Sickle Cell Disease - ClinicalKey

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FIRST CONSULT

Sickle cell diseasePublished: May 12, 2010

Copyright Elsevier BV. All rights reserved.

Summary

Description

Sickle cell anemia is a disease of the erythrocytes caused by an autosomal recessive single

gene defect in the β-globin chain of adult hemoglobin (HbA) that produces a mutant form o

hemoglobin known as sickle hemoglobin (HbS)

Sickle cell anemia occurs if HbS is inherited from both parents (HbSS genotype). Other

forms of sickle cell disease may occur if HbS is inherited from one parent and another

abnormal hemoglobin, such as hemoglobin C (HbC), or β-thalassemia is inherited from the

other parent (resulting in HbSC or HbSβ-thalassemia genotype, respectively)

The term sickle cell anemia refers to HbSS disease, whereas the term sickle cell disease

refers to all of the genotypes

HbS confers abnormal properties to erythrocytes; the cells break apart easily, and theircharacteristic crescent shape can disrupt blood flow

HbS is associated with varying degrees of anemia; a predisposition to obstruction of small

blood capillaries, causing painful (vaso-occlusive) crises; damage to major organs; and

increased vulnerability to severe infections

One of the most commonly inherited diseases worldwide, sickle cell disease is predominant

in certain ethnic groups, particularly African and African-American populations

Sickle cell trait or disease offers a protective effect against malaria. In malaria-endemic

regions, this has led to positive selection of the genetic mutation

A holistic approach to treatment is recommended, with an emphasis on patient education

and guidance on home management as well as on immediate clinical needs

Bone marrow transplantation is the only curative treatment

Associated with lifelong morbidity and reduced life expectancy


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Synonyms

Sickle cell anemia

Hemoglobin S disease

Urgent action

Dehydration: fluid replacement therapy is required, as most patients are mildly dehydrated

due to urine-concentrating difficulties, which can be exacerbated by increased sodium losseduring painful crises and by concurrent infection

Complications: urgent specialist referral and emergent management are required for painfu

crisis; swollen, painful joints; central nervous system deficits; acute sickle chest syndrome o

pneumonia; mesenteric sickling and bowel ischemia; splenic or hepatic sequestration;

cholecystitis; renal papillary necrosis resulting in colic or severe hematuria; priapism; and

hyphema and retinal detachment

Fever: consider specialist referral for fever, as infection may precipitate an acute painfulcrisis

Key points

Sickle cell anemia is characterized by abnormal erythrocytes containing HbS, which is

formed as the result of a single gene defect causing the substitution of valine for glutamic

acid in position six of the β-globin chain of hemoglobin

Specialist referral and emergent management are required for painful crisis; swollen, painf

joints; central nervous system deficits; acute sickle chest syndrome or pneumonia;

mesenteric sickling and bowel ischemia; splenic or hepatic sequestration; cholecystitis; ren

papillary necrosis resulting in colic or severe hematuria; priapism; and hyphema and retina

detachment

Infants diagnosed with sickle cell disease should receive standard well-child care,

immunizations, and prophylactic penicillin, with meticulous attention to counseling the

parent or caregiver regarding taking the infant's temperature and being observant for signs

and symptoms that might indicate an evolving illness

The Advisory Committee on Immunization Practices recommends that pneumococcal

polysaccharide vaccine be administered in all immunocompetent persons over age 2 who a

at increased risk of illness and death from pneumococcal disease owing to chronic illness,

including sickle cell disease

Many patients with sickle cell disease can be considered to be functionally asplenic

beginning in early childhood, owing to the repetitive sickling and subsequent infarctions

within the spleen


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Background

Cardinal features

Sickle cell anemia is a disease of the erythrocytes caused by an autosomal recessive single

gene defect in the β-globin chain of HbA that produces HbS

Sickle cell anemia occurs if HbS is inherited from both parents (HbSS genotype). Other

forms of sickle cell disease may occur if HbS is inherited from one parent and anotherabnormal hemoglobin, such as HbC, or β-thalassemia is inherited from the other parent

(resulting in HbSC or HbSβ-thalassemia genotype, respectively)

HbS confers abnormal properties to erythrocytes; the cells break apart easily, and their

characteristic crescent shape can disrupt blood flow

HbS is associated with varying degrees of anemia; a predisposition to obstruction of small

blood capillaries, causing painful crises; damage to major organs; and increased

vulnerability to severe infections

The most common acute clinical presentation is painful crisis

Neonates are usually asymptomatic, and clinical manifestations only become apparent as t

levels of fetal hemoglobin (HbF) decline during the first few months of life

One of the most commonly inherited diseases worldwide, sickle cell disease is predominant

in certain ethnic groups, particularly African and African-American populations

Sickle cell trait or disease offers a protective effect against malaria. In malaria-endemic

regions, this has led to positive selection of the genetic mutation

A holistic approach to treatment is recommended, with an emphasis on patient education

and guidance on home management as well as on immediate clinical needs

Bone marrow transplantation is the only curative treatment

Causes

Common causes

Sickle cell anemia is a genetic disorder caused by an autosomal recessive single gene

defect in the β-globin chain of HbA, which produces HbS

HbS is formed by the substitution of valine for glutamic acid in position six of the β-

globin chain of hemoglobin. Erythrocytes containing HbS have abnormal properties

Individuals who are homozygous for sickle cell hemoglobin (HbSS) have a constellation

signs and symptoms that characterize sickle cell anemia


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Individuals who are heterozygous for HbS are carriers of the sickle cell trait and do not

have painful crises

HbS may also be paired with other abnormal hemoglobins, such as HbC or β-thalassemi

These patients have sickle cell disease and will have varying clinical courses and disease

severity

Epidemiology

Incidence and prevalence

Incidence

4,000 to 5,000 pregnancies are at risk for sickle cell disease each year in the U.S.

6 to 9 million infants are born each year with sickle cell disease in Africa

Sickle cell disease occurs in 1 in 600 African-American infants

Sickle cell anemia accounts for 60% to 70% of sickle cell disease in the U.S.

Prevalence

Highest prevalence among people of African, African-American, Mediterranean

(Italian, Sicilian, Greek), Middle Eastern, East Indian, Caribbean, and Central or Sou

American descent

8% to 10% of African-American neonates in the U.S. are carriers of the sickle cell trai

25% to 30% of neonates in western Africa are carriers of the sickle cell trait

Demographics

Age

Affected patients characteristically are asymptomatic until approximately 4 to 6

months of age

Median age at death is approximately 42 years for men and 48 years for women

Race

Highest prevalence among people of African, African-American, Mediterranean

(Italian, Sicilian, Greek), Middle Eastern, East Indian, Caribbean, and Central or Sou

American descent

Occurs more commonly in people (or their descendants) from parts of the world such

as Sub-Saharan Africa, where malaria is or was common, but it also occurs in people o

other ethnicities


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Genetics

Sickle cell anemia is a genetic disorder caused by an autosomal recessive single gene

defect in the β-globin chain of HbA, which produces HbS

HbS is formed by the substitution of valine for glutamic acid in position six of the β-

globin chain of hemoglobin. The valine, which is now abnormally present on the β-

globin chain of one hemoglobin molecule, can fit in the hydrophobic pocket of anothe

hemoglobin molecule. Once this process starts, the hemoglobin polymerizes within therythrocyte, and this is what causes the erythrocyte to change into its classically

described sickle shape

Hemoglobinopathies are highly prevalent in malaria-endemic areas. It is thought tha

the abnormal hemoglobin provides a survival advantage, and that is why the mutation

has survived

Usually the parents of an individual with HbSS are heterozygotes and, therefore, carr

only one HbS allele and are asymptomatic. However, because of the high rate of HbScarriers in certain populations, it is possible that a parent may be homozygous (HbSS

or a compound heterozygote ( eg , HbSC)

If both parents are heterozygous for the HbS mutation (carriers), the risk of having an

affected child is 25% for each pregnancy

If one parent is homozygous (HbSS) and the other parent is heterozygous (HbS), the

risk of having an affected child is 50% for each pregnancy

If both parents are homozygous (HbSS), all offspring will be affected

If at-risk siblings of a proband are unaffected, the risk of a child being a heterozygote

(carrier) is two thirds

Each sibling for either of the proband's parents is at 50% or greater risk of being a

heterozygote. Therefore, a thorough family history should be obtained to determine i

other hemoglobinopathies ( eg , β-thalassemia) are present in family members

HbS confers a significant protective advantage (>90% in some studies) against severe

and lethal malaria. Although the malarial parasite, Plasmodium falciparum , invades

and matures in a similar fashion as seen in normal erythrocytes, enhanced

phagocytosis occurs in HbS carriers, causing premature removal of the infected cells.

An immunologic component directed at the P. falciparum erythrocyte membrane

protein 1 may further enhance this protective effect. A study investigating the

association between HbS and HbC carrier states and malaria found a negative

correlation between HbS carrier states and all major forms of severe malaria, but the

negative correlation for HbC carrier states was limited to cerebral malaria


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HbSS disease pathology:

HbS is formed by the substitution of valine for glutamic acid in the second nucleotide

of the sixth codon of the β-globin chain of HbA. This single-point mutation changes th

codon determining the amino acid from GAG coding for glutamic acid to GTG coding

for valine

Erythrocytes containing mutant HbS have abnormal properties. Although the mutant

β-hemoglobin subunits are normal in their ability to bind oxygen, they are

considerably less soluble in deoxygenated blood than normal hemoglobin. As such, an

under conditions of low oxygen tension, interaction between the abnormal valine

residue and complementary regions on adjacent molecules results in the formation of

intracellular, rod-shaped polymers. These abnormal hemoglobin polymers aggregate

to disrupt the cytoskeleton and distort the shape of the erythrocytes, making them

brittle and poorly deformable. Thus, unlike normal erythrocytes, the sickle-shaped

cells cannot squeeze through the microcirculatory vessels, blocking blood flow and

resulting in local hypoxia

In addition to causing the obvious shape change, HbS is also injurious to the

erythrocyte membrane. The hemoglobin polymers disrupt the attachment of the

membrane to the protein cytoskeleton, resulting in exposure of transmembrane

protein epitopes and negatively charged glycolipids that are normally found inside th

cell. Subsequent effects of this exposure include cellular dehydration, oxidative

damage, increased adherence to endothelial cells, and a state of chronic inflammation

and hemolysis

Codes

ICD-9 code

282.60 Sickle cell disease, unspecified

282.61 HbSS disease without crisis

282.62 HbSS disease with crisis

282.63 Sickle cell disease/HbC disease without crisis

282.68 Other sickle cell disease without crisis

282.69 Other sickle cell disease with crisis

282.41 Sickle cell thalassemia without crisis

282.42 Sickle cell thalassemia with crisis


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Diagnosis

Clinical presentation

Infants are usually asymptomatic until 4 months of age, when hemolytic anemia may first

become apparent. They may present with symptoms of moderate anemia by 6 to 12 months

of age or with more serious crisis and pain. Painful swelling of the hands and feet, known a

hand-foot syndrome or dactylitis, is often one of the first presentations of sickle cell disease

Clinical features vary greatly from patient to patient and may be due either to the acute vas

occlusive consequences of sickle cells or the chronic hemolysis and resultant anemia. Some

individuals may remain totally asymptomatic into late childhood, or the diagnosis may be

arrived at only incidentally

Symptoms

Chronic:

Excessive tiredness and fatigability

Pain, particularly in the back and hips but can occur anywhere

Breathlessness on exertion

Decreased exercise tolerance

Growth and developmental delay

Jaundice

Visual disturbances, especially new onset of floaters

Acute:

Acute chest syndrome: chest pain and fever

Painful crises: persistent pain, particularly in the skeleton, chest, and/or abdomen but

can be almost anywhere

Infection: malaise, cough and chest pain, diarrhea and/or vomiting

Dactylitis: swollen and painful hands and feet (by 2 years of age, 50% of Jamaican

children and 25% of American children with sickle cell anemia have experienced at least

one episode)

Splenic sequestration: abdominal discomfort due to splenomegaly and trapping of

erythrocytes in the spleen


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Stroke (affects 10% of patients; 6%-17% of children and young adults): sudden neurologi

deficits, including motor deficits; difficulty with language, writing, and/or reading;

seizures; sensory deficits; altered consciousness

Cholecystitis : hemolysis leads to pigment stones in the gallbladder; presents with jaundic

and abdominal pain

Loss of vision: can be preceded by floaters

Priapism

Signs

Chronic:

Notable impairment of growth and development

Hepatomegaly and/or splenomegaly

Pallor

Jaundice

Cardiomegaly, a hyperdynamic precordium, and a grade II-III systolic ejection murmur

Ocular abnormalities—proliferative retinopathy, retinal neovascularization ('sea fan'),

retinal hemorrhage

Leg ulcers, typically appearing as a shallow depression with a smooth and slightly elevated margin and a surrounding area of edema

Bony deformities of different types

Pale urine due to impaired urine-concentrating ability

Acute:

Anemia: pallor

Acute chest syndrome: sickling of erythrocytes within the pulmonary vasculature, which

can be clinically indistinguishable from pneumonia and can cause chest pain, fever,

dyspnea, tachypnea, and hypoxemia

Infection: oral temperature above 38.5°C (101.3°F), cough, watery stools, tender

abdomen

Dactylitis: swollen dorsa of hands and feet, which can be a presenting symptom in infan

and children


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Bone infarction and avascular necrosis (particularly of the femoral head): from vaso-

occlusive crisis, causing limited range of motion of the affected joint

Priapism: sustained and painful penile erection (occurs in 50% of all male patients)

Aplastic crisis: transient cessation of erythrocyte production, often triggered by a viral

infection and characterized by pallor, tachypnea, and tachycardia without splenomegaly

Splenic sequestration: splenomegaly, pallor, tachycardia, and possible shock fromtrapping of erythrocytes in the spleen

Stroke : mental status changes, neurologic deficits

Associated disorders

Nearly every organ system may be affected. Examples of associated disorders include:

Ocular: retinal hemorrhage, retinopathy, and/or blindness

Cardiac: congestive heart failure

Pulmonary: pulmonary hypertension , pulmonary embolism

Hepatic: hepatic infarction or hepatitis resulting from transfusion; cirrhosis from

transfusion-related iron overload; sickle intrahepatic cholestasis; hepatic sequestration

Gallbladder: increased incidence of pigment gallstones

Urinary: hyposthenuria, hematuria, renal papillary necrosis, chronic kidney disease , gout

Genital: decreased fertility, impotence

Neurologic: stroke

Skeletal: avascular necrosis, skull bossing, gnathopathy, and other bony deformities;

osteomyelitis

Differential diagnosis

The differential diagnosis of sickle cell anemia is dependent on the symptoms of the patient at

presentation.

Disorders involving the joints

Sickle cell disease can present with swollen joints in a child. Swelling of the joints as a

manifestation of a vaso-occlusive crisis is less common in adults. Dactylitis presents at an earl

age and occurs only in the hands and feet, which can help differentiate it from other


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rheumatologic diseases. Joint swelling in an adult requires more extensive evaluation. Adults

usually know what their typical pain feels like, and further workup is warranted when pain is

atypical.

Features

Gout : can be seen in patients with sickle cell disease who have associated renal diseas

workup should include joint aspiration to look for monosodium urate crystals

Septic arthritis : features include painful swelling of the affected joint and fever; further

evaluation with a bone scan or magnetic resonance imaging (MRI) may be indicated

Connective tissue diseases: often present with painful joints; serologic workup should

be done to exclude these diseases in patients with atypical pain or other associated

findings ( eg , rash)

Avascular necrosis: presents with pain typically in the hip or shoulder and can be

differentiated from a vaso-occlusive crisis by its chronicity; if suspected, MRI of the

affected joint can confirm the diagnosis

Acute abdominal disorders

Abdominal pain crises owing to small infarct of the abdominal viscera must be differentiated

from other acute abdominal disorders. Differential diagnoses for right upper quadrant

abdominal pain in a patient with sickle cell disease are extensive and include acute cholelithias

hepatic crises, hepatic sequestration, sickle cell intrahepatic cholestasis, biloma, hepatic vein

thrombosis, pancreatitis , pulmonary infarct, renal vein thrombosis, and focal nodular

hyperplasia of the liver in children. Full workup, including complete blood count (CBC),

comprehensive blood panel, amylase, lipase, and urinalysis, should be done in these patients.

Radiologic imaging, such as ultrasound or computed tomography (CT) scan of the abdomen,

may be useful in some cases to distinguish vaso-occlusive crises from acute abdominal

disorders.

Features

Severe abdominal pain

Signs of peritoneal irritation

Absence of bowel sounds

Osteomyelitis

Painful bone episodes in patients with sickle cell anemia are clinically indistinguishable from

those experienced by patients with osteomyelitis ; magnetic resonance bone scans using

technetium and gallium staining can be helpful in confirming a diagnosis.


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Features

Multifocal symptoms are uncommon

Positive blood culture results for Salmonella species, Staphylococcus aureus , and/or

Streptococcus pneumoniae favor the diagnosis of osteomyelitis

Presence of fever is more consistent with osteomyelitis, although fever may be presen

if a vaso-occlusive crisis is brought on by infection, making it difficult to distinguish

between the two

Pain is usually isolated to one spot and often does not resolve within the same amoun

of time as a typical vaso-occlusive crisis

Other severely painful medical conditions

The most predominant clinical symptom of sickle cell disease is recurrent episodes of pain

involving the chest, abdomen, and skeleton. The pain can be similar to that experienced in

other conditions, such as pulmonary embolism or renal colic. A careful history and physicalexamination can often help distinguish between a vaso-occlusive crisis and a more serious

complication.

Congenital syphilis

Congenital syphilis is acquired in utero by offspring of women with untreated syphilis during

pregnancy. In early infancy, children with congenital syphilis may present with dactylitis or

osteitis that mimics sickle cell dactylitis. If congenital syphilis is suspected, maternal syphilis

testing can aid in diagnosis.

Features

Usually presents with rhinitis followed by a diffuse, desquamating maculopapular

rash, which may become vesicular

Radial skin lesions around the mouth are common

Bone involvement is common; radiographic abnormalities may include multiple area

of osteitis; osteochondritis; and periostitis of the long bones and, rarely, the skull

Osteochondritis is painful and often results in irritability and refusal to move the

involved extremity

Splenomegaly, anemia, thrombocytopenia, and jaundice may result from hepatic

involvement

Immune-complex glomerulonephritis may result from renal involvement

Most cases of untreated congenital syphilis in infants who survive for 6 to 12 months


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progress to latent syphilis, and neurosyphilis develops later in life; some of the skelet

and soft tissue manifestations of congenital syphilis are permanent

Trauma

Painful crises of sickle cell disease may result in pain in the skeleton, chest, or abdomen, whic

may mimic trauma. Obtaining a history is usually very helpful, although a history of trauma is

not always obvious in infants. In the absence of a history, trauma is difficult to distinguish fro

infarction in patients with sickle cell disease, in whom peripheral blood smear frequently showsickle cell forms. If trauma is suspected in a child who cannot communicate, imaging of the

affected area, along with close observation, is helpful.

Features

Pain related to the site of trauma

Signs of injury or trauma

History consistent with symptoms

Workup

Diagnostic decision

In the U.S., universal neonatal screening is practiced in most states, as screening is the

only way to ensure that all infants with sickle cell disease are identified. Screening infan

only from specific racial or ethnic groups is not reliable

Blood samples should be collected before transfusion using the same method as for otheneonatal screening tests—by heel stick onto filter paper. Neonatal blood samples are ofte

collected and sent for analysis as a group to facilitate testing

Determination of an infant's hemoglobin type can be done by multiple laboratory

methods, but when the result is found to be abnormal, the laboratory must have a system

in place for rapid communication of results to the patient's health care provider

It is the physician's responsibility to ensure that the diagnosis is confirmed by

hemoglobin electrophoresis, along with a CBC, reticulocyte count, and blood smear

Appropriate referral to a specialty sickle cell clinic for education, genetic counseling, and

routine follow-up care is essential and should occur as soon as the diagnosis is establishe

Guidelines

The National Heart, Lung, and Blood Institute (http://www.nhlbi.nih.gov/)has produced the followin

The Management of Sickle Cell Disease

(http://www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf). NIH Publication No. 02-211

http://www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdfhttp://www.nhlbi.nih.gov/


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Bethesda, MD: National Heart, Lung, and Blood Institute; 2002

The British Society for Haematology (http://www.b-s-h.org.uk/)has produced the following:

Rees DC, Olujohungbe AD, Parker NE, Stephens AD, Telfer P, Wright J; British

Committee for Standards in Haematology General Haematology Task Force by the

Sickle Cell Working Party. Guidelines for the management of the acute painful crisis in sickle

cell disease (http://www.bcshguidelines.com/pdf/sicklecelldisease_0503.pdf). Br J Haematol.

2003;120:744-52

The American Academy of Family Physicians (http://www.aafp.org)has published the following:

Wethers DL. Sickle cell disease in childhood. Part I. Laboratory diagnosis, pathophysiology an

health maintenance (http://www.aafp.org/afp/20000901/1013.html). Am Fam Physician.

2000;62:1013-20

Wethers DL. Sickle cell disease in childhood: part II. Diagnosis and treatment of major

complications and recent advances in treatment (http://www.aafp.org/afp/20000915/1309.html) Am Fam Physician. 2000;62:1309-14

Yale SH, Nagib N, Guthrie T. Approach to the vaso-occlusive crisis in adults with sickle cell

disease (http://www.aafp.org/afp/20000301/1349.html). Am Fam Physician. 2000;61:1349-

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Don't miss!

Acute infections, which may be the cause of the crisis and can be treated with antibio

therapy

Acute abdominal problems, which may mimic a crisis or be the cause of a crisis

Questions to ask

Presenting condition

For parents or caregivers of an infant:

How long has the infant been unwell? Infants with sickle cell disease are usuallasymptomatic until 4 months of age and then often have symptoms of moderate

anemia or more serious crisis and pain by 6 to 12 months of age

Did the infant have jaundice at birth? Jaundice may be a chronic symptom of

sickle cell anemia

Has the infant ingested anything unusual? Drugs are a common cause of

hemolysis in infants

http://www.aafp.org/afp/20000301/1349.htmlhttp://www.aafp.org/afp/20000915/1309.htmlhttp://www.aafp.org/afp/20000901/1013.htmlhttp://www.aafp.org/http://www.bcshguidelines.com/pdf/sicklecelldisease_0503.pdfhttp://www.b-s-h.org.uk/


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Has the infant been growing well? Infants with sickle cell anemia may present

with failure to thrive and severe anemia and jaundice at approximately 6 months of a

Has the infant had a fever? Children with sickle cell anemia are susceptible to

acute infection due to damage to the spleen

Has the infant's abdomen been tender or appeared enlarged? Children with

sickle cell anemia may have hepatomegaly and/or splenomegaly

For older children and adults:

Have you always been pale? Have you been anemic? Have you ever had

jaundice? Pallor, intermittent icterus, and splenomegaly are common

Do you ever have pain in your stomach or joints? Patients may experience

persistent pain in the joints, skeleton, chest, and/or abdomen

Have you ever had swelling of your hands or feet? Dactylitis is common in

children with sickle cell anemia (by 2 years of age, 50% of Jamaican children and 25%

of American children with sickle cell anemia have experienced at least one episode)

Have you ever had a sustained, painful penile erection? Priapism occurs in

50% of all male patients

Have you ever had gallstones? Gallstones are a common complication of sickle

cell anemia due to increased levels of bilirubin in the blood

Have you ever had leg ulcers? Leg ulcers are a common complication of sickle ce

anemia, usually starting as small, raised, crusted sores on the lower third of the leg.

They occur more often in male patients than in female patients and usually occur in

patients over age 10. The cause of leg ulcers in these patients is unclear

Have you had a fever? Children with sickle cell anemia are susceptible to acute

infection due to damage to the spleen

For patients presenting with acute crisis:

Are you registered with a specialist clinic? All patients with sickle cell disease

should be registered with and monitored by a specialized sickle cell clinic. Sickle cell

clinics can provide important information on disease severity, past clinical

manifestations, and current and previous treatment regimen

Can you describe the severity, location, and duration of pain, if any? Acute

painful episodes represent the most frequent and prominent manifestation of sickle

cell disease, and frequent and rigorous pain assessment is required to ensure adequat

pain management


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Family history

Has either parent been diagnosed with sickle cell anemia or any other

hemoglobinopathy? Sickle cell disease is a hereditary condition involving a

recessive single gene defect of HbA

Have both parents been screened for sickle cell disease or thalassemia, or

is either parent aware of having another abnormal type of hemoglobin ( e

, HbC)? Individuals heterozygous for an abnormal hemoglobin gene areasymptomatic carriers who can pass the trait on to their offspring

Examination

Observe the patient for pallor and jaundice: indicative of hemolysis

Record presence or absence of a palpable spleen, and estimate and record

size of spleen: indicative of splenic sequestration

Record size of liver: indicative of hepatic sequestration

Note presence or absence of a cardiac murmur: indicative of cardiac

abnormalities owing to chronic anemia or a sudden change in hemoglobin level

Take measurements and note developmental stage: record and chart the patien

height, weight, and head circumference; record stage of sexual development (Tanner

stage)

Observe gait: note and record gait

Document pulse oximetry reading

Summary of tests

Prenatal diagnosis:

At-risk couples who are trying to conceive and women who are pregnant should be

offered genetic counseling to discuss available carrier detection methods and the option

of subsequent prenatal testing, if appropriate

Each parent should have full analysis of both β-globin alleles before prenatal testing is

done in the event that one parent may be a carrier of a non-HbS mutation that

predisposes to a different hemoglobinopathy ( eg , HbSβ-thalassemia or HbSC)

Methods such as isoelectric focusing and deoxyribonucleic acid (DNA)–based assays ma

be used in conjunction with high-performance liquid chromatography (HPLC) to detect

quantitative hemoglobin abnormalities, such as thalassemias

DNA analysis (ZDCDCD36_4E_145)is used for prenatal diagnosis; samples for testing are

https://ezproxy.uag.mx:2089/ZDCDCD36_4E_145


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usually obtained by chorionic villus sampling at 10 to 12 weeks of gestation or

amniocentesis at 14 to 18 weeks of gestation

A genetic counselor should always be consulted to advise and inform the parents

Testing of other family members should also be discussed once a diagnosis has been

established

Techniques for preimplantation diagnostic testing may be available for families in whichthe disease-causing mutations have been identified

Neonatal screening:

Routine neonatal screening for sickle cell anemia is done in all 50 states in the U.S., the

District of Columbia, Puerto Rico, and the Virgin Islands, allowing early diagnosis and

intervention (prevention of bacterial infection in particular)

Most screening programs favor universal testing rather than selective testing of at-risk

infants. The majority of new cases are diagnosed at birth

Hemoglobin studies (130224): blood samples are usually obtained by heel stick, and a

hemoglobin evaluation is done, usually within 3 days of birth. Confirmatory testing

should be done within 2 months

Hemoglobin solubility testing can be done at a follow-up appointment but is not

recommended in infants under 6 months of age because the high proportion of HbF in

relation to HbS in a neonate's blood may affect the results

Abnormal results can be confirmed by DNA analysis

Diagnosis in older children and adults:

CBC and reticulocyte count (ZDCE2683_185_26): may be used to evaluate the number and

quality of erythrocytes, hemoglobin content, and leukocyte count

Peripheral blood smear (59398): microscopic analysis of a blood specimen gives vital

information on erythrocyte morphology

Hemoglobin solubility testing (ZDCE1AE6_313_373): may be used first to screen for HbS;

however, it cannot distinguish between sickle cell trait (heterozygosity) and sickle cell

disease (homozygosity)

Hemoglobin studies (130224): used to define the specific hemoglobinopathy;

electrophoresis, isoelectric focusing, or HPLC are used to measure the type and relative

amounts of hemoglobin present in the erythrocytes. Indirectly, this allows the distinctio

between heterozygosity and homozygosity to be made

https://ezproxy.uag.mx:2089/130224https://ezproxy.uag.mx:2089/ZDCE1AE6_313_373https://ezproxy.uag.mx:2089/59398https://ezproxy.uag.mx:2089/ZDCE2683_185_26https://ezproxy.uag.mx:2089/130224


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DNA analysis (ZDCDCD36_4E_145): may be used to confirm the presence of sickle cell

disease or sickle cell trait. Family studies may also be done to identify sickle cell trait in

other family members

Iron studies (ZDCE26DD_201_114): may be indicated in patients presenting with anemia to

help determine whether iron deficiency is the cause

Further evaluation:

Baseline hemoglobin level, hematocrit, reticulocyte count, leukocyte count, hepatic and

renal function, and iron levels should be recorded and checked at least once a year

Urinalysis (1100141): should be done at least once a year because early signs of renal

disease can be insidious. Findings of microscopic hematuria or persistent proteinuria

should be investigated. Urinalysis should always be done in patients presenting with

acute abdominal pain to rule out acute infection or renal calculus as well as renal

thrombosis

Chemistry panel (1100147): electrolyte, blood urea nitrogen (BUN), and creatinine levels

should be obtained to look for manifestations of impairments in renal acidification and

potassium secretion as well as renal insufficiency due to sickle cell nephropathy

Bacterial cultures (130266): should be obtained as needed to exclude infection in toxic

and/or febrile patients

Chest radiograph (ZDD488F1_270_73): obtained in patients with acute chest syndrome to

exclude other disorders; should be considered in patients with respiratory symptoms,fever, or chest pain

Skeletal radiographs (59422): may be helpful in selected patients with a presumed painful

crisis not responding to standard therapy or in patients with pain that is atypical for sick

cell disease; can be used to look for avascular necrosis or osteomyelitis

Transcranial Doppler ultrasound (1100153): intracranial vessels, especially the carotid

arteries, are evaluated by Doppler flow studies to help assess the risk of stroke

Echocardiography (1100175): recommended to screen patients for pulmonary hypertensio

can be used to evaluate cardiac function as well as give an estimate of pulmonary

pressures

MRI (1100159)and bone scans (1100195)using technetium and gallium: can help

differentiate bone infarctions from osteomyelitis secondary to infection

Abdominal ultrasound (1100168): can be used to document spleen size and the presence of

biliary stones

https://ezproxy.uag.mx:2089/1100168https://ezproxy.uag.mx:2089/1100195https://ezproxy.uag.mx:2089/1100159https://ezproxy.uag.mx:2089/1100175https://ezproxy.uag.mx:2089/1100153https://ezproxy.uag.mx:2089/59422https://ezproxy.uag.mx:2089/ZDD488F1_270_73https://ezproxy.uag.mx:2089/130266https://ezproxy.uag.mx:2089/1100147https://ezproxy.uag.mx:2089/1100141https://ezproxy.uag.mx:2089/ZDCE26DD_201_114https://ezproxy.uag.mx:2089/ZDCDCD36_4E_145


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After 10 years of age, careful retinal examination (59437)should be done annually by an

ophthalmologist to assess for retinal disease

Order of tests

CBC and reticulocyte count (ZDCE2683_185_26)

Peripheral blood smear (59398)

Hemoglobin solubility testing (ZDCE1AE6_313_373)

Hemoglobin studies (130224)

DNA analysis (ZDCDCD36_4E_145)

Iron studies (ZDCE26DD_201_114)

Urinalysis (1100141)

Chemistry panel (1100147)

Chest radiograph (ZDD488F1_270_73)

Skeletal radiographs (59422)

Transcranial Doppler ultrasound (1100153)

Echocardiography (1100175)

Retinal examination (59437)

Bacterial cultures (130266)

MRI (1100159)

Bone scan (1100195)

Abdominal ultrasound (1100168)

Tests

Body fluids

CBC and reticulocyte count

Description

Venous blood sample

Laboratory analysis provides erythrocyte count, hemoglobin/hematocrit,

erythrocyte indexes, leukocyte count, platelet count, and reticulocyte count

https://ezproxy.uag.mx:2089/1100168https://ezproxy.uag.mx:2089/1100195https://ezproxy.uag.mx:2089/1100159https://ezproxy.uag.mx:2089/130266https://ezproxy.uag.mx:2089/59437https://ezproxy.uag.mx:2089/1100175https://ezproxy.uag.mx:2089/1100153https://ezproxy.uag.mx:2089/59422https://ezproxy.uag.mx:2089/ZDD488F1_270_73https://ezproxy.uag.mx:2089/1100147https://ezproxy.uag.mx:2089/1100141https://ezproxy.uag.mx:2089/ZDCE26DD_201_114https://ezproxy.uag.mx:2089/ZDCDCD36_4E_145https://ezproxy.uag.mx:2089/130224https://ezproxy.uag.mx:2089/ZDCE1AE6_313_373https://ezproxy.uag.mx:2089/59398https://ezproxy.uag.mx:2089/ZDCE2683_185_26https://ezproxy.uag.mx:2089/59437


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Useful in establishing baseline values for ongoing evaluation

Advantages/disadvantages

Advantages:

Simple, rapid, and widely available

Confirms anemia

Documents hyperproliferative anemia with elevated reticulocyte count

Capillary tube of blood can be used

Disadvantage:

Not diagnostic

Normal

Results should be within the age-specific laboratory reference ranges.

Hemoglobin: 13.1 to 16.8 g/dL (131-168 g/L) in men; 11.2 to 15.0 g/dL (112-150

g/L) in women

Erythrocytes: 4.3 to 5.7 × 106/mm3(4.3-5.7 × 1012/L) in men; 3.7 to 5.1 ×

106/mm3(3.7-5.1 × 1012/L) in women

Leukocytes: 3,800 to 11,000/mm3(3.8-11.0 × 109/L) in men; 3,600 to

11,000/mm3(3.6-11.0 × 109/L) in women

Neutrophils: 44.6% to 76.5%

Platelets: 156 to 352 × 103/mm3(156-352 × 109/L) in men; 163 to 380 ×

103/mm3(163-380 × 109/L) in women

Reticulocytes: 0.4% to 2.4%

Abnormal

Results outside of the age-specific laboratory reference ranges.

Hemoglobin


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Reticulocyte counts ranging from >2% to 30%

Cause of abnormal result

Anemia due to sickle hemoglobinopathy (homozygote, heterozygote, or compound

heterozygote with another abnormal globin mutation).

Medications, disorders, and other factors that may alter results

Multiple other conditions and etiologies of anemia can affect the CBC.

Peripheral blood smear

Description

Blood specimen is obtained, and a thin layer of blood is stained and examined

under a microscope

An estimate of the number and evaluation of the type of leukocytes, erythrocyte

and platelets is obtained to assess if the cells are normal and mature

Allows visualization of sickle-shaped cells, Howell-Jolly bodies, nucleated

erythrocytes, and cell fragments


Advantages:

Simple and inexpensive

Useful in ruling out additional causes of anemia

Disadvantages:

Subjective—requires knowledge of erythrocyte morphology, expert interpretatio

Cannot be used to determine if vaso-occlusive crisis is occurring

Normal

Normal differential

Normal appearance of cells

Abnormal

Presence of nucleated erythrocytes, sickle-shaped cells, and Howell-Jolly bodies

Elevated total leukocyte count with predominance of neutrophils

Elevated platelet count


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Presence of HbS.

Hemoglobin solubility testing

Description

Venous blood sample obtained to detect the presence of HbS

A chemical is added to the sample to reduce the amount of oxygen the blood can

carry

Reduction in oxygen will cause S-related polymers to form and the affected

erythrocytes to sickle


Advantages:

Simple and inexpensive

Detects HbS

Useful for screening

Excludes sickle cell disease in patients older than 6 months without symptoms o

signs of severe anemia or very high HbF levels

Disadvantages:

Should not be done in infants until they are 6 months old or older due to the low

amounts of HbS produced until several months after birth

Cannot distinguish between sickle cell disease and sickle cell trait

Cannot rule out or confirm the presence of specific types of abnormal

hemoglobin

Normal

Normal erythrocytes

Absence of HbS

Abnormal

10% or more HbS.



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Sickle cell disease or trait.

Hemoglobin studies

Description

Venous blood sample

Several methods are available to evaluate the type and relative amount of

hemoglobin present: electrophoresis using cellulose acetate or acid citrate agar,isoelectric focusing, or hemoglobin fractionation using HPLC

With hemoglobin electrophoresis, the sample is subjected to an electromagneti

field; different types of hemoglobin will migrate in patterns, forming unique

bands that enable confirmation of the diagnosis

All neonatal screening is done using the more sensitive hemoglobin isoelectric

focusing or HPLC fractionation

In older children and adults, cellulose acetate electrophoresis at an alkaline pH

most commonly used to determine the hemoglobin subtype; an alternative

method can be used to confirm the diagnosis


Advantages:

Confirms the diagnosis of sickle cell anemia

Can exclude other hemoglobinopathies

Identifies heterozygous HbS, sickle cell trait if the other hemoglobin is

predominantly HbA, and other forms of sickle cell disease (HbSC, HbSβ-

thalassemia)

Can also be used to determine the percentage of HbS in a blood sample. This is

particularly helpful in guiding and monitoring treatment ( eg , in determining

how effective simple or exchange transfusion has been in decreasing the level ofsickled cells)

Disadvantages:

Diagnosis in early infancy is more difficult because of the high amount of HbF

Unreliable in infants or patients who have received a blood transfusion; repeat

testing or DNA testing is required

Normal


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Presence of only normal HbF, Hbα2, and HbA (proportion depends on patient age).

Abnormal

In neonates with sickle cell disease, HbF will predominate, but some HbS will b

present

In older infants, the amount of HbS will increase as HbF decreases

By 2 years of age, the amount of HbS and HbF stabilizes

Older patients with sickle cell anemia will have no HbA

Patients who are heterozygous for two different hemoglobin variants ( eg , HbS

will usually produce varying amounts of both types

Adult patients with sickle cell trait will continue to produce a majority of norma

HbA

Distinguishing HbSβ-thalassemia from sickle cell trait can be difficult. The usua

finding is that patients with sickle cell trait have 60% HbA and 40% HbS,

whereas patients with HbSβ-thalassemia have 60% HbS and 40% HbA

Results for older children:

Sickle cell anemia: 75% to 95% HbS, 2% to 20% HbF, and notably absent HbA

Sickle cell trait: 20% to 40% HbS,


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mutation analysis is uninformative

Assesses the genes that produce hemoglobin components for alterations and

mutations

Used to determine whether a patient has one copy of the HbS mutation, two

copies, or copies of different hemoglobin variants

May be ordered for prenatal testing or to confirm a diagnosis

Family studies can be done to identify sickle cell trait or sickle cell disease in

other family members


Advantages:

Provides the most accurate diagnosis

Confirms the diagnosis of sickle cell anemia, sickle cell trait, and other HBB gen

variants

Disadvantage:

Relatively expensive

Abnormal

Presence of mutations or alterations in the HBBgene.


Replacement of both β-globin subunits with HbS confirms the diagnosis of sickl

cell anemia (HbSS)

The presence of one normal β-globin subunit and one HbS confirms the

diagnosis of sickle cell trait

Other mutations that cause sickle cell disease may be identified, such as thosecausing β-thalassemia, methemoglobinemia (hemoglobin M), and the productio

of hemoglobin variants HbC and HbE

Iron studies

Description

Venous blood sample

Serum ferritin, transferrin, and iron-binding capacity are measured


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Advantages:

Easily done in conjunction with other standard blood tests

Helps distinguish hemolytic anemia from iron-deficiency anemia

Normal

Serum ferritin: 18 to 300 ng/mL (18-300 µg/L)

Serum transferrin: 170 to 370 mg/dL (1.7-3.7 g/L)

Serum iron-binding capacity: 250 to 460 µg/dL (45-82 µmol/L)

Abnormal

Serum iron and transferrin levels and serum iron-binding capacity are either too high

or too low.


Serum transferrin levels and serum iron-binding capacity are elevated and seru

ferritin levels are decreased in patients with iron deficiency

Serum transferrin levels and serum iron-binding capacity can be decreased in

patients with hemolytic anemia

UrinalysisDescription

Used to look for microalbuminuria or frank proteinuria, hematuria, and/or

urinary tract infection in patients with sickle cell disease

Urine specific gravity can also be helpful in evaluating patients for isosthenuria


Advantage:

Important tool to detect early kidney disease and other renal complications of

sickle cell disease

Disadvantage:

Cannot quantify proteinuria

Abnormal


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Isosthenuria, especially after fluid restriction

Presence of protein in urine

Presence of erythrocytes (>27 cells/µL) in urine, suggesting hematuria

Presence of leukocytes (>27 cells/µL) in urine with positive leukocyte esterase

and/or nitrite dipstick test result, suggesting urinary tract infection


Proteinuria: kidney damage due to sickle cell disease

Erythrocytes in the urine, suggesting hematuria: papillary necrosis

Leukocytes in the urine with a positive leukocyte esterase and/or nitrite dipstick

test result: urinary tract infection

Chemistry panel

Description

Venous blood sample.


Advantages:

Simple, readily available, and inexpensive

Assesses whether renal function is impaired

Normal

Sodium: 136 to 142 mEq/L (136-142 mmol/L)

Potassium: 3.5 to 5.0 mEq/L (3.5-5.0 mmol/L)

Chloride: 96 to 106 mEq/L (96-106 mmol/L)

Bicarbonate: 21 to 28 mEq/L (21-28 mmol/L)

BUN: 8 to 23 mg/dL (3.0-8.2 mmol/L)

Creatinine: 0.6 to 1.2 mg/dL (50-110 µmol/L)

Abnormal

Sodium: 142 mEq/L (142 mmol/L)

Potassium: 5.0 mEq/L (5.0 mmol/L)


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Chloride: 106 mEq/L (106 mmol/L)

Bicarbonate: 28 mEq/L (28 mmol/L)

BUN: 23 mg/dL (8.2 mmol/L)

Creatinine: 1.2 mg/dL (110 µmol/L)


Impairments in renal acidification and potassium secretion

Renal insufficiency due to sickle cell nephropathy

Bacterial cultures

Description

Sterile collection of relevant specimens ( eg , blood, urine, and/or pus) in

appropriate culture bottles for laboratory analysis

Bacterial cultures should be obtained in patients with fever and/or those who

appear toxic

Urine and pus culture results are usually available within 24 to 48 hours, and

blood culture results are available within 48 to 72 hours


Advantages:

Allow identification of associated bacterial infection

Identify bacterial pathogen, allowing susceptibility testing to guide selection of

appropriate antibiotics

Normal

No bacterial pathogen cultured.

Abnormal

Bacterial pathogen cultured.


Associated bacterial infection.

Medications, disorders, and other factors that may alter results

Previous antibiotic therapy (could create a false-negative result)


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Inadequate quantity of blood in the culture bottle (could lead to a false-negative

blood culture result)

Failure to use sterile procedure to obtain the culture specimen (could result in

contamination by skin, mouth, or bowel flora and lead to an unreliable result)

Imaging

Chest radiograph

Description

Should be obtained if the patient has respiratory symptoms or chest pain

Presence of a new infiltrate accompanied by fever and chest pain is diagnostic o

acute chest syndrome


Advantage:

Can aid in the diagnosis of acute chest syndrome or pneumonia

Disadvantage:

Findings may be normal initially

Abnormal

Presence of pulmonary infiltrate(s), which may extend rapidly, involving one or more

lobes as well as the pleura.


Acute chest syndrome

Pneumonia

Atelectasis

Skeletal radiographs

Description

Radiologic findings of bone infarction are localized to bones containing red

marrow; therefore, the pattern of osseous changes is different in children and

adults

In children, marrow is present in all bones, including the small bones of th

hand


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In adults, marrow is limited to the bones of the axial skeleton ( ie , spine,

pelvis, skull, and the most proximal portion of the femur and humerus)

Should only be used when clinically indicated. Most bone infarctions are

diagnosed clinically on the basis of symptoms (bone pain) and signs ( eg ,

absence of fever)


Advantage:

Can confirm the presence of bone infarctions

Abnormal

Decreased bone density resulting from loss of bone owing to marrow hyperplas

Sparse trabecular pattern with wide separation, resulting in a wire mesh pattern

Bone infarctions, as seen by irregular, permeative, or moth-eaten destruction

with overlying periosteal new bone formation

Infants: seen predominantly in the small bones of the hands and feet

Older children: most common in the epiphyses

Adults: incidence of infarcts in long bones tends to increase with age


Skeletal alterations are caused by erythroid hyperplasia of the bone marrow, which fil

and expands the cancellous bone and disturbs the trabecular architecture.

Transcranial Doppler ultrasound

Description

Intracranial vessels are evaluated by Doppler flow studies to help assess the risk

of stroke

Shown to be predictive of stroke in pediatric patients

If findings suggest that the risk of stroke is elevated above baseline, children wi

sickle cell disease have been found to benefit greatly from chronic transfusion

therapy. However, once started in patients at high risk, transfusions cannot like

be safely stopped


Advantages:


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Noninvasive

Assesses cerebral blood flow

Disadvantages:

Must be performed by a skilled technician; done in consultation with a specialis

Has only been shown to be predictive of stroke in the pediatric population

Normal

Velocity through the intracranial arteries 200 cm/s).


Narrowing of intracranial vessels due to sludging of abnormally shaped erythrocytes

changes in the endothelial lining of the vessels.

Echocardiography

Description

Can be used to assess cardiac function as well as give an estimate of pulmonary

pressures

Currently recommended for screening patients for pulmonary hypertension

Tricuspid regurgitant values >2.5 m/s have been associated with a 2-year

mortality rate of 50% in patients with sickle cell disease


Advantages:

Noninvasive

Relatively inexpensive

Disadvantages:

Not useful for determining pulmonary pressures in a patient who is acutely ill, a

pulmonary pressures increase in this setting

Used for screening only—confirmatory testing with right heart catheterization

and 6-minute walk test is required


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Abnormal

Tricuspid regurgitant jet velocity >2.5 m/s: diagnostic of pulmonary

hypertension

Tricuspid regurgitant jet velocity >3.0 m/s: moderate to severe pulmonary

hypertension


Pulmonary hypertension.

MRI

Description

Imaging of the hips and shoulders in particular should be done when pain

persists for several weeks to evaluate for avascular necrosis

Can also be useful in the diagnosis of osteomyelitis


Advantages:

Can aid in diagnosing and determining the extent of avascular necrosis

Can be useful in diagnosing osteomyelitis

Disadvantages:

Cannot be tolerated by patients who are claustrophobic

Cannot always differentiate a bony infarct from osteomyelitis

Abnormal

Increased T2 signal with surrounding decreased T1 signal and collapse and

flattening of the articular surface is seen in patients with avascular necrosis

Bone marrow edema and T2 hyperintensity can be seen in patients with

osteomyelitis


Avascular necrosis

Osteomyelitis

Bone scan


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Description

Can be useful in diagnosing osteomyelitis.


Advantages:

High sensitivity

Less expensive than MRI

Disadvantages:

Low specificity

Time consuming

Abnormal

Radioactive 'hot spot' can be seen in patients with osteomyelitis.


Osteomyelitis.

Abdominal ultrasound

Description

Can be useful in determining the cause of abdominal pain

Determining the cause or right upper quadrant pain can be particularly difficult

as the differential diagnosis is extensive


Advantages:

Inexpensive and readily available

Can be diagnostic, particularly for gallstones

Disadvantages:

Must be done by a skilled practitioner

Results are not as detailed as those of CT scan or MRI

Abnormal

Presence of gallstones and dilated ducts in the setting of pain on examination


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(can be diagnostic of cholecystitis)

Enlarging liver in the setting of a decreasing hemoglobin level (can suggest

hepatic sequestration)


Cholelithiasis

Cholecystitis

Hepatic sequestration

Other tests

Retinal examination

Description

It is important to examine patients for ocular complications of sickle cell diseas

annually, looking for evidence of neovascularization. If neovascularization is

seen, laser photocoagulation can be used to prevent retinal hemorrhage

Patients reporting new onset of floaters should be seen emergently to look for

evidence of retinal hemorrhage


Advantage:

Can be used to determine if patients are at risk for retinal hemorrhage

Disadvantage:

Must be done by a skilled practitioner

Abnormal

Sea fan formation, vascular proliferation

Retinal hemorrhage


Sickle retinopathy.

Clinical pearls

Neonatal screening for sickle cell disease is now done in all states in the U.S.

Patients who report or present with fever, increased or new pain, or pain that is not typical


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of previous vaso-occlusive crises should be thoroughly evaluated with a comprehensive

history, physical examination, and focused laboratory studies so as not to miss a serious

complication

No objective laboratory data can definitively indicate that a pain crisis is occurring

Patients often do not present to the hospital with acute chest syndrome but, rather, with

severe vaso-occlusive crisis. Such patients need to monitored carefully for signs of

progressive hypoxia, and repeat chest imaging may be necessary if the patient's status

changes

Consider consult

Refer patients with bone pain that is refractory to standard therapy, associated with fever,

atypical for sickle cell disease for radiographic investigation

Refer patients presenting with severe abdominal pain for radiographic investigation and

laboratory studies

Refer patients for MRI when diagnostic doubt still exists after clinical examination and

radiographic investigation or to exclude osteomyelitis, especially in patients in whom

Salmonella infection is suspected

Treatment

Goals

Symptom control and management of disease complications are the major goals. These involve:

Management of pain, both chronic and acute

Prevention and management of acute complications

Management of hemolytic anemia

Pharmacologic amelioration of disease severity

Prophylaxis against and prompt treatment of infection

Prevention of stroke

Genetic counseling and relevant health and nutritional education for patients and relatives

Immediate action

Fluid replacement: required immediately for most patients, who are mildly dehydrated

owing to urine-concentrating difficulties; fluid and electrolyte balance is also often disrupte

during pain crises and infections, and the patient's condition is exacerbated by inadequate


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hydration

Mild dehydration: intake of an oral rehydration solution should be encouraged;

supplemental intravenous fluids may be required if the patient is unable or unwilling to tak

oral fluids

Severe dehydration: should be treated the same as shock, with isotonic fluid boluses and

strict measurement of intake and output; intravenous fluids should then be given at a rate

at least 1.5 times the maintenance rate

Keep in mind that as patients get older, they are more likely to have pulmonary

hypertension, so volume status must be vigilantly monitored during volume resuscitation

Therapeutic options

Summary of therapies

Bone marrow transplantation (ZE0EB3EA_164_147)is the only potentially curative treatment

for sickle cell anemia, but it is infrequently used due to the lack of a suitable bone marrodonor, high cost, and associated risks (10% mortality rate in children)

Blood transfusions (1020812)are indicated in patients with acute, symptomatic (shortness

breath, chest pain) exacerbations of anemia; following a life-threatening event, such as

stroke, acute chest syndrome, and splenic crisis; and/or before high-risk procedures, suc

as surgery. There are no data to suggest that transfusions are beneficial in patients with

uncomplicated pain crises, and blood transfusion is not advocated as a first-line approac

for prevention of recurrent painful crises

Hydroxyurea (ZDE47DC2_68_5)increases the production of HbF. In the presence of HbF,

HbS cannot polymerize and, therefore, sickling of the erythrocytes decreases.

Hydroxyurea is approved to reduce the frequency of painful crises and the need for bloo

transfusions in patients with recurrent moderate to severe crises. Management guideline

from the National Heart, Lung, and Blood Institute (http://www.nhlbi.nih.gov/)recommend the us

of hydroxyurea in patients with HbSS disease or HbSβ-thalassemia who have three or

more painful crises per year; patients with acute chest syndrome or other life-threatenin

complications; and patients with severe, symptomatic anemia. There are limited data on

the use of hydroxyurea in preventing stroke. Current recommendations still advocate th

use of chronic transfusion therapy to prevent stroke

Erythropoietin may be required in patients with sickle cell disease who develop end-stag

renal disease

The use of hydroxyurea and erythropoietin in combination appears to be safe in patients

with sickle cell disease. The benefit of combination therapy is that the two agents not on

increase HbS, as erythropoietin alone would do, but increase HbF as well

http://www.nhlbi.nih.gov/https://ezproxy.uag.mx:2089/ZDE47DC2_68_5https://ezproxy.uag.mx:2089/1020812https://ezproxy.uag.mx:2089/ZE0EB3EA_164_147


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In most patients with sickle cell disease, treatment is aimed at avoiding vaso-occlusive

crises, relieving chronic symptoms, and preventing acute and long-term complications

Health management interventions

Prevention of infection:

Prophylactic penicillin V should be administered from the age of 2 months until age 5 year

to prevent serious infections, such as pneumonia. Prophylaxis is usually continued untilage 6 in patients who have not had a severe pneumococcal infection or undergone

splenectomy previously and who have a comprehensive care plan

Immunization with pneumococcal vaccine should be given from the age of 2 months to

reduce the risk of pneumococcal infection

Children should also receive influenza vaccination at 6 months of age and annually

thereafter

Meningococcal polysaccharide vaccination is recommended for children with splenic

dysfunction at 2 years of age

All routine immunizations should be given in a timely fashion

Adults should receive influenza vaccination yearly and pneumococcal vaccination every

years

Counseling and education (ZDD45DF8_32E_3CE):

Education and guidance should be provided to patients and caregivers

Caregivers should be taught to be vigilant for the early symptoms and signs of serious

complications, including palpating and measuring the spleen to check for enlargement,

and should know what action to take if the patient experiences an acute crisis

Dietary supplementation:

Children with sickle cell disease can receive iron-supplemented formula and cereal as do

other children. No additional iron supplementation should be given unless there is

documented iron deficiency

Patients with sickle cell disease have an increased requirement for dietary folic acid , whi

should be given daily (especially important during pregnancy)

Protein supplements are sometimes given if weight gain is inadequate in infancy or

growth and developmental delays occur at puberty

Certain nutritional supplements, such as arginine, are thought to reduce the risk of vaso

https://ezproxy.uag.mx:2089/ZDD45DF8_32E_3CE


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occlusive crisis; however, evidence to support these claims is limited

Pain management:

Pain, both chronic and acute (crisis), is the most common and debilitating problem in

patients with sickle cell disease. Treatments are aimed at alleviating pain and reducing

the frequency of painful crises

Comprehensive pain assessment is required to guide the selection of analgesic, andfrequent follow-up is necessary to maintain optimal pain management

An age-appropriate pain scale can be used to assess the level of pain and guide treatmen

options

Acetaminophen (with or without codeine) or nonsteroidal anti-inflammatory drugs (NSAIDs)

(173386958_976)are used for mild pain, often in conjunction with comfort measures ( eg

heating pads), and are generally sufficient for pain relief in children under age 6

Stronger opioids (59467)are used for moderate to severe pain and are usually required in

older children and adults

If the pain is severe, parenteral opioid therapy may be required; morphine is generally

preferred

Self-administered analgesia may be allowed in older children, adolescents, and adults

Transcutaneous electrical nerve stimulation (TENS) (1100858)is a safe and relatively

noninvasive intervention that can be used to alleviate many different types of pain

Other pain management strategies include warm compresses, physical therapy,

hypnotherapy, biofeedback, and relaxation therapy, some of which may be available at a

specialist pain clinic

Chronic conditions:

Leg ulcers may require treatment with bed rest, standard wound care, antibiotics,

debridement, pain relief measures, and skin grafts in some cases

Cholelithiasis may require gallbladder surgery if the presence of gallstones leads to

gallbladder disease

Priapism necessitates emergent consultation with a urologist. Treatment includes

intravenous hydration, supplemental oxygen for documented hypoxia, and pain relief

with parenteral opioids. Intracorporeal injection of a vasoactive agent may be considere

and aspiration and irrigation are used if intracorporeal injection does not result in

detumescence. Penile shunt should be considered for patients with refractory episodes

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Management of acute crises

Complications of sickle cell anemia can be severe and acute, requiring immediate

treatment, and may become life threatening

Painful crisis, infection, acute splenic sequestration, aplastic crisis, acute chest syndrom

and stroke are the major acute complications

Fluid replacement therapy (59535)is usually required, as the fluid and electrolyte balance isoften disrupted during painful crises and infections, and the condition is exacerbated by

inadequate hydration

Painful crisis:

Occurs in almost all patients with sickle cell anemia and can last hours to days; some

patients have one episode every few years, whereas others have many episodes per year

Can be severe enough to require admission to the hospital for pain control and

intravenous fluids; patients should be monitored carefully for dehydration if oral intake

poor

Acetaminophen, NSAIDs, opioids, or a combination of these agents are used, depending

on the severity of the pain

Patients should be closely monitored during painful crises for the onset of other

complications, particularly acute chest syndrome, which may develop rapidly

Generally resolves within 5 to 7 days; however, a severe episode may cause pain that

persists for weeks or even months

Hydroxyurea can ameliorate the clinical course of sickle cell anemia in some adult

patients experiencing three or more painful crises per year

Infection:

Children with sickle cell disease are particularly susceptible to acute infections, sepsis ,

and meningitis

Children presenting with fever (temperature >38.5°C [101.3°F]) should be evaluated

thoroughly

Following evaluation, children who are believed to be at low risk can be given parenteral

antibiotics (ceftriaxone) and managed at home with close follow-up

Children at high risk or who appear toxic should be given a broad-spectrum parenteral

antibiotic immediately, and blood cultures should be obtained and further evaluation

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carried out as appropriate

The antibiotics used should cover encapsulated organisms, especially Haemophilus

influenzae and S. pneumoniae

In addition, vancomycin should be administered in children in whom bacterial meningitis

other severe illnesses are suspected and in those who live in communities with a high

incidence of penicillin-resistant pneumococci

Infections that are often caused by S. aureus or Salmonella species, such as osteomyelitis

should be treated initially with a broad-spectrum antibiotic and vancomycin

Additional antibiotics should be selected as appropriate based on the results of blood

cultures

Other acute complications, such as acute chest syndrome, splenic sequestration, and

aplastic crisis, should be considered during a febrile illness

Acute chest syndrome:

Diagnosed in patients with fever, chest pain, and infiltrate on chest radiograph

Early recognition and aggressive treatment with supplemental oxygen (ZDEECB23_9_171

analgesics, antibiotics, and often simple or exchange transfusions are essential and may

be lifesaving

Children in whom acute chest syndrome is suspected should be referred to a pediatric

intensive care unit immediately due to the potential for rapid deterioration to pulmonar

failure and death

Patients most at risk of developing respiratory failure are those with multilobar

involvement, cardiac disease at baseline, and a decrease in platelet count

Splenic sequestration:

Severe cases can progress rapidly to shock and death, so prompt recognition and

immediate treatment are required

Blood transfusions may be lifesaving

Surgical splenectomy to prevent recurrence may be recommended in patients with

recurrent episodes or after a life-threatening crisis

Aplastic crisis:

Often caused by acute infection with human parvovirus B19 (commonly without the

characteristic rash)

https://ezproxy.uag.mx:2089/ZDEECB23_9_171


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Human parvovirus B19 affects erythrocyte precursors, resulting in reticulocytopenia,

which, along with ongoing hemolysis, can be life threatening

Blood transfusions are given until the reticulocyte count recovers

Isolation from vulnerable individuals is essential, as parvovirus B19 is highly contagious

Stroke:

Ischemic stroke or intracranial hemorrhage is a particularly devastating complication that is

common in children with sickle cell anemia

Screening with transcranial Doppler ultrasound can identify pediatric patients at high

risk for stroke who may be candidates for primary stroke prevention with a chronic bloo

transfusion program

Treatment of stroke in children with sickle cell disease includes hydration, supportive

care, physical therapy, and chronic transfusions (every 4-5 weeks). Anticonvulsant

medication may also be indicated

Adults should be evaluated for the use of tissue plasminogen activator if treatment is

being instituted within 3 hours of ischemic stroke onset

Use of chronic transfusion therapy to prevent stroke in adults remains controversial

Pulmonary hypertension :

Defined as a tricuspid regurgitant jet velocity >2.5 m/s

Found in 30% to 40% of adults with sickle cell disease; associated with a 2-year mortalit

rate of 50%

Patients in whom screening echocardiography shows an elevated tricuspid regurgitant je

velocity can be referred for right heart catheterization and/or 6-minute walk test

Ideal therapy is unknown. Potential therapies include bosentan, sildenafil, transfusion,

and hydroxyurea. Further study is needed to determine the efficacy of these therapies in

patients with sickle cell disease

New treatments

Bone marrow transplantation has been effective in children, but due to organ damage,

adults were not considered to be eligible for transplantation. New transplant protocols

using reduced intensity chemotherapeutic regimens are being evaluated with the goal of

curing adults with sickle cell disease

Stimulation of bone marrow cells to increase production of HbF is another potential


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treatment; studies to date have used butyrate and hydroxyurea to increase HbF levels,

with promising results

Gene therapy, either through silencing of the defective HBB genes or by transferring a

normal HBB gene into stem cells from individuals with sickle cell anemia, is being

explored as a potential cure. However, there are concerns regarding the safety and

reliability of the procedures. Research into gene therapy for sickle cell anemia is still in

very early stages

Guidelines

The National Heart, Lung, and Blood Institute (http://www.nhlbi.nih.gov/)has produced the followin

The Management of Sickle Cell Disease

(http://www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf). NIH Publication No. 02-211

Bethesda, MD: National Heart, Lung, and Blood Institute; 2002

The British Society for Haematology (http://www.b-s-h.org.uk/)has produced the following:

Rees DC, Olujohungbe AD, Parker NE, Stephens AD, Telfer P, Wright J; British

Committee for Standards in Haematology General Haematology Task Force by the

Sickle Cell Working Party. Guidelines for the management of the acute painful crisis in sickle

cell disease (http://www.bcshguidelines.com/pdf/sicklecelldisease_0503.pdf). Br J Haematol.

2003;120:744-52

The American Academy of Family Physicians (http://www.aafp.org)has published the following:

Wethers DL. Sickle cell disease in childhood. Part I. Laboratory diagnosis, pathophysiology an

health maintenance (http://www.aafp.org/afp/20000901/1013.html). Am Fam Physician.

2000;62:1013-20

Wethers DL. Sickle cell disease in childhood: part II. Diagnosis and treatment of major

complications and recent advances in treatment (http://www.aafp.org/afp/20000915/1309.html)

Am Fam Physician. 2000;62:1309-14

Yale SH, Nagib N, Guthrie T. Approach to the vaso-occlusive crisis in adults with sickle cell

disease (http://www.aafp.org/afp/20000301/1349.html). Am Fam Physician. 2000;61:1349-

56

Order of therapies

Counseling and education (ZDD45DF8_32E_3CE)

Penicillin V (130279)

Acetaminophen (ZC45233E_2DB_38D)

https://ezproxy.uag.mx:2089/ZC45233E_2DB_38Dhttps://ezproxy.uag.mx:2089/130279https://ezproxy.uag.mx:2089/ZDD45DF8_32E_3CEhttp://www.aafp.org/afp/20000301/1349.htmlhttp://www.aafp.org/afp/20000915/1309.htmlhttp://www.aafp.org/afp/20000901/1013.htmlhttp://www.aafp.org/http://www.bcshguidelines.com/pdf/sicklecelldisease_0503.pdfhttp://www.b-s-h.org.uk/http://www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdfhttp://www.nhlbi.nih.gov/


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NSAIDs (173386958_976)

Opioids (59467)

Fluid replacement therapy (59535)

Oxygen (ZDEECB23_9_171)

Hydroxyurea (ZDE47DC2_68_5)

Blood transfusions (1020812)

Folic acid (2392218)

Bone marrow transplantation (ZE0EB3EA_164_147)

TENS (1100858)

Efficacy of therapies

The only potentially curative treatment is bone marrow transplantation, but its use is

limited by donor availability and the functional class of the patient

With all other treatments, including those that reduce the frequency of crises, the media

age at death is 42 years for men and 48 years for women

TENS is generally considered to be an effective, safe, and relatively noninvasive

intervention that can be used to alleviate many different types of pain

Analgesics are effective if tailored to the individual patient based on rigorous pain

assessment and follow-up

Prophylactic penicillin V substantially lowers the risk of invasive pneumococcal infection

Heptavalent conjugated pneumococcal vaccine and 23-valent unconjugated

pneumococcal vaccine have an efficacy against pneumococcal infection of at least 85%

and 56% to 81%, respectively

Hydroxyurea can ameliorate the clinical course of sickle cell anemia in some adult

patients experiencing three or more painful crises per year

Medications and other therapies

Medications

Penicillin V

Pharmacology

https://ezproxy.uag.mx:2089/1100858https://ezproxy.uag.mx:2089/ZE0EB3EA_164_147https://ezproxy.uag.mx:2089/2392218https://ezproxy.uag.mx:2089/1020812https://ezproxy.uag.mx:2089/ZDE47DC2_68_5https://ezproxy.uag.mx:2089/ZDEECB23_9_171https://ezproxy.uag.mx:2089/59535https://ezproxy.uag.mx:2089/59467https://ezproxy.uag.mx:2089/173386958_976


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Penicillin antibiotic; bactericidal; narrow spectrum; inhibits bacterial cell wall

peptidoglycan synthesis.

Indication

Prophylaxis against pneumococcal infection from the time of diagnosis to 6 yea

of age

Off-label indication

Prescribing

Prescription only.

Dose and dose information

Pediatric

Oral:

Under age 3: 125 mg every 12 hours

Over age 3: 250 mg every 12 hours

Treatment course: from the time of diagnosis to 6 years of age;

recommendations on when to discontinue prophylaxis are mixed due to

concerns regarding functional asplenia

Hepatic/renal impairment

Use caution with high doses or parenteral administration in patients with renal

impairment; rashes are more common; a dose reduction may be necessary.

Administration

Doses should be taken a half hour to 1 hour before food or on an empty

stomach

Shake oral suspensions well before use. Refrigerate at 2° to 8°C (35.6-46.4°F

do not freeze. Discard contents as instructed after opening

Contraindications

Hypersensitivity to penicillins or any other component.

Cautions

Serious and fatal hypersensitivity reactions, including anaphylaxis, have been

reported. Use caution in patients with a history of sensitivity to multiple

allergens or previous hypersensitivity to cephalosporins


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Risk of mild or life-threatening pseudomembranous colitis. Consider the

diagnosis in patients presenting with diarrhea. Use caution in patients with a

history of gastrointestinal disease, particularly colitis

Monitor

LFT results (with prolonged therapy)

Renal function (with prolonged therapy)

CBC (with prolonged therapy)

Adverse effects

Common: diarrhea, nausea, rash, urticaria, superinfection

Rare: exfoliative dermatitis, pseudomembranous colitis, angioedema, interstitia

nephritis, serum sickness–like syndrome, blood dyscrasias, electrolyte

disturbances, hemolytic anemia, Stevens-Johnson syndrome, neurotoxicity,

nephropathy, bleeding, cholestatic hepatitis

Hypersensitivity reactions, including anaphylaxis and bronchospasm, have been

reported

Interactions

Coumarins (theoretical risk of changes in INR)

Methotrexate (increased serum methotrexate level)

Probenecid (reduced excretion of penicillins)

Patient and caregiver information

Report signs and symptoms of hypersensitivity reactions, anaphylaxis,

pseudomembranous colitis, hepatic dysfunction, or rash to physician

immediately

Regular blood and laboratory tests may be required during long-term therapy

Evidence

A systematic review included three RCTs of prophylactic antibiotic regimens for

preventing pneumococcal infection in children with sickle cell disease. All three

trials found that prophylactic penicillin significantly reduced the risk of

pneumococcal infection and was associated with minimal adverse reactions [1]

Level A

References


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[1]

Acetaminophen

Pharmacology

Analgesic; antipyretic; non-narcotic analgesic; inhibits prostaglandin synthesis in the

central nervous system (CNS) and peripherally blocks pain impulse generation.

Indication

Treatment of mild pain.

Prescribing

Available over the counter

Available in combination preparations with codeine

Dose and dose information

Adult

Oral: 500 to 1,000 mg every 4 to 6 hours, as needed; maximum: 4 g/d.

Pediatric

Oral: 10 to 15 mg/kg/dose every 4 to 6 hours, as needed; maximum, 90 mg/kg/d.

Elderly

Dose selection in the elderly should be cautious, usually starting at the low end of

the dosing range. This reflects the greater frequency of decreased hepatic, renal, or

cardiac function and concomitant diseases and medications.

Hepatic/renal impairment

Use caution in patients with hepatic and renal impairment; a dose reduction may b

necessary.

Contraindications

Hypersensitivity to acetaminophen or any other component.

Cautions

Reports of hepatic and renal damage with overdose. Unless treated promptly,

overdose may lead to potentially fatal multiorgan failure. Accidental overdose

can occur if over-the-counter preparations containing acetaminophen are taken

along with prescription medications containing acetaminophen


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Use caution with alcohol consumption (>3 drinks per day)

Adverse effects

Common: nausea, vomiting, rash

Rare: blood dyscrasias

Overdose: acute pancreatitis, acute hepatic and renal failure, confusion, delirium

vascular collapse, convulsions, coma, jaundice

Hypersensitivity reactions, including urticaria and angioedema, have been

reported rarely

Interactions

Alcohol (increased risk of hepatotoxicity)

Anticoagulants (enhanced anticoagulant effect)

Anticonvulsants (increased risk of hepatotoxicity)

Barbiturates (increased risk of hepatotoxicity)

Cholestyramine (decreased absorption of acetaminophen)

Colestipol (decreased absorption of acetaminophen)

Domperidone (increased absorption of acetaminophen)

Isoniazid (increased serum acetaminophen level)

Metoclopramide (increased absorption of acetaminophen)

Rifampin (increased risk of hepatotoxicity)

Pregnancy and lactation

Considered safe for short-term use during pregnancy

Compatible with lactation

Pregnancy category

Pregnancy category B.

Patient and caregiver information

Avoid consuming alcohol during therapy

Do not take with other acetaminophen-containing preparations


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Interactions with other medications are possible. Consult physician or

pharmacist before taking other prescription, complementary and alternative

(including herbal), or over-the-counter medications

NSAIDs

Pharmacology

Anti-inflammatory; antipyretic; analgesic; inhibits prostaglandin synthesis by

inhibition of cyclo-oxygenase (COX) enzyme; nonspecific NSAIDs inhibit both COX-1

and COX-2 isoforms.

Indication

Treatment of mild to moderate pain.

Prescribing

Ibuprofen and naproxen are available over the counter

Ketorolac is ava