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PHAR 303 > 11. Toxic Responses of Blood > Flashcards

11. Toxic Responses of Blood Flashcards

1
Q

What is hematotoxicology?

A

The study of adverse effects of exogenous chemicals on blood and blood-forming tissues. It can involve Drugs and non-therapeutic chemicals.

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2
Q

What are the different types of hematotoxicity? Define them.

A

– Primary toxicity
• One or more blood components are directly affected
• Common serious effect of xenobiotics

– Secondary toxicity
• Toxicity as a consequence of other tissue injuries or systemic disturbances -> not directly on the RBC itself.

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3
Q

What are the consequences of hematotoxicity?

A

hypoxia, hemorrhage, and infection (alterations in infection susceptibility)

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4
Q

What is the composition of whole blood?

A

It is composed of 55% plasma and 45% cells.
Plasma contains:
-Plasma proteins such as albumins (60%), globulins (35%), fibrinogen (4%), and others (1%)
-Serum

The rest of the blood is cells:

  • RBC’s (99.9%)
  • Platelets + WBC’s (0.1%)
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5
Q

What process does the cell component of blood come from? Describe the location where the process occurs in different life stages.

A

The cells are generated and regenerated via hematopoiesis.

  • First 8 weeks: fetus does hematopoiesis primarily in yolk sac.
  • Month 3-7: liver and spleen
  • Next (i guess young children?): distal long bones in skeleton
  • Adult: Bone marrow of axial skeleton
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6
Q

Describe the process of hematopoiesis in bone marrow.

L11-S6 figure

A
  1. Starts with the hematopoietic stem cell which is a multipotent stem cell capable of renewal.
  2. Upon the right conditions, the hematopoietic stem cell can divide or differentiate into a CMP (common myeloid progenitor) or a CLP (common lymphoid progenitor) which are primitive progenitor cells. ->(The lymphoid progenitor gives rise to T-cells, B-cells, and NK cells)
  3. The myeloid progenitor further differentiates into different progenitors for example the megakaryocyte erythroid progenitor (MEP) and the Granulocyte macrophage progenitor (GM).
  4. The progenitors then get committed to a certain cell lineage (lineage committed cells) such as: Megakaryocytes and erythroid progenitors (EP).
  5. The megakaryocytes eventually form platelets. The EP’s undergo intermediate steps (erythropoiesis) to become erythrocytes.
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7
Q

Describe the process of erythropoiesis. How long does it take? Where does it occur?

A

Takes approximately one week and occurs in the bone marrow.

  1. Day 1: Starts with the proerythroblast (which is the erythroid progenitor). 15-30 uM in size.
  2. Day 2: Basophilic erythroblast formed which actively synthesizes hemoglobin.
  3. Day 3: Polychromatophilic erythroblast is formed where hemoglobin appears (10-12 uM).
  4. Day 4: normoblasts are formed which are nuclei pyknotic (8-10 uM) -> erythroblasts condense their nuclei and nuclei will get ejected from the cell.
  5. Day 5-7: once the nucelei is ejected, the reticulocyte is formed which still contains some RNA and other organelle remnants. It is a precursor RBC.
  6. The reticulocyte enters circulation and sheds the extra components and becomes the mature RBC (Bi-concave disk). 7-8 days (7-10 uM).
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8
Q

Define erythron.

A

All stages of erythrocytes, including developing precursors in the bone marrow, and circulating mature erythrocytes.

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9
Q

What aspects of an erythrocyte can xenobiotics affect/target?

A
  1. Production
  2. Function
  3. Survival
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10
Q

What is a common effect of xenobiotics on the erythrocyte? What are symptoms?

A

Anemia:
– A reduction in the number or volume of red blood cells
– A person’s level of circulating hemoglobin is lower than a healthy person
– Inability of blood to supply adequate oxygen: Every organ system can be affected because it interferes with oxygen delivery to peripheral tissue.

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11
Q

What are the 3 groups anemia can be divided into?

A
  1. Caused by blood loss
  2. Decreased or faulty RBC production/
    Maturation
  3. Increased destruction of RBC
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12
Q

What type of analysis can you use to assess anemia?

A

Hematocrit analysis. It’s a percentage by volume of RBC’s in blood. Any hematocrit level that is depressed below normal levels for males (42%-52%) and females (37%-47%) can be characterized as anemia.

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13
Q

What are the different reasons that RBC numbers decrease (which can cause anemia)? Why is this significant?

A
  1. Decreased production of RBC - which is dependent upon:
    - Frequent cell division and
    - High rate of hemoglobin (Hb) synthesis
  2. Increased destruction of erythrocytes

This is significant because toxicants that affect these things can affect the amount of blood cells.

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14
Q

What is hemoglobin? What is heme? What is the hemoglobin range in males and females?

A

Hemoglobin: globular protein composed of 4 peptide chains. Each hemoglobin molecule contains 2 alpha and 2 beta chains. Each chain contains 1 heme.

Heme is a porphryin ring surrounding a single ion of iron. Each heme “holds” an iron that can interact with an oxygen molecule reversibly which forms oxyhemoglobin (HbO2).

Hemoglobin range:

  • Males: 14-18 g/dl
  • Females: 12-16 g/dl
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15
Q

How many hemoglobin molecules are in 1 RBC? How many molecules of oxygen can 1 RBC carry?

A
  • 280 million Hb molecules in each RBC

- Each RBC can carry more than 1 billion molecules of oxygen

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16
Q

What is iron deficiency anemia?

A

When there is not enough iron to incorporate into the heme porphyrin ring. This is the most common cause of anemia (>60% of anemias globally).

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17
Q

What is sideroblastic anemia?

A

Defects in the synthesis of the porphyrin ring (heme).

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18
Q

What are thalassemias?

A

Inherited disorders caused by the inability to produce adequate amounts of alpha or beta chains (for hemoglobin).

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19
Q

Where do heme and hemoglobin get formed? What is the last step to form heme? What two cellular compartments do the steps occur in?

A
  1. Heme and hemoglobin get formed in erythroblasts (in bone marrow)
  2. The last step in the formation of heme in the mitochondria is the incorporation of iron from the cytoplasm into the porphyrin ring in the mitochondria. -> this is where iron deficiency anemia comes into play.
  3. The initial and final steps of heme formation occur in the mitochondria. The intermediate steps occur in the cytoplasm.
  4. Globin is added to Heme in the cytoplasm to form hemoglobin
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20
Q

What is the recommended intake of iron for adult males and females? What can inadequate iron amounts be caused by?

A 
Males: 8mg/day
Females (up to 50 yrs): 18mg/day
inadequate iron amounts can be caused by:
1. inadequate iron consumption
2. Decreased iron absorption
3. Iron loss secondary to blood loss
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21
Q

What types of drugs can contribute to iron deficiency anemia?

A

Drugs that contribute to bleeding.

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22
Q

What is the mechanism of NSAID’s and what disease can it cause?

A
  • NSAIDS inhibit cyclooxygenases which are responsible for synthesizing prostaglandins and thrombocytes.
  • COX 1 is constitutively expressed and is for homeostatic effects whereas COX 2 is inducible and has mostly inflammatory effects (some homeostatic effects).
  • NSAIDS can affect mucosal lining of GI tract which can cause an increase in bleeding and contribute to chronic iron deficiency anemia
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23
Q

What is sideroblastic anemia? How is it characterized? What causes it?

A

Characterized by the presence of ring sideroblasts in the bone marrow
– Sidero = iron; blast=immature cells
– Erythroblasts with iron-loaded mitochondria
– Visualized by Prussian blue staining as a perinuclear ring of blue granules
• Like a sapphire necklace
• Block in the incorporation of iron into heme and a buildup of iron in the mitochondria

  • Caused by: defects in the synthesis of the porphyrin ring (which occurs in the mitochondria, and that’s why the buildup of iron is in the mitochondria)
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24
Q

How can you get sideroblastic anemia?

A
  1. It can be hereditary

2. It can be acquired due to the exposure of a toxic substance (more common)

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25
Q

What toxic substances can lead to sideroblastic anemia?

A
  1. Lead

2. Isoniazid (drug)

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26
Q

How does lead cause sideroblastic anemia?

A

3 ways: all involve interfering with the synthesis of heme.
1. (in mitochondria) Lead interferes with the ferrochelatase enzyme which usually incorporates iron into the prophyrin ring to make heme.

  1. (in mitochondria) Lead interacts with the aminolevulinic acid synthase (ALAS) enzyme which is the first and rate limiting step of heme synthesis (formation of delta-aminolevulinic acid).
  2. (in cytoplasm) it also interferes with the delta-aminolevulinic dehydratase (ALAD) enzyme which is the second step in heme synthesis. Conversion of delta-aminolevulinic acid.
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27
Q

What vitamin is PLP the active form of? What step in heme synthesis is PLP involved in?

A

PLP is the active form of vitamin B6 which is obtained in the diet. PLP is an important co-factor in ALAs factor for the formation of delta-aminolevulinic acid in the mitochondria.

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28
Q

How can isoniazid cause sideroblastic anemia?

A

Can interfere with ALAS (rate-limiting step of heme synthesis in mitochondria). It’s an antibiotic used to treat tuberculosis.

-either makes vitamin B6 inactive or interferes with its ability to interact with enzyme… we’re not sure.

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29
Q

What is megaloblastic anemia?

A

– Anemia where RBC count is low
– Characterized by RBCs (RBC precursors called megaloblasts in the bone marrow) that are larger than normal
– Can be congenital (uncommon) or acquired (common)
– Any defect that causes a slowing of DNA synthesis (inhibits nuclear division) but the functions in the cytoplasm remain in tact.

30
Q

What is the most frequent cause of megaloblastic anemia? Why?

A
  • Folate (FolicAcid) or Vitamin B12 (cobalamin) deficiency

- Why? because these vitamins are essential in DNA replication and repair.

31
Q

Describe how cobalamin(vitamin B12) is used in the body.

A
  1. Cobalamin from food combines with haptocorrin (R-protein) which helps it transit to the stomach where it can bind to intrinsic factor in the upper part of the small intestine.
  2. In the ileum, intrinsic factor bound cobalamin gets taken up by the cells where it can be taken up by other cells in conjunction with transcobalamin or haptocorrin in the serum.
  3. Main storage of cobalamin is in the liver for 2-4 years.
32
Q

Describe how folate (folic acid) is used in the body.

A
  1. Folate in the diet (fruits and vegetables) eventually get converted from poly-glutamate to mono-glutamate for absorption into the upper part of the small intestine (duodenum & jejunum).
  2. Within the enterocytes (SI cells) it gets converted to N5-Methyl-THF.
  3. Folate can be stored in the liver for 3-4 months.
33
Q

Why are vitamin B12 and folate important?

See slide 40.

A
  • They are cofactors in the synthesis of Thymidylate which is the rate limiting nucleotide in DNA synthesis.
  • In order for N5-Methyl-THF (form of folate absorbed in SI) to get converted to THF, it requires cobalamin (vit. B12) as a cofactor. THF can then go through other steps to be converted into thymidylate.
34
Q

How can megaloblastic anemia be related to folic acid or vitamin B12?

A

Megaloblastic anemia can be related to defective B12 absorption, folate deficiency from malnutrition, or both.

35
Q

How is alcohol related to megaloblastic anemia?

A
  • Alcoholics usually have a low folate diet.
  • Alcohol has toxic effects on gastric mucosa and production of intrinsic factor (for B12 absorption) -> stomach
  • Alcohol affects intestinal mucosa to interfere with absorption of folic acid (jejunum) and Vitamin B12 (ileum).
36
Q

What drugs can cause drug-induced megaloblastic anemia?

A
  1. Fluorouracil
  2. Methotrexate
  3. Neomycin (antibiotic)
37
Q

How can Fluorouracil cause megaloblastic anemia?

A

Drug: Fluorouracil
It is called a suicide substrate because it blocks thymidilate synthase which is the step that generates thymidylate from deoxyuridylate via the donation of a methyl group. Rate limiting factor in DNA synthesis.

38
Q

How can Methotrexate cause megaloblastic anemia?

A

It blocks the metabolism of folic acid by blocking dihydrofolate reductase. If dihydrofolate (side product of thymidylate synthesis via thymidylate synthase) is not reduced by dihydrofolate reductase (and then methylated in subsequent steps) DNA synthesis will slow down.

39
Q

How can Neomycin (antibiotic) cause megaloblastic anemia?

A

Interferes with the absorption of vitamin B12 which affects folate pathway since Vitamin B12 is a co-factor.

40
Q

What is aplastic anemia? What are the different forms?

A

Aplastic refers to the inability of stem cells to generate mature blood cells (failure of marrow to form blood)
– Also referred to as bone marrow hypoplasia

Different forms:
– pancytopenia (deficiency in red cells, leukocytes and platelets)
– reticulocytopenia (reticulocyte count <0.2%; normal range is 0.5%-2.5%)
—->“aplastic crisis”
– Pure red cell aplasia: only red cells affected

41
Q

What is the pathogenesis of aplastic anemia? (process by which the disease develops)

A

2 ways:

  1. Immune mediated: A drug or chemical introduces new antigens on the surface of stem cells which are then targeted for immune mediated destruction.
  2. Direct toxicity: Damage to the stem cell in the bone marrow can be directly cytotoxic -> reducing proliferation and differentiation
42
Q

What does aplastic anemia look like in bones?

A

Empty marrow.

43
Q

What are the different causes of destruction for aplastic anemia?

A 
• Inherited – Rare
--> Ex: Faconi anemia (mutations affects DNA repair)
• Acquired – More common
– Toxic chemicals 
• pesticides
• arsenic
• benzene (dose response relationship -> 4months - 1 year exposure)
• mercury
– Radiation
– Chemotherapy
– Medication (chloramphenicol)
44
Q

What are the different ways we can be exposed to benzene and what is the most common way?

A

Inhalation (most common)

  • Cigarettes
  • Individual activities
  • Automobile exhaust
  • Industry
45
Q

What are some symptoms of benzene toxicity?

A

Symptoms of benzene toxicity include: drowsiness, dizziness, headaches, tremors, confusion, unconsciousness.

46
Q

Review how benzene is metabolized from lecture 10 slide 59. It’s also in this lecture in less detail on slide 53.

A

This process is also why it can cause aplastic anemia (toxic metabolites).

47
Q

What type of pathogenesis for aplastic anemia does benzene contribute to?

A

Direct toxicity. The highly reactive intermediates (like benzoquinone) can lead to direct cytotoxicity in the stem cells.

48
Q

What is hemolytic anemia? What are the two forms?

A
  • Erythrocytes are destroyed and removed before their normal life-span is over (normal is 120 days)
  • Hemolytic anemia can be hereditary (sickle cell disease) or acquired

There are 2 forms of hemolytic anemia:
– Immune hemolytic anemia
– Non-immune hemolytic anemia

49
Q

What is immune hemolytic anemia? (IHA)

A
  • A rare complication of drugs, can be called drug induced hemolytic anemia (DIHA). It’s extremely rare (1/1million cases per year)
  • Antibodies are produced against the RBC -> IgG or IgM
  • the antibodies initiate destruction of the RBC’s through complement or through phagocytic cells (macrophages)
  • Xenobiotics can affect antibody binding to the RBC. For example penicillin binds on the RBC surface and causes and immune response against the drug-coated RBC. -> hemolysis.
50
Q

What is non-immune hemolytic anemia? What is another name for it?

See slide 60

A

Another name: Oxidative hemolytic anemia

  • Can be hereditary
  • Oxidative hemolysis increases reactive oxygen species. It’s associated with a G6PD (glucose-6-phosphate dehydrogenase) deficiency. G6PD is what supplies NADPH in the pentose phosphate pathway. Without NADPH the cell is susceptible to oxidative stress.
51
Q

Why does a G6PD deficiency cause hemolytic anemia?

See slide 60

A
  • The main limiting factor in a RBC is the ability to supply NADPH to counteract oxidative stress. The only way RBCs can generate NADPH is through the pentose phosphate pathway where G6PD is the first and rate limiting step.
  • The cell deals with hydrogen peroxide (ROS) by either using catalase or Gpx (glutathione peroxidase). GPx uses glutathione (GSH), an antioxidant, to help get rid of oxidative stress. During Gpx activity, it oxidizes glutathione to make GSSG. GSSG has to be turned back into glutathione (GSH) via reduction by glutathione reductase (GR) which requires NADPH. Without NADPH, glutathione is not replenished and the cell is susceptible to oxidative stress.
52
Q

What chromosome is a G6PD deficiency linked to? Is it common?

A
  • X chromosome linked. Males are more affected.

- It is not that uncommon and affects 400 million people worldwide

53
Q

What is the physical manifestation of hemolytic anemia?

A
  1. Most people are asymptomatic unless they’re exposed to a hemolytic trigger.
  2. Can be manifested as heinz bodies (denatured hemoglobin) or Bite cells (macrophages have taken up the denatured hemoglobin)
54
Q

How do fava beans link to G6PD deficiency? What is this called?

A
  1. Fava beans contain high levels of Beta-glucosides (vicine & convicine) which are converted to divicine and isouramil (aglycones).
  2. Divicine and isouramil are released on ingestion and are highly reactive compounds which contribute to oxidative stress (ROS).
  3. In a normal cell, the ROS would be detoxified because there is ample NADPH. In a G6PD deficient cell there is not enough NADPH and therefore eating too many fava beans would cause RBC destruction due to oxidative damage.

this is called Favism.

55
Q

What is methemoglobinemia?

A
  • The RBC’s have a deficient function in their oxygen carrying capacity.
  • Under normal conditions, most of the iron attached to RBCs is ferrous (Fe 2+). Upon oxidative stress, the ferrous iron is converted to ferric iron (Fe 3+) making oxidized hemoglobin (methemoglobin).
  • The body has ways to convert the ferric iron back to ferrous iron. The main endogenous pathway to do this is catalyzed by the cytochrome b5 reductase enzyme (minor pathway is via NADPH methemoglobin reductase).
  • However, when theres too much of ferric iron, Oxygen can’t bind properly and cant be transported, which reduces oxygen carrying capacity in blood. This can cause anemia, tissue hypoxia, and cyanosis.
56
Q

What is the physiological level of methemoglobin (as a percent of hemoglobin? How much is death?

A
  1. Physiologic is less than or equal to 2%.
  2. Death is greater than 70%.

Symptoms without death fall in between. See slide 68.

57
Q

What can cause methemoglobinemia?

A
  1. Congenital/hereditary: rare, cytochrome b5 reductase deficiency.
  2. Acquired: more common, nitrite & nitrate exposure
58
Q

What can we be exposed to nitrites and nitrates from? What certain population can be more susceptible?

A
  • Nitrites (NaNO2) is in meat preservatives. Excessive dietary exposure (ex: cold cuts) can lead to the formation of methemoglobin.
  • Nitrate (NO3-) is found in fertilizers and can get int0 ground waters and food.

Infants can be susceptible because:
– Have higher proportion of Fetal Hb (may be more rapidly oxidized to MetHb than adult Hb)
– Infants have lower levels of MetHb reductase than adults: more sensitive to nitrate/nitrite toxicity.

59
Q

What can be used to treat methemoglobinemia? What is the mechanism?

A

Methylene blue.
Methylene blue activates NADPH methemoglobin reductase and acts as a substrate. Methylene blue is therefore turned into methylene leucoblue which reduces methemoglobin by transferring electrons to hemoglobin.
Remember: under normal physiological conditions, cytochrome B5-reductase is what controls methemoglobin levels. Therefore, methylene blue activates an extra system on top of the cytochrome-b5.

60
Q

What are 2 case reports of people who suffered from methemoglobinemia and why?

A
  1. A 28 year-old brought to ED- loss of consciousness and cyanosis. they had consumed 15g of sodium nitrite one hour before their visit when the estimated lethal dose is 2.6g. He had 92.5% methemoglobin levels (remember that 70% results in death). He was treated with methylene blue.
  2. 5 members of a household became sick after eating meat seasoned with “Refined Iodized Table Salt”, a sixth person who did not eat the meat did not get sick. the salt was inaccurately labeled and was actually sodium nitrite.
61
Q

What are platelets? Give some of their characteristics.

A

Platelets are:
– small blood cells (fragments) that form clots to stop bleeding.
– produced in the bone marrow from megakaryocytes
– continuously replaced
• circulates for 9-12 days
• 350,000 (range = 150,000-500,000) platelets/μL of circulating blood

62
Q

What are the 2 conditions associated with abnormal platelet levels and what are the platelet levels associated with them?

A

– thrombocytopenia = abnormal depletion of platelets (too much destruction or inadequate production)
• 80,000/μL or less
– thrombocytosis = excessive number of platelets
• may exceed 1,000,000/μL

63
Q

What is DITP? What can it be caused by?

A

DITP = drug induced thrombocytopenia
it decreases the production and increases the destruction of platelets.

Can be caused by methotrexate or alcohol which have a cytotoxic effect directly on the platelets or megakaryocytes.

64
Q

Explain why penicillin can be a DITP?

A

It can cause immune-mediated platelet destruction.
Penicillin can act as a hapten by binding to the platelet membrane and eliciting an immune response that causes removal of the platelets.

65
Q

Describe what happens in the 3 phases of blood clot formation. (slide 80)

A
  1. Vascular phase: Injury to a blood vessel lining causes release of clotting factors. The broken vessel can expose the basement membrane, and things like collagen.
  2. Platelet phase: This can cause adhesion of the platelets to the exposed collagen. The platelets then come in, the endothelial cells can also release things like ADP (platelets can too) which activates the platelets and causes them to change shape and start to form the platelet plug -> platelet phase.
  3. Coagulation phase: Fibrin strands adhere to the plug to form an insoluble clot (acts like a net).
66
Q

How does the fibrin protein get made for the last step of blood clot formation?

A
  1. The release of clotting factors from the vascular phase causes a cascade that ends with prothrombin being converted to thrombin.
  2. Fibrinogen (soluble) then converts into Fibrin (insoluble) by the action of thrombin.
67
Q

Which proteins from the clotting factor cascade are made in the liver?

A

XII, XI, IX, VII, X, Prothrombin II, Fibrinogen I, XIII.

68
Q

The activation of which specific clotting factor activates prothrombin to thrombin?

A

Factor 10.

69
Q

What is significant about certain clotting factors and vitamin K? which clotting factors are involved?

A

Many of the clotting factors produced by the liver require vitamin K such as factors IX, VII, X, and II (prothrombin). Vitamin K is acquired from the diet and is manufactured by bacteria in the large intestine.

70
Q

What is the vitamin K cycle? How does warfarin affect it?

A
  1. Dietary vitamin K (quinone) is transformed into hydroquinone (active vitamin K).
  2. Active vitamin K can act as a co-factor for GGCX which produce the clotting factor proteins (factor IX, VII, X, and prothrombin (II)).
  3. after hydroquinone is used by GGCX, it is converted to its inactive form (epoxide) and the cycle restarts at VKOR.

Warfarin interferes with VKOR which causes the reduction of synthesis of clotting factors and the depletion of active vitamin K reserves.

PHAR 303 (21 decks)

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