Hemoglobin Disorders

Question 1

Hemoglobin Formation

Answer 1

Proerythroblast through reticulocyte stage → 2 succinyl-CoA + 2 glycine → pyrrole molecule
4 pyrrole molecules combine to form protoporphyrin
Protoporphyrin + Fe → heme + globin → HEMOGLOBIN
HgbA most common 2α + 2β
4 subunit chains possible (alpha, beta, gamma, delta)

Question 2

Hemoglobin Fe & O2 Binding

Answer 2

Each hemoglobin chain contains heme group containing Fe
4 hemoglobin chains in each Hgb ჻ 4 Fe atoms
Fe binds O2 → 8 oxygen atoms
Hgb chain types determines oxygen binding affinity

Question 3

Hemoglobin Function

Answer 3

Hgb picks up oxygen in the lungs
Oxygen binds to Fe forming oxyhemoglobin
Bright red oxygenated Hgb travels to the body tissues
Releases oxygen molecule becoming darker red → deoxyhemoglobin
Oxygen release depends on oxygen need in surrounding area

Question 4

Hemoglobin O2 Dissociation Curve

Answer 4

Sigmoidal curve d/t cooperative oxygen binding to Hgb
Left vs. right shift
P50 = 50% oxyhemoglobin

Question 5

Hemoglobin Destruction

Answer 5

Kupffer cells phagocytose Hgb
Fe released back into blood & carried via transferrin to either the bone marrow to produce new RBCs or to the liver (storage)
Porphyrin portion (pyrrole rings) converted to biliverdin & then unconjugated bilirubin to be conjugated via hepatocytes & secreted in bile

Question 6

Hemoglobin Disorders

Answer 6

Methemoglobin - altered affinity
Thalassemia - globin chain quantitative disorder
Sickle cell - globin structure qualitative disorder

Question 7

Methemoglobin

Answer 7

Formed when Hgb Fe oxidized from Fe2+ → Fe3+
Ferrous → ferric
Methemoglobin unable to bind oxygen ჻ cannot carry oxygen to the tissues
Normal <1% Hgb
Excessive methemoglobin blood becomes dark blue/brown
NADH-dependent enzyme methemoglobin reductase responsible to convert MHgb back to Hgb

Question 8

NDADH

Answer 8

Methemoglobin reductase pathway utilizes nicotinamide adenine dinucleotide (NADH) cytochrome b5 reductase in erythrocyte from anaerobic glycolysis to maintain heme Fe in ferrous state

Question 9

Methemoglobin & O2 Dissociation Curve

Answer 9

Shifts the curve to the left
LESS oxygen delivered to the tissues
↑affinity in remaining heme sites in the ferrous state

Question 10

Methemoglobin %

Answer 10

Normal <1%
Patients tolerate up to 30%
30-50% oxygen deprivation S/S (muscle weakness, nausea, tachycardia)
>50% leads to coma & death

Question 11

Methemoglobinemia

Globin Chair Mutation

Answer 11

Mutations that stabilize heme Fe in the ferric state (Fe3+) → relatively resistant to reduction via methemoglobin reductase system
Cyanotic appearance
Blood blue/brown appearance
Often asymptomatic (methemoglobin levels rarely exceed 30% unless exposed to oxidizing agent toxic dose)

Question 12

Methemoglobinemia

Impaired Reductase System

Answer 12

Mutations impairing NADH & cytochrome B methemoglobin reductase
Usually results in methemoglobinemia levels <25%
Slate-gray pseudocyanosis despite normal PaO2 levels
Exposure to agents that oxidize Hgb → potentially produce life-threatening methemoglobinemia

Question 13

Acquired Methemoglobinemia

Answer 13

Rare
Life-threatening amount methemoglobin accumulate exceeding reduction rate
Infants have lower levels methemoglobin reductase in their erythrocytes → more susceptible to oxidizing agents
Topical anesthetic preparations associated w/ methemoglobinemia (Benzocaine most common)

Question 14

Methemoglobinemia Treatment

Answer 14

Supplemental O2

Methylene blue 1-2mg/kg infused over 3-5min

Question 15

Methemoglobinemia

Anesthetic Considerations

Answer 15

Avoid tissue hypoxia
Supplemental oxygen does not correct low SpO2
Pox unreliable (cannot detect methemoglobin)
Correct acidosis
Assess blood sample characteristics & coloring
EKG monitor hypoxic ischemia
Avoid oxidizing agents - LAs, nitrates, & NO

Question 16

Methylene Blue

Answer 16

1-2mg/kg
Single treatment usually effective
Repeat as needed after 30min

Methemoglobin reductase system & requires G6PD activity (contraindicated in patients w/ G6PD deficiency)
Electron donor

Question 17

β Thalassemia

Answer 17

Inherited defect in globin chain synthesis
Predominant in African Mediterranean area

Minor - asymptomatic carrier
Intermedia - variable severity w/ mild anemia
Major - severe transfusion dependent anemia

β0 alleles no β globin
β+ reduced amounts

Question 18

Defective β Globin Synthesis

Answer 18

Contributes to anemia
Inadequate HbA formation results in microcytic & poorly hemoglobinized RBCs
Excess unpaired α globin chains form toxic precipitates that damage erythroid precursor membranes → death via apoptosis

Question 19

α Thalassemia

Answer 19

Predominant in Southeast Asia
Deletion one or more α globin genes
Severity proportional to number α globin genes deleted
Ineffective erythropoiesis & hemolysis less pronounced than β thalassemia however ineffective oxygen tissue delivery to the tissue remains

Question 20

Thalassemia Major

Answer 20

Life-threatening
Requires transfusions during first few years
3 defects depress oxygen-carrying capacity
- Ineffective erythropoiesis
- Hemolytic anemia
- Hypochromia & microcytosis
Unpaired globin aggregate & precipitate damages the RBC
Some defective RBCs die w/in the bone marrow & cause bone hyperplasia
Altered morphology accelerate clearance-producing splenomegaly
Mortality often d/t arrhythmias & CHF

Question 21

Thalassemia Major Treatment

Answer 21

Transfusions
Often need chelation therapy d/t Fe overload
Splenectomy reduces transfusion requirements
- Risk post-splenectomy sepsis
- Deferred until at least age 5
Bone marrow transplantation

Question 22

Thalassemia

Anesthetic Considerations

Answer 22

Determine severity & end-organ damage
Mild forms - compensated anemia (consider preop transfusion Hgb >10g/dL)
Severe forms - splenomegaly, hepatomegaly, skeletal malformations, CHF, intellectual disability
Fe overload → cirrhosis & R sided heart failure
Broad spectrum antibiotics d/t infection risk
DVT prophylaxis
Difficult intubation risk d/t orofacial malformations
Alert blood bank about thalassemia

Question 23

Sickle Cell

Answer 23

Hemoglobin S
Exposure to low oxygen causes crystals to form inside & elongate (sickle) the RBC
Sickling prevents RBC from passing through small capillaries & the spiked end are likely to rupture the membrane

Question 24

HbS

Answer 24

Hgb synthesis genetic defect
Precipitated HbS damages the cell membrane leading to sickling crisis & ruptured cells
↓oxygen tension → sickling & RBC destruction
Severe anemia
RBCs different shapes & sizes
Recurrent painful episodes d/t ischemia

Question 25

Sickle Cell Trait vs. Disease

Answer 25

Trait - only 1 β chain affected
Does NOT ↑periop morbidity & mortality

Disease - amino acid valine substituted for glutamic acid at one point in each of the 2 β chains
Does ↑periop morbidity & mortality

Question 26

Sickle Cell

Risk Factors

Answer 26

Age
Frequency sickle cell crises
Elevated creatinine
Cardiac conditions
Surgery type

Question 27

Sickle Cell Disease

Anesthetic Considerations

Answer 27

Preop transfusion controversial
Transfusion goal ↑ratio HbA : HbS
Avoid hypothermia, hypoxemia, & hypovolemia
Pre-medicate
Avoid stress
↑narcotic requirements
Current type & cross
Tourniquet use controversial

Question 28

Acute Chest Syndrome

Answer 28

CXR resembles pneumonia
Develops 2-3 days postop
Treat hypoxemia, analgesia, & blood transfusions
Possible nitric oxide therapy
Incidence ↓preop Hct > 30%