Thalasemia and Hemoglobinopathi

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Thalassemia &Hemoglobinopathies



What is thalassemia?

Genetic blood disorder resulting in a mutation ordeletion of the genes that control globin production.

Normal hemoglobin is composed of 2 alpha and 2

beta globins Mutations in a given globin gene can cause a

decrease in production of that globin, resulting indeficiency

aggregates become oxidized damage the cellmembrane, leading either to hemolysis, ineffectiveerythropoiesis, or both.

2 types of thalassemia: alpha and beta.







Alpha Thalassemia

mutation of % or more of the & alpha globin

genes on chromosome %'

severity of disease depends on number ofgenes affected

results in an excess of beta globins



Silent Carriers (heterozygotes +/-

( functional alpha globin genes

No symptoms, but thalassemia could

potentially appear in offspring





Hemoglobin H Disease

% functional globin gene

results in very lightly coloured red blood cells

and possible severe anemia hemoglobin ) is susceptible to oxidation,

therefore oxidant drugs and foods are

avoided

treated ith folate to aid blood cell production



Alpha Thalassemia !a"or

no functional globin genes

death before birth *embryonic lethality+



#eta Thalassemia

mutations on chromosome %%

hundreds of mutations possible in the beta

globin gene, therefore beta thalassemia ismore diverse

results in excess of alpha globins



#eta Thalassemia Trait

slight lac of beta globin

smaller red blood cells that are lighter in

colour due to lac of hemoglobin no ma-or symptoms except slight anemia



#eta Thalassemia $nterme%ia

lac of beta globin is more significant

bony deformities due to bone marro trying to mae

more blood cells to replace defective ones

causes late development, exercise intolerance, andhigh levels of iron in blood due to reabsorption in the

G$ tract

if unable to maintain hemoglobin levels beteen '

gmdl / 0 gmdl, transfusion or splenectomy is

recommended



#eta Thalassemia !a"or

complete absence of beta globin

enlarged spleen, lightly coloured blood cells

severe anemia chronic transfusions re1uired, in con-unction

ith chelation therapy to reduce iron

*desferoxamine+



!ore ermanent 'ptions

one Marro Transplants 3eplacing patient4s marro ith donor marro 5irst performed on thalassemia patient in %67% 8ifficult, because donor must be exact match for

recipient 9ven a sibling ould only have a % in & chance of

being a donor

#ord lood Transplants 3ich in stem cells "lso needs to be an exact match



Strctre hemoglobin

Globin portion olypeptide chain

Normal adult hemoglobin*)b"+ is composed %&%

amino acid residues of α chain and %&' amino acid ofβ chain

)eme portion

$ron and porphyrin



Clasi)ication

Thalasemia trait Normal performance

$ntermediate )b range around %; / %% gdl

Mayor thalasemia )b < 7 gdl



Hematologic changes

)b range from 2 / 7 gdl The red cells )ypochromia

=ariation in size and shape 5ragmentosis asophilic stippling Nucleated red cells in peripheral blood, especially

after splenectomy 3eticulocyte count is elevated

)b5 level is eleveated



-Thalasemia

β;>Thalasemia : no detactable β>chain synthesis

absent β chain m3N"

β?>Thalasemia : reduced β>chain synthesis

reduced or nonfunctional β chain m3N"

)ereditary persistence of fetal hemoglobin

δβ>Thalasemia : δ and β>chain genes deleted

)b @epore : δ and β>chain genes partiallydeleted





Heterozygos states o) -Thalasemia

Type Hb A2 Hb F

β+- Thalasemia increased N to slightly increased

β0- Thalasemia increased N to slightly increased

δβ - Thalasemia Normal Increased (2% - 10%)

HPFH Normal Increased (10% - 40%)



Homozygos states o) -ThalasemiaTye !nemia δ - glo"in

chain

β- glo"in

chain

β- glo"in

m#N!

β- glo"in

$enes

β-Thalasemia e&ere Present 'ecreased 'ecreased Present

β0-Thalasemia e&ere Present !"sent !"sent ora"normal

Present

δβ-Thalasemia ild !"sent !"sent !"sent 'eleted

HPFH None !"sent !"sent !"sent 'eleted



-Thalasemia* Homozygos orms (!a"or an%

interme%ia

athogeneses =ariable reduction of β> chain syntheses *β;, β?, and

variant+

α>chain excess result in intracellular precipitation of in

soluble α> chain $ncreased but ineffective erythropoesis ith many red

cell precursors destroyed is related to α > chain

excess

!hortened red cell life span and variable splenicse1uestration




interme%ia

S,.,A, )yperplastic marro: bone marro expansion ith cortical thinning

$ncreased iron absorption and iron overload *caused of repeated

blood transfusion+ #irrhosis of the liver

9ndocrine disturbances e.g diabetes mellitus !in hyperpigmentation

#ardiac hemosiderosis

)ypersplenism lasma voleme expansion

!hortened red cell life

@euopenia

thrombocytopenia




interme%ia

H,!AT''01 "nemia: hypochromic, microcytic, lo M#=

3eticulocytosis

@euopenia and thrombocytopenia *may develop+

lood film : target cells and nucleated red cell, anisocytosis,

polychromasia, basophilia, circulating normoblast

3ed cell life span reduced

)b5 raised, )b"2 normal

one marro may be megaloblastic*due to folate depletion+,

erythroid hyperplasia Asmotic fragility decreased

!erum ferritin raised






interme%ia

C$3$CA ,AT.2,S 5ailure to thrive "nemia Baundice )epatosplenomegaly

"bnormal facies*prominence of malar eminances, frontal bossing, depression of bridge of nose,

exposure of upper central teeth+ !ull radiographs hair on end appearance 5racture *caused of marro expansion+ osteoporosis

Groth retardation * primary amenorrhea, delayed puberty+ @eg ulcer $f untreated, 7;C die in the first year of life



Clinical )eatres (

thalasemia !evere form of β thalasemia *)omozygous or#ompound heterozygous+ present ithin thefirst year of life

5ailure to thrive Mongoloid face oor feeding 5re1uent infection

General malaise ale !plenomegaly 5re1uent transfusion hemosiderosis



Complicationas a reslt o) these sitation

$nade1uate treatment in the first years of life

oor compliance

9xcessive blood consumption $nsufficient application of chelating agent



Complication

9ndocrine disturbances *retarded groth, delayed puberty,

diabetes, hypogonadism, adrenal insufficiency, hypothyroidism,

hypoparathyroidism+

@iver cirrhosis#ardiac failure

!pinal compression caused by epidural extramedullary

hematopoesis



Cases o) %eath

)epatic and cardiac failure

$ncreased susceptibility to infection post

splenectomy



!anagement

)ypertransfusion to maintain pretransfusion )b%;.D / %% gdl Groth and development are maximized

9xtramedullary hemapoesis is minimized

decreasingfacial and seletal abnormalities Number of α > chain precipitate are reduced prevent

development of splenomegaly and hypersplenism

#helation therapy iron chelating agent

*desferioxamine+ !plenectomy !upportive care



Clinical management

3egular 3ed cell transfusions < ' gdl at monthly interval @o transfusion , not exceeding 6.D gdl

)igh trnsfusion, exceeded %% gdl

$ron overload iron chelating therapy ithdeferoxamine

!plenectomyone marro transplantation



Splenectomy

3educes transfusion re1uirements in

hypersplenism

rophylactic pneumococcal and hemophilus

influenza vaccine and prophylactic life>longpenicilline are needed.

$ndication :

ersistent increase of blood transfusion re1uirement 9vidence of severe leuopenia and thrombocytopenia



Spporti4e care

5olic acid is not necessary in hypertransfusionE %mg daily is needed in untranfused*intermediapatients+

)epatitis vaccination 8igitalis and diuretics in congestive heart failure 9ndocrine intervention : thyroxine,

estrogen,testoteron #holescystectomy Genetic counseling and antenatal diagnosis



0ene therapy

$nsertion of normal globin gene into marro

stem cells

The techni1ue is not fesiable in the near

future



-Thalasemia $nterme%ia

C$3$CA ,AT.2,S

$ncidence : 2 / %;C !yndrome is clinically milder than thalasemia

mayor

Generally do not re1uire transfusion andmaintain )b 0 / %; gdl

)epatosplenomegaly, groth retardation,hyperbilirubinemia, iron over load

arvovirus %6 infection induces transienterythroblatopenia*aplastic crisis+



-Thalasemia $nterme%ia

!anagement

5olic acid % mg daily orally

8iet : avoid eating food hich is rich in iron

#helating therapy, hen serum ferritin hasrisen F2,;;; ngml

Tranfusion are not re1uiredE except aplastic

crises, acute infection

!plenectomy may be re1uired



-Thalasemia !inor or Trait (Heterozygos 5 or+

C$3$CA ,AT.2,S

"symptomatic 8iscovered on routine blood test: slightly reduced hemoglobin,

basophilic stippling, lo M#=, normal 38

8iscovered in family investigation or family history

Mild anemia

hysical examination normal



-Thalasemia !inor or Trait (Heterozygos 5 or+

D$A03'S$S

)b normal or slightly decreased

)ypochromic, microcytic cells, target cells, anisocytosis,

basophilic stippling, lo M#=, normal 3T8

)emoglobin "2 increased F&C, )b 5 midly elevated inD;C cases



re4ention

remarital counselling

8iagnostic renatal "mniocentesis

=illous sampling



Hemoglobinopathies

H )ereditary disorders that can result in

moderate to severe anemia

H asic defect is production of an abnormal

globin chain



Hemoglobinopathy 0enetics

H )omozygous: $nheritance of to genes from

each parent coding for the same type of

abnormal hemoglobin, e.g., )b !!

H )eterozygous: $nheritance of genes from

each parent hich code for a different type of

abnormal hemoglobin each, e.g., )b !#



T i l



Terminology

Hemoglobinopathy

More recently discovered hemoglobins have

been named by the city or location of

discovery:

)b #>)arlem

A i A i% S b tit ti



Amino Aci% Sbstittion

Hemoglobinopathy

Gree letter designates affected globin chain

β

A i A i% S b tit ti




Hemoglobinopathy

!uperscript number designates affected amino

acid*s+, e.g.,

β'

A i A i% S b tit ti




Hemoglobinopathy

@etters and numbers in parentheses designate the

helical segment and amino acid se1uence in that

segment affected *sometimes omitted+, e.g.,

β'*"(+

A i A i% S b tit ti




Hemoglobinopathy

"mino acid substitutions are denoted by the

three letter abbreviation for the normally

occurring amino acid folloed by an arro

folloed by the three letter abbreviation forthe substituted amino acid:

β'*"(+Glu → =al

Cl i)i ti



Classi)ication6

Hemoglobinopathy

H 5unctional "bnormalityH "ggregation

H olymerization

H #rystallization

H Instable hemoglobins

H Methemoglobin

H Axygen affinity

C % T t t



Corse an% Treatment

Sic7le Cell Disease

H !icle cell diseaseH "symptomatic at birth

H !ymptoms appear as percentage of fetal

hemoglobin decreases during first year of life

H Intreated crises increase morbidity and early

death

Co rse an% Treatment



Corse an% Treatment

Sic7le Cell Disease

H @ife span can be significantly increased ith early

and effective treatment

H !tudies of natural populations reveal that

individuals ith sicle cell disease are capable ofnormal life spans



Corse an% Treatment

$n both thalassemia and hemoglobinopathy

therapy is usually supportive rather than

curative



Corse an% Treatment

H lood transfusion is used toH #ontrol severe anemia

H 3educe the ris of complications of sicle

hemoglobinopathies *cerebrovascular accident,hypersplenism, etc.+



Corse an% Treatment

H #hronic blood transfusionH 3esults in iron overload of ma-or organs resulting

in increased morbidity

H @aboratory monitoring

H Necessitates the use of chelating agents to

remove excess iron



Corse an% Treatment

H 9xcess iron can cause the appearance of

sideroblastic conditions

H Transfusion interferes ith the typical laboratory

findings for the disorder



Corse an% Treatment

H "lternative treatmentH "ctivation of fetal hemoglobin genes

H one marro transplantation



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Thalasemia and Hemoglobinopathi