hemoglobin disorders Flashcards
Structural variants vs thalassemias
structural variants- abnormal globin chain structure due to globin gene mutation, varied clinical effects depending on location an dnature of mutation in globin chains
Thalassemias- under produtcion of normal globulin genes, microcytic/hypochromic anemias of varying severeity
normal hemoglobins
3 normal hemoglobin species in fetal and postnatal life
Hemoglobin A: adult form (a2B2)
hemoglobin F: fetal form (a2G2)
Hemaglobin A2: Alpha2delta2)
normal adult at 1 years old
Abnormal hemoglobin
More than 500 structural hemoglobin variants have been described, most are single AA replacements, any gene can be affected, most clinically silent
Consequences- depends on which globin gene is affected (dleta gene insignificant), location of substitution in the tertiary structure and quat structures
Sickling, instability, altered oxygen affinity, increased susceptibility, under production, various combination of
labratory diagnosis of hb disorders
Hemoglobin electrophoresis (GEt, capillary)
high performance liquid chromatography, etc
Routine electrophoresis
Typically performed in parallel with alkaline and acid buffer, HbA has isoelectric point of 6.8 (negative charge in alkaline buffers migrates toward anode +) and positiv goes to cathode
sickle cell disease
homozygous abnormality of the Beta globin chain
Glu to Val substitution at amino acid 6 of beta chain (beta 6 VAL)) Heterozygous HbS (Strait) confers protection against malaria, homozygous 1/600 Af am
sickle cell disease SS- pathophsysiology
deoxygenated HbS forms long polymers that distort the shape of the cell into elongated sickled form
Intermolecular contacts involve abnormal valine at amino acid 6
Extent of HbS polymerization is time and concentration dependent
Factors affecting concentration of Hb S: percentage of hemoglobin S of total hemoglobin (homozygous versus heterozygous, presence of other hemoglobin species hbF). Total heoglobin concentration in the red cells (MCHC) increased in states of cellular dehydration, decreased when there is co-existent thalessemia
time dependence of sickling
importance of transient time of red cells thru oxygen tension microvasculature
Sickling enhanced in anatomic sites with sluggish flow (spleen and bone marrow)
Blood flow through microvasculature is retarded in pathology
clinical settings predisposing to sickling
Hypoxia, acidosis, shift of oxygen dissociation curve to the right, increasing deoxygenation o fHbS
Dehydration- hypertonoicity causing RBC dehydration
Cold- peripheral vasconstriction and sluggish flow
Infections
SS cells begin to sickle at 40 mmHg, initially reversible but after multiple sickling cyclesmembrane damage is irreversible, RBC lifepan decreast to 20 days
Effects of RBC sickling
Chronic hemolysis- correlates with the number of irreversibly sickled cells
Microvascular occlusion with resultant tissue hypoxia and infarction (increased stickiness of SS RBC
Newborns ok bc of high HbF, hematologic manifestation begin at 10-12 wks severity different
clinical manifestations of sickle cell anemia
Severe anemia, acute pain crises (vasooclusion), autosplenectomy (splenic infarcts, all adults with SS, increased risk for infection of enkapsulated bacteriq), acute chest syndrom (severe complications- major cause of death, pulm infections, fat emboli) strokes (11% by age 20)
aplastic crisis- caused by acute decrease in RBC production, parvovirus B19 infection
Infections, liver damage (multifactorial) splenic sequestration crises, megaloblastic anemia, growth retadations
increase bilirubin ,SS cels, target cells,
Other sickling disorders
HB SC disease (Hb C from glu to lys substitiution on beta, causing cell dehydration and consequent sickling)
Generally milder, but variable compare to SS, Gb 10-12
Hb/S Betea thalessemia- asymtomatic-< SS severity (HbS>HbA)
Management of sca
newborn screening, infection prophylaxis, supportive care, hydroxyurea (reduces blood cell counts increases erythrocyte levels of HbF)
regular RC transfuasion, stem cell transplant
S trait
8% of Afm am clinically benign (no anemia, normal RBC survival,
May be mild subclinical kidney damage, impairment of urine concnetration ,microhematuria
60% HbA, 40% HbS
HbC disease (CC)
mild to moderate hemolytic anemia, often asymptomatic splenomegaly- may cause occasional abdominal pain
1/6k af am
pathophysiology: Glu to lys substitution of amino acid 6 of B chain, cells abnormally rigid and dehydrated, RBC life span shortened to 30-35 days not a sickling disorder
Hb levels 8-12, numerous target cells, mild microcytosis, spherocytes, occasionsal C crystals (almost all C)
no anemia with trait
thalassemias
group of inherited characteristd disorders
DECREASED production of NORMAL globin chains
highly heterogenous clinically and genetically
Beta thal - mediterranean
Alpha- africa and medittraneam
typically microcytic, hypochromic anemia of varying severity
decreased Hb production produces hypochrromia and microcytosis, cytoplasmic maturation defect
severity of hematlogic defct related to degree of chain imbalance (excess normal produced globin chain accumulate and cause intramedullary cell death and decreased RBC survival)
beta thalessemia
decreased beta globin
mutation causing splice errors, promotors, translation (rarely gene deletion)
major intermedia and minor
in both alleles mutation so excess alpha chains no tetramers- percipitate
intramedullary cell death and decreased RBC lifespan, infanks ok at birth, transfusion dependence, severity of clinical effect depends on adequacy of transfusion
inadequately transfused B thal major (no beta gene products)
stunted growth fronal bossing, mongoloid facies, skin pigmentation, bony abnormailitis, wasitn fever, hyperuricemia, spontateous fractures, hepatosplenomegaly infections, folate deficiency, death as kids
With early transfusion- normal in young adulthood but lateer on iron starts to build up (you need to chelate the iron out)- absence of pubertal growth sput and menarche, endocrine disturbances such as DM
Beta thal minor
asymptomatic
Elevated HbA2– 2 alpha 2 delta, ring
mild issures
Betathal intermida
heteorogenous
Alpha thalessema
gene deletion Siltent carrient (1 gene), Trait (2 genes)- similar to beta thal minor
Hemoglobin H disease (3 genes deleted)- beta genes can tetramerize and dont accumulate really- no O2 carrying
Hydrops fetalis- 4 genes are deleted- infant dies immediately
