Hematologic Pathophysiology Hemoglobin Disorders Flashcards
Hemoglobin is a large molecule made up of
proteins & iron
four folded chains of a protein called globin
An individual erythrocyte may contain about
300 million hemoglobin molecules
Hemoglobin A is most common & made up of
2 alpha and 2 beta
Describe the formation of hemoglobin:
synthesis begins in the proerythroblast & continues through the reticulocyte stage
2 succinyl-CoA (formed in the Kreb cycle) + 2 glycine–> pyrrole molecule
4 pyrrole molecules combine to form protoporphyrin which combines with iron to make heme
Heme + globin combine
4 subunit chains possible (alpha, beta, gamma, and delta)
In the lungs, hemoglobin picks up
oxygen, which binds to the iron ions, forming oxyhemoglobin
The bright red, oxygenated hemoglobin travels to the body tissues, where it
releases some of the oxygen molecules, becoming darker red deoxyhemoglobin
Oxygen release depends on the need for
oxygen in the surrounding tissues
Each hemoglobin chain has a heme prosthetic group containing an atom of
iron
There are _________ in each hemoglobin and therefore _____ in each hemoglobin molecule
4 hemoglobin chains; 4 iron atoms
Each of the irons can bind loosely with
oxygen (O2) making a total of 8 oxygen atoms
The type of hemoglobin chain in the hemoglobin molecule determines the
binding affinity for oxygen
The oxygen combining capacity is directly related to
hemoglobin concentration and not on the number of RBCs
The shape of the hemoglobin O2 dissociation curve is
sigmoidal due to cooperative binding of oxygen to hemoglobin
Lifespan of the RBC is
120 days
When the RBC dies, _____ is released
hemoglobin
liver Kupffer cells phagocytose the hemoglobin
Describe the destruction of hemoglobin.
hemoglobin opens up--> releases iron & heme iron is released back into the blood & carried by transferrin to bone marrow for production of new RBCs or to the liver to be store Porphyrin portion (pyrrole rings) of hemoglobin are converted to biliverdin & then unconjugated bilirubin
Disorders of hemoglobin that are commonly clinically significant include:
methemoglobin- altered affinity
thalassemia- quantitative disorder of globin chain
sickle cell disease- qualitative disorder of globin structure
Methemoglobin is formed when the
iron in hemoglobin is oxidized from the ferrous (Fe2+) to the ferric (Fe3+) state
ic=ick= it’s not a good state
Methemoglobin cannot bind
oxygen and therefore cannot carry oxygen to the tissues
Normally <1% of a person’s hemoglobin in
methemoglobin
In situations of excess methemoglobin, the blood becomes
dark blue/brown
The NADH dependent enzyme_______ is responsible for converting Mhgb back to Hgm
methemoglobin reductase
The methemoglobin reductase pathway uses
nicotinamide adenine dinucleotide (NADH)- cytochrome b5 reductase in the erythrocyte from anaerobic glycolysis to maintain heme iron in its ferrous state
How does methemoglobin move the oxyhemoglobin dissociation curve?
moves the curve markedly to the left & therefore delivers little O2 to the tissues
increased affinity in the remaining heme sites that are in the ferrous state
Patients can tolerate methemoglobin up to
30%
Between 30-50% of methemoglobin,
30-50% symptoms of oxygen deprivation occur- muscle weakness, nausea, tachycardia
> 50% of methemoglobin leads to
coma & death
Describe the three mechanisms of methemoglobinemia:
Congenital:
1. globin chain mutation (HbM)
2. methemoglobin reductase system mutation
Acquired
3. toxic exposure to substance that oxidizes normal Hb iron that exceeds the normal capacity
For patients with the globin chain mutation, the patient’s blood will
be a brownish blue color & will have a cyanotic appearance
Describe how the globin chain mutation causes methemoglobinemia.
Mutations that stabilize heme iron in the ferric (Fe3+) state, making it relatively resistant to reduction by the methemoglobin reductase system
Patients who have globin chain mutation are often
asymptomatic as their methemoglobin levels rarely exceed 30% of total Hb unless exposed to a toxic dose of oxidizing agent
For patients with impaired reductase system methemoglobinemia, exposure to
agents that oxidize hemoglobin can produce a life-threatening methemoglobinemia
Patients affected with impaired reductase system methemoglobinemia may exhibit
slate-gray pseudocyanosis despite normal PaO2 levels
Impaired reductase system methemoglobinemia occurs when
mutations impairing the NADH and cytochrome b methemoglobin reductase system usually result in methemoglobinemia levels below 25%
Acquired methemoglobinemia is a
rare, life-threatening accumulation of methemoglobin that exceeds its rate of reduction
Nearly all _______ have been associated with methemoglobinemia
topical anesthetic preparations
benzocaine is the most common
Infants & relation to acquired methemoglobinemia
Infants have lower levels of methemoglobin reductase in their erythrocytes–> greater susceptibility to oxidizing agents
What exposures for infants can lead to methemoglobinemia?
chemical exposure to nitrates in well water- new parents are advised to have well water tested or use bottle water if not breastfeeding
- infants drink more water per body weight than children & adults
- orajel
For patients experiencing toxic methemoglobinemia, treatment includes
supplemental oxygen
1-2 mg/kg methylene blue infused over 3-5 minutes
-single treatment is usually effective- may need repeated after 30 minutes
Methylene blue acts through
methemoglobin reductase system and requires the activity of G6PD
Anesthesia considerations for the patient with methemoglobinemia include
avoid tissue hypoxia
administration of supplemental oxygen does not correct low oxygen saturation levels
pulse oximetry is unreliable- cannot detect methemoglobin
arterial line- frequent ABGs and co-oximetry
blood sample- chocolate color
correct acidosis
EKG- monitor for hypoxic ischemia
avoid oxidizing agents- local anesthetics, nitrates, nitric oxide
Methylene blue acts as an
electron donor for the nonenzymatic reduction of methemoglobin
Methylene blue is contraindicated in someone with
G6PD deficiency
Which enzyme converts methylene blue to reduced form?
NADPH methemoglobin reducatse
A distinct enzyme, NADPH methemoglobin reductase, converts methylene blue to
leukomethylene blue (the reduced form), using NADPH which requires G6Pd
B- thalassemia is an
inherited defect in globin chain synthesis
Types of B-thalassemia include:
minor- carrier of the trait, asymptomatic
intermedia- variable severity, mild anemia
major- severe anemia, transfusion dependent
Beta thalassemia is predominant in
African, Mediterranean areas
Alpha thalassemia is predominant in
Southeast Asia & India
Alpha thalassemia is due to
deletion of one or more of the alpha globin genes
The disease severity of alpha thalassemia is proportional to
the number of alpha globin genes that are deleted
In alpha thalassemia, ______ are less pronounced than in Beta thalassemia however, ineffective
erythropoiesis & hemolysis
oxygen tissue delivery to the tissues remains
The defective synthesis of beta globin contributes to anemia in two ways:
1) the inadequate formation of HbA results in microcytic, poorly hemoglobinized red blood cells &
2) the excess unpaired a-globin chains form toxic precipitates that damage the membranes of erythroid precursors, most of which die by apoptosis
Beta thalassemia is the result of
two types of alleles with different single-base mutations:
betaO alleles which produce no B- globin
beta+ alleles, which produce reduced amounts of beta globin
Mortality with thalassemia major is often due to
arrhythmias & CHF
Thalassemia major is a
life-threatening condition- requires transfusions during 1st few years of life
3 defects which depress oxygen carrying capacity in thalassemia major include:
ineffective erythropoiesis
hemolytic anemia
hypochromia & microcytosis
In thalassemia major, unpaired globin
aggregate & precipitate which damage the RBC
In thalassemia major, some defective RBCs die within
the bone marrow & cause bone hyperplasia
In thalassemia major, altered morphology accelerates
clearance- producing splenomegaly
Treatment of thalassemia major includes:
transfusion
splenectomy
bone marrow tranplantation
Transfusions used to treat thalassemia major are at the cost of
iron overload & patient’s often need chelation therapy
Having a splenectomy for thalassemia major
reduces transfusion requirements
deferred until >age 5
risk of post-splenectomy sepsis
Anesthesia management for the patient with thalassemia include:
determine the severity & amount of end-organ damage
mild forms- chronic compensated anemia- consider preoperative transfusion to hgb >10
severe forms- splenomegaly, hepatomegaly, skeletal malformations, CHF, intellectual disability- iron overload leads to cirrhosis, right-sided heart failure
risk for infection- broad-spectrum abx
DVT prophylaxis
risk for difficult intubations due to oro-facial malformations
blood bank alerted that patient has thalassemia
Sickle cell disease is when
the amino acid valine is substituted for glutamic acid at one point in each of the beta chains
The sickle cell trait is when
only 1 beta chain is affected by substitution
Exposure of the sickle cell to low oxygen causes
crystals to form inside & elongate the RBC
The elongation of the RBC in sickle cell makes it impossible for the
RBC to pass through many small capillaries & the spiked end of the crystals are likely to rupture the membrane
Sickle cell-hemoglobin S is most common in
African Americans
Sickle cell hemoglobin S results in
severe anemia, RBCs of different shapes & sizes, recurrent painful episodes due to ischemia
With sickle cell, the precipitated hemoglobin also damages the
cell membrane leading the sickling crisis of rupture cells, further decrease in oxygen tension, more sickling, & RBC destruction
In terms of perioperative morbidity & mortality, the sickle cell trait
does not increase M&M
In terms of perioperative morbidity & mortality, sickle cell disease
does increase M&M
Risk factors for morbidity & mortality for patients with sickle cell disease include:
age, frequency of sickle crisis’s, elevated creatinine, cardiac conditions, & surgery type
Sickle cell preop transfusion is
controversial as to how much, when, & what
The transfusion goal for the sickle cell patient undergoing preop transfusion is
increase ratio of normal hemoglobin to sickle hemoglobin
Anesthetic management for the patient with sickle cell disease includes:
avoid 3 H's: hypothermia, hypoxia, & hypovolemia good premed- avoid stress high narcotic requirements Current T&C tourniquet use is controverisal
Acute chest syndrome looks like
pneumonia on a chest XR
Acute chest syndrome develops
2-3 days into the postop period
Acute chest syndrome demands treatment for
hypoxemia, analgesia, & blood transfusions
possible nitric oxide therapy
The incidence of acute chest syndrome is decreased if
preop hematocrit is >30%
