hemoglobin disorders

Question 1

Structural variants vs thalassemias

Answer 1

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

Question 2

normal hemoglobins

Answer 2

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

Question 3

Abnormal hemoglobin

Answer 3

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

Question 4

labratory diagnosis of hb disorders

Answer 4

Hemoglobin electrophoresis (GEt, capillary)

high performance liquid chromatography, etc

Question 5

Routine electrophoresis

Answer 5

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

Question 6

sickle cell disease

Answer 6

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

Question 7

sickle cell disease SS- pathophsysiology

Answer 7

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

Question 8

time dependence of sickling

Answer 8

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

Question 9

clinical settings predisposing to sickling

Answer 9

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

Question 10

Effects of RBC sickling

Answer 10

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

Question 11

clinical manifestations of sickle cell anemia

Answer 11

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,

Question 12

Other sickling disorders

Answer 12

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)

Question 13

Management of sca

Answer 13

newborn screening, infection prophylaxis, supportive care, hydroxyurea (reduces blood cell counts increases erythrocyte levels of HbF)
regular RC transfuasion, stem cell transplant

Question 14

S trait

Answer 14

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

Question 15

HbC disease (CC)

Answer 15

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

Question 16

thalassemias

Answer 16

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)

Question 17

beta thalessemia

Answer 17

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

Question 18

inadequately transfused B thal major (no beta gene products)

Answer 18

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

Question 19

Beta thal minor

Answer 19

asymptomatic
Elevated HbA2– 2 alpha 2 delta, ring

mild issures

Question 20

Betathal intermida

Answer 20

heteorogenous

Question 21

Alpha thalessema

Answer 21

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