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Heme I Hb & Hemoglobinopathies
Cunningham DSA - DONE
16
Medical
Graduate
03/24/2011

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Term
Describe the chromosomal location of globin genes and their expression during development
Definition
2 alpha chains - chromosome 16
2 beta chains - chromosome 11
Term
Describe the most important globin chains in normal human hemoglobins and relative concentrations
Definition
HbA (a2b2)
HbF (a2g2)
HbA2 (a2d2)
Term
Define methemoglobinemia
Definition
oxidized Hb

In intravascular hemolysis, free haptoglobin is depleted, and free Hb oxidizes to metHb (brown in color)

O2 dissociation curve shifts left

when metHb conc is i/c in RBC, tissue hypoxia can occur

conc i/c when defenses against oxidative stress are overwhelmed, and Fe++ is oxidized to Fe3+
Term
Explain which functional effect of Hb can lead to cyanosis and erythrocytosis in methemoglobinemia
Definition
central cyanosis - poor blood oxygenation

aka polycythemia - proportion of blood volume occupied by RBC i/c; overproduction of RBC by BM is a rxn to low O2 levels
Term
Describe alpha thalassemia
Definition
decreased synthesis of alpha chains
leads to aggregated beta, gamma, and delta chains in cytoplasm --> premature RBC destruction

the severity of α-thalassemia depends on how many α-globin genes are affected

Since free β and γ chains are more soluble than free α chains and form fairly stable homotetramers, hemolysis and ineffective erythropoiesis are less severe than in β-thalassemias

hydrops fatalis - most severe form - 4 gene deletions
Term
Describe beta thalassemia
Definition
decreased production of beta chains
i/c alpha chains with gamma (HbF) and delta (HbA2) --> premature RBC destruction

The deficit in HbA synthesis produces "underhemoglobinized" hypochromic, microcytic red cells with subnormal oxygen transport capacity
Unpaired α chains precipitate within red cell precursors -> insoluble inclusions -> membrane damage -> most red cell pathology/(severe: ineffective erythropoiesis -> excessive absorption of dietary Fe, massive erythroid hyperplasia & extramedullary hematopoiesis)

Little/no HbA
Primarily HbF

anisocytosis, poikilocytosis, microcytosis, hypochromia
retic count is high, but not so much b/c of ineffective erythropoiesis

"crew cut" skull
Term
List, explain the mechanism of thalassemia
Definition
The thalassemia syndromes are a heterogeneous group of disorders caused by inherited mutations that decrease the synthesis of adult hemoglobin, HbA (α2β2)
the defects in globin synthesis that underlie these disorders also impair red cell production and contribute to the pathogenesis of these disorders
Term
Define hemoglobin Bart's
Definition
In newborns with α-thalassemia, excess unpaired γ-globin chains form γ4 tetramers known as hemoglobin Barts
Term
Define hemoglobin H
Definition
In older children and adults with α-thalassemia, excess β-globin chains form β4 tetramers known as HbH
3 α-globin gene deletions
most common in Asians
Term
Hemoglobin S physiology
-explain HbS and sickling of RBCs under hypoxia
Definition
when deoxygenated, HbS molecules undergo aggregation and polymerization

red cell cytosol coverts to a viscous gel as HbS aggregates form

with cont deox, aggregated HbS molecules assemble into long fibers with red cells, producing sickle shape
Term
Hemoglobin S structure
Describe the point mutation in sickle cell anemia
Definition
point mutation at the 6th position of the beta-globin chain leading to substitution of a valine for a glutamine

beta (6) glu->val
Term
Explain the functional effect of the altered spatial and physical configuration of the hemoglobin molecule due to amino acid substitution in sickle hemoglobin
Definition
The severe derangement in membrane structure due to growing HbS polymers causes influx of Ca++
Induces the cross-linking of membrane proteins, activates ion channel, permits *efflux* of K+ and H2O

with repeated episodes of sickling, red cells become *dehydrated, dense, rigid*

eventually severely damaged cells are converted to end-stage, non-deformable, irreversibly sickled cells, retain sickle shape even when fully oxygenated

irreversibly sickled cells are sequestered, removed by mononuclear phagocytes (extravascular hemolysis *in the spleen*)

sickled red cells are mechanically fragile --> intravascular hemolysis (in circulating blood) as well

length of time red cells are exposed to low O2 tension is important; sickling of red cells is confined to microvascular beds where blood flow is sluggish in spleen and BM
Term
Explain the inheritance of the sickle cell gene and its manifestations as more than a complete dominant-recessive inheritance pattern
-manifestations as heterozygous and homozygous diseases
Definition
Heterozygous HbS - largely asymptomatic
-offspring of two heterozygotes have 25% chance of being homozygous
-red cells sickle only under profound hypoxia

Homozygous - symptomatic
Term
Recognize sickle cells in the peripheral blood in red cells with HbS
Definition
the abnormally shaped cells are prematurely destroyed

Howell Jolly bodies, nRBCs
Term
Recognize the clinical manifestation in infants and adults with sickle hemoglobin trait and disease (HbS)
Definition
in childhood, spleen is enlarged due to red pulp congestion caused by trapping of sickled red cells in the cords and sinuses

adults: chronic erythrostasis leads to splenic infarction, fibrosis, and progressive shrinkage -> autosplenectomy
Term
Explain the role of the spleen in the destruction of circulating sickled red cells
Definition
Sickled red cells aren't deformable, get trapped in the spleen
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