AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Sickle cell disease (SCD) and its variants are genetic disorders of mutant hemoglobins (Hb). The most common form found in North America is homozygous Hb S disease, first described by Herrick in 1910. Morbidity, frequency of crisis, degree of anemia, and the organ systems involved vary considerably from individual to individual.

Pathophysiology

Hb S arises from a mutation substituting thymine for adenine in the sixth codon of the beta-chain gene, GAG to GTG. This causes coding of valine instead of glutamine in position 6 of the Hb beta chain. The resulting Hb has the physical properties of forming polymers under deoxy conditions. It also exhibits changes in solubility and molecular stability. These properties are responsible for the profound clinical expressions of the sickling syndromes.

Under deoxy conditions, Hb S undergoes marked decrease in solubility, increased viscosity, and polymer formation at concentrations exceeding 30 g/dL. It forms a gel-like substance containing Hb crystals called tactoids. The gel-like form of Hb is in equilibrium with its liquid-soluble form. A number of factors influence this equilibrium, including the following:

• Oxygen tension
  • Polymer formation occurs only in the deoxy state.

  • If oxygen is present, the liquid state prevails.

• Concentration of hemoglobin S
  • The normal cellular Hb concentration is 30 g/dL.

  • Gelation of Hb S occurs at concentrations greater than 20.8 g/dL.

• The presence of other hemoglobins
  • Normal adult hemoglobin (Hb A) and fetal hemoglobin (Hb F) have an inhibitory effect on gelation.

  • These and other Hb interactions affect the severity of clinical syndromes. Hb SS produces a more severe disease than sickle cell Hb C (Hb SC), Hb SD, Hb SO Arab, and Hb with one normal and one sickle allele (Hb SA).

When red blood cells (RBCs) containing homozygous Hb S are exposed to deoxy conditions, the sickling process begins. A slow and gradual polymer formation ensues. Electron microscopy reveals a parallel array of filaments. Repeated and prolonged sickling involves the membrane; the RBC assumes the characteristic sickled shape.

• After recurrent episodes of sickling, membrane damage occurs and the cells are no longer capable of resuming the biconcave shape upon reoxygenation. Thus, they become irreversibly sickled cells (ISCs). From 5-50% of RBCs permanently remain in the sickled shape.

• When RBCs sickle, they gain Na⁺ and lose K⁺. Membrane permeability to Ca⁺⁺ increases, possibly due, in part, to impairment in the Ca⁺⁺ pump that is dependent on adenosine triphosphatase (ATPase). The intracellular Ca⁺⁺ concentration is 4 times the reference level. The membrane becomes more rigid, possibly due to changes in cytoskeletal protein interactions; however, these changes are not found consistently. Also, whether calcium is responsible for membrane rigidity is not clear.

• Membrane vesicle formation occurs, and the lipid bilayer is perturbed. The outer leaflet has increased amounts of phosphatidyl ethanolamine and contains phosphatidyl serine. The latter may play a role as a contributor to thrombosis, acting as a catalyst for plasma clotting factors. Membrane rigidity can be reversed in vitro by replacing Hb S with Hb A, suggesting that Hb S interacts with the cell membrane.

• Sickle cells express very late antigen (VLA)-4 on the surface. VLA-4 interacts with the endothelial cell adhesive molecule, vascular cell adhesive molecule (VCAM)-1. VCAM-1 is upregulated by hypoxia and inhibited by nitric oxide. Hypoxia also decreases nitric oxide production, thereby adding to the adhesion of sickle cells to the vascular endothelium. Nitric oxide is a vasodilator. Free Hb is an avid scavenger of nitric oxide. Because of the continuing active hemolysis, there is free Hb in the plasma, and it scavenges nitric oxide. This makes it less available and contributes to vasoconstriction.

• Sickle RBCs adhere to endothelium because of increased stickiness. The endothelium participates in this process as do neutrophiles, which also express increased levels of adhesive molecules.

• Deformable sickle cells express CD18 and adhere abnormally to endothelium up to 10 times more than normal cells, while ISCs do not. As paradoxical as it might seem, individuals who produce large numbers of ISCs have fewer vasoocclusive crises than those with more deformable RBCs.

• Sickle cells also adhere to macrophages. This property may contribute to erythrophagocytosis and the hemolytic process. The microvascular perfusion at the level of the prearterioles is influenced by RBCs containing Hb S polymers. This occurs at arterial oxygen saturation, before any morphologic change is apparent.

• Hemolysis is a constant finding in sickle cell syndromes. Approximately one third of RBCs undergo intravascular hemolysis, possibly due to loss of membrane filaments during oxygenation and deoxygenation. The remainder hemolyze by erythrophagocytosis by macrophages. This process can be partially modified by Fc (crystallizable fragment) blockade, suggesting that the process can be mediated by immune mechanisms.

• Sickle RBCs have increased immunoglobulin G (IgG) on the cell surface. Vasoocclusive crisis is often triggered by infection. Levels of fibrinogen and fibronectin and the D-dimer are elevated in these patients. Plasma clotting factors likely participate in the microthrombi in the prearterioles.

• These physiological changes result in a disease with the following cardinal signs: (1) hemolytic anemia, (2) painful vasoocclusive crisis, and (3) multiple organ damage with microinfarcts, including heart, skeleton, spleen, and central nervous system.

Frequency

United States

The sickle gene is present in approximately 8% of black Americans. The expected incidence of sickle cell anemia in the United States is 1 in 625 persons at birth. The actual prevalence is less because of early mortality. More than 2 million people in the United States, nearly all of them of African American ancestry, carry the sickle gene. More than 30,000 patients have homozygous Hb S disease.

International

In several sections of Africa, the prevalence of sickle cell trait (heterozygote) is as high as 30%.

Mortality/Morbidity

• SCD diagnosis is suggested with the typical clinical picture of chronic hemolytic anemia and vasoocclusive crisis. It is confirmed when the presence of homozygous Hb S is demonstrated by electrophoresis. This test documents Hb SS, Hb SC, or Hb S-beta+ thalassemia, as common examples. Patients with Hb SA are heterozygous carriers and essentially are asymptomatic. Morbidity is highly variable in patients with SCD, partly depending on the level of Hb F. Nearly all individuals with the condition are affected to some degree and experience multiple organ system involvement. Vasoocclusive crisis and chronic pain are associated with considerable economic loss and disability.
• Mortality is high, especially in the early childhood years. Since the introduction of widespread penicillin prophylaxis and pneumococcal vaccination, a marked reduction has been observed in childhood deaths. The leading cause of death is acute chest syndrome. Based on data from the cooperative study of the SCD group in 1995, the life expectancy is 42 years for males and 48 years for females. Median survival is approaching 50 years, which is considerably less than life expectancy for African Americans who do not have SCD.
• In Africa, available mortality data are sporadic and incomplete. Many children are not diagnosed, especially in rural areas, and death is often attributed to malaria or other comorbid conditions.

Race

SCD is present mostly in blacks. It also is found, with much less frequency, in eastern Mediterranean and Middle East populations.

Sex

The male-to-female ratio is 1:1.

Age

SCD is a lifelong condition. It first manifests in the second half of the first year of life and persists for the entire lifespan.

CLINICAL

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History

The presenting symptoms of SCD involve pain and anemia.

• SCD usually manifests early in childhood.
• • For the first 6 months of life, infants are protected largely by elevated levels of Hb F; soon thereafter, the condition becomes evident.

  • The following 3 prognostic factors have been identified as predictors of an adverse outcome: (1) dactylitis in infants younger than 1 year, (2) Hb level of less than 7 g/dL, and (3) leukocytosis in the absence of infection.

• The most common clinical picture during adult life is vasoocclusive crisis.
• • The crisis begins suddenly, sometimes as a consequence of infection or temperature change, such as an air-conditioned environment during a hot summer day. However, often, no precipitating cause can be identified.

  • Severe deep pain is present in the extremities, involving long bones. The abdomen is affected with severe pain resembling acute abdomen. The face also may be involved. Pain may be accompanied by fever, malaise, and leukocytosis. The person in crisis is in extreme discomfort.

  • The crisis may last several hours to several days and terminate as abruptly as it began.

• Approximately half the individuals with homozygous Hb S disease experience vasoocclusive crisis.
• • The frequency of crisis is extremely variable. Some have as many as 6 or more episodes annually, whereas others may have episodes only at great intervals or none at all.

  • Each individual typically has a consistent pattern for crisis frequency.

• Many individuals with Hb S disease experience chronic low-level pain, mainly in bones and joints. Intermittent vasoocclusive crisis may be superimposed, or chronic low-level pain may be the only expression of the disease.

• Anemia is universally present.
• • It is chronic and hemolytic in nature and usually very well tolerated.

  • While patients with an Hb level of 6-7 g/dL who are able to participate in the activities of daily life in a normal fashion are not uncommon, their tolerance for exercise and exertion tends to be very limited.

  • Anemia may be complicated with megaloblastic changes secondary to folate deficiency. These result from increased RBC turnover and folate utilization. Periodic bouts of hyperhemolysis may occur.

  • A serious complication is the aplastic crisis.
    • This is caused by infection with the Parvovirus B-19 (B19V). The virus infects RBC progenitors in bone marrow, resulting in cessation of erythropoiesis.

    • Coupled with greatly shortened RBC lifespan, usually 10-20 days, a very rapid drop in Hb occurs.

    • The condition is self-limited, with bone marrow recovery occurring in 7-10 days, followed by brisk reticulocytosis.

• During childhood and adolescence, the disease is associated with growth retardation, delayed sexual maturation, and being underweight. Several other processes also occur at this time.
• • The spleen enlarges in the latter part of the first year of life.
    • Occasionally, it undergoes a sudden very painful enlargement due to pooling of large numbers of sickled cells. This phenomenon is known as splenic sequestration crisis.

    • The spleen undergoes repeated infarction, aided by low pH and low oxygen tension in the sinusoids and splenic cords.

    • Even while enlarged, its function is impaired, as evidenced by its failure to take up particulate matter such as technetium during nuclear scanning.

    • Over time, the spleen becomes fibrotic and shrinks. This is, in fact, an autosplenectomy.

    • The nonfunctional spleen is a major contributor to the immune deficiency that exists in these individuals. Failure of opsonization and an inability to deal with infective encapsulated microorganisms, particularly Streptococcus pneumoniae, ensue.

  • Pneumococcal infections are common in childhood.
    • During adult life, infections with gram-negative organisms, especially Salmonella, predominate.

    • Of special concern is the frequent occurrence of Salmonella osteomyelitis in areas of bone weakened by infarction.

• Another problem occurring in infancy is hand-foot syndrome.
• • This is a dactylitis presenting as painful swelling of the dorsum of the hand and foot.

  • Cortical thinning and destruction of the metacarpal and metatarsal bones appear on radiographs 3-5 weeks after the swelling begins.

  • Leukocytosis or erythema does not accompany the swelling.

• The acute chest syndrome consists of chest pain, fever, tachypnea, leukocytosis, and pulmonary infiltrates.
• • This is a medical emergency and must be treated immediately.

  • It probably begins with infarction of ribs, leading to chest splinting and atelectasis.

  • Fat embolism, resulting from bone marrow infarction, plays an important etiological role in the pathogenesis of this syndrome.

  • If not attended to promptly, it may lead to acute respiratory distress syndrome (ARDS).

• Central nervous system involvement is one of the most devastating aspects of SCD.
• • It is most prevalent in childhood and adolescence.

  • The most severe manifestation is stroke, resulting in varying degrees of neurological deficit. The stroke is mostly thrombotic, but it may also be hemorrhagic.

  • Vigorous diagnostic and therapeutic efforts may have a beneficial impact on the outcome of this condition. All children with SCD should be screened with transcranial Doppler. Those in whom increased velocity is found should be considered for chronic transfusion therapy, maintaining the level of Hb S at 30% or less. The specific cut off point depends on the method used and is lower for duplex Doppler.

• The heart is involved due to chronic anemia and microinfarcts.
• • Hemolysis and blood transfusion lead to hemosiderin deposition in the myocardium.

  • Both ventricles and the left atrium are all dilated.

  • Usually, a systolic murmur is present, with wide radiation over the precordium.

• Chronic hemolysis with hyperbilirubinemia is associated with the formation of bile stones. Cholelithiasis may be asymptomatic or result in acute cholecystitis, requiring surgical intervention. In addition, a hepatopathy may be present.

• Repeated infarction of joints, bones, and growth plates leads to aseptic necrosis, especially in weightbearing areas such as the femur. This complication is associated with chronic pain and disability and may require changes in employment and lifestyle.

• Blood in the pulmonary circulation is deoxygenated, resulting in a high degree of polymer formation.
  • The lungs develop areas of microinfarction. The resulting areas that lack oxygenation aggravate the sickling process.

  • Pulmonary hypertension may develop. This may be due in part to the depletion of nitric oxide. Various studies have found that more than 40% of adults with SCD have pulmonary hypertension that worsens with age.

• The kidneys lose concentrating capacity.
  • Isosthenuria results in a large loss of water, further contributing to dehydration in these patients. Renal failure may ensue, usually preceded by proteinuria.

  • Nephrotic syndrome is uncommon but may occur.

• Paraorbital facial infarction may result in ptosis.
  • Retinal vascular changes also occur.

  • A proliferative retinitis is common in Hb SC disease and may lead to loss of vision.

• Leg ulcers are a chronic painful problem. They result from minor injury to the area around the malleoli. Because of relatively poor circulation, compounded by sickling and microinfarcts, healing is delayed and infection is established.

• Priapism is a serious complication and tends to occur repeatedly. When it is prolonged, it may lead to impotence.
• Pregnancy represents a special area of concern. The high rate of fetal loss is due to spontaneous abortion. Placenta previa and abruption are common due to hypoxia and placental infarction. At birth, the infant often is premature or has low birth weight.

Physical

• Physical findings are not specific.
• • Scleral icterus is present, and, upon ophthalmoscopic examination of the conjunctiva with the +40 lens, abnormal or corkscrew-shaped blood vessels may be seen.
  • The mucous membranes are pale.
  • A systolic murmur may be heard over the entire precordium.
  • In childhood, splenomegaly is present, although this is not present in adults due to autosplenectomy. In adulthood, leg ulcers may be found over the malleoli.

Causes

• SCD originated in West Africa, where it has the highest prevalence.
• • It also is present to a lesser extent in India and the Mediterranean region.
  
  
  • DNA polymorphism of the beta S gene suggests that it arose from 5 separate mutations, 4 in Africa and 1 in India and the Middle East.
    
    
    • The most common of these is an allele found in Benin in West Africa.
    
    
    • The other haplotypes are found in Senegal and Bantu, Africa, as well as in India and the Middle East.


• The Hb S gene, when present in homozygous form, is an undesirable mutation, so a selective advantage in the heterozygous form must account for its high prevalence and persistence.
• • Malaria is possibly the selecting agent because a concordance exists between the prevalence of malaria and Hb S. Sickling might protect a person from malaria by either of the following:
    
    
    • Accelerating sickling so that parasitized cells are removed
    
    
    • Making it more difficult for the parasite to metabolize or to enter the sickled cell
  
  
  • While children with sickle cell trait Hb SA seem to have a milder form of falciparum malaria, those with homozygous Hb S have a severe form that is associated with very high mortality rate.

DIFFERENTIALS

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Other Problems to be Considered

Other causes of vasoocclusive disease
Valvular heart disease

WORKUP

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Lab Studies

• Complete blood cell count
• • CBC and reticulocyte counts document anemia and brisk marrow response.
  • Examination of the peripheral blood smear documents the presence of sickled erythrocytes.

• Differential white blood cell count
• Reticulocyte percentage: CBC and reticulocyte counts document anemia and brisk marrow response.
• Hemoglobin electrophoresis: It establishes the diagnosis of SCD by demonstrating a single band of Hb S (in Hb SS) or Hb S with another mutant hemoglobin in compound heterozygotes.
• Liver function tests, as well as BUN, creatinine, and serum electrolytes
• Fetal hemoglobin
• Lactic dehydrogenase and haptoglobin
• • These are useful but not required.
  • Elevated levels of lactic dehydrogenase support the diagnosis of hemolysis being released from destroyed RBCs.
  • Decreased levels of haptoglobin confirm the presence of hemolysis.

Imaging Studies

• Radiograph may demonstrate areas of infarction for painful bones.
• Magnetic resonance imaging (MRI) demonstrates areas of avascular necrosis for the femoral and humeral heads and may distinguish between osteomyelitis and bony infarction for painful bones.
• Abdominal sonogram is useful to document spleen size and the presence of biliary stones.
• Transcranial Doppler ultrasonography is very useful in selecting patients at risk for stroke to participate in a chronic transfusion program. Values outside the reference range depend on the method used and are lower for duplex Doppler (180 cm/s) than for non–duplex Doppler (200 cm/s). All children with SCD should be tested.

Other Tests

• Adults should be tested for evidence of pulmonary hypertension with Doppler echocardiography.
• Less common double heterozygotes may be documented by additional special laboratory tests. The presence of sickled cells in the peripheral blood smear is a strong indicator of the diagnosis. RBCs containing nuclear remnants (Howell-Jolly bodies) are present and are a corollary of splenic malfunction; however, most routine labs now use automated methods, and the blood smear is not examined visually. The level of Hb F should be measured by alkali denaturation.

TREATMENT

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Medical Care

Probably no other disease in existence has as much scientific information and knowledge available as SCD. The genetics, pathophysiology, and molecular biology of SCD are well established. Even so, no safe, effective, and curative therapy is available. The goals of treatment strategies are symptom control and management of disease complications. Treatment strategies include the following 7 goals: (1) management of vasoocclusive crisis, (2) management of chronic pain syndromes, (3) management of the chronic hemolytic anemia, (4) prevention and treatment of infections, (5) management of the complications and the various organ damage syndromes associated with the disease, (6) prevention of stroke, and (7) detection and treatment of pulmonary hypertension.

• Vasoocclusive crisis is treated with vigorous hydration and analgesics.
  • Intravenous fluids should be of sufficient quantity to correct dehydration and to replace continuing loss, both insensible and due to fever.

  • Normal saline and 5% dextrose in saline may be used.

  • These fluids should be given intravenously, and treatment must be in an inpatient setting.

• Pain control is best achieved by the administration of opioids.
  • Morphine is the drug of choice. Morphine dosing has to be individualized (vide infra).
    • It should be given intravenously, hourly at first. Once the effective dose is established, it should be administered every 3 hours via the intravenous regimen.

    • After 24-48 hours, as pain is controlled, equivalent doses of sustained-release oral morphine should be given.

    • When marked improvement occurs, the patient may be discharged home on sustained-release oral morphine, and the dose is reduced gradually over several days.

    • Morphine elixir can be used to control breakthrough pain.

  • Chronic pain is managed with long-acting oral morphine preparations and acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs).
    • NSAIDs are particularly effective in reducing deep bone pain. Many patients may require breakthrough oral opiates as well. The weak agents, codeine and hydrocodone, are used first. Sustained-release long-acting oral morphine is reserved for more severe cases.

    • The addition of tricyclic antidepressants may reduce the dose and need for opiates by interfering with pain perception. Many patients with chronic pain are depressed, and lifting the depression has a salutary effect on the pain.

  • Hydromorphone may be used but is considerably more expensive.

  • Meperidine should be avoided.

  • Nonpharmacological approaches to pain management are very important.
    • These include physical therapy, heat and cold application, acupuncture and acupressure, hypnosis, and transcutaneous electric nerve stimulation (TENS).

    • Support groups are also useful.

    • All of these modalities may have a substantial impact on pain reduction.
• Prevention of infection improves chances of survival in SCD.
  • Penicillin prophylaxis, commencing in infancy and continued until age 5 years or early teens, and the use of a pneumococcal vaccine at age 2 years with a booster dose at age 5 years greatly reduces the frequency of infections with S pneumoniae.

  • In the adult patient, all infections must be treated promptly with broad-spectrum antibiotics until a causative organism is identified and therapy is tailored according to its antibiotic sensitivity.

• Allogeneic bone marrow transplantation (BMT) can cure the disease, but it is difficult to decide which patients should be offered BMT.
  • Many risks are associated with BMT, and the risk-to-benefit ratio must be assessed carefully.

  • With the advent of cord blood stem cell transplantation and with the development of less immunoablative conditioning regimens, perhaps BMT will gain wider acceptance and use.

  • The lack of availability of a matched donor may limit the utility of BMT.
• Although several attempts have been made to treat SCD with pharmacological agents over the years, the only drug currently approved by the US Food and Drug Administration (FDA) for the treatment of SCD is hydroxyurea.
• • Hydroxyurea increases the production of Hb F, which retards gelation and sickling. The Hb level rises, and the frequency and severity of vasoocclusive crisis declines, sometimes being eliminated altogether. The reduction in the circulating leukocytes decreases the adherence of neutrophiles to the vascular endothelium.

  • A decrease in chronic pain and the reticulocyte count occur.

  • Hydroxyurea is a potentially leukemogenic and carcinogenic agent.
    • Potential complications referable to long-term use are not yet known.

    • Its use also requires frequent blood testing and monitoring, with special attention to development of leukopenia and/or thrombocytopenia.

    • Children studied by a cooperative group remained on hydroxyurea for more than a year with only minor adverse effects.

  • A rigorous selection of patients for hydroxyurea treatment is required.
    • Candidates for this treatment have frequent painful crises (6 or more per year), severe unremitting chronic pain that cannot be controlled by conservative measures, acute chest syndrome, and a history of stroke or a high risk for stroke.

    • A good continuous doctor-patient relationship and rapport must exist to ensure that potential toxicity is identified at its onset.

• Investigational treatments
  • Oral glutamine has been used to decrease resting energy expenditure in children.

  • Nitric oxide inhalation has been investigated in the treatment of pulmonary hypertension.

  • Topical GM-CSF has been reported to hasten the healing of leg ulcers.

  • Butyrate was studied to decrease vasoocclusive crisis.

  • Arginine has been proposed to use as a precursor of nitric oxide production.

• Anemia is usually well tolerated.
• • Because of the high turnover, folate stores are often depleted. Folic acid supplementation may raise the Hb level and support a healthy reticulocyte response.

  • Women who are menstruating should be checked for coexisting iron deficiency and, if found, given iron supplements.

  • An adequate overall diet is essential.

  • Blood transfusion is indicated only in specific situations. These include acute chest syndrome, stroke, abnormal findings on transcranial Doppler in children (for stroke prevention), pregnancy, and general anesthesia.
    • The aim is to decrease the concentration of Hb S to 30% or less.

    • Transfusion may also be required during aplastic crisis.

    • Chronic and repeated transfusion leads to alloimmunization and iron overload and is associated with the risk of transfusion-transmitted infectious agents.

Surgical Care

• Surgical care is limited to treating disease complications.
• • Skin grafts can help heal chronic leg ulcers.
  • Hip replacement or other orthopedic procedures can be used to treat avascular necrosis.
  • Resistant priapism may require surgical draining of the penile corpora. If impotence occurs, insertion of a penile prosthesis may be considered.
  • Cholecystectomy may be needed for gallstones, whether acute cholecystitis is present or not. Use either the classic abdominal incision or laparoscopy.

Consultations

• Consultation with infectious disease specialists is recommended during febrile illness.
• Consultations with pain management experts, social workers, psychiatrists and physical therapists, substance abuse counselors, vocational rehabilitation workers, and orthopedists may be required.
• Each protean manifestation of SCD requires assistance from an expert in the involved area.

Diet

• A general well-balanced diet is required. No restrictions are necessary.

Activity

• Although activity is unrestricted, patients may not be able to tolerate vigorous exercise or exertion.
• Patients with avascular necrosis of the femur may not be able to tolerate weightbearing and may be restricted to bed rest.
• Patients with chronic leg ulcers may need to restrict activity that involves raising the legs.

MEDICATION

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The drugs used in treatment of SCD include antimetabolites, analgesics, antibiotics, and vaccines.

Drug Category: Antimetabolites

Hydroxyurea affects DNA. Administration results in increased production of Hb F, which inhibits sickling.

Drug Category: Opioid analgesics

Used to control acute crisis and chronic pain.

Drug Category: Nonsteroidal analgesics

Add to effects of opioids during painful crisis and allow use of lower doses of narcotics.

Drug Category: Vitamins

Folic acid replenishes depleted folate stores secondary to hemolysis and is necessary for erythropoiesis.

FOLLOW-UP

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Further Outpatient Care

• Long-term follow-up is required for patients with SCD. This is a lifelong disorder.
• The frequency of outpatient visits depends on the patient's clinical status.
• • For patients with minimal symptoms, a visit with blood work every 3-4 months is reasonable.
  • Others may need much more frequent observation.

• Educate all patients to recognize signs of infection, increasing anemia, and organ failure.
• Treat all infections, even trivial ones, very promptly and vigorously.
• Institute pain medication at the earliest symptoms of a vasoocclusive crisis.
• Patients on a chronic transfusion program must adhere to iron chelation therapy.
• Social services, occupational therapy, and counseling are essential elements in the long-term management of patients with SCD.

In/Out Patient Meds

• Hydroxyurea should be continued for patients who are selected to receive this drug.
• A long-acting NSAID is given to patients with chronic pain.
• A weak opioid, such as codeine or hydrocodone, is given to some patients with chronic pain.
• Folic acid is given to all patients.

Deterrence/Prevention

• Forty-four US states now screen for Hb S at birth. This method of case finding allows institution of early treatment and control.
• Prenatal diagnosis is also available. The laboratory procedures employed in prenatal testing are sensitive and rapid. Prenatal testing must be accompanied with genetic and psychological counseling.
• • DNA prepared from a biopsy of chorionic villi can be obtained at 8-12 weeks' gestation. This low-risk procedure is safe.
  • DNA from amniotic fluid cells can be examined at 16 weeks' gestation.
  • Investigational attempts are ongoing to isolate fetal cells from maternal blood for DNA assay.

Complications

• Acute chest syndrome is managed with analgesics, oxygen, antibiotics, and transfusion.
• • The aim is to reduce the concentration of Hb S to less than 30%.

  • If the hematocrit is 30% or higher, an exchange transfusion must be performed. This can be done by removing 1 unit of blood, transfusing 1 unit, and repeating the process or by using a continuous-flow phoresis machine.

• Strokes are managed with general support and transfusion.
• • The aim is to lower the concentration of Hb S to less than 30%.

  • An exchange transfusion may be required.

  • Because of the devastating neurological defect that may result, emphasis is placed on prevention.
    • Children should be tested using transcranial Doppler ultrasonography.

    • Those with increased flow are at risk for stroke and should be considered for a chronic transfusion program.

    • As patients grow into adulthood, the transfusion frequency may be decreased, but whether it can be discontinued remains unclear.

• Leg ulcers are treated with debridement and antibiotics.
• • Zinc oxide occlusive dressing (Unna boot) and leg elevation are employed.

  • Transfusion may accelerate healing.

  • Skin grafting may be necessary in recalcitrant cases.

• Avascular necrosis of the femoral and humeral heads is treated by not bearing weight at the site.
• • The patient may need to make career and lifestyle adjustments.

  • Occupational retraining and physical therapy may be needed.

  • In many cases, surgical intervention with hip replacement or other orthopedic procedures are needed.

• Chronic renal failure is managed with dialysis in the same manner as end-stage renal disease due to other causes.

• Priapism is treated with analgesics and hydration. Persistent priapism may require surgical evacuation of the penile corpora. If impotence results, insertion of a penile prosthesis is indicated.

• Chronic use of opioids leads to tolerance and habituation. Periodic attempts at withdrawal should be undertaken.
• • Drug addiction is uncommon among patients with SCD.

  • When drug addiction with substance abuse is present, difficult management problems ensue that require a team approach involving counselors, substance abuse specialists, hematologists, and pain management experts.

Prognosis

• Because this is a lifelong disease, prognosis is guarded. The goal is to achieve a normal life span with minimal morbidity.
• As therapy improves, the prognosis also improves.

Patient Education

• Patients must be educated about the nature of their disease. They must be able to do the following:
• • Recognize the earliest signs of a vasoocclusive crisis and seek help.
  
  
  • Treat all infections promptly.
  
  
  • Identify environmental hazards that may precipitate a crisis.


• Patients on hydroxyurea must be educated on the importance of regular follow-up with blood counts.


• Patients (including asymptomatic heterozygous carriers) should understand the genetic basis of the disease, be educated about prenatal diagnosis, and know that genetic counseling is available.


• For excellent patient education resources, see eMedicine's patient education articles Sickle Cell Crisis and Anemia.

MISCELLANEOUS

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Special Concerns

• Acute abdomen must be ruled out during painful abdominal vasoocclusive crisis.

• Sickling variants and sickle trait must be distinguished from Hb S disease.
• • Hb S exists in combination with other hemoglobins in a double heterozygous state. The clinically important diseases involved, observed in patients in the United States, are Hb C and beta thalassemia.
  • Hb SC disease is a milder sickling disorder. It is present in 1 in 1100 African Americans.
    • In the Hb C mutation, lysine replaces glutamic acid in position 6 on the beta chain. Hb A is not present. The RBCs contain 50% Hb S and 50% Hb C.

    • Anemia is much milder, with Hb levels of 11 g/dL or higher.

    • Symptoms are similar to SCD but less frequent and less severe.

    • Splenomegaly often persists well into adult life. Aseptic necrosis of the femoral head is not more common than in SCD.

    • A proliferative retinopathy may lead to progressive loss of vision.

    • The diagnosis is made with Hb electrophoresis. The peripheral blood smear may have some sickled cells and a high proportion of target cells. In addition, microcytic, dehydrated, dense RBCs are seen. These may contain crystal-like condensations.

    • Treatment and management strategies are similar to those employed in Hb S disease.
  • In Hb S-beta 0 thalassemia, only Hb S is found on electrophoresis. Hb A₂ is elevated and splenomegaly usually is present. The clinical picture is similar to SCD but is slightly less severe. Management is similar to that for SCD.

  • In Hb S-beta+ thalassemia, Hb A is present, usually between 10% and 30%. The spleen is usually enlarged. It is otherwise similar to SCD but is a milder disease.

• Sickle cell trait is the heterozygous carrier state of Hb S. These individuals have approximately 40% Hb S and 60% Hb A, less so with coexisting alpha-thalassemia trait.
• • People with sickle trait generally are well and have the following characteristics:
    • Normal life expectancy

    • Not at excessive risk for infection

    • Not subject to painful crisis under normal circumstances

    • No anemia
  • Nevertheless, providing genetic counseling to prospective parents with sickle cell trait is important.
  • Reports exist of excessive deaths under extreme conditions, such as military basic training involving strenuous exertion; however, this is very uncommon.
  • Similarly, isolated reports exist of organ infarction and crisis under unusual circumstances. Many of these patients lose urine-concentrating capacity. Painless hematuria may be present.

• Hb S variants may occur as double heterozygotes with other Hb variants. These include Hb D, Hb E, and Hb O Arab. These are observed very infrequently in the United States, and information about them can be found in hematology texts.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Molecular and cellular changes of hemoglobin S.
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Media file 2:  Peripheral blood with sickled cells at 400X magnification. Image courtesy of Ulrich Woermann, MD.
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Media file 3:  Peripheral blood smear with sickled cells at 1000X magnification. Image courtesy of Ulrich Woermann, MD.
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Media file 4:  Peripheral blood smear with Howell-Jolly body, indicating functional asplenism. Image courtesy of Ulrich Woermann, MD.
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Media file 5:  Effects of therapy with hydroxyurea.
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Media type:  Image

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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