Hemoglobin Disorders Flashcards
Hemoglobin Formation
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)
Hemoglobin Fe & O2 Binding
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
Hemoglobin Function
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
Hemoglobin O2 Dissociation Curve
Sigmoidal curve d/t cooperative oxygen binding to Hgb
Left vs. right shift
P50 = 50% oxyhemoglobin
Hemoglobin Destruction
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
Hemoglobin Disorders
Methemoglobin - altered affinity
Thalassemia - globin chain quantitative disorder
Sickle cell - globin structure qualitative disorder
Methemoglobin
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
NDADH
Methemoglobin reductase pathway utilizes nicotinamide adenine dinucleotide (NADH) cytochrome b5 reductase in erythrocyte from anaerobic glycolysis to maintain heme Fe in ferrous state
Methemoglobin & O2 Dissociation Curve
Shifts the curve to the left
LESS oxygen delivered to the tissues
↑affinity in remaining heme sites in the ferrous state
Methemoglobin %
Normal <1%
Patients tolerate up to 30%
30-50% oxygen deprivation S/S (muscle weakness, nausea, tachycardia)
>50% leads to coma & death
Methemoglobinemia
Globin Chair Mutation
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)
Methemoglobinemia
Impaired Reductase System
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
Acquired Methemoglobinemia
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)
Methemoglobinemia Treatment
Supplemental O2
Methylene blue 1-2mg/kg infused over 3-5min
Methemoglobinemia
Anesthetic Considerations
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
Methylene Blue
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
β Thalassemia
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
Defective β Globin Synthesis
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
α Thalassemia
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
Thalassemia Major
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
Thalassemia Major Treatment
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
Thalassemia
Anesthetic Considerations
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
Sickle Cell
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
HbS
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
Sickle Cell Trait vs. Disease
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
Sickle Cell
Risk Factors
Age Frequency sickle cell crises Elevated creatinine Cardiac conditions Surgery type
Sickle Cell Disease
Anesthetic Considerations
Preop transfusion controversial Transfusion goal ↑ratio HbA : HbS Avoid hypothermia, hypoxemia, & hypovolemia Pre-medicate Avoid stress ↑narcotic requirements Current type & cross Tourniquet use controversial
Acute Chest Syndrome
CXR resembles pneumonia Develops 2-3 days postop Treat hypoxemia, analgesia, & blood transfusions Possible nitric oxide therapy Incidence ↓preop Hct > 30%
