Term
| Describe the chromosomal location of globin genes and their expression during development |
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Definition
2 alpha chains - chromosome 16
2 beta chains - chromosome 11 |
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Term
| Describe the most important globin chains in normal human hemoglobins and relative concentrations |
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Definition
HbA (a2b2)
HbF (a2g2)
HbA2 (a2d2) |
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Term
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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+ |
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Term
| Explain which functional effect of Hb can lead to cyanosis and erythrocytosis in methemoglobinemia |
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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 |
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Term
| Describe alpha thalassemia |
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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 |
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Term
| Describe beta thalassemia |
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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 |
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Term
| List, explain the mechanism of thalassemia |
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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 |
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Term
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Definition
| In newborns with α-thalassemia, excess unpaired γ-globin chains form γ4 tetramers known as hemoglobin Barts |
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Term
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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 |
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Term
Hemoglobin S physiology
-explain HbS and sickling of RBCs under hypoxia |
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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 |
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Term
Hemoglobin S structure
Describe the point mutation in sickle cell anemia |
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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 |
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Term
| Explain the functional effect of the altered spatial and physical configuration of the hemoglobin molecule due to amino acid substitution in sickle hemoglobin |
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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 |
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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 |
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Definition
Heterozygous HbS - largely asymptomatic
-offspring of two heterozygotes have 25% chance of being homozygous
-red cells sickle only under profound hypoxia
Homozygous - symptomatic |
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Term
| Recognize sickle cells in the peripheral blood in red cells with HbS |
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Definition
the abnormally shaped cells are prematurely destroyed
Howell Jolly bodies, nRBCs |
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Term
| Recognize the clinical manifestation in infants and adults with sickle hemoglobin trait and disease (HbS) |
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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 |
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Term
| Explain the role of the spleen in the destruction of circulating sickled red cells |
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Definition
| Sickled red cells aren't deformable, get trapped in the spleen |
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