Hemoglobin Synthesis - PowerPoint Presentation

Slide1

Hemoglobin SynthesisSlide2

b

d

g

a

a

Chromosome 16

Chromosome 11

25%

25%

a

a

b

d

g

25%

25%

48%

48%

1.5%

0.5%

1.5%

0.5%

Hemoglobin synthesisSlide3

a

a

a

a

a

a

b

g

d

b

d

g

HbA

HbF

HbA

2

98%

~1%

<3.5%

Hemoglobins

in normal adultsSlide4

Hemoglobinopathy

definition

An inherited mutation of the globin genes leading to a qualitative abnormality of globin synthesis Slide5

Thalassemia

definition

An inherited mutation of the globin genes leading to a

quantitative abnormality of globin synthesis Slide6

Geography of HemoglobinopathiesSlide7

Separation of various hemoglobins with electrophoresis on cellulose acetate, pH 8.6. Hemolysates represented are AA (normal adult), SC (hemoglobin SC disease), SSF (homozygous sickle disease, SS, with increased F), AS (sickle trait), and AC (C trait).

Hemoglobin ElectrophoresisSlide8

Hemoglobin

Analysis by HPLCSlide9

Sickle Cell Anemia

Wide spectrum of disorders

1 / 600 African Americans affected

1 / 8 African Americans - sickle traitHb SS ~ 60% of sickle cell diseaseHb SC and Sb-thal ~ 40%Slide10

Sickle trait

β

S

/β; 8% of African-AmericansAsymptomaticPartial protection from malariaSickling may occur in renal medulla → decreased urinary concentrating ability, hematuriaRare complications at high altitude (splenic infarction)Sudden death following strenuous exercise (rare)Slide11

Genetic and Laboratory Features of Sickle Hemoglobinopathies

(Modified from Steinberg, M., Cecil Medicine 2007)Slide12

SS

SCSlide13

Pathophysiology of Sickle Cell Anemia

(Modified from Steinberg, M., Cecil Medicine 2007)

HbS Polymer

Vaso-occlusion

Hemolysis

Arginine

NOSlide14

Sickle Cell: Molecular Basis

Glutamate

 Valine at 6th position

b globinSickle Hb forms polymers when deoxygenatedPolymerized sickle Hb injures RBC membrane and distorts its shapeDistorted RBC is hemolyzedSlide15

Sickle Cells – Electron MicroscopySlide16

Sickle Cell: Pathophysiology

Deoxygenation

of mutant Hb leads to

 K+ efflux cell density / dehydration

 polymerizationSickled cells adhere to endothelial cellsEndothelial factors  vasoconstrictionBlood flow 

promotes vaso-occlusion“Vicious cycle” with decreased blood flow, hypoxemia / acidosis, increased sicklingSome cells become irreversibly sickledSlide17

FACTORS THAT INCREASE

Hgb

S POLYMERIZATION

Decreased oxygenIncreased intracellular hemoglobin S concentration (SS > SC, S-thal)Increased 2,3-DPGDecreased pHSlowed transit time through the circulationEndothelial adhesionSlide18

FACTORS THAT

DECREASE

Hgb

S POLYMERIZATIONLower concentration of Hb S (compound heterozygosity

for α thal)Increased HbF levelsGenetic basisHydroxyureaSlide19

Clinical Features of Sickle Cell Anemia

Painful episodes

Pneumococcal disease

Acute chest syndrome

Splenic infarction

Splenic sequestration

StrokeOsteonecrosis

Priapism

Retinopathy

Leg ulcersGallstones

Renal abnormalities

Osteopenia

Nutritional deficiencies

Placental insufficiency

Pulmonary hypertensionSlide20

Clinical Features of Sickle Cell Anemia

Associated

with

higher

hemoglobin

Associated with lower hemoglobin

Painful episodesStroke

Acute chest syndromePriapism

Osteonecrosis

Leg Ulcers

Proliferative retinopathySlide21

Pneumonia

Stroke

Skin ulcer

Osteonecrosis

Complications of

Sickle Cell

DiseaseSlide22

Sickle Cell – Avascular Necrosis

gait.aidi.udel.edu/.../clcsimge/sickle5

http://www.zimmer.comSlide23

Sickle Cell – Avascular Necrosis

http://www.zimmer.comSlide24

Pulmonary HypertensionSlide25

Sickle Cell – Dactylitis

http://aapredbook.aappublications.org/week/116_09.jpgSlide26

PriapismSlide27

Sickle Cell – Splenic Complications

Autosplenectomy

pathology.mc.duke.edu/.../spleen1.jpg

Splenic Sequestration

Sheth, S. et al Pediatr Radiol 2000Slide28

Sickle Cell Anemia - treatment

Opiates and hydration for painful crises

Pneumococcal vaccination

Retinal surveillanceTransfusion for serious manifestations (eg stroke); exchange transfusion

HydroxyureaStem cell transplantSlide29

Hemoglobin C

Glutamate

→ lysine at 6

th position in beta chainHb tends to crystallizePrevalent in west AfricaHomozygous state – chronic hemolytic anemiaCompound heterozygosity with

Hb S produces sickle phenotypeSlide30

Hemoglobin C

Homozygous: target cells,

tactoids

Hemoglobin SCSlide31

Other

hemoglobinopathies

Unstable

hemoglobinsHeinz body formationMultiple mutations reported; dominant inheritanceHemolytic anemia (may be precipitated by oxidative stress)

Heinz bodies (supravital

stain)Slide32

Other

hemoglobinopathies

Hemoglobin M

Congenital methemoglobinemia, cyanosisHemoglobin with low oxygen affinityRight shifted dissociation curve, decreased EPOMild anemia (asymptomatic)

Hemoglobin with high oxygen affinityLeft shifted dissociation curve, increased EPOErythrocytosisThese all have dominant inheritanceMany benign/asymptomatic mutations describedSlide33

The

Thalassemias

Syndromes in which the

rate of synthesis of a globin chain is reduced

beta thalassemia - reduced beta chain synthesis alpha

thalassemia – reduced alpha chain synthesisSlide34

THALASSEMIA

Diminished or absent synthesis of normal globin chains (

α or β); genetically heterogeneous

Heterozygous state protects from malaria, hence more common in southern European, African, Asian peoplesUnbalanced globin chain synthesis causes microcytosis, ineffective erythropoiesis and hemolysisSlide35

ThalassemiaSlide36

Decreasing globin chain production

Increasing globin chain imbalance causing:

ineffective erythropoiesis (precipitated

α

chains)

hemolysis (β tetramers or Hb H)Worsening anemia

Single α-globingene missingnormal CBC

Two

α-globin genes missing: microcytosis

, minimal anemia

One β-globin gene missing: microcytosis

, mild anemia

Three α-globin genes missing:

microcytosis, hemolysis, moderate to severe anemia

Two β-globin genes missing: transfusion-dependent anemia

Four α

-globin genes missing: fetal demiseSlide37

Alpha

thalassemia

aa /

aa

Normal

aa /

a -

Mild microcytosis

aa /

- -

Mild microcytosis

a - /

- -

Hemoglobin H disease

-

/

- -

Hemoglobin Barts – Hydrops FetalisSlide38

H

Hgb H disease

Hgb H inclusions (supravital stain)Slide39

Hydrops

fetalis

(note gross edema)

Hydrops

fetalisSlide40

Beta

thalassemia

major

No beta chain produced (no HbA)Severe microcytic anemia occurs gradually in the first year of life (as gamma chain production stops)Marrow expansionIron overloadGrowth failure and death Slide41

Beta

thalassemia

majorSlide42

ThalassemiaSlide43

Beta

thalassemia

major

Male 18 yearsSlide44

Beta

thalassemia

major

treatmentTransfusionIron chelationStem cell transplantSlide45

Β

-Thalassemia Minor

b/ b0 or b/ b

+ Microcytosis, target cellsMild anemia – often asymptomaticDecreased HbA production → Increased proportion of Hb

A2Slide46

Β

-Thalassemia

Intermedia

b

+/ b0 (small amount of b chain production)Chronic

anemiaSplenomegalyOften transfusion-dependentSlide47

Hemoglobin E

b

mutation (glutamine → lysine at amino acid 26)Altered mRNA splicing, unstable mRNAHeterozygous in 30% of SE AsiansHomozygous

Hb E: microcytosis, hypochromia, little or no anemiaHemoglobin E / b-thal causes thalassemia-like phenotype