Hemoglobinopathies And Thalassemias Flashcards
Alpha Hb genes
. On chromosome 16
. 2 zeta genes for alpha chains
. Contains gene expressed in early development as an alpha-globin like component of embryonic Hb
Beta Hb genes
. Chromosome 11
. Contains epsilon gene expressed in early embryonic development
. 2 gamma gene expression seen in Hb F
. Delta gene for globin chain found in adult HbA2
Steps in globin chain synthesis
. Starts in nucleus of blood cell precursors where it’s transcribed
. mRNA produced, 2 introns removed and 2 Econ’s join
. Mature mRNA is translated producing globin chain
Hb A
. Contain the alpha and beta tetramer structure
. HbA2 synthesized in low levels
Hb F
. Tetramer of 2 alpha and 2 gamma chains
Hb synthesis timeline
. 1 month after conception synthesis starts in yolk sac
. After 5th week the Hb synthesis switches to liver then the marrow w/ product Hb F
. Last months Hb F is 60% of rbcs
. Hb A starts in bone marrow at 8th month and gradually replaces Hb F
2,3-BPG binding to Hb F
. Weakly binds so f has higher O2 affinity than A
Why does Hb F need higher O2 affinity?
To facilitate transfer from maternal circulation across placenta to RBC of fetus
Hb A2
. Minor component of normal adult Hb that appears shortly after birth and eventually constitutes 2% total Hb
HbA1c
. HbA undergoes glycation
. Glycation dependent on [glucose] in blood plasma
. Inc. amounts found in diabetic patients
. Gives indication of blood glucose level over 120 days (RBC life span)
Glycation
NONENZYMATIC addition of glucose to HbA
Hemoglobinopathies
. Result from production of Hb w/ altered amino acid sequence
Hb S disease
. Sickle cell
. Single point mutation in gene (Val instead of Glu at position 6) for beta-globin making it beta-s
. Mutation makes HbS less negative than HbA
. Autosomal recessive gene
Sickle cell prevalence
. 50,000 Mexicans affects
. 1:500 black children
. 1/12 black people heterozygous carriers
SIckle cell characteristics
. Infant don’t show symptoms until Hb F is replaced by HbS
. Lifelong episodes of pain, chronic hemolytic anemia, inc. bilirubin, and inc. suspectibility to infection
. Lifespan of RBC w/ HbS is less than 20 days
. Cell looks sickled
How do cells look sickled?
. Replacement of Glu for Val forms protrusion on beta-chain
. Fits into complementary site on beta-chain of another Hb molecule
. Low O2, R state of HbS polymerizes inside RBC forming network of insoluble, fibrous polymers that stiffen and distort cell
How do sickle cells cause localized anoxia?
. Block blood flow in capillaries causing anoxia, pain, or death of cells
How is sickling enhanced?
. Dec. pO2 . Inc. pCO2 . Dec. pH . Dehydration . Inc. 2,3-BPG
Sickle cell treatment
. Adequate hydration, analgesics, antibody therapy for infection, blood transfusions. Intermittent transfusions packed with RBCS
Advantage of being heterozygous for HbS
. Less susceptible for malaria because cell lifespan isn’t long enough for parasite to grow
Hb C disease
. Single amino acid substitution in 6th position of beta chain (Lys for Glu)
. Causes HbC to move slower toward anode than HbA and HbS in gel electrophoresis
. Experience mild chronic hemolytic anemia but no crises
. No treatment needed
HbSC disease
. Beta globin chains have HbS mutation and other beta-globin genes carry mutation found in HbC
. Individuals affected are compound heterozygous
. Hb levels higher than in Hb levels in sickle cell disease
. Vary in symptoms
. Crises less frequent and less severe than HbS
Methemoglobinemia
. Oxidation of heme Fe to Fe 3+ (ferric) causing HbM that can’t bind to O2
. Causes by drugs, ROS, mutations in chains, NADH-cytochrome B5 reductive deficiency
Methemoglobinemia symptoms
. Chocolate cyanosis, brownish blue coloring in skin and mucous membranes from dark HbM coloration
. Tissue hypoxia, anxiety, headache, dyspnea, coma, and death (rare)
Methemoglobinemia treatment
Methylene blue that reduces Fe 3+ back o Fe2+
Thalassemia
. Hereditary hemolytic diseases that cause imbalance in globin chain synthesis
. Most common single gene disorder
. Either alpha or beta chain defective
. Varies in type of mutation causes defect
. Either no type of a globin chain is produced or some are synthesized but at reduced rate
Beta-thalassemias
. Synthesis of beta-chain is dec. or gone
. Usually point mutation issue
. Alpha chain is normal, but can’t form stable tetramers resulting in RBC precursor death
. Inc. HbA2 and HbF
Type of beta-thalassemia
. Minor: one defective copy of beta-globin gene on chromosome 11
. Cooley anemia (major): 2 defective copies of beta-globin gene on chromosome 11
Beta-thalassemia presentation
. Physical manifestations appear several months after birth
. Severely anemia during 1-2 years of life
. Skeletal changes from extramedullary hematopoiesis
Beta-thalassemia treatment
. Regular transfusions
. Can result In Fe overload so iron chelation therapy needed
. Only cure is hematopoietic stem cell transplant
Alpha-thalassemia
. Synthesis of aloha chain dec. or gone
. Usually deletion mutations
. Chromosome 16 affected by mutations
Types of alpha-thalassemia
. 1 defective gene: silent carrier/no symptoms
. 2 defective genes: alpha thalassemia traits
. 3 defective genes: Hb H (B4) disease causing hemolytic anemia of varying severity
. 4 defective genes: Hb Bart (gamma4) causing fetal death because no HbF is made
