Week 3: Hematologic Pathophysiology Hemoglobin Disorders Flashcards
What does a hemoglobin consist of?
large molecule made of proteins and iron
Define globin
four folded chains of a protein
How many hemoglobin molecules are in an individual erythrocyte?
300 million
What is a pyrrole?
an organic compound that is characterized by a ring structure composed of 4 carbons and 1 nitrogen atom
What is a protoporphyrin?
it is the precursor of heme
it lack iron
free base
Describe the formation of hemoglobin from the proerythroblast to erythrocyte
2 succinyl-CoA molecules combine with 2 glycine amino acids to from pyrrole molecule
4 pyrrole molecules combine to form protoporphyrin
Protoporphyrin forms with iron to make heme
Heme + globin
How many subunit chains are possible for a globin?
alpha
beta
gamma
delta
What is the most common hemoglobin? what is its structure?
2 alpha and 2 beta
hemoglobin A
How many globin chains are in each hemoglobin and how many iron ATOMS?
4 hemoglobin chains
4 iron atoms
How many (possible) oxygen atoms are bound to a hemoglobin?
8 oxygen atoms
What determines the binding affinity for oxygen in the hemoglobin molecule?
type of hemoglobin chain
- the oxygen combining capacity is directly related to Hb concentration and not on the number of RBCs
How is oxyhemoglobin formed?
when hemoglobin picks up oxygen binds to the iron ion
this occurs in the lungs
What is the shape of the hemoglobin-O2 dissociation curve? Why?
sigmoidal
due to its cooperative binding of oxygen to hemoglobin
How is hemoglobin destructed in the liver?
liver kupffer cells phagocytose the hemoglobin
iron released by into blood and carried by transferrin to BM (to help with RBC production) or stored in the liver
What is unconjugated bilirubin?
when free bilirubin combines with albumin
Describe the steps of bilirubin production?
macrophages spilt Hgb to heme and globin heme ring open and iron released pyrrole groups converted to biliverdin biliverdin converted to free bilirubin free bilirubin combines with albumin
What are the consequences of Hgb mutations?
impair globin folding or hemoglobin binding
heme will bind nonspecificallly to other regions of the globin chains
causes Heinz bodies
How can methemoglobin be categorized as a disorder of hemoglobin?
altered affinity
How can thalassemia be categorized by a disorder of hemoglobin?
quantitative disorder of globin chain
How can sickle cell be categorized by a disorder of hemoglobin?
qualitative disorder of globin structure
Define methemoglobin
formed when iron in Hb is oxidized from the ferrous to ferric state
What occurs in methemoglobin?
methemoglobin cannot bind o2 to tissues as effectively and therefore cannot carry oxygen to tissues
Holds onto O2 longer, doesn’t let go @ tissues
Does methemoglobin normally occur?
yes, but <1%
What converts Mhgb back to Hbg?
NADH dependent enzyme methemoglobin reductase
Why is the pulse ox unreliable and falsely high in a patient with methemoglobin?
Methemoglobin increases absorption of light at both wavelengths (>940nm) and therefore offers optical interference to pulse ox by falsely absorbing light
What pathway maintains heme iron its ferrous state?
methemoglobin reductase pathway
What reductase maintains heme iron its ferrous state?
NADH- cytochrome b5 reductase
Methemoglobin shifts the Oxy-Hb dissociation curve left or right? Why?
left
increases affinity in the remaining heme sites that are in ferrous state
delivers little oxygen to tissues
what % can a patient no longer tolerate methemoglobin?
30%
What symptoms will occur >30% methemoglobin?
oxygen deprivation
muscle weakness, nausea tachycardia
3 Mechanisms/Causes of Methemoglobin
congenital or acquired
congenital= globin chain mutation (hbM) or methemoglobin reductase system inhibition
Acquired: toxic exposure to substance that oxidized normal Hb iron that exceeds the normal capacity
Globin chain mutation is
mutations that stabilize heme iron in the ferric state, making it relatively resistant to reduction by methemoglobin reductase system
What do patients with the globin chain mutation look like? blood color?
cyanotic appearance
blood will be a blueish- brown color
often asymptomatic
Impaired reductase system is
mutations impairing the NADH and cytochrome b methemoglobin reductase system that results in methemoglobin levels below 25%
Acquired Methemoglobinemia is
rare, life-threatening amounts of methemoglobin accumulate exceeding its rate of reduction
WHo has a greater susceptibility to oxidizing agents in methemoglobinemia?
infants because of there lower levels of methemoglobin reductase in their erythrocytes
What is the most common cause of acquired methemoglobin?
topical anesthetics
benzocaine
Implications of methemoglobinemia and anesthesia
avoid tissue hypoxia
supplemental O2 will not correct low O2
frequent ABGs and co-oximetry needs arterial line
chocolate color blood sample
correct acidosis
EKG monitor for ischemia
avoid oxidizing agents: local anesthetics, nitrates, nitric oxide
Treatment to toxic methemoglobinemia
supplemental O2
1-2mg/kg methylene blue infused over 3-5 minutes
single treatment may be okay
requires activity of G6PD
MOA of Methylene blue in methemoglobinemia
acts as an electron donor for the non-enzymatic reduction of methemoglobin
G6PD donates a proton to NADP to make NADPH. NADPH methemoglobin reductases loses it H+ to convert methylene blue to leukomethylene blue to break down methemoglobin
What is contraindicated in patients with G6PD deficiency?
methylene blue
Why do we use methylene blue in the OR?
intraoperative urologic dye
confirms ureteral patency and to localize ureteral orifice for lymph node and vessel delination, and for tumor localization
Dose and pharmacokinetics of methylene blue
1mg/kg IV over 5-30 minutes
concentration 5mg/ml
1/2 life 24 hours
excreted 40% unchanged in urine
methylene blue
water soluble thiazine dye that promotes a non-enzymatic conversaion of metHb to hemoglobin
Thalassemia
an inherited defect in globin chain synthesis
Beta thalassemia
Alpha thalassemia
minor, intermedia, major
HbF
2 alpha chains and 2 gamma globin chains
Beta thalassemia is predominant in
African, mediterranean and middle east area
Beta thalassemia has two types
of alleles with different single-based mutations
B zero alleles which produce no beta globin
beta + alleles which produce reduced amounts of beta globin
What are the two defective synthesis of beta globin contributes to anemia?
the inadequate formation of HbA results in microcytic, poorly hemoglobinized red cells and
the excess of unpaired alpha chains form toxic precipitates that damage the membranes of erythroid precursors, most of which die by apoptosis
Alpha thalassemia is predominant to
southeast asia and india
Alpha thalassemia is
deletion of one or more alpha globin genes
disease severity is proportional to the number of alpha globin genes that are deleted
ineffective erythropoiesis and hemolysis are less pronounced that in b thalassemia however ineffective O2 tissue delivery still remains
What are the three defects that depress oxygen-carrying capacity in thalassemia major?
ineffective erythropoiesis
hemolytic anemia
hypochromia and microcytosis
Thalassemia major causes
unpaired globin to aggregate and precipate which damage the RBC
some die within the BM and cause bone hyperplasia
splenomegaly- d/t altered morphology from increased clearance
How does mortality occur in thalassemia major?
arrhythmias and CHF
Treatment of Thalassemia major
transfusions to treat but can cause iron overload
splenectomy- reduces transfusion requirements
bone marrow transplantation
General Anesthetic management of Thalassemia
determine severity and amount of end-organ damage
risk for infection– broad spectrum antibotics
DVT prophylaxis
risk of difficult intubation
alert blood bank
Anesthetic management of Mild Thalassemia
chronic compensated anemia
consider pre-op transfusion to hgb >10g/dl
Anesthetic management of Severe Thalassemia
splenomegaly, hepatomegaly, skeletal malformations, CHF, intellectual disability
iron overload= cirrhosis, right sided HF
Sickle Cell
exposure of this cell to low oxygen causes crystals to form inside and elongate the RBC
space change makes it impossible for RBC to pass through small capillaries and the spiked end of the crystals are likely ruptured the membrane
Sickle cell disease
amino acid valine is substituted for glutamic acid at one point in each of the 2 beta chains
does increase perioperative morbidity and mortality
sickle cell trait
only 1 beta chain effected
dose not increase perioperative morbidity and mortality
Sickle Cell Hemoglobin S
genetic defect of Hgb Synthesis
precipitated hemoglobin also damages the cell membrane leading the sickling crisis of ruptured cells further decrease in oxygen tension and more sickling and RBC destruction
severe anemia
recurrent painful episodes due to ischemia
Sickle cells risk factors for M &M
age frequency of sickle crisis's elevated creatinine cardiac conditions surgery type
Sickle Cell Disease anesthetic management
avoid 3 h's good premed (avoids stress) high narcotic requirements current type and cross tourniquet (cautious use)
what are the 3 H’s to avoid during surgery with sickle cell patients?
hypoxia
hypovolemia
hypothermia
Acute Chest Syndrome
looks like pneumonia on xray
develops 2-3 days postop
treatments for hypoxemia, analgesia, and blood transfusions
possible nitric oxide therapy
incidence is decreased if pre-op HCt is >30%
Key points of Anesthesia and Hgb disorders
history is important
high variable approach, dependent on degree of hemolysis
severe hemolysis requires transfusions
avoid oxidizing medications when possible
