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Pathophysiology - Hematology > Anemia III - Hemoglobinopathies > Flashcards

Anemia III - Hemoglobinopathies Flashcards

1
Q

What is the typical MCV found in hemolytic anemias and what is the exception?

A

Usually normal MCV (80-99)

Exception:
Thalassemias will have low MCV (microcytic) due to underproduction of proper hemoglobin

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2
Q

What is the structure of typical HbA and what will mutations cause?

A

2 alpha and 2 beta globulins

Mutations usually cause no abnormalities, though they may cause a functional abnormality if in a critical region

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3
Q

What chromosomes are alpha and beta genes made on, and how many are there?

A

Alpha and alpha-like (epsilon) = chromosome 16. There are two copies of alpha on each chromosome, for a total of four

Beta and beta-like (delta or gamma) = chromosome 11, one copy on each chromosome for a total of two.

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4
Q

What are HbA2 and HbF? What condition is the former elevated in?

A 
HbA2 = alpha2delta2 - elevated in beta thalassemia
HbF = alpha2gamma2

Remember, gamma and delta are beta-like

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5
Q

When do beta globulin abnormalities first manifest and why?

A

Around 6 months of age
-> gamma globulin production has not been totally switched off in favor of beta globulin production until 30 weeks after birth

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6
Q

What generally causes a thalassemia and what will happen to the RBCs?

A

Reduced production of whatever globulin is affected, leads to buildup of other globulins in RBC.

i.e. alpha-thalassemia will be associated with decreased alpha globulin levels and increased beta globulin levels.

This leads to RBC membrane damage and shortened survival
-> microcytic, hypochromic anemias

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7
Q

What is alpha+ trait? Its symptoms?

A

All alpha thalassemias are due to deletions in alpha gene

Alpha+ trait is deletion of one gene (of four) -> usually asymptomatic

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8
Q

Who is likely to have homozygous alpha+ trait vs alpha0 trait?

A

Homozygous alpha+ trait = two alpha genes knocked out, but on opposite chromosomes
-> trans, more common in African Americans

alpha0 trait = two alpha genes knocked out on same chromosome, other chromosome is homozygous functional
-> cis, more common in Asians

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9
Q

What are the symptoms of homozygous alpha+ or alpha 0 trait? Which would you rather have?

A

Would rather have homozygous alpha+ because you cannot give your child hydrops fetalis. If you have alpha 0 and so does your partner, you can both pass on your cis knockout chromosomes and cause hydrops.

Symptoms: mild hypochromic anemia

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10
Q

What is HbH disease and what is it caused by?

A

Only one functional copy of alpha gene, three knocked out (like a+ trait + a0 trait)

-> caused by buildup of beta4 tetramers which damage RBCs.

HbH = beta4 tetramers

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11
Q

What does four alpha genes deleted cause in alpha thalassemia? What abnormal hemoglobins are present?

A

Hydrops fetalis

In utero: Hemoglobin Barts (gamma 4) seen on electrophoresis
Later in life: HgH, if they survive

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12
Q

What RBC inclusions can be seen in alpha thalassemia? What removes them?

A

RBCs build up Heinz bodies from excess non-alpha chains

  • > kinda like how G6PDH builds up excess weird hemoglobin
  • > splenic RES removes it
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13
Q

How do you treat hydrops fetalis from alpha thalassemia 4 deletions?

A

Intrauterine transfusion to prevent high output cardiac failure

After birth, need bone marrow transplant

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14
Q

What are the three possible states of each gene in beta thalassemia?

A

Not due to deletions like alpha thalassemia, due to mutations in promoter sequences or splice sites

B0 = nearly complete suppression of synthesis

B+ = incomplete suppression

Bn = normal gene

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15
Q

What is thalassemia minor vs thalassemia major?

A

Bn / B+ or Bn / B0 = thalassemia minor

Any thalassemia without at least one Bn = thalassemia major. Worse is B0/B0

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16
Q

What are the features of beta thalassemia anemia? What is seen on electrophoresis in minor / major?

A

Hypochromic, microcytic anemia with target cell formation

Minor: decreased HbA and mildly increased HbA2 (>4%) / HbF (>2%)

Major: little to no HbA (20%), almost all HbA2 (4+%) / HbF (70+%)

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17
Q

What happens when alpha chains accumulate in thalassemia major?

A
  1. Alpha chains are toxic to cell division and arrest hematopoiesis
  2. Alpha chains make RBC deformed for splenic removal
  3. RBC damage causes K+ flux

These factors all lead to intramedullary death and short RBC survival -> hemolytic anemia

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18
Q

What happens if beta thalassemia is left chronically untreated?

A

Splenomegaly due to work hypertrophy, bone changes (especially skull and facial bones) due to expanded hematopoesis (extramedullary), increased iron absorption from elevated EPO levels, growth failure, and cardiac dysfunction

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19
Q

How long does it take for beta thalassemia major to present and why? What is the first sign?

A

Takes several months after birth, for fetal hemoglobin production to drop off

First sign is facial changes, due to erythroid hyperplasia

Crew cut appearance on Xray due to expansion of diploid spaces of skull “hair standing on end”

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20
Q

What is the primary treatment of beta thalassemia major and what is the target?

A

Hypertransfusions - target is 9 to 10 gm/dL

Improves growth, less organomegaly, fewer fractures, less facial deformity

21
Q

What needs to be added to treatment regimens on patients with chronic blood transfusions as in beta thalassemia major? Name / describe them and their limitations

A

Iron chelators

Desferrioxamine - safest but cumbersome and painful - infused daily for 8-12 hours

Desferasirox and deferiprone - taken orally, have hepatic, renal and bone marrow side effects, but much easier

22
Q

What are some possible clinical outcomes which can happen from structural changes in hemoglobin?

A
  1. Increased aggregation - HbS, HbC
  2. Unstable Hb molecule - hemolytic anemia
  3. Altered O2 affinity
  4. Decreased O2 carrying capacity - HbM
23
Q

What is the difference between an intrinsic and an extrinsic hemolytic anemia?

A

Intrinsic - changes to RBC cause anemia, i.e. membrane changes, hemoglobin changes, enzyme changes

Extrinsic - Autoimmune, microangiopathic, and macroangiopathic (i.e. mechanical)

24
Q

In what area of the world are the thalassemias more common?

A

Asia

Including alpha and beta thalassemia

25
Q

What are the various causes of sickle cell disease?

A

Although SS genotype is most common, can be S and any other major knockout of the hemoglobin beta gene (i.e. S,B0 or S,B+)

26
Q

What are the clinical characteristics of Sickle cell trait? Is it common in the US?

A

Benign because HbA is made slightly more efficiently than HbS, and need >50% HbS for disease

  • > hematuria, loss of urine concentration because hypertonicity of medulla causes sickling, causing microinfarctions
  • > problems with high altitude (hypoxia)

->10% carrier rate in US

27
Q

What causes hemoglobin S and hemoglobin C?

A

Hemoglobin S = beta gene substitutes in valine for glutamate

Hemoglobin C = beta gene substitutes lyCine for glutamate

28
Q

How does sickling occur in sickle cell disease?

A

Nucleation of adjacent hemoglobins occurs first
-> prolonged deoxygenation causes hemoglobin aggregates to act as nucleation centers, causing long polymers and sickling of whole cells

29
Q

How does a vasoocclusion snowball in sickle cell disease?

A

Sickled RBCs get stuck in blood vessels and adhere in capillaries, cause stasis of blood

Polymerization of HbS is worse with hypoxemia, dehydration, and acidosis, so the crises get worse as more cells are stopped, become deoxygenated, and begin to sickle themselves

30
Q

How does a vaso-occlusive crisis occur?

A

Whenever the sickled RBCs are stuck to the endothelial wall, they can rip off the endothelium as they are pulled away, exposing collagen and starting a clotting cascade
-> leads to thrombosis and further narrowing of vessel lumen

31
Q

What complications does vaso-occlusion cause in sickle cell?

A

Pain, acute chest syndrome, strokes, and priapism (block of blood flow from penis)

32
Q

What complications does short RBC survival cause in sickle cell?

A

Chronic anemia, CHF, sepsis, and aplastic crises (parvovirus B19)

33
Q

What organs are chronically damaged in sickle cell?

A

Spleen, liver, kidney, lung

34
Q

Why do RBCs have short survival in sickle cell disease?

A
  1. Extravascular hemolysis - splenic macrophages remove RBCs with damaged membranes
  2. Intravascular hemolysis - RBCs with damaged membranes tend to dehydrate, leading to formation of target cells on blood smear and decreased blood haptoglobin (binds free hemoglobin)
35
Q

What symptom of sickle cell disease is often mistaken for osteomyelitis?

A

Dactylitis - swollen hands and feet due to vasoocclusive infarcts in bones

36
Q

What is the most common cause of osteomyelitis in sickle cell patients and why?

A

Salmonella - due to autosplenectomy from recurrent veno-occlusions

37
Q

What is acute severe splenic sequestration? Why not just remove the spleen to prevent this?

A

Sudden pooling of blood in acutely enlarged spleen due to a viral infection, locks progress of blood thru spleen due to sickling

Can cause hypotensive shock if not treated with transfusions

We don’t want to remove the spleen because early hyposplenism is associated with high mortality from bacterial sepsis in childhood

38
Q

What prophylactic treatment is given to dramatically lower early septic death in children?

A

Twice daily oral penicillin -> prevents bacterial infection. Until age 5

Always fevers aggressively with antibiotics

39
Q

What is the most common cause of death in adult patients with sickle cell disease?

A

Acute Chest Syndrome
-> pulmonary vaso-occlusive event usually precipitated by pneumonia, leads to fever, and chest pain which may cause hypoxia

Need transfusions, supplemental O2, and antibiotics

40
Q

What kidney damage occurs in sickle cell disease? What symptoms does this cause?

A

Renal papillary necrosis and vasa recta occlusion

  • > causes microhematuria and inability to concentrate urine
  • > dehydration, daytime polyuria, nocturnal enuresis
41
Q

What is an inexpensive test to tell you if a patient may have sickle cell trait or disease?

A

Solubility test, uses a reagent to lyse RBCs and something to deoxygenate hemoglobin.

If a sample contains HbS, the solution will be turbid.

42
Q

What will blood smear show in sickle cell disease?

A

Polychromasia, target cells, and filamentous sickled cells

43
Q

How do you remember how far all the types of hemoglobin move on the hemoglobin electrophoresis?

A 
HbA = Accelerate (farthest)
HbF = Fast (second farthest)
HbS = Slow (second slowest)
HbC = Crawl (shortest)
HbA2 = 2 together with C, comigrates with C
44
Q

What is the modern technique being used to diagnose hemoglobinopathies?

A

High performance liquid chromatography

-> different hemoglobins will have different peaks

45
Q

Other than supportive hydration, narcotics, and tranfusions when required, what treatments are given to manage sickle cell disease overall?

A
  1. Hydroxyurea - Increase HbF
  2. Stem cell transplants
  3. Gene therapy - still in the works
  4. Anticoagulants like prasugrel, and P-selectin antibodies still in the works for vasoocclusive crises
46
Q

What is hemoglobin M / what does it cause?

A

Hemoglobin with a substitution near the heme pocket, results in methemoglobinemia

Is actually benign, but patients will appear cyanotic

47
Q

What is characteristic of the blood smear with hemoglobin C and what symptoms does it cause?

A

Hemoglobin C “c”rystals in RBCs, with target cells

Symptoms: mild extravascular hemolytic anemia with associated splenomegaly

48
Q

Where is Hemoglobin E found and when is it a problem?

A

Found in patients in far east (Asia)

Trait - like beta thalassemia minor
Homozygous recessive - will cause mild hypochromia and microcytosis
E/B0 - transfusion dependent, like beta thalassemia major -> this heterozygous phenotype is bone bad.

Pathophysiology - Hematology (14 decks)

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