eMedicine Specialties > Emergency Medicine > Hematology & Oncology

Anemia, Sickle Cell

Author: Ali Taher, MD, Professor of Medicine, Division of Hematology and Oncology, Assistant to the Chair-Undergraduate Program, Department of Internal Medicine, American University of Beirut Medical Center
Coauthor(s): Adlette Inati, MD, Head, Division of Pediatric Hematology-Oncology, Medical Director, Children's Center for Cancer and Blood Diseases, Rafik Hariri University Hospital; Research Associate, Balamand University; Head of Post Bone Marrow Transplant Clinic and Consultant Hematologist, Chronic Care Center, Lebanon; Ziad N Kazzi, MD, Assistant Professor, Department of Emergency Medicine, Emory University; Medical Toxicologist, Georgia Poison Center
Contributor Information and Disclosures

Updated: Dec 5, 2008

Introduction

Background

Sickle cell disease (SCD), the most common monogenetic disorder worldwide, affects an estimated 30 million persons and represents a major public health concern because of its associated significant morbidity and mortality. Modern advances in molecular and cellular biology have generated increasing knowledge of the pathophysiological basis for this disease with heterogeneous manifestations and have paved the route to the development of novel and targeted therapeutic interventions. With the increasing knowledge about this disease, it is imperative that emergency physicians orient themselves with the varied clinical presentations and the new insights into pathophysiology and treatment of this disorder. 

Genetics

1. HbSS disease or sickle cell anemia (the most common form) - Homozygote for the S globin with usually a severe or moderately severe phenotype with the shortest survival
2. HbS/B° thalassemia - Double heterozygote for HbS and B° thalassemia and clinically indistinguishable from sickle cell anemia (SCA)
3. HbS/B+ thalassemia - Mild-to-moderate severity with variability in different ethnicities
4. HbSC disease - Double heterozygote for HbS and HbC characterized by moderate clinical severity
5. HbS/hereditary persistence of fetal Hb (S/HPHP) - Very mild or asymptomatic phenotype
6. HbS/HbE syndrome - Very rare with a phenotype usually similar to HbS/B+ thalassemia
7. Rare combinations of HbS with other abnormal hemoglobins such as HbD Los Angeles, G-Philadelphia, HbO Arab, and others

Sickle cell trait or the carrier state is the heterozygous form characterized by the presence of around 40% HbS, absence of anemia, inability to concentrate urine, and hematuria. Under conditions leading to hypoxia, it may become a pathologic risk factor.

Pathophysiology

The molecular defect of sickle cell disease was unraveled more than 50 years ago. 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 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 associated with increased red cell density (dense erythrocytes) as well as red cell membrane damage favoring the generation of distorted rigid sickle cells and contributing to vaso-occlusion and premature red cell destruction (hemolytic anemia).
 
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 up-regulation of adhesion molecules. Leukocyte adhesion in small post capillary venules is emerging as a key factor that contributes to vaso-occlusion and offers an attractive therapeutic target for SCD. 
 
Hemolysis

Sickle cell disease is a form of hemolytic anemia with red cell survival of around 10-20 days. Approximately one third of the hemolysis occurs intravascularly releasing free hemoglobin (plasma free hemoglobin [PFH]) and arginase into plasma. PFH has been associated with endothelial injury including scavenging NO, proinflammatory stress, and coagulopathy, resulting in vasomotor instability and proliferative vasculopathy.  

A hallmark of this proliferative vasculopathy is the development of pulmonary hypertension (PH) in adulthood. Plasma arginase degrades arginine, the substrate for NO synthesis, thereby limiting the expected compensatory increase in NO production and resulting in generation of oxygen radicals. Plasma arginase is also associated with pulmonary hypertension and risk of early mortality.
 
Clinical presentation

Sickle cell disease is a highly phenotypically variable disease. Some individuals have very severe disease with frequent vaso-occlusive complications and early morbidity and death at a very young age, whereas, in others, the disease can go unnoticed till adulthood . This single missense mutation disease can have wide-ranging manifestations and complications that affect every aspect of the life of affected patients. Natural history studies determined features of the disease and identified risk factors for disease-related morbidity and mortality.^1,2,3 Key clinical manifestations are attributed to two major subphenotypes, one attributed to vaso-occlusion and another to hemolysis.
 
The vaso-occlusive subphenotype is manifested clinically by self-limited pain (vaso-occlusive) episodes, acute chest syndrome (ACS), joint necrosis, stroke, acute splenic sequestration (ASS), hepatic sequestration, and organ failure as renal disease and functional asplenia. Manifestations of the hemolytic subphenotype, on the other hand, are chronic anemia, gallstones, pulmonary hypertension, priapism, leg ulceration, sudden death, and possibly stroke. The most common causes of disease-related morbidity are pain and acute chest syndrome episodes. Pulmonary complications also contribute significantly to premature death. 
 
Vaso-occlusive crises

Pain

A vaso-occlusive crisis occurs when the microcirculation is obstructed by sickled RBCs, causing ischemic injury to the organ supplied and is clinically translated as pain. Pain crises constitute the most distinguishing clinical feature of sickle cell disease and are the first cause of emergency department visits and hospitalizations for affected patients. Pain crisis can involve the abdomen, bones, joints, and soft tissue, and it may present as dactylitis (bilateral painful and swollen hands and/or feet in children), acute joint necrosis, or acute abdomen.⁴ With repeated episodes in the spleen, infarctions, and autosplenectomy predisposing to life-threatening infection are usual. The liver also may infarct and progress to failure with time. Papillary necrosis is a common renal manifestation of vaso-occlusion, leading to isosthenuria (ie, inability to concentrate urine).
 
Acute chest syndrome

Vaso-occlusive crises can also involve the lungs and result in acute chest syndrome (ACS), defined as a new infiltrate on chest radiograph associated with fever or respiratory symptoms. Acute chest syndrome affects about 40% of all people with SCA and has become the most common reason for early mortality. It may be a presenting diagnosis but often develops after acute infections, painful episodes, rib or bone marrow or pulmonary infarction, surgery, and fat embolism. Previous episodes of acute chest syndrome increase the likelihood of repeated acute pulmonary events and subsequent pulmonary hypertension. Asthma and airway hyperreactivity seem to be associated with recurrent acute chest syndrome and pain.

Young children present with fever, cough, and upper lobe disease in contrast to adults who are usually afebrile and dyspneic with severe chest pain and multilobar and lower lobe disease. Overall death rate from acute chest syndrome is 1.8% and 4 times higher in adults than in children. Causes of death are pulmonary embolism and infection.
 
Stroke

Stroke is one of the most devastating complications of sickle cell disease and a leading cause of morbidity and mortality among affected children. It affects 30% of children and 11% of patients by 20 years and is mostly seen in SCA. It is usually ischemic in children and hemorrhagic in adults.⁵ Transcranial Doppler (TCD), which measures blood flow velocity in the large arteries of the circle of Willis, can detect children at risk of developing stroke months to years before the stroke and/or before magnetic resonance angiography (MRA) changes. Velocity, which is usually increased by severe anemia, becomes elevated in a focal manner when stenosis reduces the arterial diameter. As for silent cerebral infarcts, defined as MR imaging evidence of ischemia with no clinical signs and symptoms, these are seen in around 20% of SS children and can be associated with poor performance on neuropsychological tests and high risk of developing stroke.
 
Infections

Life-threatening bacterial infections are a major cause of morbidity and mortality in patients with sickle cell disease. Recurrent vaso-occlusion induces splenic infarctions and consequent autosplenectomy predisposing to severe infections with encapsulated organisms (eg, Haemophilus influenzae, Streptococcus pneumoniae). Lower serum immunoglobulin M (IgM) levels, impaired opsonization, and sluggish alternative complement pathway activation further increase susceptibility to other common infectious agents, including Mycoplasma pneumoniae, Salmonella typhimurium, Staphylococcus aureus, and Escherichia coli.

Pneumococcal sepsis continues to be a major cause of death in infants in some countries. Parvovirus B19 infection causes aplastic crises. Neonatal screening, penicillin prophylaxis, appropriate immunizations particularly against pneumococcus, and parental teaching have remarkably minimized infection-related morbidity and mortality.  
 
Pulmonary hypertension

Pulmonary hypertension, defined as a tricuspid regurgitant jet velocity (TRJV) >2.5 m/s on echocardiography, is an emergent complication seen in 32% of adult patients with sickle cell disease and is associated with a high mortality rate. Pulmonary hypertension is a complication of chronic intravascular hemolysis. Additional factors contributing to pulmonary hypertension include older age, renal insufficiency, cardiovascular disease, cholestatic hepatopathy, systolic hypertension, high hemolytic markers, iron overload, and a history of priapism. Even modestly increased pulmonary artery pressures are associated with severe reduction in exercise capacity, as assessed by both the 6-minute walk and cardiopulmonary exercise testing, and do herald a poor prognosis. Both pulmonary hypertension and cardiac sequelae, such as diastolic dysfunction, have been associated with accelerated mortality in the sickle cell disease population. 
 
Acute splenic sequestration

This life-threatening complication, seen in the first few years of life and resulting in circulatory collapse and death from anemia and hypovolemic shock, is defined as a sudden enlargement of the spleen with a decrease in Hb concentration (2 g/L at least) and substantial reticulocytosis. Early parental recognition of the signs and symptoms of this complication and its prompt therapy significantly decrease its associated morbidity and mortality
 
Aplastic crises

Severe anemia due to temporary cessation of erythropoiesis is seen mostly with parvovirus B19 infection.

Priapism

This is a well-described complication of sickle cell disease that leads to impotence and is difficult to manage. Priapism is a painful failure of detumescence clinically presenting as either scattered episodes, or a stuttering pattern, usually nocturnal with progressive clustering of more intense episodes over a short period. 
  
Survival

The cooperative study of SCD (CSSCD) estimated that the median survival for individuals with SS was 48 years for women and 42 years for men.⁶ In the Dallas newborn cohort, estimated survival at 18 years was 94%. In a recent neonatal UK cohort followed in a hospital and community-based program including modern therapy with TCD screening, the estimated survival of HbSS children at 16 years was 99.0.

This significant increase in life expectancy and survival of patients with sickle cell disease has been achieved thanks to early detection and introduction of disease-modifying therapies. Neonatal screening, penicillin prophylaxis for children, pneumococcal immunization, red cell transfusion for selected patients and chelation therapy, hydroxyurea therapy, parental and patient education and, above all, treatment in comprehensive centers have all likely contributed to this effect on longevity. However, as patients with sickle cell disease get older, new chronic complications are appearing. Pulmonary hypertension is emerging as a relatively common complication and is one of the leading causes of morbidity and mortality in adult sickle cell disease. 
 
Predictors of disease severity

Multiple cellular and genetic factors contribute to phenotypic heterogeneity. These include low HbF, dactylitis, severe anemia, leukocytosis, childhood asthma, abnormal TCD, and prolonged TRJV are all associated with severe disease. Disease ameliorating factors are coinheritance of α–thalassemia, β-thalassemia, β-C gene interaction, and specific β-globin haplotypes.

Frequency

United States

Incidence of the homozygous state among black newborns is about 0.8%. Approximately 8% of blacks carry the mutated gene.

Mortality/Morbidity

Data from Quinn et al (2004) suggest improvement in mortality rates for patients with sickle cell disease over the past 30 years.⁷ Recent information suggests 85% survival to age 18 years. This study tracked 700 children for 18 years.

Race

The highest incidence of sickle cell disease is in those of African descent.

Sex

No sex predilection exists, since sickle cell anemia is not an X-linked disease.

Clinical

History

• Pain is the most common presentation of vaso-occlusive crisis. Inquire about pain location, duration and mode of onset (acuity of onset), character, and previous similar episodes.
• Infections: Ask about, fever, cough, neck stiffness and severe headache (concerning for meningitis), and urinary symptoms (polyuria, hematuria, dysuria).
• Acute chest syndrome: Inquire about shortness of breath or dyspnea, fever, and cough.
• Stroke: Ask about aphasia, paresthesias, limb weakness, and change of level of consciousness.
• ASS: Inquire about noticeable increase in weakness or pallor, syncope, and sudden abdominal distention.
• Previous intake of analgesics (type and dose, if possible) and folic acid
• Surgical history (helps rule out other causes of abdominal pain)
• Previous hemoglobin levels and previous transfusions
• Vaccination
• Consanguinity, family history of similar episodes

Physical

• Vital signs
  • Hypotension and tachycardia may be signs of septic shock or splenic sequestration crisis. With the severe anemia that accompanies aplastic crisis, patients may exhibit signs of high-output congestive heart failure (CHF).
  • Orthostasis suggests hypovolemia.
  • Tachypnea suggests pneumonia, CHF, or acute chest syndrome. Hypoxia was commonly seen in patients with acute chest syndrome.
  • Dyspnea suggests acute chest syndrome, pulmonary hypertension, and/or CHF.
  • Fever suggests infection in children; however, it is less significant in adults unless it is a high-grade fever.
• Examine head and neck for meningeal signs or possible source of infection (eg, otitis, sinusitis).
• Auscultate the heart to search for signs of congestive heart failure.
• Auscultate the lungs to search for signs of pneumonia, CHF, or acute chest syndrome (similar to pulmonary embolism).
• Palpate for tenderness (abdomen, extremities, back, chest, femoral head) and hepatosplenomegaly.
• Observe for pallor, icterus, and erythema or edema of the extremities or joints.
• Perform a neurological examination to search for focal neurological deficits.
• Look for evidence of retinopathy on funduscopy.

Causes

• Vaso-occlusive crises are often precipitated by the following:
  • Cold weather (due to vasospasm)
  • Hypoxia (flying in unpressurized aircraft)
  • Infection
  • Dehydration (especially from exertion or during warm weather)
  • Acidosis
  • Alcohol intoxication
  • Emotional stress
  • Pregnancy
  • Data also suggest a role for exertional stress, particularly when compounded with heat and hypovolemia.
• Aplastic crises are often preceded by the following:
  • Infection with parvovirus B19
  • Folic acid deficiency
• Ingestion of bone marrow toxins (eg, phenylbutazone)
• Acute chest syndrome has been linked to fat embolism and infections, pain episodes, and asthma.

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