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209 Cards in this Set

  • Front
  • Back
Where is EPO synthesized?
1.Primarily synthesized in the renal cortex by interstitial cells in the peritubular capillary bed
List 4 conditions that increase EPO synthesis?
◦Hypoxemia, severe anemia, left-shifted O2-binding curve (OBC), high altitude
How long does it take reticulocytes to mature into RBCs? What cell helps them mature?
1) In 24 hours, they become mature RBCs
2) splenic macrophages
How are reticulocytes detected?
Detect thread-like RNA filaments in the cytoplasm via supravital stains
In a normal person what percentage is the reticulocyte count? How is it corrected with degree of anemia? If polychromasia is present what do you do?
1) <3% of total RBCs
2) Correction: Hct/45 × reticulocyte count
3) divide corrected retic by 2
When does polychromasia occur? How long do they take to mature?
1) brisk hemolytic anemia
2) 2-3 days
How do you determine if someone is has a good bone marrow response to anemia?
≥3% retic effective erythropoiesis
What are examples of a corrected retic count <3%?
untreated iron deficiency; aplastic anemia
What would cause extramedullary hematopoeisis?
a.Intrinsic bone marrow disease (e.g., myelofibrosis)
b.Accelerated erythropoiesis (e.g., severe hemolysis in sickle cell disease)
How can it be determined if someone with sickle cell disease is forming a massive amount of RBC without doing blood work?
1) Expands the bone marrow cavity
(2) Radiograph of the skull shows a "hair-on-end" appearance
When in fetal life does hematopoeisis move to the bone marrow?
5-6 month gestation
Does jaundice occur at birth or days or weeks after?
~3 days after
Do newborns, infants or children have higher levels of Hb?
newborn
Where does the oxygen binding curve of a child lie in ralation to an adults? Why
more right-shifted OBCs than adults

(1) Have a lower Hb concentration than adults
(2) Due to higher serum phosphorus levels
(a) Increased serum phosphorus increases synthesis of 2,3-bisphosphoglycerate (BPG).
At what level does a man become anemic? Why do men have higher Hb levels than women?
1) <13.5
2) (a) Due to increased testosterone
■Stimulates erythropoiesis
(b) Due to lack of cyclic bleeding
When is a woman considered to be anemic?
Anemia in a nonpregnant woman is an Hb < 12.5 g/dL.
Do pregnant women have a higher or lower Hb concentration than nonpregnant women? why? What level Hb is a pregnant woman said to be anemic?
1) lower because 2× greater increase in plasma volume than RBC mass. Note that RBCs are also increased more overall but are diluted
2) In a pregnant woman, anemia is a Hb < 11 g/dL
In thalasemia is Hb increased or decreased? Hct? RBC? MCV/RBC?
↓ Hb, Hct; ↑ RBC count; MCV/RBC < 13
In anemia what happens to the O2 sat, pO2 and O2 content?
O2 saturation and arterial Po2 normal but decreased O2 content
Is anemia a specific diagnosis?
no it is a sign of disease
What are the symptoms of anemia?
(1) Fatigue
(2) Dyspnea with exertion
(3) Inability to concentrate
(4) Dizziness
(5) Pulmonary flow murmur
■Decreased blood viscosity in severe anemia
(6) Pallor of skin, conjunctivae, palmar creases
■Indications of severe anemia
(7) High-output cardiac failure
■Decreased blood viscosity in severe anemia (<5 g/dL)
What must the MCV be to have a normocytic anemia?
Normocytic (80-100 μm3)
What does a larger than normal central area of pallor correlate with?
hypochromasia with a low MCHC
In what conditions is the MCHC low? High?
↓ in microcytic anemias; ↑ in spherocytosis
What is the RDW used for?
measure of size variation of RBCs
What is size variation of cells called?
Size variation is called anisocytosis
What would the RDW be in someone with iron deficiency?
↑ RDW (anisocytosis)
Note: Only microcytic anemia with an increased RDW
What is the Cori cycle?
lactic acid from RBCs converted to glucose in liver→ glucose back to RBC
What does the pentose phosphate pathway make?
Synthesizes NADPH which helps produce more glutathione
What is the purpose of the methmeglobin reductase pathway?
a. Methemoglobin (metHb) refers to heme iron that is oxidized (Fe+3).
■MetHb cannot bind O2.
b.Reductase system converts iron to ferrous (Fe+2) so that the RBCs can bind O2.

enzyme is cytochrom b5
What is the Luebering-Rapaport pathway responsible for? What is it a product of?
a.Synthesizes 2,3-BPG
b. glycolytic cycle
Where are senscent macrophages destroyed?
a.Phagocytosed in the cords of Billroth by splenic macrophages
Do RBCs have HLAs?
no
What cells predominately synthesize ferritin?
bone marrow macrophages
What happens to ferritin levels during inflammation? Why?
Synthesis of ferritin in macrophages increases in inflammation.

■Due to release of interleukin 1 and tumor necrosis factor-α
What conditions is serum ferritin increased in? decreased?
↓ iron deficiency; ↑ ACD, iron overload disease
What is hemosiderin? what other marker does it follow?
Insoluble degradation product of ferritin

Decreased and increased levels correlate with changes in ferritin stores.
What is the normal serum iron level and what is it measuring?
transferrin 100ug/dL
In what conditions is there increased serum iron?
sideroblastic anemia, hemochromatosis
What is the relation of TIBC to transferrin? What is the normal TIBC?
↓ TIBC = ↓ transferrin; ↑ TIBC = ↑ transferrin

normal TIBC is ∼300 μg/dL
If ferritin stores are low what happens to transferrin levels?
increased liver synthesis of transferrin
In which conditions does TIBC decrease?
ACD and iron overload disease
How is iron sat determined? What is normal?
Iron saturation (%) = serum iron/TIBC × 100

33%
When is iron sat increased? decreased?
↓ Iron saturation: iron deficiency, ACD; ↑ iron saturation: iron overload disease
What is Hb A? A2? F?
1) 2α/2β globin chains (97% in adults).
2) 2α/2δ globin chains (2% in adults).
3) 2α/2γ globin chains (1% in adults
What are disorders that have abnormal Hb?
Sickle Hb, HbH, Hb Bart
What are the microcytic anemias? Which is most common and which is least?
1.Iron deficiency (most common)
2.Anemia of chronic disease (ACD)
3.Thalassemia (α and β)
4.Sideroblastic anemias (least common)
Which microcytic anemias have a decreased synthesis of heme?
◦Iron deficiency, ACD, sideroblastic anemias
What are the precursors to heme? What enzyme is needed?
iron and protophyrin

ferrochelatase
List the sequence of stages that iron deficiency anemia occurs in?
absent iron stores; decreased serum ferritin; decreased serum iron, increased TIBC, decreased iron saturation; normocytic normochromic anemia; microcytic hypochromic anemia.
What are the types of iron?
reduced ferrous Fe+2 (heme iron in meat), oxidized ferric Fe+3 (nonheme iron in plants)
Which form of iron cannont be directly absorbed? where is it absorbed?
Fe3+ it must be reduced first then it is absorbed in duodenum
How much iron is stored in a man? in a woman?
1) 1000 mg
2) 400 mg
What reduces Fe3+ so it can be absorbed?
vit C
What regulates the amount of iron released to plasma?
(a) HFE (hemochromatosis) gene product facilitates binding of plasma transferrin with its mucosal cell transferrin receptor.
■This allows transferrin to be endocytosed (reabsorbed) by intestinal cells.
(b) Amount of endocytosed transferrin determines how much mucosal cell iron is released into the plasma to bind with transferrin.
What causes plummer vincent syndrome?
chronic iron deficiency anemia
What is plummer vincent syndrome?
1) Caused by chronic iron deficiency
(2) Esophageal web
■Dysphagia for solids but not liquids
(3) Achlorhydria
(4) Glossitis
(5) Spoon nails (koilonychia
A person has pica and dysphagia of solids but not liquids. What could they have?
chronic iron deficiency with plummer vincent syndrome
What is pica?
increased craving for ice... seen in chronic iron deficiency
What blood values are increased in iron deficiency anemia?
(3) Decreased serum ferritin (<30 ng/mL) and % saturation
(4) Increased TIBC, RDW
(5) Microcytic and normocytic cells with increased central area of pallor
(6) Increased serum free erythrocyte protoporphyrin (FEP)
How is iron deficiency treated?
Ferrous sulfate, given orally
What is the most common anemia in hospitalized patients? What are other causes of this type of anemia?
ACD

(1) Chronic inflammation
■Examples-rheumatoid arthritis, tuberculosis
(2) Alcoholism
(3) Malignancy
In ACD what is the pathogenesis?
a.Decreased synthesis of heme
b.Decrease renal production of EPO (some cases)
c.Liver synthesis and release of hepcidin
What is the function of hepcidin?
acute phase reactant protein that binds prevents transferrin from binding iron in macrophages and intestinal mucosa
In ACD is the serum iron low or high? iron sat? TIBC? ferritin?
↓ iron, TIBC, % saturation; ↑ ferritin, FEP
Someone has 7 g/dL Hb. Do they have ACD?
unlikely, ACD rarely gets below 9 g/dL
Is thalassemia dominant or recessive? What type do blacks have?
1) recessive
2) α- or β-thalassemia
Who is α-Thal comon in?
α-Thal is common in Southeast Asians and in blacks.
Who is β-thalassemia
common in?
blacks, Greeks, and Italians
Thal caused by a loss of one gene on each chromosome (α/- α/-) is common in who?
blacks
Thal caused by a loss of both genes on the same chromosome (-/- α/α) is seen in who?
south east asians and is associated with having severe types of alpha thal
What blood values are increased, decreased and normal in alph thal?
(4) Decreased MCV, Hb, and Hct
(5) Increased RBC count
(6) Normal RDW, serum ferritin, serum FEP, Hb electrophoresis
What does a peripheral blood smear of someone with alpha thal show?
Tear drop RBCs in peripheral blood.
■Damage to RBC membrane from removal of excess globin chains
Can alpha thal be treated with iron?
no this will cause iron overload. There is NO treatment
What thal has a combination of 3 gene deletions? What ensues? How is it detected?
HbH

(1) Severe hemolytic anemia
■Excess β-chain inclusions cause macrophage destruction of the RBCs (hemolytic anemia).
(2) Hb electrophoresis detects HbH
What causes Hb Bart?
4 gene deletions... Note it is incompatible with life. They have 4 gamma chains
What are the different types of alpha thal?
alpha thal trait
HbH (4 beta chains in adults)
Hb Bart (4 gamma chains)
What causes both beta Thal major and minor?
mild-DNA splicing defect; severe-stop codon
What is the genotype for someone with beta Thal minor? What type of anemia do they have?
β/β+

mild anemia
Is alph or beta Thal protective against malaria?
beta minor
What blood values are normal for someone with beta-thal minor? High and low?
■(3) Decreased MCV, Hb, and Hct
■(4) Increased RBC count
■(5) Normal RDW, serum ferritin, FEP
electrophoresis of someone with beta-Thal minor would show what?
(a) Decreased HbA (2α/2β)
β-Thal minor: ↓HbA; ↑ RBC count, HbA2, HbF
(b) Increased HbA2 (2α/2δ) and HbF (2α/2γ)
What is Cooley's anemia? What happens?
β-Thal major (Cooley's anemia; β0/β0)

severe hemolytic anemia
What is an alpha chain inclusion indicative of? What removes these cells? Why do patients develop jaundice?
1) Cooley's anemia
2) RBCs with α-chain inclusions are removed by macrophages in the spleen.
■Causes an increase in unconjugated bilirubin (jaundice)
(b) RBCs with α-chain inclusions undergo apoptosis in the bone marrow (ineffective erythropoiesis).
Electrophoresis of someone with Cooleys disease shows what?
a) No synthesis of HbA
(b) Increase in HbA2 and HbF
how is Cooleys treated?
Long-term transfusion requirement

don't give iron to anyone with any type of thalassemia
What toxin causes Fanconi's syndrome?
lead

The syndrome includes proximal renal tubular acidosis (loss of bicarbonate in urine), aminoaciduria, phosphaturia, and glucosuria.
How is sideroblastic anemia caused? Are men or woman more likely to get when inherited?
1. Chronic alcoholism (most common cause)
2. Pyridoxine (vitamin B6) deficiency
3. Lead (Pb) poisoning
4. X-linked recessive inheritance so men more likely to get
How is ALA synthase inhibited? What is the rate limiting enzyme in heme synthesis
Heme has a negative feedback relationship with δ-aminolevulinic acid synthase.
* δ-Aminolevulinic acid synthase is the rate-limiting enzyme of heme synthesis.
At the cellular level what happens in siderblastic anemia?
1) Iron accumulates in the mitochondria forming ringed sideroblasts

2) Iron-overload type of anemia

a. Increase in iron stores in the bone marrow macrophages
b. Sideroblasts die in the marrow, and iron is added to the macrophages.
What is the most common cause of sideroblastic anemia? Why? Is it commonly seen in?
alcohol is a mitochondrial toxin

Sideroblastic anemia occurs in ∼30% of hospitalized chronic alcoholics.
How does Pyridoxine deficiency cause sideroblastic anemia? What drug causes it? What is the drug used to treat
Vitamin B6 is a cofactor for δ-aminolevulinic acid synthase.
* Rate-limiting reaction of heme synthesis

2 Most common cause of deficiency is isoniazid (INH) therapy.

a. INH is used in the treatment of tuberculosis.
What is the most common cause of sideroblastic anemia in kids 1-5? What is the disorder they have prior to developing anemia?
1) lead

2) Pica (abnormal craving) for eating lead-based paint

* Common cause of childhood lead poisoning in inner cities
People working in battery or ammunition factories, Radiator repair mechanics, or someone exposed to Air contamination from smelter are at risk for developing what anemia?
sideroblastic anemia from lead
What makes lead so toxic? What products accumulate?
1) Ferrochelatase (heme synthase) denatured

(a) Iron cannot bind with protoporphyrin to form heme.
(b) Increase in serum FEP, which is proximal to the enzyme block

(2) Aminolevulinic acid (ALA) dehydrase

* Causes an increase in δ-ALA, which is proximal to the enzyme block

(3) Ribonuclease

(a) Ribosomes cannot be degraded and persist in the RBC. resulting in basophilic stippling
Basophilic stippling is seen in RBCs. What type of anemia is it and what is causing it?
sideroblastic anemia caused by lead inhibiting ribonuclease which normally degrades ribosomes
In lead poisoning what are common findings in the GI tract? CNS? Bone and growth? kidneys? PNS?
(1) Abdominal colic with diarrhea
(a) Pb is visible in the gastrointestinal tract on plain abdominal radiographs (Fig. 11-15).
(b) Usually occurs in children

(2) Encephalopathy in children
(a) δ-ALA damages neurons, increases vessel permeability (cerebral edema), and causes demyelination.
(b) Learning disabilities in children
(3) Growth retardation in children
(a) Pb deposits in the epiphysis of growing bone
(b) Radiographs show increased density in the epiphyses.
(4) Peripheral neuropathy in adults
(5) Nephrotoxic damage to proximal renal tubules
(6) Pb line in the gums
o Usually in adults with Pb poisoning and gingivitis
(7) Increased whole blood and urine Pb levels
o Best screen and confirmatory test for Pb poisoning
What are examples of how the PNS is effected by lead?
o Examples-foot drop (peroneal nerve palsy), wrist drop (radial nerve palsy), claw hand (ulnar nerve palsy)
What is the Best screen and confirmatory test for Pb poisoning? how is lead poisoning treated?
Increased whole blood and urine Pb levels

Chelation therapy-succimer, dimercaprol, EDTA (ethylenediaminetetra-acetic acid)
What does an iron panel show in sideroblastic anemia? bone aspirate?
↑ serum iron, iron saturation, ferritin; ↓ MCV, TIBC

Ringed sideroblasts are present in a bone marrow aspirate
What are common causes of blood loss leading to microcytic anemia? specifically in adults over 50?
1) Meckel's diverticulum (older children)
2) PUD (most common cause in adult men)
3) Gastritis (e.g., NSAID)
4) Hookworm infestation
5) Polyps/colorectal cancer (most common cause in adults > 50 years of age); positive stool for blood
6) Menorrhagia Most common cause in women < 50 years of age
What is the Most common cause of iron deficiency in young children? Iron deficiency can also be found in a condition that has Anti-tissue transglutaminase IgA. What is the condition?
low intake

Celiacs
How are macrocytic anemias classified?
Macrocytic anemias are subdivided into megaloblastic (e.g., folate or vitamin B12 deficiency) and nonmegaloblastic anemia (e.g., macrocytosis related to alcohol intoxication).
What food sources is vit B12 found in?
meat, eggs, and dairy products
What is Free vitamin B12 is bound to?
R-binders from salivary glands
Where is IF-B12 complex absorbed?
terminal ileum
How is B12 secreted into blood? Where is it stored and long can someone go without taking in any B12?
Vitamin B12 binds to transcobalamin II and is secreted into plasma.

Delivered to metabolically active cells or stored in the liver (6-9 years)
What is the most common cause of B12 deficiency?
pernicious anemia
What foods have folate? What form is it in?
Present in green vegetables and animal proteins

* In the form of polyglutamates
Describe how folate is absorbed and circulated in body? How long can someone go without eating any folate?
Converted to monoglutamates by intestinal conjugase

Monoglutamates are reabsorbed in the jejunum. Then:

1. Converted to methyltetrahydrofolate, the circulating form of folate
3. There is only a 3- to 4-month supply of folate in the liver.
Intestinal conjugase is inhibited by what drug? Monoglutamate reabsorption is inhibited by what?
1) phenytoin.

2) alcohol and oral contraceptives
What is the most common cause of folate deficiency?
alcohol
What is the pathogenesis of folate or B12 deficiency? What cells are effected? What processes continue unabated in cell synthesis?
Impaired DNA synthesis
1. Delayed nuclear maturation
* (1) Causes a block in cell division leading to large, nucleated hematopoietic cells
* (2) Enlarged cells are called megaloblasts

2. Affects all rapidly dividing cells
* Examples-RBCs, leukocytes, platelets, intestinal epithelium
3. Cellular RNA and protein synthesis continue unabated.
* Cytoplasmic volume continues to expand.
The most common cause of increased serum homocysteine levels in the United States is?
folate deficiency
Why is homocysteine toxic?
damages endothelial cells leading to vessel thrombosis.
Cellularly how is folate/B12 characterized?
pancytopenia; apoptosis, macrophage phagocytosis
Describe B12's action in the cell? What accumulates? What is falsely elevated?
1) Vitamin B12 removes the methyl group from methyltetrahydrofolate (N5-methyl-FH4) and Produces tetrahydrofolate (FH4)
2) Methyl-vitamin B12 transfers the methyl group to homocysteine to produce methionine.

* Deficiency of vitamin B12 traps N5-methyl-FH4 in its circulating form; may falsely increase the serum folate in 30% of cases.
Does deficiency of folate or vit B12 increase homocysteine levels?
both do
Thymidylate synthase is irreversibly inhibited by what drug?
5-fluorouracil.
Dihydrofolate reductase converts dihydrofolate (FH2) to FH4. What inhibits the enzyme? what drug inhibits it reversibly?
methotrexate (reversible) and trimethoprim
How does vit B12 function in odd chain fatty acid metabolism? What does a B12 deficiency lead to? What accumulates?
1) Propionyl CoA is converted to methylmalonyl CoA.
2) Methylmalonyl CoA is converted to succinyl CoA.
* Vitamin B12 is a cofactor for methylmalonyl CoA mutase.

3) Vitamin B12 deficiency causes an increase in propionyl and methylmalonyl CoA and their corresponding acids.

* Propionyl CoA replaces acetyl CoA in neuronal membranes resulting in demyelination.
Achlorhydria due to destruction of parietal cells occurs in pernicious anemia. what hormone is elevated? What blood group is most common with pernicious anemia?
gastrin

blood group A
What type of hypersensitivity is pernicious anemia? What antibodies are seen in pernicious anemia? Which is most specific?
type II

against IF (most specific), parietal cells, B12-IF complexes to ileal receptors
What is there an increased risk of with pernicious anemia?
gastric adenocarcinoma
What are the peripheral nerve symptoms with B12 deficiency? Is it Possible to have neurologic disease without anemia?
1. Peripheral neuropathy with sensorimotor dysfunction
2. Subacute combined degeneration (demyelination) of the spinal cord
a) Posterior column dysfunction
o Decrease in vibratory sensation and proprioception (joint sense)
b) Lateral corticospinal tract dysfunction with spasticity
3. Dorsal spinocerebellar tract demyelination
* Produces ataxia
4. Dementia
5. yes it is Possible to have neurologic disease without anemia
What test has been used in the past to demonstrate impairment of reabsorption of vitamin B12? how does it work?
Shilling test: combining orally administered radioactive vitamin B12 with IF, or with pancreatic extract, or alone after pretreatment with antibiotics followed by a 24-hour urine collection to measure radioactive vitamin B12. Lack of reabsorption of radioactive vitamin B12 excludes a potential cause of impaired reabsorption, while the presence of reabsorption confirms the cause of the impaired reabsorption. For example, if the combination of radioactive vitamin B12 + IF leads to an increase in radioactive vitamin B12 in the urine, the patient has pernicious anemia; if it does not, the diagnosis of pernicious anemia is excluded. Similarly, correction with pancreatic extract implicates chronic pancreatitis as the cause or bacterial overgrowth as the cause, if antibiotics correct the reabsorption.
What is the most sensitive test for Vit B12 deficiency? What is seen on a peripheral blood smear?
↑ Methylmalonic acid

1 Pancytopenia
2 Oval macrocytes
3 Hypersegmented neutrophils
What is a complication of folate deficiency in pregnant women? What is the best indicator of folate stores?
Increased risk for open neural tube defects in the fetus

RBC folate levels
Pharmacologic doses of folate will correct the hematologic findings in both folate and vitamin B12 deficiency; however, neurologic disease is not corrected. How are neurologic symptoms treated?
IM vit B12
How are macrocytic nonmegaloblastic anemias different from megaloblasic anemias?
1. Macrocytes are round rather than oval
2. Hypersegmented neutrophils are not present.
3. Leukocytes and platelets are quantitatively normal.
4. Absence of glossitis and neuropathy
5. Anemia may not be present.
6. Alcohol excess is the most common cause for all types of the macrocytosis.
What is the RBC appearance in chronic alcoholism? Why do they look that way? What happens to the lifespan of the RBCs and how severe is the anemia?
round macrocytic target cells

Excess RBC membrane due to increased membrane cholesterol

Life span of the RBCs is not decreased; there is no anemia
What are the direct effects of alcohol on RBCs? Can they be reversed?
1. MCV ranges from 100 to 110 μm3.
2. Vacuolization of RBC precursors in bone marrow
3. Abstinence from alcohol reverses the macrocytosis and anemia.
How are the following affected by iron deficiency?
1) MCV
2) Serum iron
3) TIBC
4) Percent saturation
5) Serum ferritin
6) RDW
7) RBC count
8) Hb electrophoresis
9) Ringed sideroblasts
10) Coarse basophilic stippling
MCV ↓
Serum iron ↓
TIBC ↑
Percent saturation ↓
Serum ferritin ↓
RDW ↑
RBC count ↓
Hb electrophoresis Normal
Ringed sideroblasts None
Coarse basophilic stippling None
How are the following affected by ACD?
1) MCV
2) Serum iron
3) TIBC
4) Percent saturation
5) Serum ferritin
6) RDW
7) RBC count
8) Hb electrophoresis
9) Ringed sideroblasts
10) Coarse basophilic stippling
MCV ↓
Serum iron ↓
TIBC ↓
Percent saturation ↓
Serum ferritin ↑
RDW Normal
RBC count ↓
Hb electrophoresis Normal
Ringed sideroblasts None
Coarse basophilic stippling None
How are the following affected by alpha/beta minor thal?
1) MCV
2) Serum iron
3) TIBC
4) Percent saturation
5) Serum ferritin
6) RDW
7) RBC count
8) Hb electrophoresis
9) Ringed sideroblasts
10) Coarse basophilic stippling
MCV ↓
Serum iron Normal
TIBC Normal
Percent saturation Normal
Serum ferritin Normal
RDW Normal
RBC count ↑
Hb electrophoresisα-Thal trait: normal
Ringed sideroblasts None
Coarse basophilic stippling None
How are the following affected by Lead?
1) MCV
2) Serum iron
3) TIBC
4) Percent saturation
5) Serum ferritin
6) RDW
7) RBC count
8) Hb electrophoresis
9) Ringed sideroblasts
10) Coarse basophilic stippling
MCV ↓
Serum iron ↑
TIBC ↓
Percent saturation ↑
Serum ferritin ↑
RDW Normal
RBC count ↓
Hb electrophoresis lower
Ringed sideroblasts Present
Coarse basophilic stippling Present
What drugs can cause or resemble folate deficiency?
5-Fluorouracil
Methotrexate,
trimethoprim-sulfamethoxazole
Phenytoin
Oral contraceptives,
alcohol
What causes normocytic normochromic anemia? What are clinical findings? How long does it take before the reticulocyte count to be observed?
Acute blood loss: external, internal

↓ blood pressure, ↑ pulse

Requires 5 to 7 days
Is anemia of chronic disease normocytic or microcytic? What is most useful to distinuish acute and chronic ACD?
ACD is microcytic in only 10% to 30% of cases

Serum ferritin
What causes most cases of aplastic anemia? Of the known cases what is the most common cause?
Approximately 50-70% of cases are idiopathic

drug induced
What drugs cause reversible aplastic anemia? Irreversible? What toxins cause aplastic anemia? What infections cause aplastic anemia?
alkylating agents

chloramphenicol

Toxic chemicals in industry and agriculture (e.g., benzene, insecticides-DDT, parathion)

EBV; CMV; parvovirus; non-A, non-B hepatitis, HCV
What are 2 mechanisms that cause aplastic anemia?
1) Antigenic alteration of myeloid stem cells
* Causes T-cell activation and release of cytokines that suppress myeloid stem cells
2. Defective or deficient myeloid stem cells (acquired or hereditary)
What are clinical findings in aplastic anemia?
1. Fever due to infection associated with neutropenia
2. Bleeding due to thrombocytopenia
3. Fatigue due to anemia
What are lab findings in aplastic anemia?
1 Pancytopenia
2 Reticulocytopenia
3 Hypocellular bone marrow
How is aplastic anemia treated?
1. Discontinue drug, if it is responsible
2. Broad-spectrum antibiotics to prevent infection
3. Transfusions with irradiated blood (if not a bone marrow transplant candidate)
* Prevents graft-versus-host reaction
4. Immunosuppressive therapy
* Examples-antilymphocyte globulin, cyclophosphamide, cyclosporin
5. Bone marrow transplantation
* Good prognosis if patient is young and a compatible donor is found
What are burr cells and what condition are they found in?
RBCs with an undulating membrane found in CRF
What are blood work findings in CRF?
(1) Thrombocytopenia
(2) Defect in platelet aggregation that is reversible with dialysis
o Prolonged bleeding time
3) normocytic anemia
What is myelophthisic anemia? what is seen on a blood smear?
Malignant cells that displace normal marrow hematopoietic cells into peripheral blood

nucleated RBCs and immature myeloid cells into the peripheral blood is called leukoerythroblastic smear
What is haptoglobin?
acute phase reactant that combines with Hb to form a complex that is phagocytosed and degraded by macrophages causing a decrease in serum haptoglobin
Where does extravascular hemolysis occur?
RBC phagocytosis by macrophages in the spleen (most common site) and liver
Is there decreased haptoglobin in intravascular or extravascular hemolysis? Which has hemoglobinuria?
intravascular

Note: Renal tubules convert iron in Hb into hemosiderin
What type of genetic disorder is hereditary spherocytosis? What happens in the disorder? what is the most common defect?
autosomal dominant

Intrinsic defect with extravascular hemolysis via increased permeability of spherocytes to sodium

Mutation in ankyrin is the most common defect.
What occurs clinically in hereditary spherocytosis?
1. Jaundice due to increased unconjugated bilirubin
2. Increased incidence of calcium bilirubinate gallstones
* Due to increased concentration of conjugated bilirubin in bile
3. Splenomegaly
4. Aplastic crisis
* May occur in children especially after a viral infection (e.g., parvovirus)
What are laboratory findings in hereditary spherocytosis?
1. Normocytic anemia with spherocytosis
2. Increased MCHC
3. Increased RBC osmotic fragility

Note: Spherocytes rupture in mildly hypotonic salt solutions.
What are causes of spherocytosis other than the hereditary type?
* Other causes of spherocytosis-warm immune hemolytic anemia, ABO hemolytic disease of newborn
How is spherocytosis treated?
splenectomy
What causes hereditary ellyptocytosis? What are clinical features? What are lab findings? How is it treated?
1. Autosomal dominant disorder
2. Defective spectrin and band 4.1
3. Majority have no anemia or a mild hemolytic anemia.
4. Splenomegaly
5) Elliptocytes > 25% of RBCs in peripheral blood
6) osmotic fragility
7) splenectomy
What causes PNH? What is defective?
Acquired membrane defect in myeloid stem cells

1) Mutation causes loss of the anchor for decay accelerating factor (DAF).
2) Normally DAF destabilizes C3 and C5 convertase adhering to RBCs, platelets, and neutrophils * Prevents activation of the membrane attack complex and subsequent lysis of RBCs, neutrophils, and platelets
Why does PNH occur at night? What cells are effected?
Intravascular complement-mediated lysis of RBCs, neutrophils, and platelets
* Occurs at night, because respiratory acidosis enhances complement attachment to these cells
What are clinical findings in PNH? What is some at risk of developing?
1. Episodic hemoglobinuria
* May cause iron deficiency
2. Increased incidence of vessel thrombosis (e.g., hepatic vein)
* Due to the release of aggregating agents from destroyed platelets
3. Increased risk for developing acute myelogenous leukemia
What are lab findings in PNH?
1. Normocytic anemia with pancytopenia
* Microcytic if iron deficiency develops from hemoglobinuria
2. Decreased leukocyte alkaline phosphatase
3. Decreased serum haptoglobin
4. Increased serum/urine Hb
How is PNH diagnosed?
1. Identify the defect on hematopoietic cells
* Most sensitive test
2. Older tests
a) Screening test is the sucrose hemolysis test (sugar water test).
o Sucrose enhances complement destruction of RBCs.
b) Confirmatory test is the acidified serum test (Ham test).
o Acidified serum activates the alternative pathway causing hemolysis.
Who does sickle cell predominately occur in? What type of genetic mutation is it? Is hemolysis intra or extravascular?
1 Autosomal recessive disorder where valine for glutamic acid at sixth position of β-globin chain
2 Most common hemoglobinopathy in blacks
3 extravascular
What are factors that induce sickling in SCD?
1) HbS molecules aggregate and polymerize into long needle-like fibers.
2) Sickle Hb (HbS) concentration greater than 60% is the most important factor for sickling.
3) Increase in deoxyhemoglobin (correlates with decreased O2 saturation) increases the risk for sickling.
(a) Acidosis
o Right-shifts the OBC causing O2 release from RBCs
o (b) Volume depletion
o Intracellular dehydration causes an increase in concentration of deoxyhemoglobin
* (c) Hypoxemia
o Decrease in arterial Po2 decreases O2 saturation of Hb.
In SCD the Initial sickling is reversible with administration of? What do irreversible sickled cells do?
oygen

Irreversibly sickled cells have increased adherence to endothelial cells in the microcirculation.

* Microvascular occlusions (vaso-occlusive crises) produce ischemic damage.
What can prevent sickling in SCD both genetically and with drugs?
HbF

hydroxyurea increases HbF
what are clinical findings of HbSS in the extremities? who does it most commonly occur in?
Dactylitis (hand-foot syndrome)
1) Painful swelling of hands and feet
o Pain due to bone infarctions
2) Occurs in infants (usually 6-9 months old)

3) Aseptic necrosis of the femoral head
Acute chest syndrome is the most common cause of death in people with SCD. What causes it and what are the symptoms?
Precipitated by
(a) Pneumonia
o Streptococcus pneumoniae, Mycoplasma, viruses
(b) Infarction
(c) Fat embolism

Clinical findings
(a) Chest pain
(b) Wheezing
(c) Dyspnea
Note: Chest x-ray reveals lung infiltrates
When are Howell-Jolly bodies seen?
In SCD they are Nuclear remnants that appear in RBCs indicating loss of macrophage function
What are common pathogens that cause disease in SCD? What is the most common cause of death in children with SCD? What organism predominately causes osteomyelitis in SCD?
Streptococcus pneumoniae sepsis, Salmonella paratyphi osteomyelitis

S pneumoniae sepsis

Salmonella paratyphi; less frequently to Staphylococcus aureus
Aplastic crisis can occur in SCD. What is it associated with?
parvovirus
What occurs in sequestration crisis in SCD?
1) Rapid splenic enlargement
o Entrapment of RBCs causing hypovolemia
2) Reticulocytosis
What occurs in the kidney of someone with SCD?
Sickling may occur in peritubular capillaries in the medulla.
* Due to the low O2 tension in the medulla

Presents with microhematuria due to infarctions
* Always order a sickle cell screen in black patients with unexplained hematuria.

Renal papillary necrosis may occur.
What is the sickle cell screen?
Sodium metabisulfite reduces O2 tension, which induces sickling
What occurs in HbAS and HBSS on gel electrophoresis?
(1) HbAS profile-HbA 55% to 60%, HbS 40% to 45%
(2) HbSS profile-HbS 90% to 95%, HbF 5% to 10%, no HbA
prenatal screening can be done to determine SCD with blood smear. What is seen if SCD is present? What other disease of the mother can cause this?
Target cells: excess RBC membrane; sign of hemoglobinopathy or alcoholism
What are treatment and preventive measures in SCD?
Treatment
1. Treat infections
2. Pain relief (e.g., morphine)
3. Transfusion
* Acute chest syndrome (noninfectious vasoocclusive crisis of the pulmonary vasculature), aplastic crisis

Preventive measures
1. Hydroxyurea
2. Routine immunizations all current
3. Pneumococcal vaccine
4. Folic acid supplementation
Why in G6PD are neutrophils impaired?
Decrease in NADPH impairs neutrophils and monocyte killing of bacteria by the O2-dependent myeloperoxidase (MPO) system which requires NADPH as a cofactor for NADPH oxidase.
What is the most common enzyme deficiency causing hemolysis? What the genetics of it?
G6PD
X-linked recessive disorder
What are the subtypes of G6PD?
(1) Mediterranean variant in Greeks and Italians
(2) Black variant
Do people G6PD have intravascular or extravascular hemolysis?
intrinsic defect causing primarily intravascular hemolysis
What pathway is defective in G6PD? How does it work? What are Heinz bodies?
Decreased synthesis of reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH) in the pentose phosphate pathway
* (1) GSH normally neutralizes hydrogen peroxide, an oxidant product in RBC metabolism.
* (2) In G6PD deficiency, peroxide oxidizes Hb, which precipitates in the form of Heinz bodies.
(a) Heinz bodies damage the RBC membranes causing intravascular hemolysis.
(b) Heinz bodies removed from RBC membranes by splenic macrophages produce bite cells.
Is the mediteranean or black variant of G6PD worse?
Half-life of G6PD in the Mediterranean variant is markedly reduced.
* Produces a severe, chronic hemolytic anemia

Half-life of G6PD in the black variant is moderately reduced.
* Episodic type of hemolytic anemia after exposure to oxidant stresses
What drugs cause hemolysis in G6PD people? What food?
primaquine, chloroquine, dapsone, sulfonamides, nitrofurantoin

Fava beans (mainly in Mediterranean variant)
What are clinical findings in G6PD?
Sudden onset of back pain with hemoglobinuria 2 to 3 days after an oxidant stress
What are laboratory findings in G6PD? What is the best confirmatory test?
1. Normocytic anemia
2. Heinz bodies
G6PD deficiency: active hemolysis screen with Heinz body prep
(1) Identified with a supravital stain
(2) Best screen during active hemolysis
3. RBC enzyme analysis
* Confirmatory test after hemolysis has subsided
4. Peripheral blood findings
* Bite cells macrophage removal of membrane
What is PK? What causes it? What doesn't form? What pathway is involved?
1. Autosomal recessive disease
2. Most common enzyme deficiency in the Embden-Meyerhof pathway
* PK normally converts phosphoenolpyruvate to pyruvate leading to a net gain of 2 ATP.
What type of cell is present in PK deficiency? Is it intra or extravascular hemolytic?
Intrinsic defect with extravascular hemolysis

Chronic lack of ATP causes membrane damage.

* Results in dehydration of the RBC - echinocytes
What are clinical features of PK? Is there compensation/
1 Hemolytic anemia with jaundice beginning at birth
2 Increase in 2,3-BPG synthesis proximal to enzyme block
* Right shift of OBC causes increased release of O2, which somewhat offsets the clinical effects of the anemia.
What are laboratory findings in PK? What is the confirmatory test?
1. Normocytic anemia
2. RBCs with thorny projections (echinocytes)
3. RBC enzyme assay is the confirmatory test.
Is warm or cold Immune hemolytic anemia more common? What is the most common cause? Are they intra or extravascular hemolytic?
autoimmune warm type (IgG) most common cause

SLE

both
What are common findings in immune hemolytic anemia?
1. Jaundice due to unconjugated hyperbilirubinemia
* Occurs in extravascular types of hemolysis
2. Hepatosplenomegaly
* Due to work hyperplasia of splenic and liver macrophages
3. Raynaud's phenomenon
* May occur in cold types of AIHA
What is DAT an important test for and what does it do?
DAT detects RBCs sensitized with IgG and/or C3b and is most important marker of immune hemolytic anemia
What is the indirect Coombs test? When is it used?
Positive indirect antihuman globulin test---- Detects antibodies in the serum and is used in immune hemolytic anemia
What does a peripheral blood smear show in immune hemolytic anemia (both cold and hot)?
(1) Normocytic anemia
(2) Spherocytosis due to macrophage removal of RBC membrane (IgG type)
(3) RBC agglutination (IgM type
How is immune hemolytic anemia treated?
1. Discontinue any offensive drug
2. Corticosteroids
3. Immunosuppressive agents if corticosteroids are not effective
4. Splenectomy in selected cases
5. Intravenous immunoglobulin
* IgG coats all the macrophage receptors so they cannot phagocytose RBCs.
* Only used when most of the above treatments are not working
What causes macroangiopathic hemolytic anemias?
aortic stenosis most common cause, other valvular defects
Are Micro- and macroangiopathic hemolytic anemias intrinsic or extrinsic hemolytic anemias?
both
Microcirculatory lesions cause RBC fragmentation in microangiopathic hemolytic anemia called what?
schistocytes
What are blood findings in Micro- and macroangiopathic hemolytic anemias? Is haptoglobin increased/decreased? type of anemia?
1. Normocytic anemia
* Long-standing hemoglobinuria causes iron deficiency anemia.
2. Decreased serum haptoglobin, hemoglobinuria
3. Schistocytes in the peripheral blood
What transmits malaria? Why is there occasional fever? Is malaria intra or extravascular hemolytic?
Female Anopheles mosquito

intravascular hemolysis correlates with fever spikes

predominantly intravascular hemolysis, but there is extra
What is the most common type of malaria infection? When are the fever spikes? What protects people against this strain?
Plasmodium vivax

tertian fever pattern every 48 hours

# Duffy (Fy) antigen on RBCs is the binding site.

Duffy antigen often absent in blacks; protective
What malarial species produces Quotidian fever patterns?
Plasmodium falciparum has no fever pattern
Which malaria species causes nephrotic syndrome? What is its fever pattern?
Plasmodium malariae

Quartan fever pattern (every 72 hours)
What conditions causes microangiopathic hemolytic anemia?
1 Hemolytic uremic syndrome
2 Thrombotic thrombocytopenic purpura
3 Disseminated intravascular coagulation
4 HELLP syndrome: H, hemolytic anemia; EL, elevated transaminases; LP, low platelets; associated with preeclampsia
What are normocytic anemias with reticulocyte count <3%?
Acute blood loss
Early iron deficiency
Early ACD
Aplastic anemia
Chronic renal failure
What are examples of normocytic anemias with reticulocyte count >3%?
Hereditary spherocytosis
Hereditary elliptocytosis
Paroxysmal nocturnal hemoglobinuria
Sickle cell anemia
G6PD deficiency
Pyruvate kinase deficiency
Acute blood loss
Warm AIHA
Cold AIHA
Drug-induced immune hemolytic anemia
Alloimmune hemolytic anemia
Micro- and macroangiopathic hemolytic anemia
Malaria
What is the indirect Coombs test?
The indirect Coombs test (also known as the indirect antiglobulin test or IAT) is used to detect in-vitro antibody-antigen reactions
What is the direct Coombs test?
The direct Coombs test (also known as the direct antiglobulin test or DAT) is used to detect if antibodies or complement system factors have bound to RBC surface antigens in vivo.