Hemoglobin Disorders Flashcards
hemoglobin
- large molecule made up of proteins and iron
- four folded chains of a protein called globin
how many hgb molecules are in one erythrocyte?
300 million
formation of hemoglobin
- synthesis begins in proerythroblast and continues through reticulocyte stage
- 2 succinyl-CoA + 2 glycine –> pyrrole molecule
- 4 pyrrole molecules –> protoporphyrin which combines with iron to make heme
- heme + globin combine
- 4 subunit chains possible
what are the four subunit chains of hemoglobin
alpha
beta
gamma
delta
what is the most common hemoglobin?
hemoglobin A
2 alpha
2 beta
hemoglobin iron and O2 binding
- heme prosthetic group containing an atom of iron
- 4 Hgb chains so 4 iron atoms
- each iron can bind losely with O2 making a total of 8 oxygen atoms
- the type of Hgb chain in the hemoglobin molecule determines the binding affinity for oxygen
oxyhemoglobin
in the lungs, hemoglobin picks up oxygen which binds to the iron ions
deoxyhemoglobin
- darker red
- blood when oxygen is dropped off
destruction of Hgb
- RBC dies
- Hgb released
- liver kupffer cells phagocytose the hgb
- iron released back into the blood and carried by transferrin to either the bone marrow for production of new RBCs or to the liver to be stored
- porphyrin portion of Hgb is converted into biliverdin and then unconjugated bilirubin to be conjugated by hepatocytes and secreted in bile
methemoglobin
- formed when the iron in Hgb is oxidized from the ferrous to ferric state (Fe2+ –> Fe3+)
- cannot bind O2 and therefore cannot carry oxygen to tissues
- normally <1% of person’s Hgb
- in excess, blood become dark blue/brown
what is responsible for converting Mhgb back to Hgb?
NADH-dependent enzyme methemoglobin reductase
methemoglobin reductase pathway
-uses nicotinamide adenine dinucleotide (NADH) cytochrome b5 reductase in the erythrocyte from anaerobic glycoslysis to maintain heme iron in its ferrous state
methemoglobin and oxy-hgb dissociation curve
- moves the curve markedly to the left and therefore delivers little oxygen to the tissues
- increased affinity in the remaining heme sites that are in the ferrous state (i.e. normal Hgb holds on to O2 more)
30% methemoglobin
patients can tolerate this but normie is <1%
30-50% methemoglobin
symptoms of oxygen deprivation
- muscle weakness
- nausea
- tachycardia
> 50% methemoglobin
leads to coma and death
methemoglobinemia 3 mechanisms
- globin chain mutation (HbM) (congenital)
- methemoglobin reductase system mutation (congenital)
- toxic exposure to substance that oxidizes normal Hb iron that exceeds the normal capacity (acquired)
globin chain mutation
- mutations that stabilize heme iron in the ferric state, making it relatively resistant to reduction by the methemoglobin reductase system
- patient’s blood brownish blue color and will have a cyanotic appearance
- often asymptomatic as their methemoglobin levels rarely exceed 30% of total Hb unless exposed to a toxic dose of oxidizing agent
impaired reductase system
- mutations impairing the NADH and cytochrome B methemoglobin reductase system usually result in methemoglobinemia levels below 25%
- affected patients may also exhibit slate gray pseudocyanosis despite normal PaO2 levels
- exposure to agents that oxidize Hgb can produce a life-threatening methemoglobinemia
acquired methemoglobinemia
- rare, life-threatening amounts of methemoglobin accumulate exceeding its rate of reduction
- infants have lower levels of methemoglobin reductase in their erythrocytes so greater susceptibility to oxidizing agents
- nearly all topical anesthetic preparations have been associated with methemoglobinemia
- benzocaine most common
methemoglobinemia anesthetic considerations
- avoid tissue hypoxia
- admin of supplemental oxygen dose not correct low oxygen sat
- pulse ox is unreliable
- art line (frequent ABGs and co-oximetry)
- blood sample is chocolate
- correct acidosis
- EKG - monitor for hypoxic ischemia
- avoid oxidizing agents - LAs, nitrates, nitric oxide
toxic methemoglobinemia treatment
- supplemental oxygen
- 1-2 mg/kg of methylene blue infused over 3-5 min (may need to repeat after 30 min)
methylene blue
- acts as an electron donor for the nonenzymatic reduction of methemoglobin
- NADPH methemoglobin reductase converts methylene blue (the oxidized form of the dye) to leukomethylene blue (the reduced form), using NADPH which requires G6PD
- methylene blue is contraindicated in someone with G6PD deficiency
thalassemia
- inherited defect in globin chain synthesis
- over 300 mutations
- RBC sickling
- Dx by Hgb electrophoresis
minor beta thalassemia
carrier of trait, asymptomatic
intermedia beta thalassemia
variable severity, mild anemia
major beta thalassemia
severe anemia, transfusion dependent
beta thalassemia
- predominant in African, Mediterranean, and Middle East
- two types of alleles with different single-base mutations (B0 alleles which produce no B globulin; B+ alleles which produce reduced amounts of B globulin)
defective synthesis of B globulin contributes to anemia in two ways
- inadequate formation of HbA results in microcytic, poorly hemoglobinized red cells
- excess of unpaired alpha globin chains form toxic precipitates that damage the membranes of erythroid precursors most of which die by apoptosis
alpha thalassemia
- predominant in southeast asia
- deletion of one or more of the alpha globin genes
- disease severity proportional to the number of alpha globin genes that are deleted
- ineffective erythropoiesis and hemolysis are less pronounced than in beta thalassemia BUT ineffective oxygen tissue delivery to the tissue remains
thalassemia major
- life-threatening requires transfusions during 1st few years of life
- 3 defects that suppress oxygen carrying capacity –> ineffective erythropoiesis, hemolytic anemia, hypochromia and microcystosis
- unpaired globin aggregate and precipitate with damage the RBC
- some defective RBCs die within the bone marrow and cause bone hyperplasia
- altered morphology accelerate clearance-producing splenomegaly
- mortality often due to arrhythmias and CHF
thalassemia major treatment
- transfusions to treat but often at the cost of iron overload (often need chelation therapy)
- splenectomy - reduces transfusion requirements (risk of post-splenectomy sepsis)
- bone marrow transplant
thalassemia anesthesia management
- determine severity and amount of end-organ damage
- mild forms chronic compensated anemia (consider preop transfusion to Hgb >10)
- severe forms - splenomegaly, hepatomegaly, skeletal malformations, CHF, intellectual disability, iron overload
- risk for infection
- DVT prophylaxis
- risk of difficult intubation due to oral facial malformations
- blood bank alerted that pt has thalassemia
sickle cell disease
- amino acid valine is substituted for glutamic acid at one point in each of the 2 beta chains
- does increase preop morbidity and mortality
sickle cell trait
- only 1 beta chain affected
- does not increase preop morbidity and mortality
hemoglobin S
- 0.3-1.0% of African Americans
- genetic defect in Hgb synthesis
- precipitated hemoglobin also damages cell membrane leading to sickling crisis of ruptured cells, further decrease in oxygen tension and more sickling and RBC destruction
risk factors for sickle cell M&M in periop
- age
- frequency of sickle cell crises
- elevated Cr
- cardiac conditions
- surgery type
sickle cell preop transfusions
- controversial as to how much, when and what
- goal = increase ratio of normal Hgb to sickle Hgb
sickle cell anesthetic management avoid 3 H’s
hypothermia
hypoxia
hypovolemia
sickle cell other anesthetic management
- good pre-med to avoid stress
- high narcotic requirements
- current type and cross
- tourniquet (not necessarily contraindicated but can increase the risk of crisis)
acute chest syndrome
- looks like pneumonia on CXR
- develops 2-3 days into post-op period
- demands treatment for hypoxemia, analgesia, and blood transfusions
- possible nitric oxide therapy
- incidence is decreased if preop Hct is > 30%
