Exam 13 - Heme13 - Hemoglobinopathies

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Hemoglobinopathies:

RBC disorders that result in ... of abnormalities of RBC structure that result in clinical problems from the abnormal physical properties of the hemoglobin

... result in defects in hemoglobin chain synthesis of one or more of the globin chains, unbalanced hemoglobin production, ineffective erythropoiesis, hemolysis and varying degrees of anemia

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inheritance
Thalassemias

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A hemoglobinopathy is the result of a genetic defect causing an abnormal ... of one or more globin chains of the hemoglobin molecule
-Most hemoglobinopathies are not clinically evident
-Only a few hemoglobinopathies cause serious disease

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structure

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Genetic defects of hemoglobinopathies:

May be substitution of one amino acid for another; single nucleotide polymorphism

Deletion or reorganization of part of the amino acid sequence

Result from the abnormal hybridization of the globin chains

Most severe hemoglobinopathies are characterized by ... and anemia

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hemolysis

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Genetic defects of hemoglobinopathies:

... result from genetic defects that cause production of an abnormally low amount of one or more hemoglobin chains
-The genetic mutation may affect the α, β, γ, or δ chain or a combination of β, γ, and δ chains but never ... and ... chains together

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Thalassemias
α and β

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Pathophysiology of hemoglobinopathies:

Some positions on the protein globin chain can tolerate extensive substitution without altering hemoglobin integrity; while even single nucleotide changes in ... sites may greatly alter the physiology of hemoglobin and cause clinical effects

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sensitive

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Pathophysiology of hemoglobinopathies:

Increase oxygen affinity
-Arise from mutations that affect regions of contact between α and β chains and regions that form the pocket where the oxygen affinity molecule ... resides
-... binding strength of oxygen but ... oxygen release to tissue
-Erythropoietin is produced as a result of low oxygen delivery and results in ...

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2,3-DPG
Increases
lowers
erythrocytosis

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Pathophysiology of hemoglobinopathies:

Decreased oxygen affinity
-The hemoglobin binds to and holds oxygen ...
-The hemoglobin holds less oxygen and carries less oxygen out to the tissues
-When the quantity of poorly oxygenated hemoglobin exceeds 5 gm/dl ..., a bluish discoloration of the skin occurs

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poorly
cyanosis

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Pathophysiology of hemoglobinopathies:

...
-Low oxygen affinity hemoglobin variants usually containing heme that binds iron in the ferric (Fe+++) rather than ferrous (Fe++) form
-These methemoglobins are designated by the locale where they were discovered and are characterized as “M” hemoglobins

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Methemoglobinemia

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Pathophysiology of hemoglobinopathies:

Unstable hemoglobins
-Particular mutations in the globin chain create hemoglobins that are inherently unstable
-When the hemoglobin destabilizes it forms an RBC inclusion called a ...
-... inclusions attach to the inner membrane of the RBC and lower cell deformability causing cell destruction usually in the spleen causing hemolysis; these disorders are inherited as autosomal ... diseases

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Heinz body
Heinz body
dominant

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Pathophysiology of hemoglobinopathies:

Sickling and crystallization
-Characteristic of hemoglobin S and hemoglobin C diseases, respectively
-The hemoglobin changes of sickling and crystallization mediate the RBC damage that is associated with the clinical consequences of hemoglobin ... diseases

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S and C

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Epidemiology and genetics: Hgb S

-Hb S found mainly in tropical ... populations where incidence of the gene is as high as 40%
-Incidence in African-Americans is about 8%
-Found in some populations in aboriginal peoples of India, the Middle East and the Mediterranean

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African

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Epidemiology, Pathophysiology, and Genetics of Hb S:

SNP with substitution of glutamate for valine in the sixth amino acid position of the β chain

Genetic change developed in tropical African population and persisted, probably because heterozygous expression offers some protection against P falciparum ...

An autosomal recessive disorder; ... carry sickle cell trait

... demonstrate sickle cell disease; that is a chronic hemolytic anemia and vaso-occlusive disease

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malaria
heterozygotes
Homozygotes

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Pathophysiology of Hb S:

Hb S expresses its biochemical instability by precipitating out of solution and forming microtubular arrays called ...

RBC membrane stretches around ... creating long curved cell shapes called “sickle cells” and is very poorly deformable

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tactoids
tactoids

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Pathphysiology of Hb S:

Tactoids formed only from ... Hb S

The greater the proportion of Hb S, the greater the likelihood of sickling; therefore sickle cell is ... dependent

Homozygotes sickle daily while heterozygotes sickle only under unique circumstances

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deoxygenated
density

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Pathophysiology of Hb S:

Hb S is a ... chain mutation and sickling typically does not manifest until after 6 months of age when Hb ... has declined (Hb S density increases)

Homozygotes for Hb S result in 97% or more Hb S with the remainder being Hb A2

Several co-existing mutations common in African populations may ... sickling

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β
F
minimize

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Pathophysiology of Hb S:

Ameliorating co-existing mutations
-Alpha thalassemia and to a lesser degree beta thalassemia cause lower mean corpuscular volume that ... the vaso-occlusive effects
-Sickle-thalassemics have ... vaso-occlusive events and generally live longer than homozygous sickle cell patients
-Hereditary persistence of ... hemoglobin allows Hb F to continue to be made and dilute the Hb S so that sickling does not occur

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lowers
fewer
fetal

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Clinical effects of Hb S:

Effects of chronic hemolysis
-Anemia
-... from rapid heme turnover
-... from excess bilirubin production
-Aplastic crisis results in severe anemia because of shortened RBC survival and parvovirus-suppressed RBC production
-Hemolytic crisis from sudden exacerbation of chronic hemolysis

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Jaundice
Cholelithiasis

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Clinical effects of Hb S:

Effects of vaso-occlusion
-... is ischemia or infarction of bones of hands and feet causing swelling and pain
-... is the gradual infarction of the spleen due to excess activity and ischemia
-... is painful, sustained penile erection due to sludging of sickled cells
-Renal papillary necrosis from inhospitable renal medullary environment producing sickling

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Dactylitis
Autosplenectomy
Priapism

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Clinical Effects of Hb S:

Effects of vaso-occlusion
-Infarctive crisis can brought on by increased sickling from any stress, particularly ...
-Sequestration crisis occurs primarily in ... and results in sequestration of RBC’s in the reticuloendothelial system, mainly the ...
-Leg ulcers from sickling causing deep, non-healing ulcers of the skin and SQ tissues

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infection
children
spleen

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Epidemiology, Genetics and Pathophysiology of Hb C:

Hb C occurs in 2-3% of African-Americans

Hb C is inherited as an autosomal ... trait

Hb C involves the substitution of lysine for glutamic acid in the N-terminal end of the ... chain

Hb C forms blunt-ended intracellular ...

Decreased RBC survival occurs but ... is not as severe as in sickle cell and vaso-occlusive events occur uncommonly

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recessive
β
crystalloids
hemolysis

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Pathophysiology of Hb C:

Hb C trait is ... but homozygotes and some heterozygotes have target cells with the Hb C crystals only seen occasionally

Prognosis of Hb C disease is quite good and usually does not require treatment

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asymptomatic

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Epidemiology and Pathophysiology of Hb SC Disease:

May inherit Hb S from one parent and Hb C from the other

Severity is intermediate between Hb S and Hb C disease

... damage from ischemia and vascular occlusion is often severe in Hb SC disease

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Retinal

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Pathophysiology of Hb SC Disease:

... of the femoral head is a particularly morbid complication of ischemia and vascular occlusion

The intracellular bodies of SC disease are hybrids of the Hb S ... and the Hb C ...

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Aseptic necrosis
tactoids
crystalloids

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Treatment of Hb S and SC Disease:

Vaso-occlusive crisis
-IV fluids, antibiotics, oxygen, IV or oral narcotics, or NSAID’s, and blood transfusion for moderate or severe episodes
-... increases HbF by an unknown mechanism and may work effectively as a preventive

Aplastic crisis
-IVIG may be a direct therapy of parvovirus infection
-IV fluids and blood transfusion for ... blood volume

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Hydroxyurea
low

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Treatment of Hb S and SC Disease:

Splenic sequestration crisis; (circulatory collapse)
-Analgesia, IV fluids, and when stabilized, ...

Hemolytic crisis
-IV fluids and blood ...
-Oxygen
-IV or PO analgesia

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splenectomy
transfusion

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Treatment by Prophylaxis:

Avoid crisis-producing factors: dehydration, anoxia, infection, circulatory stasis, and ... of the skin surface

Good nutrition, hygiene, ... acid

Vaccination for pneumococcus, H. flu, meningococcus, Hepatitis B

Oral ...

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cooling
folic
penicillin

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Thalassemia:

Normal Hemoglobin Structures
-Hgb ...: α2β2; contains 2 alpha and 2 beta chains
-Hgb ...: α2δ2; contains 2 alpha and 2 delta chains
-Hgb ...: α2γ2; contains 2 alpha and 2 gamma chains

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A
A2
F

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Definition, Pathophysiology and Genetics of Thalassemia:

Most common single gene disease trait in man; autosomal ... inheritance

Occur at high frequency in Mediterranean, Middle Eastern, and Southeast Asian areas from India through the Malay Peninsula

Occur in large numbers in ... populations

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recessive
immigrant

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Consequences of Thalassemia:

... rate of globin chain synthesis

Imbalance of globin chains; named for the chain that is ... produced

Defective hemoglobin production

May result in damage to RBC’s from the globin chains that are produced in relative excess

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Reduced
deficiently

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Forms of Thalassemia:

Beta thalassemia
-Primarily a consequence of a ... mutation
-Mutations may occur within the β gene itself, promoter, enhancer or other expression-controlling sites

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point

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Beta thalassemia:

Beta0 (β0): no beta chain production
-β thalassemia ... generally requires two separate mutations affecting β genes and β globin synthesis
-Manifests as ... Hb F; hepatosplenomegaly from excess RBC destruction and extramedullary hematopoiesis

Beta+ (β+): decrease in beta chain production
-Primarily manifest by an elevated level of hemoglobin ...

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major
elevated
A2

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Forms of Thalassemia:

Beta thalassemia
-β thalassemias result from mutations in the HBB gene on chromosome 11 and are inherited as an autosomal ... trait
-β chain deficiency results in ... chain excess causing RBC membrane defects and in high concentrations toxic aggregates of alpha chains and hemolysis
-β gene clusters on the short arm of chromosome ... contain highly-preserved and predictable areas as well as highly variable areas

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recessive
α
11

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Forms of Thalassemia:

β thalassemia
-Heterogeneous with nearly 200 different characterized mutations
-Primarily point and non-deletion mutations occur that affect transcription, processing or translation; ... have β0 and ... have β+ thalassemia
-Each worldwide population effected is characterized by two or three common defects with a large number of rare mutations

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homozygotes
heterozygotes

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β thalassemia:

Gene deletions
-Roughly 20 deletions have been described and are rare except for a 619 bp deletion common in India and Pakistan
-... have β0 thalassemia while those who are ... have β+ thalassemia with high δ chain production and ... hemoglobin A2

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Homozygotes
heterozygotes
increased

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Delta-beta (δβ) thalassemia:

In some patients no delta or beta globin chains are produced
-Delta-beta+ results from production of an abnormal hemoglobin from an alpha chain combined with a non-alpha chain created by fusion of N-terminal portion of a delta chain and C-terminal portion of an alpha chain: called hemoglobin ...

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Lepore

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Forms of thalassemia:

Delta (δ) thalassemia results in reduced delta chain production therefore lower or absent Hgb ... generally not clinically significant

Epsilon-gamma-delta-beta (εγδβ) thalassemia not compatible with life in homozygous state and therefore only seen in its ... form

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A2
heterozygous

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Alpha Thalassemia:

Alpha (α) globin chains are found in both fetal and adult hemoglobin and effect hemoglobin production in all ages
-Reduced alpha chain production in fetal setting ... the amount of gamma chains produced
-Excess gamma chain production leads to gamma tetramer production and hemoglobin ...

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increases
Bart’s

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Forms of thalassemia:

Alpha thalassemia
-α (alpha) globin chains are encoded by two closely linked genes on chromosome ...
-The genes HBA1 and HBA2 are responsible for production of α1 and α2 globin chains
-Decreased alpha globin chains results in excess ... chains in adults and excess ... chains in newborns

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16
β
γ

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Forms of thalassemia:

Alpha thalassemia
-Alpha0 (α0) thalassemia describes the situation when both linked genes on the same chromosome are defective and no ... chain is produced from that chromosome
-Alpha+ (a+) thalassemia occurs when ... gene in a linked pair is dysfunctional; these are very diverse molecularly

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alpha
one

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Forms of Thalassemia:

Alpha thalassemia
-If one alpha locus is affected, ... Hb but ... MCV and MCH; silent carrier
-If two alpha loci affected, mild MC/HC ...; alpha thalassemia trait; cis and trans positions
-If three loci affected called ... disease with two unstable Hb’s, Hb Barts (fetal) from tetrameric γ chains and Hb H (adult) from tetrameric β chains

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normal
low
anemia
Hb H

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Forms of Thalassemia:

Alpha thalassemia
-Hb H results in MC/HC anemia with target cells and Heinz bodies on peripheral smear, and ...
-If all four loci affected, fetus dies in utero or shortly after birth, hydrops fetalis; have only tetrameric γ chains, Hb Barts

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splenomegaly

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Forms of Thalassemia:

Alpha thalassemia
-α gene clusters on chromosome 16 contain three functional and several non-functional genes
-Comparing the alpha1 and alpha2 variants of the alpha globin genes; ... produces 1.5 to 3 times as much m-RNA

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alpha2

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Forms of Thalassemia:

Alpha thalassemia
-α1 exons are identical to one another and α2 exons are identical to each other but α1 differs in number and order of bases from α2
-... that separate and surround α exons contain hypervariable regions and are highly polymorphic

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Introns

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Forms of Thalassemia:

Alpha thalassemia
-α globin introns contain single nucleotide polymorphisms and with characteristic ... regions allow for tracing inheritance of thalassemia mutations

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hypervariable

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Globin gene clusters and expression:

Some regions flanking globin genes are highly conserved and affect and are essential for globin gene expression
-... box identifies site of transcription initiation and influences transcription rate
-Upstream promoter elements required for optimal transcription

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TATA

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Globin gene clusters and regulation:

Primary transcript is a large mRNA product that is extensively processed

Introns are “spliced” out of the primary transcript and errors in ... may cause thalassemia

The primary mRNA transcript is stabilized at the 5’ and 3’ ends by a methyl-... group and polyadenylation respectively and errors in this process can result in thalassemic mutation

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splicing
guanosine

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Globin gene clusters and expression:

-Globin gene switching from fetal to adult hemoglobin is a critical transition
-Unclear how switching is regulated but it is coordinated among hematopoietic tissues
-Fetal hemoglobin production can be reactivated at times of ... in hematopoiesis

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stress

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Treatment of Thalassemias:

Thalassemia major; severe form of β thalassemia
-Frequent blood ... for symptoms of anemia and to sustain normal growth and development; maintain Hb of ...; folic acid
-Iron ... therapy to remove excess iron with various toxicities; vitamin C for chelation
-... to reduce transfusion requirements

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transfusions
10
chelation
Splenectomy

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Treatment of Thalassemias:

Thalassemia ...
-Wide variation in severity; treat those in need (Hb < 6)

Thalassemia ...
-May have mild to moderate anemia; rare treatment
-Associated with asthma and depression

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intermedia
minor

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Treatment of Thalassemias:

Chelation therapy for ... overload
-Iron damaging to heart; iron evident on T2 MRI and inferrable by serum ferritin but ferritin not as reliable
-Iron chelators
*... by acute or continuous IV infusion; 2/3 excreted in urine; better with vitamin C
*Deferiprone or Deferasirox are oral agents with urine and stool excretion respectively

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iron
Deferoxamine