Sickle Cell Anaemia

Hemoglobin is critical for normal oxygen delivery to tissues; it is also present in erythrocytes in such high concentrations that it can alter red cell shape, deformability, and viscosity. Hemoglobinopathies are disorders affecting the structure, function, or production of hemoglobin

The sickle cell syndromes are caused by a mutation in the -globin gene that changes the sixth amino acid from glutamic acid to valine. The prototype disease, sickle cell anemia, is the homozygous state for HbS.

!" # TH" $H% !&$ $ '()&$*T& ! # S&$+)" $")) ,&S"*S" &S S&$+)" $")) *!*"'&*

When oxygenated

single Hb S molecules in free in solution; allows red cell to be soft, round, and deformable

When deoxygenated

- O2

Hb S molecules polymerize into long fibers; mishapen, dehydrated and adherent sickle cells.

(*TH (H-S& ) .-/0.'olecular pathology 1.2iochemical pathology 3.$ellular pathology 4.5ascular pathology 6.$linical pathology

' )"$7)*% (*TH ) .-

&t all started in the genes8 TH" S&$+)" '7T*T& !

!ormal versus sickle beta globin

9 :th $odon of -.lobin .ene The s 'utation

The same mutation found in all s genes around the ;orld GAG .lutamic acid GTG 5aline

$)&!&$*) (*TH ) .0.*!*"'&* 1.5*S $$)7S& ! 3.$H% !&$ %.*! ,*'*."

9 &n Sickle cell anemia the $linical *bnormalities are 5asoocclusive crises ;ith infarction of spleen, brain, marro;, kidney, lung; aseptic necrosis of bone; gallstones; priapism; ankle ulcers 9 Hemoglobin )evel/- <=0>g?d) 9 '$5,f) /- @>=0>> Hemoglobin Electrophoresis:9 Hb S?*/0>>?> 9 Hb #/1=16A

Objectives
9 &nheritance of sickle cell disease 9 Health maintenance for sickle cell disease 9 'anagement of acute illness

The 'anagement of a child and adult ;ith sickle cell disease is best provided in consultation ;ith a hematologist.

What Is Sickle Cell isease!

9 *n inherited disease of red blood cells 9 *ffects hemoglobin 9 (olymerization of hemoglobin leads to a cascade of effects decreasing blood flo; 9 Tissue hypoxia causes acute and chronic damage

Wh" o Cells Sickle!

9 .lutamic acid is substituted for valine 9 *llo;ing the polymerization of sickle hemoglobin ;hen deoxygenated

#ormal $s% Sickle &e' Cells

#ormal
9 ,isc-Shaped 9 ,eformable 9 )ife span of 01> days

Sickle
9 Sickle-Shaped 9 %igid 9 )ives for 1> days or less

Hemolysis and 5aso-occlusion

Hemol"sis:
The anemia in S$, is caused by red cell destruction, or hemolysis, and the degree of anemia varies ;idely bet;een patients. The production of red cells by the bone marro; increases dramatically, but is unable to keep pace ;ith the destruction.

$aso-occl(sion:
ccurs ;hen the rigid sickle shaped cells fail to move through the small blood vessels, blocking local blood flo; to a microscopic region of tissue. *mplified many times, these episodes produce tissue hypoxia. The result is pain, and often damage to organs.

Hemolysis and 5aso-occlusion

DcontinuedE

*cute 'anifestations/
9 9 2acterial Sepsis or meningitisC %ecurrent vaso-occlusive pain Ddactylitis, muscoskeletal or abdominal painE Splenic SeFuestrationC *plastic $risisC *cute $hest SyndromeC StrokeC (riapism Hematuria, including papillary necrosis

$hronic 'anifestations/
9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 *nemia Baundice Splenomegaly #unctional asplenia $ardiomegaly and functional murmurs Hyposthenuria and enuresis (roteinemia $holelithiasis ,elayed gro;th and sexual maturation %estrictive lung diseaseC (ulmonary HypertensionC *vascular necrosis (roliferative retinopathy )eg ulcers Transfusional hemosiderosisC

9 9 9 9 9 9

C(otential cause of mortality

Sickle Cell isease

SC Genot"pe .enotype .enotype prevalence

9 Sickle cell anemia DSSE 9 Sickle Hb $ disease DS$E 9 Sickle S beta plus DSGH thalassemia E 9 Sickle 2eta zero DSGI thalassemiaE

9 :6A 9 16A 9 @A 9 1A

Historical istrib(tion o) Hemoglobin $ariants

Hemoglobin S

Hemoglobin C

Hemoglobin Hemoglobin E
'alarial %egions of *frica and *sia *lpha thalassemia occurs in all these regions as ;ell

(revalence?&ncidence of S$,
9 &n *frican-*mericans the incidence of S$, is 0 in 3<6 for HbSS, 0 in @36 for HbS$ and 0 in 0,::< for Sickle beta-thalassemia. &n addition, 0 in 01 *frican-*mericans are carriers for the disorder 9 &n other 7.S. populations, the prevalence of sickle cell disease is 0 in 6@,>>> $aucasians; 0 in 0,0>> Hispanics Deastern statesE; 0 in 31,>>> Hispanics D;estern statesE; 0 in 00,6>> *sians; and 0 in 1,<>> !ative *mericans

Sickle Cell *e'igree

9 9 9 9

(arents ;ith sickle cell trait/ hemoglobin *S (robability of child ;ith hemoglobin **/ 16A (robability of child ;ith sickle cell trait *S/ 6>A (robability of child ;ith sickle cell disease SS/ 16A

Sickle Cell Anaemia

Health +aintenance An' +anagement

+anagement
9 9 9 9 9 Health maintenance &nfection prevention (ain management Sickle emergencies $hronic disease management

Health +aintenance
9 (hysical exam ;ith attention to/
= .ro;th and development, Jaundice, liver?spleen size, heart murmur of anemia, malocclusion from increased bone marro; activity, delayed puberty

9 )ab evaluations/
= $2$ ;ith differential and reticulocyte count, urinalysis, renal K liver function

Health +aintenance
Special studies 9 2rain- Transcranial doppler ultrasonography, '%&?'%* 9 )ungs- (ulmonary function tests, "cho cardiogram for pulmonary hypertension 9 !eurologic- neuropsychological testing

C(rrent &ecommen'ations
9 (enicillin (rophylaxis/ SS= 1 months to 3 years/ 016 mg ( 2&, = ver 3 years/ 16> mg ( 2&,
9 Lhen to discontinue is controversial

9 Special $ircumstances
= History of repeated sepsis, surgical splenectomy

E"e E,amination
9 %etinal vessel disease
= &ncidence 33A in hemoglobin S$ = &ncidence 3A in SS Sea #an

9 *nnual evaluation after age 0> years by ophthalmologist

= )aser photocoagulation for vessel disease

Salmon (atch/ S$

Emergencies
9 9 9 9 9 9 9 -ever.in)ection Ac(te chest s"n'rome E"e tra(ma /h"phema0 *riapism Stroke Splenic se1(estration Severe pain

-ever an' In)ection

9 #ever M 3@.6I $ D0>0I#E is an "'"%."!$9 2asic laboratory evaluation/
= $2$ ;ith differential and reticulocyte count, blood, urine, and throat cultures, urinalysis, chest x-ray 9 &ndications for hospitalization K &5 antibiotics/ -$hild appears ill -*ny temperature M 4>I$ -*bnormal laboratory values 9 Start &5 antibiotics &''",&*T")- if child appears ill or temperature M 4>I$ D, ! T L*&T # % )*2SE

Ac(te Chest S"n'rome

* leading cause of death in sickle cell disease

$linically/ *cute onset of fever, respiratory symptoms, ne; infiltrate on chest x-ray $auses
= &nfection = #at emboli = )ung infarct

Since you cannot distinguish bet;een acute chest syndrome and pneumonia clinically there is no change in treatment.

E"e Tra(ma
"ye trauma is an emergency in *)) sickle conditions Dincluding sickle traitE .et sickle prep -rapid testif sickle status unkno;n $omplications if untreated/ -glaucoma, -optic nerve atrophy, -retinal artery blockage

*riapism
$ommonly occurs in children and adolescents ;ith SS or S$ Treatment is difficult
= pioid pain medication = &ntravenous fluids = *spiration and irrigation of the corpus cavernosum = Surgery = 2lood Transfusions

9 &mpotence ;ith severe disease or recurrent episodes

Urethra Corpus cavernosum

Stroke
*ny acute neurologic symptom other than mild headache, even if transient, reFuires urgent evaluation. 9 Historically @ to 0>A of children ;ith SS 9 NSilent StrokeO in 11A of children ;ith hemoglobin SS Treatment/ $hronic transfusion therapy to maintain sickle hemoglobin at or belo; 3>A

Splenic Se1(estration
9 Sudden trapping of blood ;ithin the spleen 9 7sually occurs in infants under 1 years of age ;ith SS 9 Spleen enlarged on physical exam, may not be associated ;ith fever, pain, respiratory, or other symptoms 9 $irculatory collapse and death can occur in less than thirty minutes

9%ecurrence very common D6>AE 9*ssociated ;ith high mortality D1>AE

Splenic Se1(estration
9 Hemoglobin SS
= &ncidence increased/ : and 3: months
9 verall incidence about 06A

Treatments -or Splenic Se1(estion

9 &ntravenous fluids
= 'aintain vascular volume

9 $autious blood transfusion

= Treat anemia, seFuestered blood can be released from spleen

9 Spleen removal or splenectomy

= &f indicated

*ain +anagement
*cute pain
9 9 9 9 9 9 9 9 Hand-foot syndrome DdactylitisE (ainful episodes/ vasoocculsion Splenic seFuestration *cute chest syndrome $holelithiasis (riapism *vascular necrosis %ight upper Fuadrant syndrome

*ain +anagement
*ain is an emergenc"
Hospital evaluation/ 9 Hydration/ 0.6 times maintenance unless acute chest syndrome suspected 9 *ssess pain level and treat
= ,o not ;ithhold opioids = #reFuently reassess pain control

9 *ssess for cause of pain?complications

*ain +anagement
'ild-moderate pain
9 Acetaminophen
= Hepatotoxic

9 #on-steroi'al anti-in)lammator" agents /#SAI s0 -$ontraindicated in patients ;ith gastritis?ulcers and renal failure -'onitor renal function if used chronically

*ain +anagement
9 'oderate-severe pain
= pioids are first-line treatment = 'orphine sulfate or hydromorphone = 'eperidine ! T recommended
9 D'etabolite causes seizures K renal toxicityE

9 'oderate or less severe pain

= *cetaminophen or !S*&,Ps in combination ;ith opioids = ther adJuvant medications Dsedatives, anxiolyticsE
9 'ay increase efficacy of analgesics

Han' -oot S"n'rome act"litis

9 "arly complication of sickle cell disease 9 Highest incidence : months to 1 years 9 (ainful s;elling of hands and feet 9 Treatment involves fluids and pain medication 9 #evers treated as medical emergency

&enal isease
9 %enal findings
= = = = ,ecreased ability to concentrate urine ,ecreased ability to excrete potassium &nability to lo;er urine pH normally Hematuria ? papillary necrosis

9 %isk factors for progressive renal failure

= *nemia, proteinuria, hematuria

Gall 2la''er an' 3iver

9 .all stones and biliary sludge
= 'onitor by ultrasound every 0-1 years

9 $holestasis
= 'ay progress, leading to bleeding disorders or liver failure

9 &ron overload
= ,ue to chronic transfusions

9 $hronic hepatitis

2one isease iagnosis an' Treatment

9 *vascular necrosis of hips and shoulders
= &ndex of suspicion
9 (ersistent hip or shoulder pain 9 (lain film or '%&

9 Treatment
= $onservative
9 !S*&,Qs and : ;eeks of rest off affected limb 9 (hysical therapy

Screening A$#
9 *vascular !ecrosis
= Hip #ilms = Hip '%& = .rading of *5!
9 9 9 9 9 .rade &/ '%& .rade &&/ #ilm?'%& .rade &&&/ #ilm .rade &5/ #ilm .rade 5/ #ilm

= !o grade for *5! of the shoulder

Chronic Complications
9 9 9 9 9 9 9 *nemia?Baundice 2rain ,amage?Stroke +idney failure ,ecreased lung function "ye disease Dbleeding, retinal detachmentE )eg ulcers $hronic pain management

Anemia 4 5a(n'ice
9 $ommon and starting in the first year of life 9 ,ecreased lifespan of sickle red cells
= = = = Hemolysis *nemia Hyperbilirubinemia %eticulocytosis

Stroke
9 &ntracranial hemorrhage
= 'ore common in adults

9 SeFuela overt and Nsilent strokesO

= (aralysis/ overt stroke = !europsychologic changes/ both overt and silent strokes
9 5isual-spatial impairment 9 &mpaired memory 9 (oor impulse control

&enal isease
9 (roteinuria?!ephrotic syndrome 9 4>A of S$, patients ;ith nephrotic syndrome develop end-stage renal disease 9 ccurs in R 1>A of all patients 9 ccurs in 4.6A of all pediatric patients- increased in hemoglobin SS to :.6A
= &ncreased incidence ;ith age = &ncreased ;ith anemia, increased '$5, and increased leukocyte count

9 %enal failure common in adults

3eg 6lcers
9 ccurs in about 16A of all hemoglobin SS patients 9 (redominantly males
= &ncidence increased ;ith 9 *ge 9 ,ecreased hemoglobin = &ncidence decreased ;ith alpha thalassemia

9 %ecurrence rate is R <6A

$hronic (ain
9 (ain lasting M3 to : months 9 (atients should receive comprehensive psychologic and clinical assessment 9 Treatment
= = = = = *nalgesics Hydroxyurea T"!S units %elaxation techniFues (hysical and occupational therapy

*dolescents and Transition of $are

9 -oung adults DM1> yearsE ;ith freFuent pain crises at greatest risk for early death 9 2arriers to care for young adults
= )ack of adult S$, providers = )oss of medical coverage = ,evelopmental Dlevel of independence, denial of chronic illnessE = &neffective coping skills Dpassive versus activeE

.enetic $ounseling
9 Lho should receive counselingS
-(arents of ne;borns ;ith sickle disorders or traits -(regnant ;omen? prenatal counseling

9 Lhat is the purpose of counselingS

-"ducation -&nformed decision-making

9 $ontent should include/

-.enetic basis, chances of disease or trait Dpotential pregnancy outcomeE, disease-related health problems, variability?unpredictability of disease, family planning, average life span

TH*!+&!. - 7