Hemoglobin Disorders

Question 1

hemoglobin

Answer 1

• large molecule made up of proteins and iron

- four folded chains of a protein called globin

Question 2

how many hgb molecules are in one erythrocyte?

Answer 2

300 million

Question 3

formation of hemoglobin

Answer 3

• 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

Question 4

what are the four subunit chains of hemoglobin

Answer 4

alpha
beta
gamma
delta

Question 5

what is the most common hemoglobin?

Answer 5

hemoglobin A
2 alpha
2 beta

Question 6

hemoglobin iron and O2 binding

Answer 6

• 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

Question 7

oxyhemoglobin

Answer 7

in the lungs, hemoglobin picks up oxygen which binds to the iron ions

Question 8

deoxyhemoglobin

Answer 8

• darker red

- blood when oxygen is dropped off

Question 9

destruction of Hgb

Answer 9

• 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

Question 10

methemoglobin

Answer 10

• 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

Question 11

what is responsible for converting Mhgb back to Hgb?

Answer 11

NADH-dependent enzyme methemoglobin reductase

Question 12

methemoglobin reductase pathway

Answer 12

-uses nicotinamide adenine dinucleotide (NADH) cytochrome b5 reductase in the erythrocyte from anaerobic glycoslysis to maintain heme iron in its ferrous state

Question 13

methemoglobin and oxy-hgb dissociation curve

Answer 13

• 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)

Question 14

30% methemoglobin

Answer 14

patients can tolerate this but normie is <1%

Question 15

30-50% methemoglobin

Answer 15

symptoms of oxygen deprivation

• muscle weakness
• nausea
• tachycardia

Question 16

> 50% methemoglobin

Answer 16

leads to coma and death

Question 17

methemoglobinemia 3 mechanisms

Answer 17

• 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)

Question 18

globin chain mutation

Answer 18

• 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

Question 19

impaired reductase system

Answer 19

• 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

Question 20

acquired methemoglobinemia

Answer 20

• 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

Question 21

methemoglobinemia anesthetic considerations

Answer 21

• 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

Question 22

toxic methemoglobinemia treatment

Answer 22

• supplemental oxygen

- 1-2 mg/kg of methylene blue infused over 3-5 min (may need to repeat after 30 min)

Question 23

methylene blue

Answer 23

• 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

Question 24

thalassemia

Answer 24

• inherited defect in globin chain synthesis
• over 300 mutations
• RBC sickling
• Dx by Hgb electrophoresis

Question 25

minor beta thalassemia

Answer 25

carrier of trait, asymptomatic

Question 26

intermedia beta thalassemia

Answer 26

variable severity, mild anemia

Question 27

major beta thalassemia

Answer 27

severe anemia, transfusion dependent

Question 28

beta thalassemia

Answer 28

- 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)

Question 29

defective synthesis of B globulin contributes to anemia in two ways

Answer 29

- 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

Question 30

alpha thalassemia

Answer 30

- 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

Question 31

thalassemia major

Answer 31

- 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

Question 32

thalassemia major treatment

Answer 32

- 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

Question 33

thalassemia anesthesia management

Answer 33

- 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

Question 34

sickle cell disease

Answer 34

- amino acid valine is substituted for glutamic acid at one point in each of the 2 beta chains - does increase preop morbidity and mortality

Question 35

sickle cell trait

Answer 35

- only 1 beta chain affected | - does not increase preop morbidity and mortality

Question 36

hemoglobin S

Answer 36

- 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

Question 37

risk factors for sickle cell M&M in periop

Answer 37

- age - frequency of sickle cell crises - elevated Cr - cardiac conditions - surgery type

Question 38

sickle cell preop transfusions

Answer 38

- controversial as to how much, when and what | - goal = increase ratio of normal Hgb to sickle Hgb

Question 39

sickle cell anesthetic management avoid 3 H's

Answer 39

hypothermia hypoxia hypovolemia

Question 40

sickle cell other anesthetic management

Answer 40

- good pre-med to avoid stress - high narcotic requirements - current type and cross - tourniquet (not necessarily contraindicated but can increase the risk of crisis)

Question 41

acute chest syndrome

Answer 41

- 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%