HemoglobinophatiesHemoglobinophaties

Hemato-oncology Division Pediatrics DepartmentPediatrics Department

Medical Faculty, USU/ HAM Hospital

Hemoglobin structure• Hemoglobin is a heterotetramer

Two alpha and two beta chains pOne chain coordinates one heme group• Four heme groups per hemoglobin

Oxygenation of Hemoglobin

• An atom of iron is held within the hemeThe iron binds oxygenThe iron binds oxygen

• Oxygenation pulls on the amino acid chain by distorting the domed shape of d t d hdeoxygenated heme

Planar form

Fetal and Adult Fetal and Adult HemoglobinsHemoglobinsFetal and Adult Fetal and Adult HemoglobinsHemoglobins

δ

GenesChromosome 11 Chromosome 16

δγ β α

Hb Fα2γ2

Hb A2α2δ2

Hb Aα2β2

AdultFetus

Embryonic Embryonic HemoglobinsHemoglobinsEmbryonic Embryonic HemoglobinsHemoglobinsyy ggyy gg

Genes Chromosome 11 Chromosome 16

ε γ ζ α

Hb Gower 1 Hb Portland Hb Gower 2ζ2ε2 ζ2γ2 α2ε2

Expression of Hemoglobin types as a function of gestational ageg g

Normal Hemoglobin Variants – The Globin Genes and Developmental Globin Genes and Developmental Expression

NORMAL HUMAN HEMOGLOBINSNORMAL HUMAN HEMOGLOBINSO U OG O SO U OG O S

Hemoglobin A (a2 b2)e og ob (a b )97% of adult hemoglobin, 5% is composed of glycosylated Hb A (Hb A1c)g y y ( )

Hemoglobin F (a2g2) 75% at birth 75% at birth < 5% at 6 months < 1% in adults< 1% in adults

Hemoglobin A2 (a2d2)2 5% of adult hemoglobin2.5% of adult hemoglobin

Hemoglobinophatiesg pDefinisi:

H dit di d th t lt iHereditary disorders that can result in moderate to severe anemia

Basic defect is production of an abnormal globin chain

HomozygousInheritance of two genes from each parentInheritance of two genes from each parent coding for the same type of abnormal hemoglobin, e.g., Hb SS

H tHeterozygousInheritance of genes from each parent which code for a different type of abnormal hemoglobin each, e.g., Hb SC

MECHANISMS OF DISEASE IN MECHANISMS OF DISEASE IN MECHANISMS OF DISEASE IN MECHANISMS OF DISEASE IN HEMOGLOBINOPATHIESHEMOGLOBINOPATHIESHEMOGLOBINOPATHIESHEMOGLOBINOPATHIES

Intracellular polymerization and gelation of Hb as in RBCs containing large amounts of Hb SFormation of unstable Hb leading to denaturation and precipitationF ti f th l bi hi h t bi d t O2Formation of methemoglobin which can not bind to O2 leading to cyanosis as in Hb MFormation of hemoglobin with high affinity to O2 as inFormation of hemoglobin with high affinity to O2 as in Hb C leading to failure of tissue oxygenation

General Classification of Genetic Disorders of Hemoglobin g

Structural variantsCommon variants assosiated with disease

Hbs S, C and ERare variants

Associates with disease‘Silent’

ThalassemiasStructural variants that result in a thalassaemic

phenotypeHereditary persistence of fetal hemoglobin (HPFH)Hereditary persistence of fetal hemoglobin (HPFH)

Structural variantsDi l i f l h l bi iDiseases resulting from structural hemoglobins variants

Hemolytic anemiaHbS, HbCUnstable hemoglobins

Hereditary polycythemiaHereditary polycythemiaHigh-oxygen affinity hemoglobins

Hereditary cyanosisM haemoglobinsLow-oxygen affinity hemoglobins

Thalassemia phenotypeThalassemia phenotypeHighly unstable hemoglobinsChain-termination hemoglobins variantsFusion-chain hemoglobin variants

Morphologic FindingsHb SS vs Hb SC vs Hb CCHb SS vs. Hb SC vs. Hb CC

=+

Hb S Hb C Hb SC

+ =

SICKLE CELL ANEMIADefinitionchronic hemolytic anemia characterized by sickle-shaped red cells(RBCs) caused by homozygous inheritance of Hemoglobin S

Normal RBCs Sickled RBCs

Pathogenesis

In HbS, valine is substituted for glutamic acid in the sixth amino acid of the ß chainsixth amino acid of the ß chainDeoxy-HbS is much less soluble than deoxy HbA; it forms a gelatinous network of fibrous polymers thatforms a gelatinous network of fibrous polymers thatcause RBCs to sickle at sites of low pO2

Hemolysis - because sickle RBCs are too fragile to y gwithstand the mechanical trauma of circulationOcclusion in microvascular circulation caused by

f Cdistorted, inflexible RBCs adhering to vascular endothelium

Clinical featuresUncomplicated sickle-cell anemia

AnemiaMild icterusSplenomegaly in early lifeSpleen regress rarely palpableSpleen regress, rarely palpableNon-specific cardiac sign

Acute and life-threatening complicationAcute and life threatening complicationSerious infectionVaso-oclussive crisis bone painHand-and-foot syndromeLung, brain crisisSequestration (spleen and liver) crisis Aplastic crisis

Clinical features

Clinical complications due to severe hemolytic anaemia

Slowed growth and development in childrenbilirubins stones

l ti i iaplastic crisiscongestive heart failure from chronic anemias

and cardiac overload compensationand cardiac overload compensationConsequences of vaso-occlusion of themicrocirculations (tissue ischemia and infarction)

infarction of spleen, brain, marrow, kidney, lung, aseptic necrosis, central nervous system and ophtalmic vascular lesionsp

Laboratory Findingsy g

1. Anemia-normocytic or slightly macrocytic, moderate to se eremoderate to severe

2. Leukocytosis (chronic neutrophilia)3 Thrombocytosis - usually mild<1000G/l3. Thrombocytosis usually mild<1000G/l4. Reticulocytosis (10-20 %)5. Peripheral smearp

sickle shaped red cells, polychromatophilia, Howell-Jolly bodies

6 Hb l t h i hi h f li id6. Hb –electrophoresis or high-performance liquid chromatography (HPLC):

Hbs S and A2, variable level of HbF (2-25%)Hbs S and A2, variable level of HbF (2 25%)

Therapy

Suportive:infections (penicillin prophylaxis and pneumococcal vaccination), fever, dehydratation, acidosis, hypoxemia, cold exposure, painBlood transf sions for er se ere anemiaBlood transfusions for very severe anemiaNew approaches to therapy;Activation of HbF synthesisActivation of HbF synthesis

hydroxyurea, 5-azacytidine, decytabineAntisickling agents acting on hemoglobin orAntisickling agents acting on hemoglobin or

membrane (preclinical testing, clinical trials)Bone marrow transplantationBone marrow transplantationGene therapy

Hb SC disease

• Milder anemia, fewer crises• Complications:

high frequency aseptic necrosis of the femoral d h l h d h t i lif tiand humoral heads, hematuria, proliferative

retinopathy, thrombotic tendency• Clinical findings• Clinical findings

Splenomegaly• Peripheral blood smear• Peripheral blood smear

target forms and intracellular cristals, sickeld forms, modest reticulocytosis lower than sickle-, ycell anemia

Hb C

• Hb C is less solulable with a tendency to cristal formation than Hb A lower oxygen affinity than Hb Aformation than Hb A, lower oxygen affinity than Hb A

• Contains less water and export higher level of K+

Hemolysis and increased red-cell turnover• Clinical manifestation:

mild hemolytic anemia and moderate splenomegaly• Symptomaticc in stress stage:

Anemia, reticulocytosisP i h l bl d• Peripheral blood smear:

target cells and intracellular crystals

Hb E

• Most common hemoglobin variant• Hb E heterozygotes (30% Hb E):yg ( )

Clinically normal, only minor hrmatological changes• Hb E homozygotes:

Mild anemia, similar to those of heterozygous ß thalassemia