Hemoglobinopathies - Kroft

Question 1

How are hemoglobinopathies subdivided?

Answer 1

Into disorders of structural variation (qualitative problem) and thalassemias (quantitative problem).

Question 2

Recall the normal three hemoglobin species found in an adult, their compositions, and their relative levels.

Answer 2

HbA (a₂b₂) - 96%

HbF (a₂y₂) - 1%

HbA₂ (a₂d₂) - 3%

Question 3

How do diseases of abnormal hemoglobin arise?

What factors determine their clinical behaviors?

Answer 3

Generally genetic disorders; many types of mutations can affect globin genes (deletions, insertions, elongations, fusion, but mainly point mutations)

Behavior depends on what gene is affected and how the globin’s resulting tertiary and quaternary structures are impacted. Most are silent.

Question 4

What are some potential consequences of abnormal hemoglobin structure?

Answer 4

Sickling, instability, altered oxygen affinity, susceptibility to oxidation, altered production.

Question 5

Describe two techniques used to diagnose disorders of abnormal hemoglobin.

Answer 5

Electropheresis (Hb made to migrate in an alkaline or acidic buffer depending on its charge and interactions)

HPLC (cation exchange along a resinous column; speed of elution identifies the globin)

Question 6

What is the isoelectric point of HbA?

Answer 6

6.8

Question 7

Sickle Cell Disease

Describe its epidemiology.

What is the responsible mutation?

Answer 7

Sickle Cell Disease

Occurs in 1/600 African Americans.

Glu to Val substitution at amino acid 6 of the beta-globin: E6V

Question 8

What physiological factors contribute to the sickling of RBCs in sickle cell anemia?

Describe some clinical settings that will affect sickling.

Answer 8

Concentration of HbS (percentage of total, MCHC)

Time (sickling increased in sluggish flow)

Oxygenation (only deoxygenated polymerizes)

Dehydration (increased hypertonicity)

Hypoxia, Acidosis, Dehydration, Cold temperatures, Infections

Question 9

Sickle Cell Disease

At what oxygenation do SS cells begin to sickle?

What is a typical RBC lifespan here?

What Hb level is typical?

Answer 9

Sickle Cell Disease

40mm Hg O₂

20 days

Hb 5-11 g/dL (usually 7)

Question 10

By what mechanism do sickled RBCs cause disease?

Answer 10

Occlusion of small vessels with resultant hypoxia and infarction.

Question 11

There are about 20 given manifestations of Sickle cell. Do your best to name about 10 or so.

Answer 11

Megaloblastic anemia, acute pain crises, auto-splenectomy, acute chest syndrome, strokes, aplastic crisis, infections, liver damage, splenic sequestration, growth retardation, bony abnormalities, renal dysfunction, leg ulcers, cholelithiasis.

Question 12

Explain the pathophysiology behind auto-splenectomy and splenic sequestration in sickle cell disease.

Answer 12

Auto-splenectomy: Repeated infarction causes shrinking and fibrosis. This happens commonly, and increases risk for infection by encapsulated bacteria.

Splenic sequestration: Large amounts of blood rapidly pool in the spleen, potentially causing hypovolemic shock.

Question 13

Explain the pathophysiology behind acute chest crisis and aplastic crisis in sickle cell disease.

Answer 13

Acute chest syndrome: Pulmonary infections or fat emboli from infarcted marrow exacerbate occlusion because of the decreased flow, and vice versa.

Aplastic crisis: A parvovirus B19 infection infects erythroid precursors causing a 7-10day red cell aplasia.

Question 14

Describe the pathophysiology behind the megaloblastic anemia and strokes seen in sickle cell disease.

Answer 14

Megaloblastic anemia: Chronic proliferation of the erythroid precursor to replace destroyed RBCs eventually exhausts folate supply.

Strokes: Just micro-infarcts. Happens in very young patients!

Question 15

What lab findings are seen in sickle-cell disease?

Answer 15

Anemia, increased bilirubin, increased reticulocytes, sickle/target/polychromasic cells with normal MCV (?)

Question 16

Name two sickling disorders asides from sickle-cell disease.

Answer 16

Hemoglobin SC disease: Instead of homozygous E6V mutation, one copy has E6K (HbSC!). Milder, but sickling occurs with dehydration.

Hb S/beta-thalassemia: Instead of homozygous E6V mutation, one copy is missing. Milder, but HbS still exceeds HbA.

Question 17

How is sickle cell disease treated/managed?

Answer 17

Newborn screening, transfusions, prophylaxis for infection, red cell tranfusions.

Hydroxyurea upregulates HbF to reduce sickling.

Question 18

What are the major causes of death in sickle cell disease?

Answer 18

Liver dysfunction, pulmonary hypertension, stroke, vaso-occlusive crisis, acute chest syndrome.

Question 19

What is the condition of having a single copy of E6V mutated beta-globin?

Describe its presentation and lab findings.

Answer 19

Sickle-trait (present in 8% of African americans)

Clinically benign, some sub-clinical kidney damage (hematuria). HbA predominates over HbS.

Question 20

HbC Disease

What is the etiology?

Demography?

Clinical presentation?

Answer 20

HbC Disease

E6K (lysine) mutation in the beta-globin gene (homozygous).

1 in 6000 African Americans.

Usually asymptomatic, maybe some splenomegaly.

Question 21

HbC Disease

What is the average lifespan of an RBC in this disease?

What causes this short lifespan?

Describe the blood smear and hemoglobin profile.

Answer 21

HbC Disease

30-35 days.

RBCs are abnormally rigid & dehydrated–however, no sickling.

Target cells, microcytosis, spherocytosis. Hb 8-12, largely HbC (no HbA).

Question 22

Describe HbC trait.

Answer 22

Heterozygous mutation E6K; present in 2% of African Americans but benign (no anemia, a few target cells, HbA predominates).

Question 23

What is a thalassemia?

Describe the distribution of alpha and beta thalassemias.

Answer 23

Inherited disorders resulting in decreased production of otherwise normal globin chains.

Alpha: Africa, mediterranean, middle east, SE asia.

Beta: Mediterranean, middle east, India/Pakistan, SE asia.

Question 24

What does the blood smear of a thalassemia look like?

Answer 24

Hypochromia and microcytosis.

Question 25

What defines a major beta-thalassemia?

What Hb level is seen? What morphology?

What are the consequences of this?

Answer 25

Decrease or abscence of beta-chain production of BOTH beta alleles (homozygous).

Hb of 2-3; nearly all HbF. Morphology is bizarre (hypochromia, targeting, erythroblastosis).

These patients are dependent on red cell transfusions for life.

Question 26

What are the consequences of an inadequately treated beta-thalassemia?

What are the consequences of it is treated without sufficient iron chelation?

Answer 26

Stunted growth, bony abnormalities (frontal bossing, mongoloid facies), increased skin pigmentation, wasting, hyperuricemia, etc etc etc DEATH

Endocrine disturbances like DM, adrenal insufficiency, absence of puberty/menarche, death from cardiac disease.

Question 27

Beta-thalassemia (Minor)

Describe the etiology and demography.

What is the clinical presentation?

What are its lab features?

Answer 27

Beta-thalassemia (Minor)

Heterozygous for decreased beta-globin expression. Seen in mediterranea, asian, and african american populations.

Asymptomatic.

Mild anemia, microcytosis, mild anisopoikilocytosis (target cells), basophilic stippling, elevated HbA₂

Question 28

Alpha Thalassemia

Describe its four subtypes.

What is HbH?

Answer 28

Alpha Thalassemia

Silent (1 deletion), Alpha-thal trait (2 deletions, mild anemia), HbH disease (3 deletions, chronic hemolysis), Hydrops fetalis (4 deletions, incompatible with life).

HbH is a tetramer of beta globin. It doesn’t work very well, and will precipitate with time.

Question 29

Bonus Questions

What is the mutation seen in HbCC disease?

Does delta-globin expression increase or decrease with age?

Besides sickled cells, what morphology is seen in Sickle-cell disease?

Answer 29

Bonus Question

E6K

Increase (barely)

Target cells, polychromasia

Question 30

Bonus Questions 2

Why do most hemoglobinopathies take a few weeks or months after birth to manifest?

What disease can present with mild, subclinical kidney damage?

Why is folate seen in many hemoglobinopathies?

Answer 30

Bonus Questions 2

Fetal hemoglobin is usually unaffected by the relevant mutations.

Sickle-trait.

Failure of the erythrocytes causes erythropoiesis; with chronic expansion, folate stores become depleted.