in hemoglobinopathy. The presentation of thalassemia depends on the number of defective chains present and can range from being asymptomatic to rendering the more severely affected patients to be transfusion dependent. Thalassemia (no beta globin is produced)
      • HbSC disease: symptoms similar to SCD but less severe
Sickle cell inheritance

Autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritanceinheritance of sickle cell disease and trait

Image: “Sickle cell 02” by National Heart Lung and Blood Insitute (NIH). License: Public Domain

Pathophysiology

Normal adult hemoglobin molecule (HbA1) consists of 2 pairs of chains called alpha and beta. 

  • HbS is produced by a point mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations on chromosome 11, causing substitution of valine ( amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids) for glutamic acid at the 6th position in the beta-globin chain.
  • HbS is prone to polymerization with other Hb molecules under conditions of low oxygen tension.
  • Polymerization alone does not account for the pathophysiology but leads to:
    • A rigid cell structure that distorts the membrane of the RBC 
    • Membrane damage →  influx of calcium, efflux of potassium and water → dehydrates the RBC → sickling
    • Tendency of sickled RBCs to adhere to vascular endothelium →  vasoocclusion
    • Reduction of nitric acid, which becomes bound to hemolyzed cells → vascular smooth muscle cell contraction and platelet aggregation → further vasoocclusion 
    • A shortened half-life of the HbS-containing RBCs to 17 days (normally 120 days), which further promotes hemolysis 
  • Sickling is aggravated by conditions of low oxygen tension, including:
    • Infection
    • Dehydration
    • Hypoxia (e.g., high altitudes, pulmonary disorders, airway obstruction Airway obstruction Airway obstruction is a partial or complete blockage of the airways that impedes airflow. An airway obstruction can be classified as upper, central, or lower depending on location. Lower airway obstruction (LAO) is usually a manifestation of chronic disease, such as asthma or chronic obstructive pulmonary disease (COPD). Airway Obstruction)
    • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
    • Acidosis
Sickle cell

Abnormal hemoglobin results in RBC sickling and adhesion of the sickled cells to endothelium and to WBCs and platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets, causing occlusion of small vessels.

Image: “Sickle cell 01” by The National Heart, Lung, and Blood Institute (NHLBI). License: Public Domain

Clinical Presentation

Most symptoms result from the anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and vasoocclusive events seen in individuals with SCD or complications including infection.

Sickle cell disease (HbSS)

  • Infants with SCD are generally healthy at birth. Symptoms develop after about age 6 months, when HbF levels start to diminish (protective in neonates) 
  • Major acute manifestations:
    • Vasoocclusive events: present suddenly with severe pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain and infarction of the affected tissue
    • Infection:
      • Sepsis Sepsis Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. The etiology is mainly bacterial and pneumonia is the most common known source. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Sepsis and Septic Shock
      • Pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia
      • Meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis
    • Anemia
      • Transient aplastic episode: worsening of anemic symptoms plus purpura, petechiae, and mucosal bleeding
      • Can be brought on by infection with human parvovirus B19 Parvovirus B19 Primate erythroparvovirus 1 (generally referred to as parvovirus B19, B19 virus, or sometimes erythrovirus B19) ranks among the smallest DNA viruses. Parvovirus B19 is of the family Parvoviridae and genus Erythrovirus. In immunocompetent humans, parvovirus B19 classically results in erythema infectiosum (5th disease) or "slapped cheek syndrome." Parvovirus B19 → transient slowing of bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow erythropoiesis Erythropoiesis Erythropoiesis starts with hematopoietic stem cells, which develop into lineage-committed progenitors and differentiate into mature RBCs. The process occurs in stages, and extrusion of the nuclei and organelles occurs prior to maturation. Thus, mature RBCs lack nuclei and have a biconcave shape. Erythrocytes 
    • CNS: ischemic stroke Ischemic Stroke An ischemic stroke (also known as cerebrovascular accident) is an acute neurologic injury that occurs as a result of brain ischemia; this condition may be due to cerebral blood vessel occlusion by thrombosis or embolism, or rarely due to systemic hypoperfusion. Ischemic Stroke or TIA TIA Transient ischemic attack (TIA) is a temporary episode of neurologic dysfunction caused by ischemia without infarction that resolves completely when blood supply is restored. Transient ischemic attack is a neurologic emergency that warrants urgent medical attention. Transient Ischemic Attack (TIA)
    • Lung: 
      • Pulmonary embolism Pulmonary Embolism Pulmonary embolism (PE) is a potentially fatal condition that occurs as a result of intraluminal obstruction of the main pulmonary artery or its branches. The causative factors include thrombi, air, amniotic fluid, and fat. In PE, gas exchange is impaired due to the decreased return of deoxygenated blood to the lungs. Pulmonary Embolism or microemboli (eventually leading to pulmonary hypertension Pulmonary Hypertension Pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure, which can lead to chronic progressive right heart failure. Pulmonary hypertension is grouped into 5 categories based on etiology, which include primary PAH, and PH due to cardiac disease, lung or hypoxic disease, chronic thromboembolic disease, and multifactorial or unclear etiologies. Pulmonary Hypertension) and pulmonary fibrosis Pulmonary Fibrosis Idiopathic pulmonary fibrosis is a specific entity of the major idiopathic interstitial pneumonia classification of interstitial lung diseases. As implied by the name, the exact causes are poorly understood. Patients often present in the moderate to advanced stage with progressive dyspnea and nonproductive cough. Pulmonary Fibrosis
      • Acute chest syndrome: chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain, fever, pulmonary infiltrates, hypoxemia
    • Kidney: 
      • Renal infarction
      • AKI AKI Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury
      • Hematuria or proteinuria
      • Renal papillary necrosis (coagulative necrosis of the renal medullary pyramids and papillae)
    • Bones and joints: 
      • Pain in the long bones, hands and feet, back, joints
      • Avascular necrosis
      • Dactylitis (painful inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of the fingers and/or toes)
    • Heart: MI MI MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction
    • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver:
      • RUQ abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
      • Jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice due to acute enlargement of the liver/hepatic sequestration 
    • Eyes: retinal artery occlusion, retinal detachment Retinal detachment Retinal detachment is the separation of the neurosensory retina from the retinal pigmented epithelium and choroid. Rhegmatogenous retinal detachment, the most common type, stems from a break in the retina, allowing fluid to accumulate in the subretinal space. Retinal Detachment
    • Spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen
      • Children: enlarged, may have pooling of blood causing LUQ abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, weakness, hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension, and shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of Shock (splenic sequestration)
      • Adults: autosplenectomy occurs with age, leading to infectious complications
    • GI: severe abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, with or without vomiting
    • Penis Penis The penis is the male organ of copulation and micturition. The organ is composed of a root, body, and glans. The root is attached to the pubic bone by the crura penis. The body consists of the 2 parallel corpora cavernosa and the corpus spongiosum. The glans is ensheathed by the prepuce or foreskin. Penis: priapism (sustained erection that lasts > 4 hours); can also be seen in children with SCD
  • Major chronic manifestations:
    • Chronic pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain from:
      • Tissue infarction
      • Osteonecrosis
    • Chronic infection: 
      • Leg Leg The lower leg, or just "leg" in anatomical terms, is the part of the lower limb between the knee and the ankle joint. The bony structure is composed of the tibia and fibula bones, and the muscles of the leg are grouped into the anterior, lateral, and posterior compartments by extensions of fascia. Leg ulcers
      • Osteomyelitis Osteomyelitis Osteomyelitis is an infection of the bone that results from the spread of microorganisms from the blood (hematogenous), nearby infected tissue, or open wounds (non-hematogenous). Infections are most commonly caused by Staphylococcus aureus. Osteomyelitis
    • Chronic hemolysis (intravascular and extravascular) → anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview:
      • Fatigue
      • Pallor
      • Tachycardia
      • Cognitive delay and delayed growth in children
      • Folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 deficiency can worsen chronic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview.
    • Osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis
    • Blindness from chronic retinopathy
    • Hemolysis of RBCs can cause pigment gallstones.
  • Complications: 
    • Recurrent vasoocclusive events and tissue infarctions → organ damage:
    • Acute chest syndrome can be life-threatening; it is the most common cause of death in patients with SCD.
    • Heart: cor pulmonale Cor Pulmonale Cor pulmonale is right ventricular (RV) dysfunction caused by lung disease that results in pulmonary artery hypertension. The most common cause of cor pulmonale is chronic obstructive pulmonary disease. Dyspnea is the usual presenting symptom. Cor Pulmonale and heart failure
    • Kidney: CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease, hypertension
    • Musculoskeletal: osteonecrosis, osteoporosis, and short stature in children Short stature in children Short stature in children is defined as a height more than 2 standard deviations below the mean for age and gender or growing below the 3rd percentile when plotting height on standardized growth charts. Short stature can be pathological or due to a normal variant in growth pattern. Short Stature in Children
    • Infections:
      • Increased risk of infection with encapsulated bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview (e.g., Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus pneumoniae,  Haemophilus Haemophilus Haemophilus is a genus of Gram-negative coccobacilli, all of whose strains require at least 1 of 2 factors for growth (factor V [NAD] and factor X [heme]); therefore, it is most often isolated on chocolate agar, which can supply both factors. The pathogenic species are H. influenzae and H. ducreyi. Haemophilus influenzae, Neisseria Neisseria Neisseria is a genus of bacteria commonly present on mucosal surfaces. Several species exist, but only 2 are pathogenic to humans: N. gonorrhoeae and N. meningitidis. Neisseria species are non-motile, gram-negative diplococci most commonly isolated on modified Thayer-Martin (MTM) agar. Neisseria meningitidis) due to loss of splenic function 
      • Hepatitis
      • Osteomyelitis Osteomyelitis Osteomyelitis is an infection of the bone that results from the spread of microorganisms from the blood (hematogenous), nearby infected tissue, or open wounds (non-hematogenous). Infections are most commonly caused by Staphylococcus aureus. Osteomyelitis
      • Septic arthritis Septic arthritis Septic arthritis is an infection of the joint due to direct inoculation, contiguous extension, or hematogenous spread of infectious organisms into the joint space. This process causes an acute, inflammatory, monoarticular arthritis. Septic Arthritis
      • Pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia
      • Meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis
      • Sepsis Sepsis Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. The etiology is mainly bacterial and pneumonia is the most common known source. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Sepsis and Septic Shock

Sickle cell trait (HbSA)

  • Usually asymptomatic or only mild symptoms
  • May have painless hematuria due to renal papillary necrosis 
  • Decreased (hyposthenuria) or loss of (isosthenuria) ability to concentrate the urine 
  • Rarely:
    • Sickle cell acute episode, rhabdomyolysis Rhabdomyolysis Rhabdomyolysis is characterized by muscle necrosis and the release of toxic intracellular contents, especially myoglobin, into the circulation. Rhabdomyolysis, and death if exposed to high altitudes or with extreme dehydration or exercise
    • CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease
    • Pulmonary embolism Pulmonary Embolism Pulmonary embolism (PE) is a potentially fatal condition that occurs as a result of intraluminal obstruction of the main pulmonary artery or its branches. The causative factors include thrombi, air, amniotic fluid, and fat. In PE, gas exchange is impaired due to the decreased return of deoxygenated blood to the lungs. Pulmonary Embolism
    • Rare medullary carcinoma of the kidney
  • Benefit of sickle cell trait: improved survival with malarial infection
  • Sickle cell homozygotes (HbSS) have no benefits from SCD; they are harmed by malarial infections, which worsen the preexisting anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview.

Diagnosis

Sickle cell disease is usually diagnosed prenatally or at birth by mandatory neonatal screening. Methods vary from state to state.

  • Testing:
    • Prenatal: 
      • PCR or direct DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure testing
      • Genetic screening can be performed on samples of chorionic villi at 8–12 weeks of gestation
    • Universal newborn Newborn A neonate, or newborn, is defined as a child less than 28 days old. A thorough physical examination should be performed within the first 24 hours of life to identify abnormalities and improve outcomes by offering timely treatment. Physical Examination of the Newborn screening in all 50 U.S. states:
      • Early recognition of affected infants has reduced morbidity from infections
      • Prophylactic penicillin and regular medical care have significantly reduced mortality in young children 
      • Methods: Hb electrophoresis, isoelectric focusing, or high-performance liquid chromatography (HPLC) followed by DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure sequencing if abnormal
    • Children and adults:  
      • Individuals with signs or symptoms
      • Individuals with a family history of sickle cell disease
      • Hb electrophoresis differentiates homozygotes from heterozygotes (carriers)
  • Hb electrophoresis patterns:
    • In patients with HbSS genotype: 
      • HbFS pattern suggests sickle cell disease
      • No HbA1 or HbA2 present 
    • HbFSA pattern suggests a compound state involving a sickle cell mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations
      • Sickle-beta thalassemia Thalassemia Thalassemia is a hereditary cause of microcytic hypochromic anemia and results from a deficiency in either the α or β globin chains, resulting in hemoglobinopathy. The presentation of thalassemia depends on the number of defective chains present and can range from being asymptomatic to rendering the more severely affected patients to be transfusion dependent. Thalassemia
      • HbSC disease
    • HbFAS pattern suggests sickle cell trait
  • CBC results:
    • Chronic compensated hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia with SCD (HbSS):
      • Hemoglobin level approximately 8.0–10.0 g/dL (normal: 12.0–15.5 g/dL for women, 13.5–17.5 g/dL for men)
      • Hematocrit approximately 20%–30% (normal: 36%–44% for women, 41%–50% for men)
      • Normal MCV
      • ↓ Hct
      • ↑ WBC
    • Peripheral blood smear:
      • Sickle cells
      • Howell-Jolly bodies in individuals with autosplenectomy (immature RBCs with basophilic nuclear remnants)
      • Reticulocytes
      • Target cells with HbSC disease
  • Other tests
    • ↑↑ Reticulocyte count
    • ↓ Erythrocyte sedimentation rate (ESR)
    • ↑ Bilirubin
    • ↑ BUN, ↑ creatinine
    • Liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests: ↑ AST/ALT
Sickle cell anemia - peripheral blood smear

Peripheral blood smear showing a mixture of RBCs, some with round normal morphology and some with sickling (elongation and bending)

Image: “Sickle Cell Anemia” by Ed Uthman. License: CC BY 2.0

Management

Treatment of painful episodes includes analgesics and general supportive measures. Transfusions may be needed on occasion if the individual has symptomatic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview

  • Hydroxyurea for prevention and treatment of vasoocclusive events:
    •  Mechanism of action:
      • Increases HbF levels, RBC water content, deformability of sickle cells
      • Alters adhesion of RBCs to endothelium
    • Reduces pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain and other vasoocclusive complications
    • Decreases hospitalization rates
    • Improves survival
  • Infection prevention:
    • Age-appropriate vaccinations:
      • S. pneumonia (pneumococcal conjugate and polysaccharide vaccines)
      • Seasonal influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza
      • N. meningitidis
      • H. influenzae type b (Hib)
      • Hepatitis B Hepatitis B Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B Virus
    • Penicillin prophylaxis:
      • Start within the first 3 months of life.
      • Erythromycin if penicillin allergy
      • Continue until age 5 years.
  • Folic acid supplementation
  • Indications for transfusion:
    • Symptomatic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview
    • Preoperatively
    • Acute stroke
    • Multiorgan failure
    • Acute chest syndrome
    • Recurrent priapism
  • Hematopoietic stem cell transplantation is the only curative option.
  • Therapies not used for acute vasoocclusive episodes:
    • O2: unless saturation is below baseline or there are pulmonary symptoms
    • Ice: may precipitate sickling
    • Meperidine: associated with accumulation of metabolites, leading to seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
    • Ketorolac: due to toxicities
    • Transfusion for acute vasoocclusive pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain without symptomatic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview
    • Granulocyte colony-stimulating factor (G-CSF): due to risk of multiorgan failure and death (with rare exceptions) 
Summary of the management of sickle cell disease
Presentation Management
Acute pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain episodes/ vasoocclusive events
  • Oral hydration
  • Pain control with fast-acting oral (or IV if needed) opiate analgesics
  • IV fluids IV fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids if hypovolemic and for pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain control
  • Incentive spirometry to reduce the risk of acute chest syndrome
  • Thromboembolic prophylaxis
  • Hydroxyurea
  • Folic acid (for folate deficiency)
  • Exchange transfusion (in case of Hb < 6 g/dL or acute chest syndrome)
Acute splenic sequestration
  • Exchange transfusion
  • Splenectomy (delay until the age of 3–5 years)
Infections Prevention:
  • Vaccinations as above
  • Prophylactic penicillin for children < 5 years
Priapism
  • Hydration
  • Analgesics
Prophylactic screening
  • Stroke: annual transcranial Doppler exam (age 2–16 years)
  • Retinopathy: annual retinal exam (beginning at age 10 years)
  • Echocardiography: for pulmonary hypertension Pulmonary Hypertension Pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure, which can lead to chronic progressive right heart failure. Pulmonary hypertension is grouped into 5 categories based on etiology, which include primary PAH, and PH due to cardiac disease, lung or hypoxic disease, chronic thromboembolic disease, and multifactorial or unclear etiologies. Pulmonary Hypertension (childhood/early adulthood)
  • Urinalysis: annually for proteinuria/casts
Refractory
  • Hematopoietic stem cell transplant (HSCT) if:
    • Refractory to hydroxyurea
    • End-organ damage
    • Child (age < 18)
  • Gene therapy or gene-editing techniques that reduce the amount of HbS are currently in clinical trials.

Differential Diagnosis

  • Hemolytic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview: group of conditions defined by the breakdown of RBCs, reduction in hemoglobin levels, and reticulocytosis. Sickle cell disease is a form of hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia with vasoocclusive episodes. Other causes of hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia must be considered in the differential diagnosis. 
    • Thalassemia: inherited deficiency in either alpha- or beta-globin chain resulting in hypochromic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview. Presentation is mainly with severe anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview, and more severely affected individuals are transfusion-dependent. Diagnosis is confirmed by Hb electrophoresis. Management includes folate supplementation, transfusions, iron chelation, and splenectomy.
    • Autoimmune hemolytic anemia Autoimmune Hemolytic Anemia Autoimmune hemolytic anemia (AIHA) is a rare type of hemolytic anemia characterized by antibody production against self RBCs, leading to destruction of these cells in the spleen and other reticuloendothelial tissues. The disease is generally categorized as warm or cold, depending on the thermal reactivity of the autoantibodies. Autoimmune Hemolytic Anemia: rare type of anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview resulting from immune-mediated tagging and destruction of RBCs by the spleen. Presentation is with symptoms of hemolysis, and the diagnosis is made by a positive Coombs test. Management involves supportive care, removal of the inciting agent, use of steroids and immunosuppressive agents, and splenectomy in refractory cases.
    • Hereditary spherocytosis Hereditary Spherocytosis Hereditary spherocytosis (HS) is the most common type of hereditary hemolytic anemia. The condition is caused by a cytoskeletal protein deficiency in the RBC membrane. This results in loss of membrane stability and deformability of the RBC, giving the cell its spherical shape (spherocyte). Hereditary Spherocytosis: most common type of hereditary hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia. Hereditary spherocytosis Hereditary Spherocytosis Hereditary spherocytosis (HS) is the most common type of hereditary hemolytic anemia. The condition is caused by a cytoskeletal protein deficiency in the RBC membrane. This results in loss of membrane stability and deformability of the RBC, giving the cell its spherical shape (spherocyte). Hereditary Spherocytosis is caused by an abnormality in the RBC membrane protein, resulting in RBCs with a spherical shape that get trapped within the splenic tissue. Presentation is with hemolysis, anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview,  jaundice, and splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly. Management is with splenectomy.
    • G6PD deficiency G6PD Deficiency Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a type of intravascular hemolytic anemia. The condition is inherited in an X-linked recessive manner. Patients have episodic hemolysis due to an oxidative stressor that causes damage to red blood cells, which lack sufficient NADPH to protect them from oxidative injury. Glucose-6-phosphate Dehydrogenase (G6PD) Deficiency: type of intravascular hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia. Individuals experience episodic hemolysis due to an identified oxidative stressor that causes damage to RBCs and presents with classic signs of hemolysis and anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview. Diagnosis is made by lab testing; peripheral blood smear may show Heinz bodies and bite cells. Management includes avoiding oxidative stressors and transfusion, if needed.
    • Paroxysmal nocturnal hemoglobinuria Paroxysmal Nocturnal Hemoglobinuria Paroxysmal nocturnal hemoglobinuria (PNH) is a rare but serious acquired hemolytic anemia with periodic exacerbations. This anemia is caused by nonmalignant clonal expansion of ≥ 1 hematopoietic stem cells that have acquired a somatic mutation of the phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIG-A) gene. Paroxysmal Nocturnal Hemoglobinuria: acquired mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations that leads to  intravascular hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia that is Coombs-negative and episodic. Presentation is with the classic triad of hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia, bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow failure, and thrombophilia. Individuals may also have progressive renal failure with a very high risk of thrombosis in atypical locations. Individuals may be treated with the monoclonal antibody eculizumab or with stem cell transplantation.
  • Gaucher disease Gaucher disease Gaucher Disease (GD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of glucocerebrosidase enzyme activity, resulting in accumulation of glucocerebroside in cells and certain organs. The disease is categorized into 3 types with variable clinical presentation. Gaucher Disease (GD): inherited disorder that leads to the accumulation of undegraded glycolipid substrates in cells and certain organs, with bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow infarction and splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly. These symptoms contrast with the splenic infarction seen in patients with SCD. Symptoms of GD are bruising, lethargy, anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview, and hepatosplenomegaly. Diagnosis is based on clinical suspicion and confirmed by measurement of glucocerebrosidase activity. Management is supportive, with enzyme replacement therapy for symptoms and to improve quality of life. 

References

  1. Vichinsky, E.P. (2020). Overview of the clinical manifestations of sickle cell disease. UpToDate. Retrieved November 4, 2021, from https://www.uptodate.com/contents/overview-of-the-clinical-manifestations-of-sickle-cell-disease
  2. Vichinsky, E.P. (2020). Diagnosis of sickle cell disorders. UpToDate. Retrieved November 8, 2021, from https://www.uptodate.com/contents/diagnosis-of-sickle-cell-disorders
  3. Lubeck, D., Agodoa, I., Bhakta, N., et al. (2019). Estimated life expectancy and income of patients with sickle cell disease compared with those without sickle cell disease. JAMA Network Open 2(11):e1915374. doi:10.1001/jamanetworkopen.2019.15374
  4. Braunstein, E.M. (2020). Sickle cell disease (Hb S Disease). MSD Manual Professional Edition. Retrieved October 26, 2020, from https://www.msdmanuals.com/professional/hematology-and-oncology/anemias-caused-by-hemolysis/sickle-cell-disease
  5. Vichinsky, E.P., Field, J.J. (2020). Overview of the management and prognosis of sickle cell disease. UpToDate. Retrieved November 8, 2021, from https://www.uptodate.com/contents/overview-of-the-management-and-prognosis-of-sickle-cell-disease
  6. Vichinsky, E.P. (2021) Overview of compound sickle cell syndromes. UpToDate. Retrieved November 8, 2021, from https://www.uptodate.com/contents/overview-of-compound-sickle-cell-syndromes

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