57 terms

Hematology Exam IV Prep Anemias, Hemoglobinopathies, Intro to Leukemia


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Classifications of hemolytic anemias
-acute vs chronic
-inherited vs acquired
-intrinsic vs extrinsic
-intravascular (fragmentation) vs extravascular (macrophage mediated)
Most RBC degradation occurs
extravascularly (macrophages in the liver and spleen mostly)
Hemoglobin is broken down to
heme and globin
Iron from broken down hemoglobin is
Globin from broken down hemoglobin
goes to amino acid stores
Heme from broken down hemoglobin
is broken down to biliverdin, then bilirubin
binds to albumin and goes to the liver, becomes conjugated, goes to the intestines as urobilinogen
Free hemoglobin
-filtered by the kidney
Hemoglobin bound to haptoglobin
-not filtered
-goes to liver
Intracorpuscular defects
-defects in cell membrane
-enzyme defects
-paroxysmal nocturnal hemoglobinuria
Anemia dependent on
-degree of hemolysis
-compensatory response of bone marrow
Diagnostic test for hemolysis
-indirect bilirubin
-serum haptoglobin level (low)
-A1c glycosolated hemoglobin (increases as cells age)
-retic count, elevated MCV
-abnormal RBC morphology
Hereditary defects of RBC membrane
dehydration of red blood cells
-autosomal recessive form of hemolytic anemia, characterized by abnormal sensitivity of RBC's to heat
RBC Biconcave disk
vertical and horizontal interactions of transmembrane (ankyrin) and skeletal proteins (spectrin)
RBC elasticity of membrane
due to spectrin/ junctional interactions and unfolding/ refolding of spectrin
RBC cytoplasmic viscosity
Proper functioning of pumps and channels
-concentration of hemoglobin
-passage of ions, water, and macromolecules
Most common cause of hereditary spherocytosis
spectrin deficiency
Hereditary spherocytosis
-spectrin deficiency
-loss of surface area resulting in decreased surface-to-volume ratio
-cells become less deformable, destroyed in spleen
-abnormal permeability to cations
Hereditary spherocytosis is inherited as
-autosomal dominant 75%
-non dominant, some autosomal recessive 25%
clinical findings of hereditary spherocytosis
-jaundice (severity of hemolysis)
-splenomegaly (enlarged from constant removal of red cells)
lab findings of hereditary spherocytosis
-normal MCV, MCH (structural abnormality)
-elevated MCHC (mild cellular dehydration)
-spherocytes identified on peripheral smear
-osmotic fragility increases (as salt concentration decreases cells swell and lyse, spherocytes lyse at higher concentrations
autohemolysis test
within 48 hours, cells will lyse with no additional glucose (no longer performed)
Red cell membrane electrophoresis
determines protein deficiencys
Complications of further heridatary spherocytosis lab studies
-viral infections (parvovirus 819)
-folic acid deficiency due to erythroid hypoplasia
Hereditary elliptocytosis/ poikilocytosis
-defects in proteins that disrupt the horizontal
(spectrin mutation)
-decreased thermal stability (cell fragmentation upon heating)
-asymptomatic pts need no treatmentt
-symptomatic pts may need splenectomy or transfusions
Membrane cation permeability
-sodium and potassium determine water content of cell
-greater passive permeability of sodium into cell (overhydrated)
-increased cell volume with decreased surface-to-volume ratio
Most common cause of potassium leaking out of RBC (dehydrated)
hereditary xerocytosis
Most common hereditary enzyme deficiency
-sex linked (more common in males)
-G6PD catalyzes the first step in the hexose monophosphate shunt
-keeps iron in ferrous state for oxygen transport
-activity highest in youngest cells and decreases with cell aging
-reduced glutathione causes more oxidative denaturation hemoglobin
G6PD is typically
Clinical syndromes of G6PD
acute hemolytic anemia
-oxidative stress with certain drugs, infections, fava beans
neonatal jaundice
-can cause kernicturus
-mutation in G6PD gene for enzyme to conjugate and excrete indirect bilirubin
chronic nonsperocytic hemolytic anemia
-increased extravascular hemolysis
Lab findings in G6PD
-moderated to severe normocytic normochromic anemia
-marked anisocytosis, poikilocytosis, spherocytosis, shistocytosis (may see bite cells where splenic removal of Heinz body
Pyruvate kinase deficiency
-block in anaerobic glycolysis due to lack of enzyme pyruvate kinase
-inherited as autosomal recessive
-decreased capacity to generate ATP
-shifts oxygen disassociation curve to the right (decreased oxygen affinity of hemoglobin, affected people tolerate lower levels of hemoglobin
clinical manifestations of pyruvate kinase deficiency
-anemia can be mild to severe
-increased 2,3 DPG in cell which allows oxygen to be readily released
-pts tolerate exercise well
-symptoms of chronic hemolysis (jaundice, splenomegaly, increased incidence of gallstones due to excessive bilirubin)
Lab testing for pyruvate kinase deficiency
-normocytic, normochromic anemia
-increased reticulocytes, polychromasia
-low hemoglobin hematocrit
-increased osmotic fragility as cells age
-PK assay (fluorescence screening test NADH fluorescence)
-abnormal hemoglobin is synthesized (1000 structural varients)
Point mutation
substitution of one amino acid
Deletions or insertions
addition or deletion of one or more amino acids affecting the structure and function
Chain extension
mutation in stop codon producing longer globin chains so molecule folds wrong affecting structure and function
gene fusions
genes break between nucleotides, switch positions, and link to opposite gene, different folding
number of gene mutations
-4 copies of α and γ and 2 copies of β and δ
-A1 hemoglobin composed of α and β, so β chain mutations are more likely to cause clinical condition
-heterozygous is trait and homozygous is disease
Abnormal Hb S and Hbc result in
sickle cell anemia
Abnormal Hb S
substitution of valine for glutamic acid in the sixth position from the NH terminus of beta chain
Abnormal Hb C
substitution of lysine for glutami acid in the sixth position from the NH terminus of beta chain
pathophysiology of sickle cell
oxygen tension decreases Hb S becomes polymerized
-changes in ionic charge of +1
red cells become deformed and sickle
-sickling may be reversible or irreversible
-depends on degree of oxygenation, pH, and dehydration
-sickle cells plug small vessels resulting in tissue necrosis organ infarction, and pain
clinical features of sickle cell
anemia due to hemolysis
-polymerized cells may rupture
-abnormal cells removed by spleen
increased erythropoiesis
-marrow spaces widen
-thinning of bone
-may see extramedullary hematopoiesis in extreme cases
complications of sickle cell
-infarction can occur anywhere in the body
(pulmonary most common)
-cutaneous manifestation is ulcers or sores
-infection (more severe than in normal people, malaria less severe in SCD because parasitized cells sickle more quickly and parasites are phagocytized by WBCs)
Nephropathies in SC
sickling occurs more often in kidney due to low oxygen tension, hypertonicity, acidosis
Stroke in SC
infartion or hemorrhagic lesion in a cerebral vessel
sickle cell trait
-inheritance of one normal β-globin gene and one sickle-globin gene
-produce Hb A (60%) and Hb S (40%)
-usually asymptomatic
-crisis occurs with drastic lowering of pH or reduction in oxygen tension
treatment for SC
-blood transfusion
-bone marrow transplantation being investigated
laboratory test for SC
Peripheral smear
-anisocytosis, poikilocytosis, normochromia
-sickle cells (in crisis, diagnostic) target cells, normocytes
Tube solubility screening test
-sodium dithionite bings to oxygen
-Hb S polymerizes and precipitate forms
Hemoglobin electrophoresis
Hemoglobin C is found primarily in the
black population
Hemoglobin C is a
substitution of lysine