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Medical Laboratory Science > Hematology 1 - Exam 3 > Flashcards

Hematology 1 - Exam 3 Flashcards

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1
Q

What are normal values for:
WBC
RBC
Hgb:
Hct:
MCV:
MCH:
MCHC:
RDW:
Plts:

A

WBC: 3.6.-10.6
RBC: 4.2-6.0
Hgb: 12-18
Hct: 35-54
MCV: 80-100%
MCH: 26-34
MCHC: 31-37
RDW: 11.5-14.5
Plts: 150-450 * 10^

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2
Q

What are MVC, MCH, MCHC values like in normocytic/normochromic cells?

A

MCV: Normal
MCH: normal
MCHC: normal

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3
Q

What are MVC, MCH, MCHC values like in macrocytic/normochromic cells?

A

MCV: high
MCH: high
MCHC: normal

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4
Q

What are MVC, MCH, MCHC values like in microcytic/normochromic cells?

A

MCV: low
MCH: normal
MCHC: normal

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5
Q

What are MVC, MCH, MCHC values like in microcytic/hypochromic cells?

A

MCV: low
MCH: low
MCHC: low

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6
Q

What is the normal range for:
Serum Fe:
Serum ferritin:
Transferrin:
FEP or ZPP(free erythrocyte protoporphyrin):
TIBC:

A

Serum Fe: 50-160 ug/dL
Serum ferritin: 40-400 ng/mL
Transferrin: 20-55% saturation
FEP (free erythrocyte protoporphyrin): < 80 ug/dL
TIBC: 250-400 ug/dL

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7
Q

What causes IDA? What are some symptoms/situations commonly seen with this anemia?

A
  • Microcytic/hypo chronic
  • pallor, weakness, fatigue
  • Pica
  • Associated with chronic blood loss, inadequate intake, states of increased demand (pregnancy).
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8
Q

Lab findings in IDA?

A

MVC: decrease
MCH: decrease
MCHC: decrease
Serum Ferritin: down
TIBC: increase
Serum Fe: down
Transferrin saturation: down
FEP: increase
Bone marrow sideroblasts: decrease

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9
Q

IDA treatments:

A
  • treat underlying cause
  • oral supplement
  • transfusions in life threatening cases
  • dimorphic population seen with treatment
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10
Q

What is hepcidin? What condition is associated with it?

A
  • A hormone produced by hepatocytes and regulates iron blood levels.
  • It reduces the amount of iron absorbed from intestine and influences the ability of the macrophages and hepatocytes to retain iron.
  • When iron levels increase, hepcidin increases, and macrophages retain iron (and vice versa).
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11
Q

Symptoms and lab findings with ACI?

A
  • decreased serum Fe and % Tf saturation
  • normal to increased ferritin levels
  • TIBC decreased
  • ZPP increased
  • TfR (Transferrin receptors) are normal (increased in IDA).
  • can be normo-, normo- or micro-, hypo-.
  • no reticulocytosis
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12
Q

ACI treatment?

A
  • treat underlying condition
  • give EPO and Fe supplements
  • never take Fe without EPO
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13
Q

IDA vs ACI findings?

A
  • IDA has decreased ferritin and increased TIBC. Decreased bone marrow Fe levels.
  • ACI has increased to normal ferritin and decreased TIBC. Increased bone marrow Fe levels.
  • Both IDA and ACI have:
    increased FEP (ZPP)
    decreased %Tf sat.
    decreased serum Fe
    normal>decreased MCV & MCHC
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14
Q

Disorders of Iron metabolism?

A
  1. Iron deficiency anemia (IDA): deficiency of iron.
  2. Anemia of chronic inflammation (ACI): defective released of stored Fe from macrophages.
  3. Sideroblastic anemia (SA): defective usage of Fe within the bone marrow sideroblast.
  4. Lead intoxication: actually a type of sideroblastic anemia.
  5. Hemochromatosis: excessive “Fe overload.”
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15
Q

What are some characteristics of sideroblastic anemias?

A

A diverse group of anemias characterized by:
- Hypochromic anemia
- Ineffective erythropoiesis
- An increase in serum and tissue Fe
- The presence of ringed sideroblasts in the bone marrow
- Very diverse group of disorders that can be inherited or acquired.
- An enzyme disorder in which the body has adequate iron which enters normoblasts, but is unable to incorporate it into hemoglobin.
- Identified deficiencies of delta-ALA synthase (needs vitamin B6 as coenzyme) and uroporphyrinogen decarboxylase.
- Characteristic ringed sideroblast (sideroblasts in which iron is accumulated in the mitochondria that surround the nucleus.

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16
Q

Types and Treatment of sideroblastic anemias?

A
  1. Hereditary SA: involves detect of delta-ALA synthase. Heme synthesis is impaired as iron enters the erythroid precursor which cannot be incorporated into the heme molecule because protoporphyrin ring cannot be formed. Iron builds up in mitochondria. Very rare. Treatment is pyridoxine (B6), however many patients don’t respond. Death can occur due to Fe overload (cardiac arrhythmias, liver disease, & multiple organ failure).
  2. Acquired SA: primary or idiopathic anemia. Refractory anemia with ringed sideroblasts (RARS). Actually a type of myelodysplastic disorder (which some consider to be a preleukemia). Treatment is rarely done because disease is usually non-progressive and non-incapacitating (unless it convers into a leukemia).
  3. Secondary SA: typically follows exposure to drugs or toxins (alcohol, lead, chemotherapeutic agents). Is treated by removing toxin or drug.
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17
Q

Lab findings of sideroblastic anemias?

A
  • Mod. > severe anemia in peripheral blood, but WBCs and plts normal.
  • Micro, hypo with dimorphic population, so RDW normal to decreased.
  • Anisocytosis, poikilocytosis, target cells, Pappenheimer bodies, and basophilic stippling.
  • TIBC normal to slightly decreased.
  • Increased ferritin, serum Fe, and %Tf sat.
  • Excessive iron stored in bone marrow normoblasts as ringed sideroblasts.
  • Tf receptor level —-
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18
Q

What are Pappenheimer bodies?

A

Iron

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19
Q

What are some acute phase reactants and their purpose?

A
  • Hepcidin: an acute phase reactant. During inflammation (unrelated to Fe levels), there is a decrease in iron absorption and macrophages retrain iron.
  • Lactoferrin: an iron-binding protein in neutrophilic granules (importance in phagocytosis). During inflammation, lactoferrin is released into plasma and scavenges available iron. RBCs do not have lactoferrin receptors.
  • Ferritin: also binds iron in plasma. RBCs lack ferritin receptors.
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20
Q

Define sideroblast and siderocyte. Where are they found?

A

Sideroblast: normoblast containing free Fe granules (not yet incorporated into heme) in its mitochondria. Found in the bone marrow, NOT the peripheral blood.
Siderocyte: mature RBC in peripheral blood containing free Fe granules (aka. siderotic granules or Pappenheimer bodies).

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21
Q

What are characteristics of Lead (Pb) Intoxication?

A
  • an acquired condition leading to SA.
  • Chronic or acute
  • Occurs in adults and children via Pb paint, Pb in water, cooking pottery, and vehicle emissions.
  • Affects 3 major tissues: renal, hematopoietic, and central nervous system.
  • Pb inhibits activity of 3 enzymes in heme synthesis pathway (PBG synthase, coproporphyrinogen oxidase, and heme synthase/synthetase (ferrochelatase).
  • Symptoms: abdominal pain, constipation, vomiting, muscle weakness, motor disturbances, leadline (blue-black deposit of lead sulfide in gums near teeth or in nailbeds), psychiatric disturbances, seizures, coma, can cause birth defects.
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22
Q

Lab findings in Lead intoxication.

A
  • Mild > moderate micro, hypo, but can be normo, normo.
  • Normal serum Fe, ferritin, & TIBC
  • Increased FEP (ZPP)
  • Hallmark basophilic stippling, but not always.
  • Increased RPI
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23
Q

Treatment for Pb intoxication.

A
  • Removal of drug or toxin
  • Chelation therapy (i.e. with EDTA or other chelating salts, which chelate Pb & allow its urinary excretion.
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24
Q

What are the Porphyrias?

A
  • A group of disorders due to an impaired production of heme.
  • Can be hereditary or acquired.
  • Results in ineffective hematopoiesis and sideroblastic anemia.
  • When an enzyme is missing, the products from earlier stages in the pathway accumulate in the blood and may be excreted in urine or feces.
  • Associated with photosensitivity, motor dysfunction, sensory loss, mental disturbances, and some abdominal pain.
  • Most common porphyria is: Acute Intermittent Porphyria - missing enzyme porphobilinogen deaminase and causing massive build up of porphobilinogen and ALA in urine.
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25
Q

What is Hemochromatosis? What are some characteristics?

A
  • Accumulation of excess Fe, resulting in tissue damage.
  • Excess Fe stored in the liver, heart, and pancreas (leading to damage of these organs).
  • Can cause bronze skin pigmentation.
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26
Q

Lab findings in Hemochromatosis.

A
  • Increased %Tf sat. (1st indication of HH).
    Diagnosis requires %Tf sat. > 50% for females and > 60% for males.
  • Increased serum iron
  • Increased serum ferritin
  • Normal or decreased TIBC.
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27
Q

Treatments of Hemochromatosis.

A

Therapeutic phlebotomy or blood letting.
Chelation therapy for acute poisoning.

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28
Q

Clinical symptoms of Hemochromatosis.

A
  • Males between 40-60 mostly
  • Joint pain and chronic fatigue
  • Homozygotes show majority of symptoms: CVD, liver cancer, osteoarthritis, & diabetes mellitus.
  • Also causes some cardiomegaly, early menopause, depression, infertility, and impotence.
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29
Q

Types of Hemochromatosis.

A
  1. Hereditary Hemochromatosis (HH): One of the most frequent genetic diseases is northern European Caucasians.
    Tf receptors appear to be permanently turned on (maybe due to mutant hepcidin).
    Patients absorb normal amount of iron, but transport more of it into the plasma.
  2. Acquired Hemochromatosis: occurs secondary to other inherited hemolytic anemias.
    Common characteristics are anemia, ineffective erythropoiesis, and Fe overload.
    Usually have multiple transfusions, which leads to increased Fe storage due to no mechanism for iron excretion.
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30
Q

Pathogenesis of Hemochromatosis.

A

When excess iron is present:
- increased ferritin
- increased hemosiderin
- free Fe increases (ferrous form)
- ferrous Fe + O2 = superoxide & free radicals, leading to cell death.
- All cells (except mature RBCs) require iron, and have the potential for damage.

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31
Q

Hemochromatosis screening issues & recommendations.

A

Issues:
- asymptomatic individuals frequently will have identifiable lab value abnormalities, so screening is a hot issue.
- at home cheekbrush test is now available. Sample is mailed in for PCR and analysis, but is expensive.

Recommendations:
- have the genetic test only if you have a relative diagnosed with hemochromatosis.
- middle-aged men should donate blood at least once per year.
- otherwise healthy adults should avoid Fe supplements unless they have been specifically prescribed by a doctor.

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32
Q

Differentiation of Iron Metabolism Disorders.

A

IDA:
Bone Marrow Fe - low or absent
Serum ferritin - decreased
Serum Fe - decreased
TIBC - increased
FEP - increased

ACI:
Bone Marrow Fe - normal or increased
Serum ferritin - normal or increased
Serum Fe - decreased
TIBC - normal or decreased
FEP - increased

SA:
Bone Marrow Fe - increased
Serum ferritin - increased
Serum Fe - increased
TIBC - normal or decreased
FEP - variable

Pb poisoning:
Bone Marrow Fe - normal
Serum ferritin - normal
Serum Fe - variable
TIBC - normal
FEP - increased

Hemochromatosis:
Bone Marrow Fe - increased
Serum ferritin - increased
Serum Fe - increased
TIBC - normal or decreased

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33
Q

What are Thalassemias?

A
  • Genetically diverse group of disorders (which may appear clinically similar) that are caused by decreased or absent production of globin chains.
  • Defect lies in the rate of synthesis of the chains (causing imbalanced globin chain production).
  • Occurs in high frequency in Mediterranean, middle East, India, and SE Asia.
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34
Q

When is the Beta-Gamma switch?

A

Right before birth.
- Gamma globin switches off, beta globin switches on.

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35
Q

What are the globin chains in:
Portland
Gower I
Gower II
Fetal
A1
A2

A

Portland: ZG
Gower I: EZ
Gower II: AE
Fetal: AG
A1: AB
A2: AD

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36
Q

Pathophysiology of Thalassemias.

A
  • Micro, hypo RBCs
  • Increased mitosis of RBC precursors in order to make up for chronic hypoxia, frequently causes an increase RBC count & more numerous, but smaller RBCs, which consequently have less [Hgb].
  • Occurs more in beta-thalassemias than alpha-thalassemias because betas have the greater hemolytic anemia due to precititation of highly unstable alpha4 tetramers. Greater hemolytic anemia = greater reticulocytosis = increased RBC count with worse MCV & MCH.
  • In alpha-thalassemia, defective chain production results in excess chain production in fetal and adult life. Involves a lack of hgb synthesis - cells have a shortened life span and cannot carry O2 effectively.
37
Q

Classification of alpha-thalassemias.

A
  • Large deletions are the prominent cause, may be in 1-4 alpha genes.
  • Severity ranges from no clinical abnormality with only 1 alpha gene deleted or suppressed, to lethal with all 4 alpha genes deleted or suppressed.
  • 2 loci on chromosome 16 = 4 alpha genes.
  • With decreased alpha chains, excess gamma or beta chains accumulate to form tetramers. (Hgb Bart = Gamma4, Hgb H = Beta4)
  • Without alpha chains, Hgb F in fetus & Hgb A1 in infant are both affected, so symptoms of (a-) thalassemias appear before birth and continue thereafter.
38
Q

Alpha-Thalassemias: 5 clinical syndromes.

A
  1. Hgb Bart or Hydrops Fetalis (- -/- -): alpha-thalassemia major or homozygous alpha thalassemia. No alpha globin produced, so Hgb Bart (gamma4) is primary hgb. It is nonfunctional, so condition is lethal. Infants are grossly edematous due to onset of congestive heart failure early in gestation and are commonly born stillborn (fetus survives until 3rd trimester due to hgb Portland, but then dies of anoxia). Disease may trigger toxemia in mom during pregnancy & postpartum hemorrhage later.
  2. Hgb H Disease (- -/- a): hgb H = beta4. Caused by deletion of 3/4 hgb chains. Occurs after beta-gamma switch as hgb H replases hgb Bart.
    Huge decrease in alpha chain synthesis means RBC makes mostly B4 tetramers, which also has increased O2 affinity (10x hgb A). Symptomatic, but not fatal. Lifelong mild to moderate anemia (due to instability of Hgb H & instability of bone marrow to compensate.
  3. Hgb H - Constant Spring Disease (- -/a^CS a): also classed as hemoglobinopathy because it is also an elongated hgb, due to alpha chain mutation. This disease is 1 normal & 1 mutated alpha gene on 1 chromosome 16, and 2 deleted genes on the other chromosome 16. So there are 2 normal beta chains, 1 normal alpha chain, & 1 abnormal alpha chain with 31 extra amino acids.
  4. Alpha-thalassemia minor (- -/aa or - a/- a) or a-thal trait: caused by 2 normal and 2 abnormal genes. No real clinical disease.
  5. Alpha-Thalassemia Silent Carrier (- a/a a): caused by only 1 deletion. 30% prevalence in African Americans.
39
Q

Alpha-Thalassemias: Electrophoresis results

A
  1. Hgb Bart (- -/- -): Alkaline Hgb electrophoresis shows 80% hgb Bart, 20% hgb Portland (little or or no hgb H & no hgb A1). Peripheral blood smear loaded with nRBCs. Mostly found in Southeast Asians (especially Filipinos).
  2. Hgb H Disease (- -/- a): electrophoresis shows Hgb H, decreased Hgb A1 & A2, and normal Hgb F. Peripheral blood smear (brilliant cresyl blue stain) shows target cells and micro, hypo. Treatments include transfusion therapy and splenectomy.
  3. Hgb H - Constant Spring Disease (- -/a^CS a): alkaline electrophoresis shows Hgb H, A1, A2, and 1-3% Hgb constant spring. Peripheral blood shows target cells and micro, hypo. Lack of treatment and prognosis is same as Hgb H disease.
  4. Alpha-Thalassemia minor (- -/aa or - a/- a) or alpha-thal trait: alkaline electrophoresis is virtually normal. Very few Hgb H inclusions. Decreased MCV & MCH. Peripheral blood shows poikilocytosis with target cells. No real clinical disease.
  5. Alpha-Thalassemia Silent Carrier (- a/aa): alkaline electrophoresis is normal, thus condition is benign. Slightly decreased or normal MCV & MCH.
40
Q

Classification & Intro to Beta-Thalassemias.

A
  • 1 locus on chromosome 11 = 2 beta genes.
  • Without beta chains, excess alpha chains will accumulate. However, they are too unstable to stay as tetramers, so they precipitate instead and cause plasma membrane damage. Causes hemolytic anemia.
  • B^0 = no beta chain production, thus no Hgb A1 (similar in severity to SCD).
  • B^+ = reduced beta chain production, decreased Hgb A1, with variable severity.
41
Q

Lab results of all Beta-Thalassemias.

A
  • Increased RBC count
  • Decreased MCV & MCH
  • Normal or slightly decreased MCHC
  • Increased Hgb F
42
Q

Beta-Thalassemia: 4 Clinical Syndromes.

A
  1. Beta-thalassemia Major (Cooley’s Anemia): severe anemia. Symptoms appear in first 2 years of life with failure to thrive and skeletal abnormalities due to massive bone marrow expansion.
  2. Beta-thalassemia Intermedia: moderate anemia, but normal growth in children.
  3. Beta-thalassemia Minor: 1 normal beta gene. Mild or no anemia.
  4. Beta-thalassemia Silent Carrier: genotype B^SC/B. No anemia & no treatment.
43
Q

Beta-thalassemias: electrophoresis results.

A
  1. Beta-thalassemia Major: alkaline electrophoresis = increased Hgb F, slight increase Hgb A2, and absent Hgb A. Increased RBCs with decreased MCV & MCH. Peripheral blood = basophilic stippling, targets, teardrops, nRBCs. Treat with regular transfusions, Fe chelation therapy, and maybe bone marrow transplant.
  2. Beta-thalassemia Intermedia: alkaline electrophoresis = increased Hgb F, decreased Hgb A. Increased RBCs, decreased MCV & MCH. Peripheral smear = some basophilic stippling & nRBCS, moderate targets. Treat with supportive care as needed. Few transfusions when needed.
  3. Beta-thalassemia Minor: increased RBCs, decreased MCV & MCH. Peripheral blood = slight basophilic stippling & few targets. Commonly confused with IDA, however RBC count is > than you would expect for degree of micro, hypo.
  4. Beta-thalassemia Silent Carrier: no anemia and no treatment. Very slight peripheral smear changes.
44
Q

Differentiation between IDA and Beta-thalassemia minor.
RBC count -
FEP/ZPP -
RDW -
Ferritin -
Serum Fe -
TIBC -
%Tf Sat. -

A

Iron Deficiency Anemia:
RBC count - < 5.5
FEP/ZPP - increased
RDW - increased
Ferritin - decreased
Serum Fe - decreased
TIBC - increased
%Tf Sat. - decreased

Beta-thalassemia minor:
RBC count - > 5.5
FEP/ZPP - normal
RDW - normal to slightly increased
Ferritin - normal to slightly increased
Serum Fe - normal
TIBC - normal
%Tf Sat. - normal

45
Q

Beta-thalassemia Hgb comparison.

A

Minor:
Hgb A - 80-95%
Hgb A2 - 3.5-7.5%
Hgb F - 1-5%

Intermedia:
Hgb A - 0-30%
Hgb A2 - 3.5-5.5%
Hgb F - 20-70%

Major:
Hgb A - 0%
Hgb A2 - 3.5-5.5%
Hgb F - 90-96%

46
Q

What are some rare thalassemia possibilities?

A
  1. Hgb S-Thal Disease: genotypes S/B-thal or S/a-thal are double heterozygotes (a hemoglobinopathy and thalassemia in one).
    Hgb S/B^0 thal = like Hgb SS.
    Hgb S/B^+ thal = like Hgb AS.
    Similar treatments as well.
  2. Delta/Beta Thalassemia: caused by decreased or absent [dB]. Both chains have thalassemia. Abnormal RBC morphology (micro, hypo) & variable anemia (mild-moderate).
    Alk electrophoresis = increased hgb F, decreased hgb A1, and variable A2.
  3. Hgb Lepore (dB^lepore/dB^lepore): alpha chain is ok, but beta chain is a delta-beta fusion caused by unequal crossovers. Both a hemoglobinopathy and a thalassemia.
    Stable, has normal function except for slightly increased O2 affinity (shift to left).
    Severity depends upon whether other mutations are present in dB chains.
  4. Hereditary Persistance of Fetal Hgb (HPFH): increased F in adults, but without clinical/hematologic features of a thalassemia (even through it is a thalassemia).
    Caused by deletion/inactivation of dB gene complex, resulting in persistence of gamma chains.
    Less symptomatic than dB-thal.
    No significant clinical abnormalities.
    2 subpopulations: homozygous (100% Hgb F with slight micro, hypo cells) & heterozygous (much less Hgb F (15-35%) and near normal lab results).
47
Q

Laboratory Tests used in Diagnosing Thalassemias.

A
  1. Hgb Electrophoresis - at alkaline & acid pHs.
  2. Hgb F Quantitation - alkaline denaturation tube test (accurate and precise).
    - Principle = since Hgb F resists denaturation, it stays soluble, can be filtered out of the remaining supernatant & then measured.
    • Add strong alkali to blood sample to denature Hgbs. Incubate.
    • Add saturated ammonium sulfate (NH4+)2SO4 to precipitate all denatured Hgb.
    • Expressed as % of alkaline-resistant Hgb.
  3. Hgb A2 Quantitation - ion exchange microcolumn chromatography.
  4. Brilliant Cresyl Blue Stain - for Hgb H inclusions (blueish-green).
  5. Acid Elution Test (Kleihauer-Betke (K-B) Slide Test)- for Hgb F. KB can be used to distinguish HPFH from a thalassemia with increased Hgb F.
    - Principle = at pH 3.5, all Hgbs will elute from RBCs except for Hgb F. Peripheral blood smear is immersed in acidic buffer, then stained. All other hgbs elute from RBCs & thus don’t pick up the stain. Hgb F containing cells will stain, white RBCs with eluted hgb appear as “ghosts.”
    (Also used by blood bank to determine extent of Fetal Maternal Hemorrhage [FMH], for use in calculating Rhogam dosages.)
    • HPFH has pancellular increase in Hgb F (all cells dark, in uniform pattern).
    • Thalassemias have heterocellular increase in Hgb F (non-uniform staining, with variable intensity).
  6. FEP/ZPP levels - normal in thalassemias, but increased in IDA.
  7. Genotype analysis - using PCR & gene sequencing.
48
Q

What is hemoglobinopathy?

A
  • A disease state involving the Hgb molecule.
  • Due to genetic mutation in 1 or more genes that affect Hgb synthesis.
  • Mutation affects either the quality or quantity of Hgb synthesis.
    • Structural defects = qualitative
    • Thalassemias = quantitative
49
Q

Where are the globin genes?

A

There are 6 functional human globin genes located on 2 different chromosomes.
- Alpha & zeta are located on chromosome 16 and are alpha-like genes. (2 alpha & 1 zeta gene per chromosome).
- Beta, gamma, delta, and epsilon are located on chromosome 11 and are beta-like genes. (2 gamma & 1 beta, delta, and epsilon gene per chromosome).

50
Q

Characteristics of Hemoglobinopathies.

A
  • Inherited as codominant traits.
51
Q

Lab testing for Hemoglobinopathies.

A
  • Traditional Hematology: CBC and microscopic.
  • Hgb carries an electrical charge depending on the amino acid sequence of globin chains and the pH of the surrounding environment. Allows for Hgb electrophoresis testing using cellulose acetate (pH = 8.4) and citrate agar gel (pH = 6.2).
  • HPLC (high performance liquid chromatography).
  • PCR
52
Q

Types of Beta-Hemoglobinopathies.

A
  • Homozygous Beta-hemoglobinopathies: both beta genes are mutated, resulting in absence of Hgb A. (Hgb SS or Hgb CC).
  • Heterozygous Beta-hemoglobinopathies: only one gene is mutated, the other is normal. Attempt to minimize the impact of abnormal Hgb presents variant Hgb in lesser amounts than Hgb A. (Hgb AS or Hgb AC).
53
Q

Where and what is the mutation in Hgb S?

A

Point mutation at 6th amino acid in beta chain.
Valine substitutes for glutamic acid.

54
Q

Why is the heterozygous sickle cell trait (AS) useful?

A
  • Presence of just one sickle cell gene confers resistance to cerebral infection by Plasmodium falciparum (when a malaria infected RBC sickles, the parasite dies).
  • Common in African populations.
55
Q

Pathophysiology of SCD.

A
  • Deoxygenation in capillaries is normal process for all RBCs, causing Hgb to switch from relaxed to tense forms as it offloads O2.
  • When this occurs in SCD, Hgb S structure changes shape, bringing its hydrophobic, sticky, and mutated valines into contact. It results in polymerization of Hgb, locking up of spectrin’s flexibility, and bizarre deformation of the RBC.
  • Usually reversible sickling, but dependent on time, temperature, pH, and O2 tension.
  • Deformation damages K+ channels, so RBC loses K+, and dehydration results, leading to formation of intracellular crystals & further deformation. Hgb molecules can stack up like fire wood.
  • RBCs become more fragile & lyse more easily.
  • Sickle cells lead to increased blood viscosity and slow blood flow. Reduced blood flow prolongs exposure to hypoxic environment, and lower tissue pH decreases the oxygen affinity, which further promotes sickling.
  • Some RBCs sickle irreversibly, which are removed by spleen.
  • Reversible sickle cells are responsible for vaso-occlusive complications.
  • Chronic injury response means “sickle cell crisis.” Patients have increased #s circulating endothelial cells, which triggers the extrinsic coagulation pathway & promotes formation of microthrombi, which cause further necrosis.
56
Q

What causes Sickle cell Crisis?

A

Any situation that produces excessive deoxygenation of RBCs.
Hyperthermia & hypothermia
Dehydration
Infection
Violent exercise
Labor & delivery
High altitude transitions

57
Q

What are the types of Sickle cell crisis?

A
  1. Vaso-Occulusive or Pain Crisis: rigid, sickled cells increase blood viscosity & cause vascular occlusions & micro-thrombi (i.e. strokes), resulting in tissue necrosis.
    This type is the #1 cause of death in adult SS patients.
  2. Infectious Crisis: precipitated by infection (S. aureus, S. pneumoniae, H. flu).
    Primary cause of death in SCD children.
  3. Bone and Joint Crisis: pain occurs in bones and joints as sickled cells accumulate in bone shafts. The bone marrow actually infarcts.
  4. Splenic Sequestration Crisis: occurs when enough sickled cells are trapped in hypoxic, convoluted, splenic microcirculation. This becomes a vicious cycle as the spleen enlarges & then traps even more cells. Hypovolemic shock can ensue.
  5. Aplastic Crisis: decreased bone marrow hematopoiesis thought to be triggered by infection/fever. Common with parvovirus B19 infection. Results in temporarily (5-10 days) decreased RBC count, Hgb, Hct, & RPI.
58
Q

What is Dactylitis?

A

Due to painful extramedullary hematopoiesis. Usually first clinical finding in infants with severe SCD.
(Huge, swollen hands/fingers!!)

59
Q

Lab findings in peripheral blood smear for SCD crisis or SCD.

A
  • Normo, normo anemia (cells are normal when produced in bone marrow).
  • Moderate > marked Anisocytosis
  • Target cells & sickled cells
  • Polychromasia (due to reticulocytes)
  • Basophilic stippling
  • Increased RDW
  • Howell-Jolly & Pappenheimer bodies present (indicates overwhelmed or nonfunctional spleen).
  • Less present without crisis.
60
Q

Describe the Hemoglobin Solubility Test.

A
  • Hgb Solubility Test - most common screening test:
    > blood added to reducing agent sodium dithionite, and a lysing agent that releases the hgb from the RBCs.
    > Deoxygenated hgb S is insoluble and precipitates remain clear.
    > False positive results with hyperlipidemia.
    > False negative results with low Hct or RBC counts.
61
Q

Useful lab tests for SCD.

A
  1. Hgb Electrophoresis: alkaline. Shows 80-90% Hgb S. Remainder is F & A2.
  2. HPLC (high performance liquid chromatography): can quantify low amounts of A2 and F.
  3. DNA sequencing: definitive test.
62
Q

Treatments for SCD.

A
  1. Prevent crises by avoiding precipitating situations (get enough sleep, good nutrition, & adequate prenatal care).
  2. Hydroxyurea - for ages 3 & ^, anitineoplastic drug somehow induces increased Hgb F production, which reduces sickling & RBC stickiness.
    Since it decreases WBC count, it also inhibits overall inflammatory response. Side effect is macrocytosis.
  3. During crisis:
    > Keep patient hydrated
    > Provide pain relief with opiates
    > Exchange transfusions as needed can create chronic problems with Fe overload & alloimmunization since “average” SS patient with frequent cries receives 1 transfusion per month.
  4. Bone Marrow Transplant - only known cure (but requires HLA-matched sibling without SCD (although AS is okay), so only 200 patients world-wide have been treated this way so far).
  5. Gene therapy - predicted useable in 10-20 years (already cured SCD in mice).
  6. New anti-sickling Agents - NAC (N-acetylcysteine) - strong reducing agent, still in clinical trials. Sickled cells produce increased fee radicals, but have less GSH to mop them up. NAC actually reverses irreversibly sickled cells in vitro.
  7. Prophylactic Penicillin - begins at 3 months of age, dramatically reduces infectious crises, morbidity, and mortality in children.
  8. Pneumococcal Vaccine in Children - disease was a major cause of death.
  9. Stem cell transplants from cord blood - requires huge donor bank.
63
Q

Prognosis in SCD.

A

With treatment, lifespan 45-50 years.

64
Q

Characteristics of Sickle Cell Trait (AS).

A
  • Caused by heterozygous AS.
  • Hgb A compensates for presence of abnormal S, so these patients usually have no symptoms.
  • On rare occasion can have crises in states of extreme tissue hypoxia (severe hypothermia, acute respiratory infections, and pulmonary embolisms (PEs)).
65
Q

Lab findings in Sickle Cell Trait.

A
  • RBC morphology mostly normal except for a few targets & very rare sickled cells (even when not in crisis).
  • Positive solubility test.
  • 30-45% Hgb S on Hgb electrophoresis (~60% hgb A).
66
Q

Treatment and prognosis of Sickle Cell Trait (AS).

A
  • Usually no treatment.
  • Typically have normal life span & quality of life.
  • Have increased resistance to malaria.
67
Q

Characteristics of Hemoglobin C Disease (CC).

A
  • Amino acid point substitution of lysine for glutamic acid at 6th position beta chain position.
  • 2nd most common Hgb variant after Hgb S.
  • Milder than Hgb S.
  • Particularly common in black populations.
  • Hgb C polymerizes under low O2 tension, but the structure of the polymers differs from Hgb S.
    > Hgb S polymers are long and thing, and Hgb C polymers form a short, thick crystal within the RBC.
    > Hgb C crystals do not change the shape of RBC.
    > Vaso-occlusion does not occur.
  • These crystals are removed by spleen, but if the spleen is nonfunctional, crystals will appear in peripheral blood RBCs.
  • Patients may exhibit splenomegaly & abdomial pain, but usually no other clinical symptoms.
  • No treatment required.
68
Q

Lab findings in CC disease.

A
  • Mild to moderate normo, normo anemia.
  • Some microcytosis and mild hypochromia.
  • Variable target cells, few spherocytes.
  • No symptoms or anemia.
  • 40% target cells
  • % Hgb A > % Hgb C
  • Increased retic count (4-8%).
  • Decreased RBC survival (due to spleen removal).
  • Hgb C crystals in peripheral blood (shaped like thick or elongated hexagons) - may appear free with no evidence of cell membrane.
  • Negative hemoglobin solubility test.
  • Definitive diagnosis made with electrophoresis.
  • With Hgb CC, cellulose acetate electrophoresis shows no Hgb A & shows Hgb C (co-migrating with A2, E , and O).
  • With Hgb AC, electrophoresis shows 60% Hgb A, and 30% Hgb C.
  • C will migrate as separate band on citrate agar at an acid pH.
69
Q

Characteristics of Hgb SC Disease.

A
  • The most common double heterozygous syndrome resulting in a structural defect of the Hgb molecule.
    > Involves 2 different amino acid substitutions on each of the 2 beta globin chains.
  • Milder clinical symptoms than SCD. Less frequent and less disabling vaso-occlusive complications.
  • Normo, normo anemia.
  • Many target cells & folded or “pocketbook” cells.
70
Q

Test results, treatment, and lifespan of SC disease.

A
  • SC crystals have fingerlike projections, producing “Washington monument” or “mitten cells.”
  • Positive solubility test results.
  • On cellulose acetate electrophoresis, Hgb C & Hgb S in equal amounts.
  • When crises occur, supportive therapy same as for SS patients.
  • Relatively normal life span (60-70 years), but can have diminished quality of life (retinal lesions).
71
Q

Characteristics of Hgb E.

A
  • 3rd most common Hgb variant
  • Southeast Asian populations (13%).
  • Laos, Cambodia, Thailand.
  • Substitution of lysine for glutamic acid in 26th position.
  • Homozygous state (>90% Hgb E) presents as a micro, normo anemia with many target cells.
  • Hgb AE trait state exists.
  • Can occur in combination with beta-thalassemia.
72
Q

Characteristics of Hgb D & Hgb G.

A
  • Group of variants that migrate in an alkaline pH at the same electrophoretic position of Hgb S (due to their charge).
  • Mild, hemolytic anemia (like CC & AC).
  • Negative solubility test, no sickling.
  • Cellulose acetate electrophoresis shows 95% Hgb D, which migrates to same position as S.
  • On citrate agar, Hgb D co-migrates with Hgb A1 & A2.
  • HPLC (high performance liquid chromatography) for confirmation.
  • Patients clinically normal, but may have some splenomegaly.
73
Q

Characteristics of Hgb O (arab)

A
  • Common in Arabic populations.
  • Mild hemolytic anemia with many target cells.
  • Needs to be differentiated from Hgb C by electrophoresis.
  • Glutamic acid replaced by lysine in 121st amino acid of beta chain (same as Hgb C, but with different substitution point).
74
Q

Characteristics of unstable Hgb.

A
  • Involves amino acid substitutions that disrupt physical contact between heme & globin.
  • Result is Hgb denaturation, then precipitation of globin chains, leading to formation of Heinz bodies.
  • Predisposes RBCs to develop hemolytic anemia.
75
Q

What are Heinz bodies?

A

Denatured hemoglobin.

76
Q

Symptoms of unstable Hgb.

A
  • Mild to severe, with episodes of hemolysis & subsequent jaundice.
  • Most common = Hgb Koln (old name: congenital Heinz body hemolytic anemia).
  • All patients are heterozygous.
77
Q

Lab findings in unstable Hgbs.

A
  • Decreased MCV, MCH, & MCHC (due to Hgb lost when Heinz bodies removed by spleen).
  • Anisocytosis, poikilocytosis, polychromasia, basophilic stippling, and “bite cells.”
78
Q

What are the Hgbs with altered O2 affinity?
Pathophysiology?

A
  1. Hgb Chesapeake: increased O2 affinity = shift to left. (alpha chain variant).
  2. Hgb Kansas: decreased O2 affinity = shift to right.
  • substitution mutations are such that they:
78
Q

What are the Hgbs with altered O2 affinity?
Pathophysiology?

A
  1. Hgb Chesapeake: increased O2 affinity = shift to left. (alpha chain variant).
  2. Hgb Kansas: decreased O2 affinity = shift to right.
  • substitution mutations are such that they:
    > Disrupt 2,3 DPG binding sites
    > Disrupt binding of heme to globin
    > Stabilize iron in oxidized Fe3+ state
    > All of these will cause either an increase or decrease in delivery of O2.
79
Q

What causes MetHgb?
Facts about it?

A
  • Inherited MetHgb reductase deficiency.
  • Toxin exposure in newborns - overwhelms GSH’s reducing ability.
  • Inherited cytochrome deficiencies - interferes with NADH regeneration via electron transport chain.
  • Genetic mutation in globin chain sequence (only one called Hgb M).
  • 5 genetic variants known (can affect alpha or beta chain).
  • Most common in Japanese populations.
  • Amino acid substitution prevents Fe3+ reduction, so Fe remains in ferric state.
  • This is a type of auto-oxidation, which denatures globin chains, triggers Hgb precipitation, and forms hemolytic anemia.
80
Q

Characteristics of Hgb M.

A
  • Only heterozygous (20-35% Hgb M). Homozygous condition is not consistent with life.
  • Brownish blood due to chronic cyanosis (which appears cutaneously as a lavender-blue, rather than normal blue-gray seen in ordinary cyanosis).
  • No treatment available.
  • Compensatory Erythrocytosis develops to compensate for chronically low O2 delivery.
81
Q

What is the principle of the Kleihauer Betke test?

A
  • Acid elution cytochemical method used to quantitate feto-maternal hemorrhage.
  • Identifies cells containing Hgb F based on the fact that they resist acid-elution to a greater extent than normal cells.
  • Can also be used when persistence of hgb F is suspected such as hereditary persistence of hgb F in sickle cell anemia, acquired aplastic anemia, thalassemia, and other hemoglobinopathies.

Fetal cell % = (# fetal cells * 100%) / total # RBCs counted

82
Q

Describe the process behind erythropoietin production.

A
  • Receptors in kidney are sensitive to changes in O2 tension/concentration.
  • Decrease in O2 tension = more EPO made by kidney & released into bloodstream to stimulate bone marrow normoblasts.
  • Bone marrow then allows for the early release of reticulocytes, increases number of mature erythrocytes, and increases the rate of maturation of erythroid precursors, so there’s accelerated release effect into peripheral blood.
  • EPO can cause increased retic count & increased RPI (retic production index).
  • Normal bone marrow response can increase erythropoiesis 6-8 fold, but takes a full week for complete response to occur.
83
Q

How are red cell disorders classified?

A
  1. Erythrocytosis - erythrocytosis & polycythemias are disorders that present with an increase in circulating RBC (increased Hct).
  2. Anemias - disorders that present with decrease in circulating RBCs (decreased Hct).
84
Q

Relative vs absolute anemia.

A

Relative: apparent decrease in RBC mass, but there is no true hemolytic disorder (caused by fluid shifts in pregnancy & IVs).
Absolute: true decrease in RBC mass resulting from impaired RBC production, blood loss, or accelerated RBC destruction or hemolysis.

85
Q

Laboratory tests for anemia?

A

CBC
◦ Hemoglobin
◦ Hematocrit - packed red cell
volume
◦ MCV - mean cell volume
◦ MCH - mean cell hgb
◦ MCHC - mean cell hgb
concentration
◦ RDW - red cell distribution width

Reticulocyte Count
Schilling’s Test – tests for B12 in urine
TIBC – total iron binding capacity
Serum Ferritin – primary form of iron
storage
Serum Iron – amt of iron bound to
transferrin
Transferrin – transports iron

86
Q

Laboratory diagnosis of anemia requires?

A

 CBC results
 Retic count
 Peripheral Blood Smear Evaluation (Differential)
 Assessment of RBC morphology
 Bone Marrow Evaluation
 Other lab tests

87
Q

How can different types of anemia be classified?

A
  • Reticulocyte count divides the anemia into 2 groups:
    ◦High result means there’s shortened RBC survival
    ◦Low result means there’s decreased production of RBCs
  • The anemia can then be divided into further subgroups based upon MCV, MCH, and MCHC values
    ◦Microcytic, macrocytic, normochromic, normocytic, and hypochromic

Can be classified on the basis of their physiological
cause
◦Heme and globin disorder
◦DNA disorder
◦Bone marrow failure
◦RBC survival disorders

Can also be classified according to their common RBC
morphology
◦Macrocytic
◦Microcytic
◦Normocytic

88
Q

Differentiate between effective, ineffective, and insufficient erythropoiesis.

A

Effective: bone marrow is able to produce functional RBCs that replace the daily loss of RBCs.

Ineffective: bone marrow produces erythroid precursor cells that are defective.

Insufficient: decrease in erythroid precursors in bone marrow, resulting in decreased RBC production and anemia.

Medical Laboratory Science (13 decks)

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