PB#78: Hemoglobinopathies In Pregnancy Flashcards
Number of interlocking polypeptide chains per Hgb
Four
Possible Hgb polypeptide chains (6)
α, β, γ, δ, ε, ζ
Possible structures of adult Hgb (3)
Hgb A, Hgb F, Hgb A2
Structure of Hgb A
Two α-chains + two β-chains
Structure of Hgb F
Two α-chains + two γ-chains
Structure of Hgb A2
Two α-chains + two δ-chains
Gestational ages from which Hgb F is primary Hgb
12-24wga
Transition from Hgb F to Hgb A
3rd tri (via increased production of β-chains
Location of genes that code for α-chain
Short arm of chromosome 16
Location of genes that code for β-chain
Short arm of chromosome 11
Inheritance of SCD
Autosomal recessive
Nucleotide substitution that changes Hgb A to Hgb S
T>A in β-chain
Amino acid substitution that changes Hgb A to Hgb S
Val>gln at position 6 of β-chain
Nucleotide substitution that changes Hgb A to Hgb C
A>G in β-chain
Amino acid substitution that changes Hgb A to Hgb C
Lys>gln
Condition that arises in Hgb S heterozygote; condition that arises in Hgb S homozygote
SCT; sickle cell anemia
Condition that arises from Hgb S heterozygote + Hgb C heterozygote
Hgb SC disease (can also cause SCD)
Other hemoglobinopathy combos that can cause clinically significant SCD
Hgb S/β-thalassemia
Demographic w/ highest rate of SCD
Blacks
Rate of SCT, rate of SCD, rate of sickle cell anemia among black individuals
1 in 12, 1 in 300, 1 in 600
Other demographics (besides Blacks) w/ higher frequency of Hgb S (6)
Greeks, Italians (particularly Sicilians), Turks, Arabs, Southern Iranians, Indians
Physiologic features of RBCs in SCD
Distortion (sickling) of RBCs when under O2 tension, leading to increased viscosity/hemolysis/anemia w/ further decrease in oxygenation
Etiology of vaso-occlusive crises
Sickling in small vessels can lead to logjams that interrupt blood supply to vital organs
Potential outcome of repeated vaso-occlusive crises
Widespread microvascular obstruction w/ interruption of normal perfusion/function of several organs (spleen/lungs/kidneys/heart/brain)
Consideration for adults w/ SCD (re a specific organ)
Functional asplenia 2/2 autosplenectomy by adolescence; resultant increased incidence/severity of infections
Most significant threat to pts w/ SCD
Acute chest syndrome
Clinical characteristics of ACS
Pulmonary infiltrates (not infectious in origin, but rather 2/2 vaso-occlusion from sickling or embolization of marrow from long bones affected by sickling) w/ fever that leads to hypoxemia/acidosis
How to diagnose SCD
Hgb electro
Hgb electro results for SCD/Hgb SS
Nearly all Hgb S, w/ small amount of Hgb A2 and Hgb F
Hgb electro results in SCT/Hgb AS
Large percentage of Hgb S, though also w/ larger percentage of Hgb A than in SCD
General characteristics of thalassemias
Reduced synthesis of globin chains, resulting in microcytic anemia
Genetic cause of α-thal
Gene deletion of 2+ copies of the four α-chains
Allele notation, lab testing, and clinical course when one α-chain is deleted
(α-/αα), mild asymptomatic microcytic anemia, clinically unrecognizable
Condition, lab testing when two α-chains are deleted
α-thal trait/α-thal minor, mild asymptomatic microcytic anemia
Two possible allele notations for α-thal trait
αα/– (cis), α-/α- (trans)
Primary concern for α-thal carriers
Increased risk for having offspring w/ more severe α-thal
Demographics w/ higher rates of α-thal trait (4)
Southeast Asians, Blacks, West Indians, Mediterraneans
Allele formation more often seen in Southeast Asians w/ α-thal trait, and clinical concern for offspring
More likely to have cis deletion, so offspring at higher risk for Hgb Bart’s or Hgb H disease
Allele formation more often seen in Blacks w/ α-thal trait, and clinical concern for offspring
More likely to have trans deletion, so offspring typically do not develop Hgb Bart’s
Condition, allele notation, lab testing when three α-chains are deleted
Hgb H disease, α-/–, mild-mod hemolytic anemia
Condition, allele notation when four α-chains are deleted
α-thal major (Hgb Bart’s), –/–
Fetal risks associated w/ α-thal major/Hgb Bart’s (3)
Hydrops fetalis, IUFD, pre-E
Can you inherit α-thal and SCT/SCD?
Yes (because Hgb S affects β-chain and α-thal affects α-chain)
Effect of α-thal on pts w/ SCT; effect of α-thal on pts w/ SCD
Lowers proportion of Hgb S; lessens severity of SCD
Alternative genetic etiology for α-thal (instead of gene deletion)
Gene mutation (so genes are present but not functioning normally)
Hgb Constant Spring
Mutation in stop codon, leading to synthesis of longer/unstable α-chain
Hgb Qong Sze
Substitutions impairing αβ dimer formation
αTSaudi
Point substitutions in poly A region at 3’ end of gene
Genetic cause of β-thal
Mutation in β-chain gene, causing deficient or absent β-chain production, resulting in absence of Hgb A
Clinical condition associated w/ heterozygous β-chain mutation
β-thal minor
Clinical conditions associated w/ homozygous β-chain mutation (2)
β-thal major (Cooley’s anemia), β-thal intermedia (milder form)
Clinical sxs associated w/ β-thal major
Severe anemia w/ resultant extramedullary erythropoiesis, delayed sexual development, poor growth
Considerations for fetuses affected by β-thal major
Elevated levels of Hgb F partially compensate for absence of Hgb A (though death usually occurs by 10 y/o unless tx is begun early w/ periodic blood transfusions)
Purpose of transfusions for pts w/ β-thal major (2)
Severe anemia is reversed and extramedullary erythropoiesis is suppressed
Sequelae associated w/ β-thal intermedia
Variable but decreased amounts of β-chains are produced, and as a result, variable amounts of Hgb A are produced
Inheritance for Hgb S relative to β-thal
Usually behave as alleles (though only one gene inherited from each parent)
Sequelae associated w/ sickle cell-β0-thal
No normal β-chains, and therefore no Hgb A produced
Demographics w/ higher rates of β-thal minor (5)
Mediterraneans, Asians, Middle Easterners, Hispanics, West Indians
Clinical presentation of β-thal minor
Asymptomatic mild anemia (though varies depending on amount of β-chain production)
Who should be offered carrier screening for hemoglobinopathies in pregnancy?
All pts (w/ emphasis on high-risk Black, Southeast Asian, and Mediterranean pts)
Hemoglobinopathy carrier screening in pregnancy lab testing (2)
Hgb electro, CBC
Low-risk ethnic groups for hemoglobinopathies (5)
Northern Europeans, Japanese, Native Americans, Inuit/Eskimos, Koreans
Next step if pt tests positive as carrier for hemoglobinopathy on Hgb electro
Partner testing
Next step if both parents are found to be carriers for hemoglobinopathy
Genetic counseling
Next step if pt is found to have anemia w/ low MCV
Iron studies/ferritin to r/o IDA
MCV suggesting microcytic anemia
<80
Hgb electro results for pt w/ β-thal
Elevated Hgb F, elevated Hgb A2 (>3.5%)
Hgb electro results for pt w/ α-thal
Normal
Testing to confirm α-thal
DNA-based testing
When to test for α-thal
MCV is low, IDA is excluded, Hgb electro not c/w β-thal
When to offer fetal genetic testing for α-thal and/or β-thal
If specific mutation/deletion is known
Prenatal genetic testing options for thalassemias (2)
CVS (10-12wga), amnio (>15wga)
Pre-pregnancy testing option for couples w/ known hemoglobinopathy or who are known to be carriers
PGT (most successfully done for SCD and most cases of β-thal)
Percentage of families in whom antenatal dx confirms fetus w/ SCD who elect to continue pregnancy
~70%
Increased risks in pregnancy associated w/ SCD (8)
sAB, PTL/PTD, PROM, antepartum hospitalization, PP infection, FGR, LBW, IUFD
Which pregnancies are higher-risk between SCD and Hgb SC disease?
SCD
Supplementation recommended for pts w/ SCD, and why
Folic acid supp (4mg per day), 2/2 continual turnover of RBCs
Are C/S and/or epidural analgesia contraindicated in pts w/ SCD?
No (as long as care taken to avoid hypotension and hypoxemia)
Precipitating factors that could cause vaso-occlusive crises (4)
Cold environment, heavy physical exertion, dehydration, stress
Med used for tx of SCD that is contraindicated in pregnancy 2/2 teratogenicity
Hydroxyurea
Important management considerations for pain crises in pregnancy (2)
Prompt administration of analgesia, assessment of pain/RR/sedation level
Meds to provide for pain control during pain crisis
PO/IV/IM/subQ opiates
Vital sign to watch during pain crises, and management strategy if abnormal
SpO2, provided supp O2 if <95%
Specific consideration for pain crises during 3rd tri
Pain crises may have prolonged course, and may not resolve until PP
General risks associated w/ blood transfusion (3)
Alloimmunization, viral infections, iron overload
Major complications in SCD that may require exchange transfusion (4)
Worsening anemia, intrapartum hemorrhage/septicemia/C/S, pain crises, ACS
Hct value below which pRBC transfusion is definitively indicated for SCD
No exact value
Transfusion goals in SCD (2)
Lower Hgb S to ~40%, raise Hgb to ~10
How to determine need for additional transfusions in pregnancy after initial transfusion
Serially monitoring of Hgb levels and Hgb S percentage
Is ppx pRBC transfusion recommended?
No
Fetal surveillance recs for SCD, and special consideration
Serial growths and ANT recommended, results interpreted w/ caution if pts having pain crises (but revert back to normal w/ resolution of episode)
Pregnancy course for pts w/ α-thal trait
Not significantly altered
Pregnancy course for pts w/ Hgb H disease
Favorable outcomes w/ exception of mild-mod anemia
Pregnancy recs for pt w/ β-thal major
Pregnancy not recommended unless normal cardiac function who have had prolonged hypertransfusion therapy to maintain Hgb >10 and iron chelation therapy
Med used for iron chelation therapy, and safety in pregnancy
Deferoxamine, not recommended in pregnancy
Hgb minimum below which pRBC transfusion should be recommended in pts w/ β-thal major
10
Fetal surveillance recs for pts w/ β-thal major
Serial growths, and if suboptimal add on ANT
Pregnancy course for pts w/ β-thal minor
Mild asymptomatic anemia
Is iron supp recommended in pts w/ β-thal minor?
Only if documented iron deficiency
Risks associated w/ β-thal minor in pregnancy (2)
FGR, oligo (though no differences observed in APGAR scores, congenital malformations, perinatal mortality)
