Sickle Cell Disease and Trait: What Every Primary Care Physician Needs to Know

Objectives
Pathophysiology of sickle cell disease Inheritance of sickle cell disease Health maintenance for sickle cell disease Management of acute illness

The Management of a child with sickle cell disease is best when overseen by a comprehensive sickle cell disease center. If unavailable, care should be provided in consultation with a pediatric hematologist.

Sickle Cell Disease

Patho hysiolo!y

What "s Sickle Cell Disease#

n inherited disease of red blood cells ffects hemoglobin Polymeri!ation of hemoglobin leads to a cascade of effects decreasing blood flow Tissue hypo"ia causes acute and chronic damage

Why Do Cells Sickle#

#lutamic acid is substituted for valine llowing the polymeri!ation of sickle hemoglobin when deo"ygenated

Normal $s% Sickle &ed Cells

Normal
$isc%&haped $eformable 'ife span of ()* days

Sickle
&ickle%&haped +igid 'ives for )* days or less

Hemolysis and ,aso%occlusion

)emolysis:
The anemia in &.$ is caused by red cell destruction, or hemolysis, and the degree of anemia varies widely between patients. The production of red cells by the bone marrow increases dramatically, but is unable to keep pace with the destruction.

$aso'occl(sion:
-ccurs when the rigid sickle shaped cells fail to move through the small blood vessels, blocking local blood flow to a microscopic region of tissue. mplified many times, these episodes produce tissue hypo"ia. The result is pain, and often damage to organs.

Hemolysis and ,aso%occlusion

4continued5

cute Manifestations/
3acterial &epsis or meningitis2 +ecurrent vaso%occlusive pain 4dactylitis, muscoskeletal or abdominal pain5 &plenic &e6uestration2 plastic .risis2 cute .hest &yndrome2 &troke2 Priapism Hematuria, including papillary necrosis

.hronic Manifestations/
nemia 0aundice &plenomegaly 1unctional asplenia .ardiomegaly and functional murmurs Hyposthenuria and enuresis Proteinemia .holelithiasis $elayed growth and se"ual maturation +estrictive lung disease2 Pulmonary Hypertension2 vascular necrosis Proliferative retinopathy 'eg ulcers Transfusional hemosiderosis2

2Potential cause of mortality

Sickle Cell Disease

SCD *enoty e #enotype #enotype prevalence

&ickle cell anemia 4&&5 &ickle Hb . disease 4&.5 &ickle S beta plus 4&78 thalassemia 5 &ickle 3eta !ero 4&79 thalassemia5

:;< );< =< )<

)istorical Distrib(tion o+ )emo!lobin $ariants

)emo!lobin S

)emo!lobin C

)emo!lobin D )emo!lobin E
Malarial +egions of frica and sia lpha thalassemia occurs in all these regions as well

Prevalence>Incidence of &.$
In frican% mericans the incidence of &.$ is ( in ?@; for Hb&&, ( in =?; for Hb&. and ( in (,::@ for &ickle beta%thalassemia. In addition, ( in () frican% mericans are carriers for the disorder In other A.&. populations, the prevalence of sickle cell disease is ( in ;=,*** .aucasiansB ( in (,(** Hispanics 4eastern states5B ( in ?),*** Hispanics 4western states5B ( in ((,;** siansB and ( in ),@** Cative mericans

Sickle Cell Pedi!ree

Parents with sickle cell trait/ hemoglobin & Probability of child with hemoglobin / );< Probability of child with sickle cell trait &/ ;*< Probability of child with sickle cell disease &&/ );<

Sickle Cell Disease

Newborn Screenin!

Newborn Screenin! +or Sickle Cell Disease

D@ states, Eashington $., Puerto +ico, and the ,irgin Islands provide mandatory universal newborn screening &pecimen must be drawn prior to transfusion Prevention of pneumococcal septicemia Farly $etection and treatment of splenic se6uestration 'inkage to timely diagnostic, parental education, and comprehensive care markedly reduces morbidity and mortality in infancy and childhood.

"nter retin! Newborn Screenin! &es(lts Sickle )emo!lobino athies

Screenin! &es(lts, 1& 1&. 1& 1&F 1& ,ariant -ssociated Disorder && or &79thalassemia &. & G8 thalassemia & Hemoglobin F & ,ariant

2.onfirmatory testing re6uires hemoglobin separation by electrophoresis 4cellulose acetate and citrate agar5, isoelectric focusing, and>or high performance lipid chromatography. &olubility testing should never be used for confirmation.

"nter retin! Newborn Screenin! &es(lts )emo!lobino athy Carriers

Newborn Screenin! &es(lt 1 1 1 1 & . F ,ariant -ssociated Carrier State &ickle .ell Trait Hb . .arrier Hb F .arrier Hb ,ariant .arrier

Sickle Cell Disease

)ealth .aintenance -nd .ana!ement

.ana!ement
Health maintenance Infection prevention Pain management &ickle emergencies .hronic disease management

)ealth .aintenance
1re6uent visits/ every ? to : months Immuni!ations
H +outine immuni!ations H Hib% : months and older H )? valent Pneumova" at five years

Penicillin prophyla"is beginning no later than two months Cutrition and fluids
H 1olate supplementation is controversial

)ealth .aintenance
Physical e"am with attention to/
H #rowth and development, Iaundice, liver>spleen si!e, heart murmur of anemia, malocclusion from increased bone marrow activity, delayed puberty

'ab evaluations/
H .3. with differential and reticulocyte count, urinalysis, renal J liver function

)ealth .aintenance
&pecial studies 3rain% Transcranial doppler ultrasonography, M+I>M+ 'ungs% Pulmonary function tests, Fcho cardiogram for pulmonary hypertension Ceurologic% neuropsychological testing

C(rrent &ecommendations
Penicillin Prophyla"is/ &&, &KThalassemia
H ) months to ? years/ (); mg P- 3I$ H -ver ? years/ );* mg P- 3I$
Ehen to discontinue is controversial

Penicillin Prophyla"is/ &. and &8 Thalassemia

H &. warrants penicillin prophyla"is similar to && H &8 Thalassemia/ penicillin prophyla"is can be safely discontinued at ; years
+outine use in infants and children is controversial

&pecial .ircumstances
H History of repeated sepsis, surgical splenectomy

Eye E/amination
+etinal vessel disease
H Incidence ??< in hemoglobin &. H Incidence ?< in && &ea 1an

nnual evaluation after age (* years by ophthalmologist

H 'aser photocoagulation for vessel disease

&almon Patch/ &.

Emer!encies
0ever1in+ection -c(te chest syndrome Eye tra(ma 2hy hema3 Pria ism Stroke S lenic se4(estration Severe ain

0ever and "n+ection

1ever L ?=.;9 . 4(*(915 is an FMF+#FC.M 3asic laboratory evaluation/
H .3. with differential and reticulocyte count, blood, urine, and throat cultures, urinalysis, chest "%ray Indications for hospitali!ation J I, antibiotics/ %.hild appears ill % ny temperature L D*9. % bnormal laboratory values &tart I, antibiotics IMMF$I TF'M if child appears ill or temperature L D*9. 4$- C-T E IT 1-+ ' 3&5

-c(te Chest Syndrome

leading cause of death in sickle cell disease

.linically/ cute onset of fever, respiratory symptoms, new infiltrate on chest "%ray .auses
H Infection H 1at emboli H 'ung infarct

&ince you cannot distinguish between acute chest syndrome and pneumonia clinically there is no change in treatment.

Eye Tra(ma
Fye trauma is an emergency in '' sickle conditions 4including sickle trait5 #et sickle prep %rapid test% if sickle status unknown .omplications if untreated/ %glaucoma, %optic nerve atrophy, %retinal artery blockage

Pria ism
.ommonly occurs in children and adolescents with && or &. Treatment is difficult
H -pioid pain medication H Intravenous fluids H spiration and irrigation of the corpus cavernosum H &urgery H 3lood Transfusions

Impotence with severe disease or recurrent episodes

Urethra Corpus cavernosum

Stroke
ny acute neurologic symptom other than mild headache, even if transient, re6uires urgent evaluation. Historically = to (*< of children with && N&ilent &trokeO in ))< of children with hemoglobin && Treatment/ .hronic transfusion therapy to maintain sickle hemoglobin at or below ?*<

S lenic Se4(estration
&udden trapping of blood within the spleen Asually occurs in infants under ) years of age with && &pleen enlarged on physical e"am, may not be associated with fever, pain, respiratory, or other symptoms .irculatory collapse and death can occur in less than thirty minutes

+ecurrence very common 4;*<5 ssociated with high mortality 4)*<5

S lenic Se4(estration
Hemoglobin &&
H Incidence increased/ : and ?: months
-verall incidence about (;<

Hemoglobin &.
H Incidence increased/ ) and (@ years
Mean age =.P years .an occur in adolescence and adulthood Incidence about ;<

Treatments 0or S lenic Se4(estion

Intravenous fluids
H Maintain vascular volume

.autious blood transfusion

H Treat anemia, se6uestered blood can be released from spleen

&pleen removal or splenectomy

H If indicated

Pain .ana!ement
cute pain
Hand%foot syndrome 4dactylitis5 Painful episodes/ vasoocculsion &plenic se6uestration cute chest syndrome .holelithiasis Priapism vascular necrosis +ight upper 6uadrant syndrome

Pain .ana!ement
Pain is an emer!ency
Hospital evaluation/ Hydration/ (.; times maintenance unless acute chest syndrome suspected ssess pain level and treat
H $o not withhold opioids H 1re6uently reassess pain control

ssess for cause of pain>complications

Pain .ana!ement
Mild%moderate pain
-cetamino hen
H Hepatoto"ic

Non'steroidal anti'in+lammatory a!ents 2NS-"Ds3 %.ontraindicated in patients with gastritis>ulcers and renal failure %Monitor renal function if used chronically

Pain .ana!ement
Moderate%severe pain
H -pioids are first%line treatment H Morphine sulfate or hydromorphone H Meperidine C-T recommended
4Metabolite causes sei!ures J renal to"icity5

Moderate or less severe pain

H cetaminophen or C& I$Qs in combination with opioids H -ther adIuvant medications 4sedatives, an"iolytics5
May increase efficacy of analgesics

)and 0oot Syndrome ' Dactylitis

Farly complication of sickle cell disease Highest incidence : months to ) years Painful swelling of hands and feet Treatment involves fluids and pain medication 1evers treated as medical emergency

&enal Disease
+enal findings
H H H H H $ecreased ability to concentrate urine $ecreased ability to e"crete potassium Inability to lower urine pH normally Hematuria > papillary necrosis nemia, proteinuria, hematuria

+isk factors for progressive renal failure

*all 5ladder and 6iver

#all stones and biliary sludge
H Monitor by ultrasound every (%) years

.holestasis
H May progress, leading to bleeding disorders or liver failure

Iron overload
H $ue to chronic transfusions

.hronic hepatitis

5one Disease Dia!nosis and Treatment

vascular necrosis of hips and shoulders
H Inde" of suspicion
Persistent hip or shoulder pain Plain film or M+I

Treatment
H .onservative
C& I$Rs and : weeks of rest off affected limb Physical therapy

Screenin! -$N
vascular Cecrosis
H Hip 1ilms H Hip M+I H #rading of ,C
#rade I/ M+I #rade II/ 1ilm>M+I #rade III/ 1ilm #rade I,/ 1ilm #rade ,/ 1ilm

H Co grade for ,C of the shoulder

Chronic Com lications

nemia>0aundice 3rain $amage>&troke Sidney failure $ecreased lung function Fye disease 4bleeding, retinal detachment5 'eg ulcers .hronic pain management

-nemia 7 8a(ndice
.ommon and starting in the first year of life $ecreased lifespan of sickle red cells
H Hemolysis H nemia H Hyperbilirubinemia H +eticulocytosis

Stroke
Intracranial hemorrhage
H More common in adults

&e6uela overt and Nsilent strokesO

H Paralysis/ overt stroke H Ceuropsychologic changes/ both overt and silent strokes
,isual%spatial impairment Impaired memory Poor impulse control

&enal Disease
Proteinuria>Cephrotic syndrome D*< of &.$ patients with nephrotic syndrome develop end%stage renal disease -ccurs in T )*< of all patients -ccurs in D.;< of all pediatric patients% increased in hemoglobin && to :.;<
H Increased incidence with age H Increased with anemia, increased M.,, and increased leukocyte count

+enal failure common in adults

6e! 9lcers
-ccurs in about );< of all hemoglobin && patients Predominantly males
H Incidence increased with ge $ecreased hemoglobin H Incidence decreased with alpha thalassemia

+ecurrence rate is T @;<

.hronic Pain
Pain lasting L? to : months Patients should receive comprehensive psychologic and clinical assessment Treatment
H H H H H nalgesics Hydro"yurea TFC& units +ela"ation techni6ues Physical and occupational therapy

dolescents and Transition of .are

Moung adults 4L)* years5 with fre6uent pain crises at greatest risk for early death 3arriers to care for young adults
H 'ack of adult &.$ providers H 'oss of medical coverage H $evelopmental 4level of independence, denial of chronic illness5 H Ineffective coping skills 4passive versus active5

dolescents and Transition of .are

$evelop e"plicit plan for transition Team approach% pediatric and adult providers, social work, school>vocational staff, support groups Plan gradual transition 4start ( year before5 .ontinue communication between pediatric J adult providers after transition

#enetic .ounseling
Eho should receive counselingU
%Parents of newborns with sickle disorders or traits %Pregnant women> prenatal counseling

Ehat is the purpose of counselingU

%Fducation %Informed decision%making

.ontent should include/

%#enetic basis, chances of disease or trait 4potential pregnancy outcome5, disease%related health problems, variability>unpredictability of disease, family planning, average life span

Information about sickle cell disease can be found through the merican cademy of Pediatrics or from the Cational Institute of Health on line at/
http/>>www.nhlbi.nih.gov>health>prof>blood>sickle>scVmngt.pdf