What is Thalassemia Trait ?

Introduction

This book contains basic informationabout the thalassemia trait.

Whether you have been diagnosedwith the thalassemia trait or are simplyinterested in finding out more about it,we encourage you to consult yourphysician or a hematologist. If youcarry the thalassemia trait and are considering having children, we alsosuggest that you seek the advice of agenetic counselor.

The Cooley’s Anemia Foundation’smessage concerning the thalassemiatrait is simple: Being tested for the thalassemia traitis easy. And it is in everyone’s bestinterest, working in partnership withthe health care professional of theirchoice, to be informed and takeresponsibility for their own health care.

Being tested for the

thalassemia trait is easy

What is Thalassemia Trait? - Table of Contents

What is the Thalassemia Trait? 2

What is Thalassemia? 4

Alpha Thalassemia 6

Silent Carrier State - Alpha Thalassemia Minor 7

Inheritance of Hemoglobin H Disease 8

Inheritance of Hydrops Fetalis 9

Beta Thalassemia - Beta Thalassemia Minor 10

Inheritance of Beta Thalassemia Major

(Cooley’s Anemia) 11

Inheritance of Beta Thalassemia Intermedia 11

Inheritance of E Beta Thalassemia 12

Inheritance of Sickle Beta Thalassemia 13

Who Carries the Thalassemia Trait 14

Thalassemia Trait Testing 16

Prenatal Testing for Thalassemia 18

About the Cooley’s Anemia Foundation 20

1

Because it is agenetic trait and not

a health condition,except for extremely

rare cases, the thalassemia trait has

no symptoms andrequires no

treatment

If you have been diagnosed with thethalassemia trait, this is simply anotherway of saying that you carry the genetic trait for thalassemia.

A genetic trait is a kind of message orcode contained in your body. You maypass this code on to your children, andthey may pass it on to their children.

You may, for instance, carry the genetic trait for blue eyes, even if youyourself have brown eyes.

Thalassemia trait is not a disease orcondition but a kind of genetic possi-bility that you pass on to your descen-dants.

What is the thalassemiatrait?

The thalassemia trait is not a disease.

Medical personnel often tell peoplewho carry the thalassemia trait thatthey "have thalassemia" which canlead trait carriers to believe that theyhave some kind of health-threateningmedical condition. This is not true.

Medical terminology refers to the tha-lassemia trait as "thalassemia minor."So while it may be technically correctto say that trait carriers "have tha-lassemia" (or, more properly, "tha-lassemia minor"), trait carriers shouldbe aware that carrying the genetic traitfor thalassemia is not the same thingas having a disease.

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Even though the thalassemia trait hasno symptoms and cannot directlyaffect your health, it can indirectlyaffect your health and directly affectthe health of your children. Doctorsmay mistake your thalassemia trait fora different condition and prescribeunnecessary and potentially harmfultests or treatments.

Also, when two thalassemia trait carriers have a child, there is a one-in-four chance with each pregnancy thatthe child will be born with a seriousblood disorder.

The thalassemia traitrequires no medicaltreatment.Thalh

Physicians sometimes mistakenly prescribe iron supplements for tha-lassemia trait carriers, usually becausethey mistake the small size of the traitcarrier’s red blood cells with iron-defi-ciency anemia.

The only way to properly determinethe need for iron supplements is tohave a physician test iron levels in thepatient’s blood. Without a test ofblood iron levels, iron supplementsshould not be prescribed for tha-lassemia trait carriers.

The thalassemia traitcannot become worseor turn into a seriousdisease.

Because the thalassemia trait is agenetic trait and not a health condition,it cannot "become worse" or changeinto one of the more serious forms ofthalassemia that may require medicaltreatment.

Similarly, except for extremely rarecases, the thalassemia trait has nosymptoms and requires no treatment.

Why should I be concerned about the thalassemia trait?

4

What is Thalassemia?

To understand howthalassemia affects

the human body,you must first

understand a littleabout how blood is

made

Thalassemia is the name of a group of genetic blood disorders.

To understand how thalassemia affectsthe human body, you must first under-stand a little about how blood is made.

Blood carries oxygen from your lungsto other parts of your body. Oxygen iscarried inside the red blood cells by asubstance called hemoglobin.

Hemoglobin is made of two differentkinds of proteins, called alpha andbeta globins. These globin proteins aremade by genes located on pairs ofchromosomes. If one or more of theseglobin-producing genes is abnormal ormissing, there is a drop in globin pro-duction.

Hemoglobin

Beta 1

Beta 2

Alpha 2

Alpha 1

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When only one beta globin gene orone or two alpha globin genes aremissing (as is the case with trait carri-ers), the drop in globin production isso small it rarely affects the person’shealth.

But when two beta globin genes orthree alpha globin genes are missing(as is the case with the more seriousthalassemia disorders), the drop in glo-bin production is so great that the redblood cells do not form properly andthe blood cannot carry enough oxygen.

The result is anemia that begins inearly childhood and lasts throughoutlife. When all four alpha genes aremissing, the result is usually death inthe womb.

Since thalassemia is not a single disorder but a group of related disorders that affect the human bodyin similar ways, it is important tounderstand the differences betweenthe various types of thalassemia.

Alpha Thalassemia

6

αα

Physicians often mistake

alpha thalassemiaminor for iron

deficiency anemiaand prescribe ironsupplements that

have no effect on the anemia.

Normal alpha globin genes chromosomes 16

People who do not produce enough alpha globin proteinhave alpha thalassemia. It is commonly found in Africa, theMiddle East, India, Southeast Asia, southern China, andoccasionally the Mediterranean region.

Alpha globin is made by four genes, two on each strand ofthe chromosome 16. Individuals who have one or twoabnormal alpha globin genes have alpha thalassemia trait.

An individual with alpha thalassemia trait defined by thepresence of one abnormal alpha globin gene is said to havethe silent carrier state. This condition, in which one of thefour alpha globin genes is missing or defective, generallycauses no health problems because the lack of alpha globinprotein is so small that there is no anemia.

It is called "silent carrier" because of how difficult it is todetect. Silent carrier state is "diagnosed" by deductionwhen an apparently normal individual has a child with hemo-globin H disease or alpha thalassemia minor. It can also bediagnosed by special DNA testing.

αα

αα αα

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Alpha Thalassemia Minor. In this condition, in which two of the fouralpha globin genes are missing or defec-tive, the lack of alpha globin protein issomewhat greater. Patients with this condi-tion have smaller red blood cells and a mildanemia, although they do not experiencesymptoms.

Physicians often mistake alpha thalassemia minor for iron deficien-

cy anemia and prescribe ironsupplements that have no

effect on the anemia. Bothabnormal alpha globin genesmay be on the same chro-mosome (cis position) orone may be on each chro-mosome in the pair (trans

position).

α α

An individual with alpha thalassemiatrait defined by the presence of twoabnormal alpha globin genes is said tohave alpha thalassemia minor.

alpha thalassemiaminor

α α

α α

− − − −

− −

If both parents carry alpha thalassemia minor in which the two abnormalgenes of each parent are on opposite chromosomes, their children willinherit alpha thalassemia minor.

..then there is a 25% chance with each pregnancy that their child will be born withhemoglobin H disease in which three ofthe four alpha globin genes are abnormal.

In this condition, the lack of alpha protein isgreat enough to cause moderate to severe

anemia and may cause serious health problems such as

an enlarged spleen, bonedeformities and fatigue.

8

if...one parent has alphathalassemia minor withtwo abnormal alpha globin genes on the samechromosome

alpha thaltrait

alpha thalsilent carrier

25%

normal hemoglobin

25%hemoglobin H

disease

α α

25% 25%

and the other parent hasthe silent carrier state witha single abnormal alpha glo-bin gene on one chromosome

The alpha thalassemia traits combine in differentways to produce blood disorders that range frommild to severe in their effect on the human body.

α α

− α

α −α α − α

− −

α −

α −

α α

α −

− α

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..thenthere is a 25% chance with each pregnancy that their child will inherithydrops fetalis or alpha thalassemiamajor, in which all four alpha globin genesare abnormal.

Most individuals with this condition diebefore or shortly after birth. In some

extremely rare cases, in utero bloodtransfusions have allowed the

birth of children with hydropsfetalis who then require life-long blood transfusions andmedical care.

both parents carry alpha thalassemia minor with twoabnormal alpha globin genes on the same chromosome

if...

alpha thaltrait (cis Type)

25%

normal hemoglobin

50% 25%hydrops fetalis

(alpha thal major)

α −

α α

α α

α −α −

− −

− −

α − α −

α −

Beta Thalassemia

People who do not produce enough beta protein have betathalassemia. It is found in people of Mediterranean descentsuch as Italians and Greeks, and is also found in the ArabianPeninsula, Iran, Africa, Southeast Asia, and southern China.

Beta globin is made by two genes, one on each chromo-some 11. Individuals who have one abnormal beta globingene have beta thalassemia trait.

BETA THALASSEMIA MINOR or BETA THALASSEMIA TRAIT.

In beta thalassemia trait, one of the two genes is abnormalbut the lack of beta protein is not great enough to causeproblems in the normal functioning of the hemoglobin. A person with this condition simply carries the genetic traitfor beta thalassemia and will usually experience no health problems other than a mild anemia.

As in alpha thalassemia minor, physicians often mistake thesmall red blood cells of the person with beta thalassemiaminor as a sign of iron-deficiency anemia and incorrectly pre-scribe iron supplements.

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In beta thalassemiatrait, one of the two

genes is abnormalbut the lack of betaprotein is not great

enough to causeproblems in the

normal functioning ofthe hemoglobin

ß

Normal beta globin genes chromosomes 11

ß

11

..thenthere is a 25% chance with each pregnancy that their child will inherit twoabnormal beta globin genes. In its mostsevere form, this may cause beta thalassemia major or Cooley’s anemia, a blood disorder in which the lack of betaprotein causes a life-threatening anemia thatrequires regular blood transfusions and extensive ongoing medical care. Lifelongtransfusions lead to iron overload which mustbe treated with chelation therapy to preventearly death from organ failure.

In a somewhat milder form, the inheritance oftwo abnormal beta globin genes may cause

beta thalassemia intermedia, in whichthe lack of beta protein in the hemo-

globin causes a moderately severeanemia and significant healthproblems including bone deformities and enlargementof the spleen.

Due to the wide range inseverity of this condition, the

borderline between thalassemiaintermedia and thalassemia

major can be confusing. When apatient is more dependent on blood

transfusions he is likely to be classified asthalassemia major.

ß − ß −

both parents carry the beta thalassemia trait,

if...

beta thaltrait

50%

ß −

normal hemoglobin

ß ß

25% 25%Cooley’s anemia

− −

25%

..then there is a 25% chance with each pregnancythat their child will be born with E beta thalassemia, a moderately severe anemiathat has similar symptoms to beta thalassemia intermedia but on occasion maybe as severe as thalassemia major.

Hemoglobin E is one of the most common abnormal hemoglobins. It is usually

found in people of SoutheastAsian ancestry, such as

Cambodians, Vietnamese andThai.

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The beta thalassemia trait can also combinewith "variant" hemoglobins to

produce other related blood disorders.

hemoglobin Etrait

normal hemoglobin

if... ß −

one parent carries the beta thalassemia trait

ß ß

and the other parent carries thehemoglobin E trait

ß ßE

ßE ß

25%

beta thalassemiatrait

− ß

25%

− ßE

25%E beta

thalassemia

13

..then there is a 25% chance with each pregnan-cy that their child will be born with sicklebeta thalassemia. Hemoglobin S is com-monly found in people of African orMediterranean ancestry, such as Africans,Italians, Greeks, Turks, and in people fromthe Caribbean.

The severity of the condition variesaccording to the amount of nor-

mal beta globin produced bythe beta gene. When no betaglobin is produced by thebeta gene, the condition isalmost identical to sicklecell disease. When somebeta globin is produced bythe beta gene, the condition

is less severe.

if... ß −

one parent carries the beta thalassemia trait

and the other parent carries the hemoglobin Strait (the abnormal hemoglobin found in people with sickle celldisease)

ß ßS

− ßS

25%sickle-beta

thalassemia

normal hemoglobin

ß ß

25%

sickle cell trait

ß ßS

25%

beta thal trait

− ß

25%

Thalassemia was originally believed to be common only topeople of the Mediterranean region, such as Italians,Greeks and Turks. (An early name for thalassemia major orCooley’s anemia was Mediterranean anemia.)

It is estimated thatover 2 million peoplein the United States

carry the genetictrait for thalassemia

Who Carries the Thalassemia Trait?Thalh

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Since then, scientists have discovered that the thalassemiatrait is found in people of many other regions, including theArabian Peninsula, Africa, the Indian subcontinent, China,Southeast Asia, and the Caribbean.

Today, due to the migration and intermarriage of differentethnic populations, the trait for thalassemia is found in peo-ple with no obvious ethnic connection to the disorder. Forthis reason, the New York State Department of Health pro-vides couples seeking a marriage license with informationabout thalassemia.

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Thalassemia Trait Testing

Finding out if you have the genetic traitfor thalassemia begins by determiningthe size of your red blood cells.

If you have a routine blood test knownas a Complete Blood Count, or CBC,already on file at your doctor’s office,ask your doctor to look at the MeanCorpuscular Volume, or MCV. TheMCV reading determines the size ofyour red blood cells. For adults, if theMCV reading is less than 75 and youare not iron deficient, you may be atrait carrier. For children, the MCVreading may be lower and variesaccording to their age.

Finding out if youhave the genetic

trait for thalassemiabegins by

determining the sizeof your red blood

cells

If your MCV reading indicates that youmay have the thalassemia trait, yourdoctor should then perform additionaltests to confirm that you have the tha-lassemia trait and to determine whatkind.

Although the MCV reading is a goodindicator of whether a person mayhave either the alpha or the beta thalassemia trait, finding out for certainif you have either trait involves addi-tional tests.

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Special tests called hemoglobin electrophoresis and quantitation ofhemoglobin A2 and hemoglobin F area reliable way of determining whetheror not a person has the trait for betathalassemia (beta thalassemia minor).These tests are available at most largehospitals and clinics.

Testing for alpha thalassemia trait(alpha thalassemia minor) is usuallydone by a process of exclusion; people who have low MCV (not due toiron deficiency), a normal hemoglobinelectrophoresis, quantitative hemoglo-bin A2 and quantitative hemoglobin F,and are of the appropriate ethnic originare presumed to have alpha thalassemia minor.

In some circumstances, more definitive "molecular" testing is performed to determine the presenceor absence of thalassemia trait. Asthese genetic tests are developed further, they will be used more widelyto test for thalassemia trait.

Remember that the first step to findingout if you have the thalassemia trait iseasy. Just call your doctor and ask himor her to check your MCV reading.Testing for thalassemia can be done atmost hospitals. When you go in foryour test bring this book with you toshare with your doctor.

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If you have alpha or beta thalassemiatrait and are considering having a childor are already pregnant, your partnershould be tested to see if he or shehas the thalassemia trait. If you bothhave thalassemia trait, there are several things you can do.

Inform your obstetrician about yourthalassemia trait. Discuss what itmight mean for your unborn child. Ifnecessary, share this book with yourdoctor.

If you want to determine whether your unborn child has any form of thalassemia, there are two kinds oftests you can request.

Inform your obstetrician aboutyour thalassemia

trait. Discuss what itmight mean for your

unborn child

Prenatal Testing for Thalassemia

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AMNIOCENTESIS

Amniocentesis is performed in thesecond trimester of pregnancy, afterabout 15 weeks of gestation. Usingultrasound as a guide, the doctor with-draws 2-3 tablespoons of amnioticfluid from the mother’s womb througha very thin needle inserted in themother’s abdomen. Fetal cells that arefloating free in the amniotic fluid arethen analyzed for the thalassemiamutations.

CHORIONIC VILLUS SAMPLING(CVS)CVS can be performed somewhat ear-lier than amniocentesis, at about 10-11 weeks of pregnancy. In this test,the doctor removes a small sample ofthe chorionic villi, or the cells that willform the placenta. The cells areremoved either with a thin needleinserted in the mother’s abdomen orwith a thin catheter inserted in thevagina. These cells, which contain thesame genetic information as the fetus,are analyzed for the thalassemia muta-tions.

If you are interested in either of thesetests, ask your obstetrician to referyou to a prenatal testing center.

About the Cooley’s Anemia Foundation

The Cooley’sAnemia Foundationis the only national

non-profit health organization

dedicated to servingpatients afflicted

with various formsof thalassemia,most

notably the majorform of this genetic

blood disease, Cooley’s Anemia

The Foundation’s mission is:

Advancing the treatment and cure for this genetic blood disease.

Enhancing the quality of life of patients.

Educating the medical profession, thalassemia trait carriers andthe public about thalassemia.

For more information about thalassemia and what the Cooley’sAnemia Foundation is doing to fight it,call 800-522-7222 or visit our website (www.cooleysanemia.org)

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This publication was made possible by a grant from the New York State Department of Health.

Written by David Surface. Designed by MediumBlend.

Our thanks to Dr. Alan Cohen of Children’s Hospital of Philadelphia for his invaluable assistance in preparing this publication.

129-09 26th Avenue Suite 203 Flushing, NY 11354 (718) 321-CURE (800) 522-7222 www.cooleysanemia.org