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RBC development/Anemias
day 1
88
Biology
12/17/2012

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Term
How do the sites of erythrogenesis change during development?
Definition
1) Yolk Sac
- Following fertilization blood cells originate here

2) Liver and spleen are sites of production early in utero

3) Bones- children

4) Axial skeleton and proximal extremities- Adults
Term
What does "Myeloid metaplasia" mean in the clinical context of hepatosplenomegaly?
Definition
Myelofibrosis- A myeloproliferative syndrome where bone marrow fibroblasts proliferate and shift RBC production back to extramedullary spaces
Term
Describe the role of the stem-cell "micro-enviornment" in hematopoiesis.
Definition
**Aplastic anemia occurs with pancytopenia due to micro-enviornment/HSC damage- treated by transplant or T cell inhibition **

1) HSC “home” to marrow

2) Bind to adhesion molecules expressed on accessory cells

3) Are stimulated to proliferate by growth factors on glycocalyx
Term
What are the 2 major types of Erythroid Progenitors?
Definition
Characterized "in vitro"

1) Burst Forming Unit (BFU)
- high proliferative rate; insensitive to erythropoietin (Epo)
- Epo is a "late, lineage-specific transcription factor"

2) Colony Forming Unit (CFU)
- lower proliferative rate; sensitive to Epo
Term
What is Epo and how is it regulated?
Definition
1) Oxygen-sensitive protein produced by peritubular interstitial cells within kidney (90% production) and liver (10% production)

2) When oxygen is low, Epo both increases proliferation of RBC development and accelerates maturation
- Begins with CFU-E/pronormoblast progenitor, which generates 16 RBC (7-8d)
Term
What are the basic changes that occur to CFU-E/pronormoblast progenitors as they mature into erythrocytes?
Definition
1) Cell and nucleus size shrink

2) Hemoglobin content increases

3) Nucleus is extruded to produce reticulocyte

4) Reticulocytes remain within marrow 2-3 days to mature
Term
How is Hemoglobin synthesized?
Definition
1) HEME (cytosol and mitochondria)
- Iron is transported to developing RBC by transferrin (Tf), where it binds Tf receptors and is internalized

- Iron is incorporated within heme ring (ferrochelatase) or stored as ferritin

**Sideroblastic anemia occurs when iron cannot be incorporated into Heme, and mitochondria are laden with the metal- treat with Pyridoxone**

2) Globin (cytosol)
- Two alpha globin loci on each chromosome 16 are used
- Non-alpha globin loci on chromosome 11 are used
- Globin chains are paired
a2g2 – Hb F (fetal)
a2b2 – Hb A (adult)
a2d2 – Hb A2 (minor adult)

3) Globin chains are paired (via H+ bonds or 2,3-BPG) with incorporated Heme (uneven production can produce Thalasemia)
Term
Which of the following does NOT affect oxygen binding affinity for Hemoglobin?

1. pH
2. CO2 content
3. Temperature
4. N2 content
5. 2,3 BPG
Definition
4

Right shift decreases affinity
Left shift increases affinity

1,2. Acidosis (low pH or high CO2 content) facilitates unloading
** chronic acidosis leads to decreases in 2,3, BPG to compensate

3. Higher temperatures facilitates unloading

5. 2,3 BPG increases unloading.
Term
Why might a patient with COPD have low 2,3 BPG levels?
Definition
Compensation for chronic acidosis, which has increased O2 un-loading.

Low 2,3 BPG will shift O2 saturation curve to left, increasing affinity
Term
Why do patients with beta-thalasemia have "expanded" bone marrow?
Definition
1) Defective beta-globin leads to shift from Hb-A to Hb-F, which has a high affinity for Oxygen.

2) To increase O2 delivery to tissues, Epo is upregulated, leading to increased production and maturation of RBCs.
Term
What are the major components of the RBC membrane?
Definition
1) Integral membrane proteins
- band 3; glycophorins

2) Cytoskeletal proteins
- actin; spectrin

3) Linker proteins
- ankyrin; protein 4.1
Term
Why might a patient with early-onset gallstones have an abnormal "osmotic fragility" screening test?
Definition
1) Hereditary elliptocytosis or spherocytosis (abnormal RBC membrane structure) leads to compensated hemolytic anemias

2) Spleen is site of RBC destruction, and they drain to portal circulation which gets to the liver and gallbladder.
Term
Explain the basics of RBC metabolism
Definition
1) Relies on glycolysis for production of NADPH (pentose phosphate) and 2,3 BPG (Luebering-Rapoport Pathway)

2) Glutathione production (requires NADPH from G6P) protects RBCs from oxidation

**In G6P deficiency, oxidation damage precipitates globulin (Bite salts), which is removed by spleen/liver macrophages**
Term
What are the major elements of a CBC?
Definition
1) Measured values
- Red cell number (~5 X 106/mm3)
- Hemoglobin (g/dL) **
- Mean cell volume (MCV) **

2) Values calculated
- Hematocrit
- Mean corpuscular hemoglobin (MCH)
- Mean corpuscular hemoglobin concentration (MCHC)
- ***Red cell distribution width (RDW) (high RDW means Anisocytosis)
Term
When might you clinically see elevated RDW with a normal MCV?
Definition
Increased RDW means Anisocytosis, so you may have both small (Fe deficient) and large (folate deficient/B12) MCV components, which average out to a normal MCV.
Term
What are the MOST common etiologies of anemia?
Definition
- Majority due to inappropriately low reticulocyte response to the degree of anemia present

1) Chronic inflammation
- Inflammatory cytokines suppress erythropoiesis (IL6 and hepcidin)
- Induce state of relative resistance to Epo
- Decreased iron re-utilization

**chronically may see normal-high iron storage (ferritin) with low transport (Transferrin)

2) Iron deficiency account
Term
What features define a macrocytic anemia?
Definition
Below normal Hgb/Hct levels with larger than normal RBCs measured by MCV

1) Megaloblastic (DNA damage)
- Vitamin B12 (Cobalamin) deficiency
- Folate deficiency
- Myelodysplastic syndrome
- drug induced.

2) Non-Megaloblastic
- Liver disease
- Thyroid disease,
- anemias with reticulocytosis (Hemolytic)
Term
In what type of anemia do you see "nuclear-cytoplasmic dyssynchrony" and what does it mean?
Definition
Megaloblastic macrocytic anemias (B12, folate, drugs, Myelodysplastic) where DNA synthesis is altered.

1) Cells are in S-phase arrest, vainly trying to double their own DNA

2) Cytoplasmic growth occurs as normal, but nucleus remains immature and proper mitosis cannot occur.
Term
Which of the following regarding cobalamin is false?

1. Takes 3-4 years to deplete cobalamin stores completely

2. Obtained only in the diet through animal material

3. Deficiency produces non-megaloblastic macrocytic anemia

4. Preferentially binds IF over R-protein (haptocorrin) in the duodenum

5. Binds methymalonyl-CoA-mutase and methionine synthase inside cytoplasm of target cells
Definition
3- Produces megaloblastic macrocytic anemia with nuclear-cytoplasm desynchrony.

- B12 is degraded slowly and must be obtained in the diet. In the stomach (acid pH), B12 is degraded by pepsin and preferentially binds R-protein (haptocorrin from salivary glands). Once delivered to the duodenum, R-protein is degraded by alkaline pH and B12 binds IF, which takes it to the terminal illeum, where the IF-B12 complex binds to receptors.

- In the illeum, B12 is transfered to TCII, and carried via Portal circulation to bind to and become internalized by other tissues (significant amounts in the liver).

- Following receptor mediated endocytosis, TCII is broken down by lysosomes and B12 is bound by methymalonyl-CoA-mutase and methionine synthase (forms methionine from homocysteine).

**Functions with folate**
Term
Which of the following would not produce a significant B12 deficiency?

1. Autoimmune attack of intrinsic factor in the duodenum
2. Low gastric acid
3. Hypothyroidism
4. Vegan diet
Definition
3. Thyroid disease is associated with non-megaloblastic, macrocytic anemias, NOT with B12 deficiency (magaloblastic form).

1. Produces pernicious anemia (MOST COMMON) because B12 cannot be reabosrbed in illeum

2. Patients on PPi's chronically may not have low enough pH for R-protein to bind B12 or for pepsin to degrade dietary B12

4. Low dietary intake of B12
Term
Patient presents complaining of muscular weakness, tingling sensations on his trunk and extremeties and difficulty with balance.

Labs:
- low reticulocyte count,
- elevated LDH
- elevated bilirubin
- low haptoglobin.

You get a peripheral blood smear: what do you see?
Definition
Severe combined degeneration of spinal chord due to Cobalamine deficiency (Megaloblastic, macrocytic anemia)

1) macroovalocytes, hypersegmented polymorphonuclear leukocytes (PMN), giant bands, and giant platelets

**severe pancytopenia in the setting of a hypercellular marrow.

Term
How can you distinguish between macrocytic anemias produced by folate and B12 deficiencies?
Definition
Homocysteine and methylmalonic acid levels.

1) B12
- Elevation of both homocysteine and methylmalonic acid

2) Folic acid
- Elevation of homocysteine with a normal methylmalonic acid
Term
Based on a patients presentation, you suspect the presence of a macrocytic anemia.

Describe your workup.
Definition
1) CBC
- MCV, reticulocyte count and peripheral blood smear

2) If macrocytic/megaloblastic changes are noted, order B12/folate levels

- If "borderline," check a homocysteine and methymalonic acid (MMA) level

**elevated homocysteine and MMA= B12**
** Just homocysteine= folic acid**

3) If vitamin levels are normal, perform bone marrow aspiration biopsy (myelodysplastic changes)

- If no evidence, check reticulocyte (elevated in hemolytic process)

4) If Hemolytic anemia suspected, measure LDH (elevated), bilirubin (elevated) and haptoglobin (decreased)

5) If Not HA, then liver disease and hypothyroidism as causes of macrocytosis should be considered
Term
What should be on your ddx if the following blood work results were obtained.

- Low Hct with High MCV,
- Hypersegmented polymorphonuclear leukocytes (PMN), giant bands, and giant platelets on peripheral blood smear
- Normal MMA and homocysteine levels
Definition
1) Megaloblastic macrocytic anemia not due to folate/B12.
- Myelodysplastic syndrome or Drug-induced
- Get bone marrow biopsy and check reticulocyte count to look for hemolytic changes (increased)
Term
What are the 2 major functions of B12?
Definition
1) Participates in the generation of methionine from homocysteine

2) Participates in the generation of succinyl Co A from methyl malonyl Co A

Both substrates elevated in deficiency
Term
What is the basic "laboratory" picture of a Megaloblastic anemia?
Definition
1) CBC

↓ Hb, plt, neutrophils (pancytopenia)
↑ RDW
↑ MCV
[Caution: MCV may be low or nl in the presence of thalassemia trait]

2) Ineffective erythropoiesis
↑ or high nl LDH, AST, indirect bilirubin
↓ haptoglobin
retics not increased

3) Iron measures
↑ ferritin, iron, Tf sat
Term
Which drugs should be suspected as the causative agents of a folate acid deficiency producting megaloblastic, macrocytic anemia?
Definition
1) Inhibitors of dihydrofolate reductase (regeneration of active tetrahydrofolate)
- methotrexate
- trimethoprim, pyrimethamine
- sulfasalazine, sulfamethoxazole

2) Alcohol
3) Phenytoin
- Blocks absorption; increases utilization
Term
What should be done in a patient with unexplained hematological and neurological symptoms, but with normal Hbg/Hct levels on CBC?
Definition
1) Workup for Cbl deficiency even if:
- anemia not present
- MCV not ↑‘d
- serum Cbl only borderline low

2) Serum MMA & Hcys useful ancillary tests
Term
True or False:

Microcytic anemias are due to diminished nuclear maturation, resulting in generation of smaller erythrocytes.
Definition
FALSE- abnormal Hb production with MCV <80 fL

MAcrocytic (MCV > 100 fL) is issue with nuclear maturation (megaloblastic involves DNA damage)
Term
Why is iron load higher in normal males than females?
Definition
Higher red blood cell mass in males and greater losses in females (menstruation).

Men have 50 mg/kg (but absorb 6%)
Women have 35 mg/kg (absorb 12%)
Term
How is Iron normally metabolized/absorbed?
Definition
1) Consumed in diet from animal protein and reduced to Fe2+ form in stomach (Ferrireductase of brush border)

2) Fe2+ crosses proximal intestinal membrane via DMT-1 and is transported in blood bound to Transferrin

**Men absorb 6%, while females absorb 12%**

3) Transferrin with 2 bound Fe2+ molecules bind cells with TfR, and is stored in hepatocytes (Ferritin) and macrophages (liver, spleen, marrow)
Term
27 year old woman presents complaining of difficulty swallowing and a desire to eat clay.

On PE, they exhibit rapid breathing, heart rate and pallor.

You notice angular fissures at the corners of their mouth and their fingernails look like 'spoons'

What could be causing these symptoms?
Definition
Sounds like this patient has Esophageal webs (Plummer-Vinson syndrome) and Pica, which are classically due to Iron deficiency (PE is clear anemia)

Key findings:
- Fissures= Cheilosis
- Nails= Koilonychia

1) Increased demand (pregancny, EPO therapy)
2) Loss (menses, blood donation, phlebotomy)
3) Intake/absorption/use (Malabsorption, diet, Inflammation)
Term
What are the classic laboratory findings associated with the microcytic anemia that presents with "spoon nails" and "angular fissures at the corner of the mouth"

How do you treat?
Definition
Koilonychia and Cheilosis are caused by iron deficiency anemia (IDA)

1) Labs
TIBC= elevated (transferrin binding capacity)
Serum iron= low (subject to diurnal rhythm)
Soluble TfR= high (shed receptor)
Ferretin= low
Bone marrow (prussian blue)= GOLD standard

2) Treat with oral iron for 3 months and continue until TIBC sat is 33% (below 7% causes IDA)
**may be given parenterally if gastric issues**
Term
What should you immediately think of if you notice an MCV of 64 with a hgb of 12 and 5 million RBC/ul in a patient with anemia?

What is the basic pathophysiology?
Definition
MCV is disproportionally low, relative to H/H and RBC count, which suggests microcytic anemia from Thalassemia (primary reduction in globin chain synthesis)

1) Excess of normally synthesized globin is insolbuble and binds RBC membrane leading to oxidation and intramedullary hemolysis (marrow)

2) EPO rises to compensate and marrow expands, producing boney abnormalities in children.

Term
What are the different types of genetic abnormalities associated with alpha-thalassemia?
Definition
Most prevalent genetic disorder of mankind!

**Gene deletion is most common (vs. mutation in 5' or 3' regulatory regions in mRNA splicing in beta thalassemia)**

1) Gene deletion (silent carrier)- seen in 25% of AA, clinically asymptomatic

2) Gene deletion (a-thalassemia trait)- mild decrase in MCV and anemia
- Can be cis or trans deletion on chromosome 16

3) Gene deltion [Hb H (4 beta chains)]
- Deletion of 3 of 4 alpha genes leads to production of Hb H, which is very unstable
- Severe anemia, jaundice and splenomegaly
- Common in SE asia
Term
What do each of the following mean?

1) HbA
2) HbA2
3) HbF
4) HbH
5) Bart Hb
6) B+
Definition
1) 2 alpha and 2 beta chains
2) 2 alpha and 2 delta chains (beta thalassemia)
3) 2 alpha and two gamma (beta thalassemia)
4) 4 beta chains (alpha thalassemia)
5) 4 gamma chains (alpha thalassemia)
6) Deficient Hb
Term
True or False:

Beta thalassemias are generally produced by mutations in regulatory regions of the 5'' or 3'' splice sites of beta globin mRNA sequences.
Definition
True

Alpha is due to gene deletions.

Diagnose by Hb electrohoresis
1) B0-thalassemia (major)
- one mutation from each parent, with NO HbA
- mostly see HbF, but also some HbA2
- after hemoglobin "switching" occurs, patients become severely anemia and develop hepatosplenomegaly and CHF

2) B+-thalassemia
- Decreased but present HbA (10-20%, vs. 80% HbF)
- Minor or moderate phenotype
Term
What are the 2 major types of beta thalassemia and how is it diagnosed?
Definition
Both produce microcytic anemias.

Diagnose by Hb electrohoresis (also used to rule out beta in favor of alpha)

1) B0-thalassemia (major)
- one mutation from each parent, with NO HbA
- mostly see HbF, but also some HbA2
- after hemoglobin "switching" occurs, patients become severely anemia and develop hepatosplenomegaly and CHF

2) B+-thalassemia
- Decreased but present HbA (10-20%, vs. 80% HbF)
- Minor or moderate phenotype
Term
What are the major causes of microcytic anemia?
Definition
MCV <80

1) Iron deficiency
2) Thalassemia
3) Chronic inflammation
4) Sideroblastic (myelodysplastic)- iron-laidened mitochondria that encircle RBC nuclei
5) Lead
Term
How can chronic inflammation produce anemia?
Definition
DECREASED TIBD of <300 (decreased transferrin production) distinguishes inflammatory cause for IDA (>360).

1) Decreased utilization of stored Fe produces microcytic (may be normocytic) anemia.

- "inflammatory block" on utilization of Fe from macrophages in liver, spleen and marrow (TNF-a and IL-1 suppress erythropoesis).

- Macrophages secrete compounds that compete for iron binding (lactoferrin)
Term
What is the role of Hepcidin in iron storage?
Definition
More Hepcidin means more storage

-Iron stores and Erythropoesis decrease Hepcidin
Inflammation increases Hepcidin

Hepcidin is produced by liver and induces internalization and degradation of ferroportin on basolateral surface of enterocytes in GI tract.

Ferroportin internalization leads to iron trapping and increased storage in liver.
Term
How can lead ingestion produce anemia?
Definition
Inhibition of ferrochelatase (insertion of iron into heme ring)

- Results in hemochromia and microcytosis (similar to IDA)
- "Basophilic strippling" of RBCs

**MUST document elevated blood level**
Term
How are RBC normally removed from circulation after they are >120d old?
Definition
1) Those aged RBCs that cannot protect themselves from oxidative stress are removed from circulation by tissue macrophages (reticulo-endothelial cells)

2) Reticulo-endothelial cell breaks down RBC to AA (from gobin), bilrubin (from heme ring) and CO

3) Bilirubin is sent to liver for conjugation and secretion into the bile. Iron is stored (2-4g) or transferred via transferrin (3mg)
Term
Under what conditions should hemolytic anemia be suspected?

Definition
See elevated indirect Hb and LDH and decreased haptoglobin (alpha2 globulin that binds Hb in free plasma)

1) Unexplained jaundice (unconjugated bilirubin)
2) Unexplained drop in [Hb]
3) Elevated reticulocyte count
Term
What can haptoglobin levels tell you about hematological disease etiology?
Definition
Acute phase protein that binds free Hb in plasma and prevents bacteria from accessing iron.

Decreased haptoglobin + elevated LDH (MOST SENSITIVE/SPECIFIC= Hemolytic anemia!

1) Decreased haptoglobin with elevated reticulocyte count suggests Hemolytic anemia

2) Normal haptoglobin with elevated reticulocyte count suggests RBC destruction outside blood, in liver or spleen (Drug-induced hemolysis or red cell dysplasia)

3) Decreased haptoglobin with normal reticulocyte count (no other signs of anemia) suggests liver disease, since it is produced by liver.

4) If both haptoglobin and reticulocyte count are normal, it is NOT hemolytic, and you should think aplastic anemia.
Term
Why might you see "shift cells" in a patient with elevated LDH levels and low haptoglobin levels?
Definition
Hemolytic anemia with increased reticulocyte count.

Epo influence increases proportion of immature RBCs in serum (i.e. "shift cells")
Term
What type of etiologies could produce the following:

Hemoglobinemia, Hemoglobinuria, Hemosidinuria and Methmalbuminemia
Definition
Intravascular hemolytic anemia

1) Transfusion reaction G6PD deficiency
2) PNH
3) Sepsis (C. perfringens, amlaria, bartonelosis)
4) Snake bite
5) Mechanical heart valve dysfunction.

- RBCS are destroyed in lumen; free Hb binds to haptoglobin (Hemoglobinemia), which is removed by liver.

- When liver is overwhelmed, Hb-haptoglobin spills into kidney, where it is reabsorbed in renal tubules (Hemoglobinuria and Hemosidinuria)

- If Haptoglobin is consumed, Hb will bind to albumin, forming Methmalbumienia.
Term
What are the major types/causes of extravascular hemolysis?
Definition
RBCs destroyed intracellularly by RES, with jaundice, splenomegaly and decreased [Hb]

1) Immune-mediated (cold or warm)
- Direct Coombs (wash RBCs with anti-IgG and complement and measure agglutination (does NOT predict severity)
- Indirect Coomb's (incubate RBCs with patient serum, add Coomb's reagant and grade agglutination)

2) Non immune-mediated
- DIC (consumption of fibrinogen and platelets with organ damage.
- TTP, HUS, vasculitis, Marathoner's
Term
What is the difference between the direct and indirect Coomb's tests and why are they used?
Definition
To look for immune-mediated hemolytic anemias (can be warm or cold)

IgG-mediated shows spherocytes


1) Direct
- incubate patient RBCs with coomb's reagent (anti-IgG and anti-C3b)
- can be positive in normal or negative in diseased
- Used for diagnosis, but NOT severity

2) Indirect
- Normal RBCs incubated with patient serum and coomb's reagent
- detects target protein in serum and used to predict reactions to transfusions
Term
What patients should be kept at body temperatures higher than their "thermal amplitude"?
Definition
Those with cold-reactive IgM immune-mediated hemolytic anemia (vs. warm IgG)

Above this temperature, RBC agglutination does not occur.
Term
What kind of anemia does TTP cause and how?
Definition
Non-immune hemolytic

Characterized by MAHA, thrombocytopenia, something renal, something CNS and fever (vs. HUS, which involves the first 3 and is self-limited)

1) Excess vWF stored within granules in platelets and endothelial cells promotes platelet adhesion and aggregation.

2) usually vWF is cleaved by serum protease, but without the protease or with antibody-inhibition of the protease, you get accumulation

3) Treat with plasmaphereesis with plasma infusion and steroids
Term
How can G6PD deficiency cause anemia?
Definition
Produces an intrinsic-type, non-immunologic, hemolytic anemia.

1) Low G6PD means that there is not enough NAPDH to produce adequate glutathione

2) Without glutathione, RBCs are not protected from oxidative stress in vessels, and hemolysis occurs with the production of "bite cells"

**Sometimes G6PD levels are normal during acute attacks, since new reticulocytes produce large mounts of the enzyme**
Term
What types of hemolytic anemias as due to issues intrinsic to the RBC membrane?
Definition
1) Metabolic defect
- G6PD deficiency

2) Hemoglobin disorders
- Thalassemias and sick cell disease
- SCD

3) RBC surface defects
- Hereditary spherocytosis/eliptocytosis
- Paroxysmal noctural hemoglobinuria (PNH)
Term
What are the clinical consequences of thalassemias?
Definition
Quantitative deficiency in alpha or beta globin producing hypochromia and microcytosis.

1) Beta Thalasemia major (HbF and a little HbA2)
- Extramedullary hematopoiesis in non-hematopoietic organs
- Chronic hemolysis and iron overload (endocrine organs)
- Splenomegaly
- Need bone marrow T/X

2) Alpha thalassemia (DNA deletions)
Term
Describe the pathogenesis of Sickle Cell Disease (SCD). How can it be treated?
Definition
Hemoglobinopathy that produces an intrinsic hemolytic anemia.

1) Homozygous HbS or coinheritance of HbS with other hemoglobin abnormalities alter the solubility of Hb and cause it to precipitate in its deoxygenated form, forming polymers.

- Chronic hemolysis and PAINFUL episodic vaso-occlusion (adhesion to post-cappillary venules)

- Splenic infarction in childhood leads to susceptibility to pneumococcal sepsis/90% (CN prophylaxis and vaccination)

- Watch out for "acute chest syndrome"/requires transfusion and Parvovirus B19 infection/aplastic crisis

2) Treat with Hydroxyurea (increase HbF levels) or Hematopoietic stem cell transplant
Term
What are the 2 major types of Congenital RBC surface defects that produce intrinsic hemolytic anemias?
Definition
1) Hereditary spherocytosis
- Spectrin deficiency leads to RBC membrane loss
- Confirmed by osmotic fragility in setting of suggestitve FM and clinical presentation
- Hemolysis can be treated by splenectomy

2) Hereditary elliptocytosis
- Abnormalities of proteins of RBC cytoskeleton
- Usually asymptomatic
Term
What is the basic pathogenesis/treatment of Paroxysmal nocturnal hemoglobinuria (PNH)?
Definition
1) PNH is acquired clonal disorder of HSCs derived from PIG-A mutations that encode enzyme involves in GPI biosynthesis.

- Lack of GPI-anchored proteins, CD59 and CD55, prevents protection from complement-mediated lysis

- Patient gets chronic hemolytic anemia, thrombosis and cytopenias.

2) Steroids, warfarin and eculizumab (anti-C5 antibody)
Term
True or False:

The site of normal hematopoiesis depends upon the age of the patient. Up to about 3 months after fertilization production occurs in the Liver and spleen; thereafter production switches gradually from the liver and spleen to the long bones
Definition
False!

The sites of normal hematopoiesis depends upon the age of the patient. Up to about 3 months after fertilization production occurs in the yolk sac; thereafter production switches gradually from the yolk sac to the liver and spleen (while in utero to 3 months of age), to the long bones (from 3 months of age to 30 years), and then to the axial an proximal skeleton. This is of practical importance. In adults bone marrow sampling is best performed from axial skeleton sites. If radiation therapy is delivered to the axial skeleton in older patients, a greater proportion of the bone marrow may be effected than when the same radiation port is used in younger patients
Term
True or False.

Proliferation of fibroblasts leads to excess blood cell production in the marrow and expansion of the bone marrow cavity resulting in intense pain and inability of the red cell precursors to develop normally and move from the marrow cavity into the peripheral blo
Definition
True:

Myelofibrosis is a disorder of the microenvironment of the bone marrow. Fibroblast proliferation and release of cytokines in the bone marrow causes blood production to shift to other extra-medullary (aka: myeloid metaplasia; outside of the marrow space) sites such as the spleen, liver, and lymph nodes. This process can be characterized by both splenic and hepatic enlargement. Common causes of extramedullary hematopoiesis includes infiltration of the marrow space with various kinds of hematologic and nonhematologic cancers, hepatocellular injury, chronic hemolysis, growth factor treatment, marrow regeneration after injury, autoimmune assaults, or for reasons unknown
Term
True or False:

Aplastic anemia is characterized by pancytopenia; may be the result of injury to the bone marrow microenvironment or to the HSC or as a result of immune dysregulation of HSC development.
Definition
True:

Present data indicates that all blood cells are likely derived from the same hematopoietic stem cell (HSC). The HSC diverges early in development into the GEMM (a precursor cell to granulocytes, rbcs, megakaryoctyes, and monocytes) and a lymphoid precursor cell. Hematopoiesis is hierarchical (eg. development progresses in a series of daughter cells of increasing maturity); clonal or polyclonal (the emergence of a predominance of a specific type of daughter cell), and deterministic or stochastic (a specific type of descendent cell predominates due to survival advantage or simply by chance).

Under ideal conditions the bone marrow microenvironment provides a favorable mileau for rbc development and survival. The HSC ‘home” to the bone marrow and bind to adhesion molecules expressed on specific accessory cells, and are subsequently stimulated to proliferate. Unfortunately some individuals have either damage to the bone marrow micro-environment (eg. chemical exposure), damaged or dysfunctional HSC, or abnormal immune regulation of HSC development which leads to aplastic anemia.
Term
True or False

Erythropoietin (Epo) is a 34 kd glycoprotein produced in the peritubular interstitial cells of the kidney (90%) and also to a small degree in the liver (10%). It is sensitive to the presence of oxygen in the blood. .
Definition
True:

Peritubular cells produce increasing amounts of Epo when they detect a decrease of oxygen in their vicinity (because of hypoxia, ischemia, hemoglobinopathies that do not normally release oxygen at the tissue level).

As a consequence to this, patients who have blood loss anemia or hemolysis may have marked increases in the amount of Epo detected in their serum. Patients who have a condition in which red cell production is not under the control of Epo (eg polycythemia vera) have low or undetectable levels of Epo. Paradoxically, patients who have secondary polycythemia (caused by pulmonary disease in which not enough oxygen gets to the Hb molecule), Epo levels are usually normal. This is because once compensation occurs (ie. the number red blood cells increases to a point that a sufficient concentration of oxygen is detected by the peritubular cells), Epo production decreases to within the expected range. Also, Epo is a product available commercially that can used to treat some kinds of anemia.
Term
True or False:

Sideroblastic anemia is a disorder caused by the excessive administration of iron supplements to a patient incorrectly thought to be iron deficient or the excessive delivery of packed red cell replacement (there is approximately 250mg of elemental iron in each unit of packed red cells transfused).
Definition
False!

Sideroblastic anemia is a disorder caused by the ineffective production of heme, results in the accumulation of iron-laden mitochondria. It is sometimes responsive to pyridoxine (a cofactor for the initial steps in heme synthesis), may be idiopathic, and may be commonly seen in patients with alcohol abuse.

This disease is characterized by >15% of normoblasts in the bone marrow having excessive iron deposits or iron located as a ring around the nucleus because the iron is retained in the mitochondrial. Keep in mind that normal heme synthesis depends upon the delivery of elemental iron via its transport protein ferritin to red cell precursors. The iron-transferrin complex is internalized in the precursor and the iron is either stored as ferritin or incorporated into the heme synthesis process.

Heme synthesis occurs in both the cytoplasm and mitochondria in a step wise fashion. Glycine and succinyl choline combine to form aminolevulinic acid (ALA) in the mitochondria. A series of reactions occur in the cytoplasm which converts ALA to porphobilinogen, uroporphorinogen, and coproporphrynogen which is converted to protophorphyrin. Within the mitochondria protophoryrin is converted to heme by the addition of elemental iron. It is the disruption of incorporation of elemental iron into the heme molecule that leads to sideroblastic changes
Term
Hb‘s ability to act as an oxygen transport is facilitated by the association of beta globin chains in the tetramer, the modulation of oxygen loading and unloading by 2,3 BPG (biphosphogluconate) and the pH. These relationships are reflected by the oxygen-Hemoglobin dissociation curve are often referred to as the Hb affinity for oxygen. The oxygen-Hb dissociation curve is derived from measuring the oxygen saturation of Hb relative to the partial pressure of oxygen (pO2). As the pO2 increases do also as does the O2 saturation. The curve takes on sigmoidal shape because accession of each oxygen molecule to heme facilitates the binding of others. Alteration in pH, CO2 content, temperature, Hb affinity, 2,3 BPG can affect binding and release of oxygen.

True or False. Increasing acidosis causes more oxygen to be retained by the hemoglobin molecule and as a consequence less oxygen is released to the tissues resulting in functional hypoxemia and tissue malfunction.
Definition
False.

The addition 2,3 BPG to the hemoglobin tetramer results in a restructuring of the relationship between the globin chains making it difficult for oxygen to reach heme. When 2,3 BPG is not associated with the hemoglobin molecule the globin chains assume a “relaxed” position to each other allowing oxygen to bind to heme. Acidosis shifts the curve to the right (decreased Hb affinity for oxygen) and alkalosis shifts the curve to the left (increased Hb affinity for oxygen). Chronic COPD may produce chronic respiratory acidosis and concurrently increased 2,3 BPG production. In this setting, the curve which is shifted to the right by acidosis is partially corrected by the addition of 2,3-BPG which counter-shifts the curve to the left.
Term
Reticulocytes provide an indication of effective erythropoiesis. Stored in the bone marrow, they are released into circulation where they complete maturation within 24 hours. Detection in the peripheral blood requires a special stain, although their presence can be inferred by the presence of ‘polychromatic red cells’ or “shift cells”. With bleeding or hemolysis, reticulocytes may be ‘shifted’ into the circulation due to stress. These ‘shift cells’ may require 2 days or more to mature. One way to categorize anemia is according to the accompanying reticulocyte response. A hyperproliferative anemia may have a high reticulocyte count or increased reticulocyte production index and a hypoproliferative anemia is characterized by an inadequate reticulocyte response and a lack of increase in the reticulocyte production. The absolute reticulocyte count can be determined by an automated cell counter and can be estimated clinician by taking into account the proportion of reticulocytes relative to the amount of RBCs in the peripheral blood.

True or False. The determination of the reticulocyte production index requires examination of the peripheral blood smear.
Definition
True:

One way to categorize anemia is by the reticulocyte response. In order to do this you must either look at the absolute reticulocyte number which is derived from the automated cell counter or estimate the reticulocyte production index (RPI) from the reported uncorrected reticulocyte count (reported as a % of the red blood cells). First, the corrected reticulocyte count is determined by multiplying the uncorrected reticulocyte count by the proportion of the patient’s hematocrit (or Hb concentration) relative to a normal gender-specific hematocrit (or Hb concentration). This product is then multiplied by 100 and reported as a %. Second, the peripheral blood smear is inspected for the presence of shift cells (prsesumed to be reticulocytes). If present, the previously determined corrected reticulocyte count is divided by the estimated of maturation time of the circulating reticulocytes. This estimated maturation time depends upon the patient’s hematocrit (or Hb concentration). An RPI > 3 implies the presence of hemolysis or blood loss and an RPI<2 implies either a hypoproliferative anemia or a maturation disorder.
Term
Anemia of chronic disease (ACD) is characterized by normocytic, normochromic red cells and a lack of an appropriate reticulocyte count. It is a kind of iron restricted anemia in that inflammatory cytokines (eg IL-6) up-regulate plasma hepcidin levels which in turn prevents the normal absorption of elemental iron from the GI tract and inhibits the release of iron from the RES by down-regulating ferroportin. Ferroportin is the carrier protein responsible for transporting iron across cell membranes. As a result, less iron is available to the red cell precursors for Hb development.

True or False. The patients with the ACD characteristically have a low serum iron, elevated tranferrin (or TIBC), decreased transferring saturation, and low ferritin.
Definition
False:

Patients with the anemia of chronic disease often have low serum iron levels, decreased iron binding capacity and transferrin (because protein synthesis in the liver is down-regulated), and serum ferritin is normal or elevated (ferritin reflects increased iron stores to due iron entrapment in the RES).

This is contrast to another iron restricted anemia called iron deficiency anemia in which patients have a hypochromic, microcytic hypoproliferative anemia with a low serum iron, high iron binding capacity and transferrin, and depleted ferritin. In the case, there are decreased iron stores due to blood loss, hemolysis, or more rarely a nutritional deficiency. When a patient is otherwise thought to have the ACD in the setting of a normal or decreased ferritin, it is likely that concurrent iron deficiency is present. To absolutely confirm that a combination of ACD and iron deficiency is present often requires a bone marrow examination to be performed and an iron stain of the bone to be examined. The lack of stainable iron confirms the presence of the iron deficiency. When only ACD is present, stainable iron is present in excess (a reflection of the entrapment of iron in the RES (bone marrow macrophages) and there is decreased stainable iron in red cell precursors (due to decrease incorporation of iron in the RBC).
Term
A way to categorize anemia is according to the size of the RBC. The mean RBC volume (MCV) is an expression of the average size of the red cells evaluated on an automatic cell counter. Although there are variations according to the laboratory and population evaluated, generally an MCV < 80fL is considered to indicate the presence of a microcytic anemia; an MCV 80-100fL is considered to indicate the presence of a normocytic anemia; an MCV >100 implies the presence of a macrocytic anemia.

True or False. A common cause of a microcytic anemia is the presence of either a deficiency in folate or vitamin B12.
Definition
False:

Common causes of microcytic anemia include iron deficiency, siderablastic anemia, lead intoxication, anemia of chronic disease, and some hemoglinopathies (e.g. Hb E). Elemental iron is essential for normal hemoglobin production. In the presence of iron restriction (where iron is not available to red cell precursors), less hemoglobin is produced in the individual red cells. For this reason, the cells will often take on a hypochromic appearance (the cells are pale and the central pallor of the cell is increased) and are smaller than normal. When iron restriction is severe (e.g. severe iron deficiency), the RBCs may become fragmented, hypochromic ellipotocytes begin to appear (these are elongated cells in which the opposite cell membranes are parallel to each other), and begin show some targeting (due to the presence of excess cell membrane relative to the Hb content within the cell).
Term
Elemental iron is usually absorbed via the proximal small bowel. First the ferric (Fe+3) form of iron must be converted the ferrous (Fe+2) form of iron. This conversion is helped along by the presence of an acidic mileau. An enzyme ferriredcutase located in the brush border of the intestine, also converts the ferric to ferrous iron, which allows it to bind to its tranporter protein within the intestinal cell membrane. The transfer of iron across the intestinal cell membrane is facilitated by DMT-1 (divalent metal transporter protein) and then iron is transported in the plasma by the carrier protein transferrin (2 iron molecule are carried on each transferrin molecule).

True or False. A patient undergoing total gastrectomy is expected to have normal iron absorption.
Definition
False.

The pH of the proximal small bowel is largely dependent upon the dumping of gastric acid through the pyloric valve into the duodenum. It is this gastric acid which lowers the pH and facilitates the reduction of Fe+3 to Fe+2. If the stomach is removed, no gastric acid is available to lower the pH of the proximal small bowel and as a consequence iron is not absorbed normally. In this setting treating the patient with ascorbic acid will often permit medicinal iron to be absorbed in quantities high adequate to replace depleted iron stores. If this is not successful, patients may require parental iron replacement.
Term
Signs and symptoms of iron deficiency anemia (IDA) include those associated with anemia (tachycardia, tachypnea, pallor) but there are also unique clinical features of iron deficiency anemia. Cheilosis (angular fissures at the corners of the mouth) may be observed. Fingernails may form a ‘spoon’ termed koilonychia. Patients may complain about dysphagia due to the development of esophageal webs (Plummer-Vinson syndrome). Finally, a unique symptom seen in patients with IDA is pica, the compulsive eating of clay, corn starch or ice (pagophagia). Causes of IDA are increased demand for iron (rapid growth, pregnancy, response to erythropoietin therapy), increased loss of iron (acute or chronic blood loss; menses; blood donation; phlebotomy as treatment for polycythemia vera), and decreased intake, absorption, or use of iron (inadequate diet; malabsorption (disease: sprue, Crohn‟s disease; surgery: post-gastrectomy); acute or chronic inflammation. It is imperative that gastrointestinal bleeding be ruled out since this is the most common cause of IDA in males and post-menopausal females. Stool hemoccult cards should be tested yearly and non-menstruating individuals with IDA should be considered for a GI evaluation to eliminate peptic ulcer disease, polyps or cancer as etiologies for the IDA.

A 15 year old boy is active in cross-country and has become an accomplished long distance runner for his age. He attributes this at least partly to the fact that his stride has increased since he first started cross-country at age 13 years. On occasion, after a long run, he notices that his urine has changed color and sometimes appears to be red tinged. Lately he has noticed that he has less “energy” than usual and although he can complete his runs his timing is a bit off. The coach arranges for him to be seen by the team physician, who draws some blood for testing. The results are the following: Hb low, MCV< 80fL, serum iron low, transferring saturation low, TIBC high, and serum ferritin<8 (low). A fecal occult blood test is negative for blood. A urinalysis is normal. You conclude that he has iron deficiency. The physician notes that this boy has gained 2 inches in height since age 13 years.

True or False. The most likely cause of this boy’s iron deficiency is either GI blood loss or dietary deficiency.
Definition
FALSE:

A GI bleed in a patient of this age group would be rare and is unlikely. On occasion, long distance runners will develop GI bleeding secondary to what is thought to be decreased blood flow to the intestine resulting in transient bowel ischemia, tissue damage, and localized bleeding. At age 15 years, he has entered the time when a growth spurt is expected. This appears to be the case since his height and running stride has increased during the course of his athletic endeavors. Also, he reports, a change in color of his urine. Sometimes runners develop what is referred to as “March Hemoglobinuria” in which RBCs are mechanically broken down (presumably from trauma as the blood passed through the blood vessels of the feet while the individual is running). Although this “loss” of hemoglobin may contribute to his iron deficiency, it is unlikely to be its major cause.
Term
Iron deficiency anemia (IDA) and the Anemia of Chronic Disease (ACD) (also referred to as the Anemia of Inflammation) are both “iron restricted” anemias in which not enough iron is available to the RBC precursors to produce appropriate amounts of hemoglobin. Although the anemia of chronic disease is often normochromic and normocytic, if severe enough it can present with peripheral blood smear findings similar to that seen in iron deficiency (hypochromic, microcytic RBCs). Sometimes the only way you can tell the difference is to examine the bone marrow. In IDA, there is no stainable iron. In ACD, stainable iron is present in the reticulum of the bone marrow, but there is poor incorporation of iron the RBC precursor cells.

A 60 year old lady with severe, poorly controlled rheumatoid arthritis comes to your with the complaint of fatigue. She appears pale. You suspect that she is anemic. A CBC shows a Hb<8.0, MCV<80, the red cells appear hypochromic. Serum Iron is low, TIBC normal, transferrin saturation decreased, and ferritin is 20 (normal>12)

True or False. This patient’s anemia is definitely caused by the presence of the ACD.
Definition
True:


This patient is presenting with a common diagnostic dilemma. She more than likely has a mixed cause of her anemia (ACD+IDA). Patients with severe RA often have both iron deficiency and the ACD. The ACD is caused by intense inflammatory process which leads to increases in cytokines (eg IL6) which in turn stimulates increased hepcidin production from the liver. Hepcidin inhibits ferroportin. Ferroportin is the carrier protein which allows iron to leave the intestinal wall and macrophages in the bone marrow and elsewhere so that it can be transported by transferrin to the red cell precursors for incorporation into Hb. Because of increased hepcidin, iron is not absorbed from the GI tract and also becomes trapped within the reticuloendolthelial cells in the bone marrow. The major source of serum iron and iron bound by transferring is the iron released from the reticuloendothelial system. Only a small amount of iron is absorbed via the GI tract on a daily basis. GI iron absorption contributes little to the total amount of iron circulating in the serum at any one time. Patients with RA often suffer from GI blood loss resulting in a concurrent iron deficiency. In this case the serum iron and transferring saturation are both depressed. These findings can be indicate that presence of either ACD or IDA. The TIBC is normal. In iron deficiency The TIBC is expected to be raised. In ACD it is expected that it would be decreased. The fact that it is normal in this patient implies the presence of both ACD and IDA. The ferritin is in a range higher than expected for IDA. However, when considering concomitant ACD+IDA, a ferritin < 40 the positive predictive value (+PPV) for IDA 92%; sensitivity 71%; specificity 100%. Transferrin receptors occur on red cell precursors. Portions of the transferrin receptor are soluble and appear in the serum. For this reason, soluble transferring receptor levels can be used to indirectly judge whether eryrhroid hyperplasia is occurring in the bone marrow. Erythroid hyperplasia is characteristic of IDA (unless it is extremely severe) and not of ACD. For this reason soluble transferring receptors may elevated in IDA but not in ACD. The only way to know for sure whether this patient has IDA is to examine the bone marrow as described previously.
Term
Normal RBCs survive in the circulation for approximately 100-120 days. During the time a RBC circulates it is repeatedly passing through the sinusoids of the spleen and liver and bone marrow traversing the endothelium.

True or False. In a fashion similar to platelets, normal RBCs are removed from the circulation randomly. This removal is dependent primarily upon the frequency that a RBC interacts with the endothelial cell surface and the macrophage.
Definition
False:


ormal RBCs survive in the circulation for approximately 100-120 days. During the time a RBC circulates it is repeatedly passing through the sinusoids of the spleen and liver and bone marrow traversing the endothelium. Normal RBCs are removed from the circulation according to their age. Aged (senescent) RBCs are not able to protect themselves from oxidative stress and are preferentially removed from the circulation. The RBCs are removed by tissue macrophages (also called reticulo-endothelial cells). As RBCs age they accumulate IgG immunoglobulin on their surface. In the presence of membrane-bound IgG, the RBC becomes vulnerable to scavenging by the macrophages.
Term
Compared to other types of anemia, hemolytic anemia is relatively unusual. It is important to remember that often hemolytic anemias occur in combination with other forms of anemia (e.g. warm autoimmune hemolytic anemia + anemic of chronic disease). The presence of hemolytic anemia should always be suspected if a patient has unexplained jaundice (especially if it is predominantly due to unconjugated bilirubin) or unexplained drop in the Hb concentration (but always remember that the removal of senescent RBCs is accelerated during infection, fever, or inflammation) or an elevated reticulocyte count (without evidence of blood loss or recent re-establishment of adequate nutritional status).

True or False. A common way of inferring the presence of hemolytic anemia is to evaluate the LDH and haptoglobin. If the LDH and haptoglobin are both elevated in the absence of other explanations there is a reasonable indication that hemolysis is occurring.
Definition
False:

The presence of hemolytic anemia should always be suspected if a patient has unexplained jaundice (especially if it is predominantly due to unconjugated bilirubin) or unexplained drop in the Hb concentration (but always remember that the removal of senescent RBCs is accelerated during infection, fever, or inflammation) or an elevated reticulocyte count (without evidence of blood loss or recent re-establishment of adequate nutritional status). When hemolysis is present the LDH (a ubiquitous intracellular enzyme) and the total in indirect bilirubin are usually elevated. Haptoglobin binds Hb that is free in plasma. The reticuloendothelial system removes the haptoglobin-hemoglobin complex from the body. A decrease in haptoglobin supports a diagnosis of hemolytic anemia, especially when correlated with a decreased RBC count, Hemoglobin, and Hematocrit, and also an increased reticulocyte count. The combination of a decreased haptoglobin and elevated LDH are highly specific (95%) and sensitive (95%) for the presence of hemolysis. If only one of the haptoglobin is low or the LDH elevated the sensitivity and specificity declines to 50%, respectively. If both tests are normal, there is < 5% chance that hemolysis is occurring.
Term
Hemolytic anemia can be categorized as being either intravascular or extravascular. During intravascular hemolysis RBCs are destroyed within the lumen of blood vessels; in this setting, free Hb is released into the plasma, bound by haptoglobin, the haptoglobin-Hb complex is removed by the reticuloendothelial system, and non-bound Hb excreted in the urine.

True or False. In contrast, during extravascular hemolysis the RBC is removed by the spleen. For this reason, the haptoglobin is never decreased during intravascular hemolysis and, therefore, a decrease in haptoglobin concentrations can be used to reliably tell the difference between intravascular and extravascular hemolysis.
Definition
False:

The haptoglobin in commonly depressed in both intravascular and extravascular hemolysis, therefore, the finding of a decreased haptoglobin cannot be used to reliably differentiate between intravascular and extravascular hemolysis. During a brisk intrasvascular, partial phagocytosis of RBCS and inability of the liver to appropriately process the Hb load may result in “leakage” of free Hb back into the plasma resulting the decrease in haptoglobin via the formation and removal of haptoglobin-Hb complexes.
Term
Tests that infer a hemolytic process to be immune-mediated include the direct (direct antiglobulin test; DAT) and indirect Coomb’s (indirect antiglobulin test; IDAT) test. In the direct Coomb’s test, washed human RBCs are incubated with rabbit anti-human IgG or rabbit anti-complement antibodies (Coomb’s reagent) and the degree of visible RBC agglutination graded by the laboratory technician. The indirect Coomb’s test is done by incubating normal RBCs to patient serum, adding a Coomb’s reagent, and grading the degree of agglutination observed. In contrast to the direct tests, which detect IgG or C3d on the red cell surface, this test detects target protein in the patient serum. Unlike the direct Coomb’s test, the indirect test is only rarely used to diagnose a medical condition. More often, it is used to determine whether a person might have a reaction to a blood transfusion.

True or False. The grading of the degree of RBC agglutination in the direct Coomb’s test of great clinical importance, since the clinician can infer from these results that the immune hemolytic episode can be expected to be severe and difficult to treat.
Definition
False:

The degree of agglutination does not correlate with the severity of hemolysis nor the response to appropriate intervention.
Term
Immune hemolytic anemias can be categorizes according to their reactivity by temperature. Cold reactive antibodies are antibodies which bind to the RBC surface and activate complement at temperatures below body temperature.

True or False. A characteristic of cold reactive antibody mediated hemolysis is the presence of spherocytes in the peripheral blood smear.
Definition
False!

Warm IgG-mediated immune hemolysis is characterized by the presence of spherocytes in the peripheral blood. The spherocytes are formed are present because the RBCs loose a portion of their membranes as the antibody and/or complement coated RBC is assaulted by macrophages in the sinusoids of the RES. Cold-reactive hemolysis is characterized by red cell agglutination on a peripheral blood smear. It usually caused by cold-reactive IgM that fixes complement on the red cell surface and lysis the RBC in the blood vessel. The IgM is often directed against the I antigen. In the setting cold reactive hemolysis the determination of “cold agglutinin titers are often useful. Cold agglutinin titers reflect the ability of the cold reactive antibody to cause RBCs to agglutinate at temperatures below body temperature. The titer is the maximum dilution of plasma in which agglutination can still occur. In general, cold agglutinin titers greater than 1:64 are abnormal.
Term
The term “thermal amplitude” refers to the variation in reactivity according to temperature of some antibodies with their targets on RBCs. This is of clinical importance, since the thermal amplitude can be important when patients undergo surgical procedures requiring cardioplegia (where the heart surgery is done while the heart is stopped and under cold conditions) or receiving non-warmed intravenous infusions of blood products or solutions. Also, patient with cold agglutinins may be hemolyzed when they are exposed to cold ambient temperatures.

True or False. It may be important to keep a patient with cold agglutinin disease at a temperature less than the thermal amplitude.
Definition
False:

Since Cold reactive IgM binds to RBCs at temps less than body temperature, once bound they cause the incomplete or complete fixation of complement. As the temperature rises the IgM may elute from the RBC and complement fixation is not completed and no hemolysis occurs. Thermal amplitude refers to the highest temperature in which RBC agglutination, hemolysis or antibody binding is detected. Patients should be kept at a temperature > the thermal amplitude. This is particularly critical during cardioplegic surgery where ambient temperatures in the OR are kept below normal body temperature.
Term
Causes of Non-immunologically mediated hemolysis include disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS), vasculitis (eclampsia, autoimmune), and march hemoglobinuria/Marathoners hemolysis.

True or False. The hallmark of non-immune mediated hemolysis in a peripheral blood smear is the occurrence of spherocytes because the mechanism of their formation is similar as that seen in cold hemolytic anemia.
Definition
It is characterized by the presence of schistocytes caused by the shearing of RBCs and fibrin consumption within small blood vessels, over intravascular devices like heart valves or ventricular assist devices, and due to pressure from bone of the feet when running.
Term
Cold reactive hemolysis is characterized by red cell agglutination on a peripheral blood smear. It is usually caused by the reactivity of a cold-reactive IgM antibody to a RBC surface antigen. The IgM, being a large antibody, tends to cause the complement fixation process to progress to “completion” in which the terminal attack complex of complement is able to violate the cell membrane resulting to intravascular hemolysis.

True or False. The treatment of choice for cold reactive hemolysis is the ablation of the spleen by either splenectomy or emoblization of the spleen. In this way, less RBCs are removed from the circulation and the survival of RBCs is increased to acceptable levels.
Definition
Since cold reactive IgM antibodies cause intravascular hemolysis rather than extravascular hemolysis, ablation of the spleen is ineffective. Likewise, the use of corticosteroids (it is postulated that a mechanism of their action may be inhibition of phagocytosis) are not effective.

Recent evidence indicates that the anti-CD20 monoclonal antibody rituximab may be useful for the treatment of this disorder, if the avoidance of cold exposure is not successful and the disorder is severe enough to warrant this level of intervention.
Term
True or False:


The most common enzymatic defect of the red blood cell associated with hemolysis is G6PD deficiency.
Definition
True:

G6PD deficiency is the most common enzymatic defect. G6PD deficient RBCs cannot generate adequate NADPH and reduced glutathione and are sensitive to oxidative stress resulting in hemolysis and bite cell formation. The hemolytic episode is commonly triggered by medications or fava bean ingestion. The diagnosis is made by measuring G6PD enzyme levels after cessation of an acute hemolytic episode, since reticulocytes have a higher enzyme level and reticulocytosis (a characteristic of hemolysis) may confound the diagnosis. Treatment for G6PD is the avoidance of precipitating causes. The second most common enzyme deficiency associated with hemoysis is Pyruvate Kinase (PK) deficiency.
Term
True or False:

Hemoglobinopathies are qualitative disorders of portions of the hemoglobin molecule due to amino acid substitutions causing a structurally abnormal globin and may be either congenital or acquired. Acquired forms of hemoglobinopathies include the following: methemoglobin, sulfhemoglobin, and carboxyhemoglobin.
Definition
True:

Hemoglobinopathies are due to amino acid substitutions causing a structurally abnormal globin (eg. HbS, HbE, HbC, HbG-Philadelphia, HbD, HbO-Arabia). Interactions among thalassemias and hemoglobinopathies are common (eg. HbS and HbC). Some congenital hemoglobinopathies are characterized by an altered affinity for oxygen (eg. M Hb). Acquired hemoglobinopathies associated with altered affinity for oxygen include methemoglobin, sulfhemoglobin, and carboxyhemoglobin.
Term
True or False:

Thalassemias are quantitative deficiencies of either the alpha or beta chains of the hemoglobin molecule. The most severe form of beta-thalassemia (which can be caused by >150 different mutations) is characterized by extra-medullary hematopoiesis, chronic hemolysis, iron overload with iron deposition, and splenomegaly.
Definition
True:

The imbalance of globin chain production causes decreased Hb amount in each RBC. The excessive production of one globin chain results in its precipitaton in the RBC leading to damage to the RBC precursors and circulating cells, intra- and extravascular hemolysis and ineffective erythropoiesis.
Term
True or False:

Hemoglobin switching refers to the change in globin chain production from the neonatal period to postnatal period. This change consists of the “switching” in production of the alpha and beta chains in the postnatal period with the alpha chain replacing the beta chain in adult hemoglobin.
Definition
False:

The term “Hb switching” refers to the substitution of the gamma globin chain found in fetal Hb (alpha2, gamma2) by the beta chain found in adult Hb (alpha2, beta2). Typically, gamma chain production begins to decrease and beta chain production begins to increase at about 30 weeks of gestation. 2-3 months after birth beta chain production supercedes that of the gamma chain and adult Hb begins to replace fetal Hb. This is an important phenomenon since diseases which affect the beta globin chain (eg sickle cell) may not be evident at birth.
Term
True or False:

Sickle cell disease (SCD) is characterized by homozygous HbS (sickle cell anemia) or coinheritance of HbS with other Hb abnormalities (most commonly HbSC or S/beta thalassemia). The hallmark features of SCD are chronic hemolysis and episodic vaso-occlusion, acute vaso-occlusive pain crises, acute chest syndrome, acute on chronic anemia, and splenomegaly
Definition
False:

he chronic hemolysis and episodic veno-occlusion of sickle cell disease is characterized by adhesion of sickle reticulocytes to post-capillary venules, hypoxia, sickling of the RBC, ischemia, necrosis, and end-organ damage. The acute vaso-occlusive pain crises (which are the hallmark of the disease) are characterized by intense, unpredictable acute pain in bones and joints and are treated with parenteral opiates and other supportive measures. The acute chest syndrome is an acute lung injury syndrome likely caused by fat embolism from the bone marrow, infection or intrapulmonary sickling and presents like pneumonia.It is treated with transfusion, antibiotics and other supportive measures. Patients may develop aplastic crises from parvovirus B19 infection in childhood and develop acute anemia from bone marrow suppression together with chronic anemia. Splenic infarction in childhood (due vaso-occlusive disease) leads to a small atrophic and non-functioning spleen (autosplenectomy) in almost all patients with HbSS. This causes a susceptibility to pneumococcal sepsis and sepsis from other encapsulated organisms. Thus, splenomegaly is not a hallmark of the disease. Exceptions are patients with HbSS and HPFH or patients with compound heterozygosity for HbS and other hemoglobins (such as HbC or beta thalassemia). These patients may retain their spleen throughout adulthood and even suffer from splenomegaly
Term
True or False:

Hydroxyurea is a chemotherapy agent usually used to treat hematological malignancies which reduces the number of painful episodes and the rate of other complications associated with sickle cell disease. Hydroxyurea does protect the body from the damaging effects of sickled RBCs primarily by transforming endothelial cells in such a way that the sickled RBCs no longer adhere to their surface and vaso-occlusion no longer occurs. (actually this cannot be completely ruled out, as a secondaty effect of decreased sickling, so I added the word primarily)
Definition
Hydroxyurea (and other drugs which are not practical to use in the sickle cell population) has the capacity of increasing fetal Hb (Hb F) production. This increase in Hb F concentration in each RBC prevents the sickling of the RBC, increases blood flow through the capillaries, and prevents vaso-occlusion. Increased Hb F results in an increase of RBC survival from 15-30 days (in patients with Hb SS) to 60-90 days (when the Hb in the RBCs become HbSS/HbF). A normal RBC lives about 90-120 days in the circulation.
Term
True or False:

The osmotic fragility test is diagnostic of hereditary spherocytosis.
Definition
False:


Hereditary spherocytosis (HS) is a congenital disorder of autosomal inheritance. Patients typically present with chronic, compensated hemolysis, pigmented gallstones, and splenomegaly. Examination of the peripheral blood smear shows the presence of spherocytes. This disorder has a clinical course similar to that of hereditary elliptocytosis (HE) and hereditary pyropoikilocytosis (HP). All of these disorders have defects in the cytoskeleton of the RBC which allow the affected RBCs to take on the shape of spherocyties (HS), elliptocytes (HE) or strange shaped cells (HP). The defective RBCs are removed in the spleen and for this reason, in severe cases; splenectomy may be effective in reducing hemolysis and its complications. Red cell aplasia may occur secondary to folate deficiency or parvovirus B19 infection. The osmotic fragility test detects the ease in which RBCs are lysed in increasingly dilute aliquots of NaCl solution. Spherocytes from any cause (eg. warm auto-immune hemolytic anemia) are detected by the osmotic fragility. For this reason, this test is not diagnostic of HS. An abnormal osmotic fragility test must be interpreted in the clinical context of the patient.
Term
True or False:

Paroxysmal hemoglobinuria is a hereditary disease characterized by episodes of extra-vascular hemolysis and hemoglobinuria
Definition
False:

Paroxysmal hemoglobinuria (PNH) is an acquired disorder in which the phosphatidylinositol glycan (PIG) linkages for key cell surface proteins are missing from the cell surface. Among the proteins usually attached to the PIG linkages are CD55 and CD59 which normally prevent complement mediated hemolysis. In the absence of CD55 and CD59, the affected RBCs undergo complement-mediated intravascular hemolysis characterized by hemoglobinuria, a predisposition to venous and arterial thrombosis, renal failure, and profound fatigue. The diagnosis is made by doing a flow cytometric analysis of the patient’s peripheral blood for the absence of CD55 and CD59 on RBCs, granulocytes, and monocytes.
Term
Hypoproliferative anemias are generally characterized by a reticulocyte production index of less than:

1) 1.0
2) 1.5
3) 2.0
4) 2.5
5) 3.0
Definition
3) <2.0
Term
Which of the following best describes the clinical significance of the poikilocyte?

1) Sickle cells are a manifestation of immune-mediated hemolytic anemia
2) Elliptocytes suggest underlying beta thalassemia trait
3) Oval microcytes indicate B12 or folate deficiency
4) Tear drop cells indicate anemia of chronic disease
5) Target cells are suggestive of underlying liver disease
Definition
5
Term
How do you calculate/interpret a reticulocyte production index?
Definition
Retic count * (Hct/normal Hct)

<2= hypoproliferative
>3= hyperproliferative