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Block F: Defence > W1P1 > Flashcards

W1P1 Flashcards

Covers first half of W1: 1. CBCs and WBCs 2. Barrier Defenses and Innate Immunity 3. Normal and Abnormal Hematopoiesis 4. Approach to RBCs 5. Fever 6. Anti Pyretics

1
Q

Difference between Antigen and Epitope

A

Antigen: something that induces an immune response
Epitope: the smallest component of an antigen that is recognized by the immune system

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2
Q

What is an Antibody

- Where is it produced

A

aka: Immunoglobulin
It is a serum protein

Produced by: B cells, which become mature plasma cells that bind antigens and release Antibodies

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3
Q

what are Chemokines

A

They are proteins released by cells that attract other cells (like neutrophils and macrophages) to the area (from the blood, bone marrow and surrounding tissues)

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4
Q

The following symptoms are signs of what condition?

  • High fever
  • Headache
  • Myalgia
  • Nausea
  • Skin Rash
  • Hypotension
A

Cytokine Storm

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5
Q

What are the three functions of the immune system?

A
  1. Fight infections
  2. Prevent Cancer (TNF)
  3. Develop a memory response
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6
Q

What are examples of EARLY inflammatory mediators released by infected cells?

A

TNF: Tumour Necrosis Factor
CCL: chemokines, a type of cytokine
IFN: Interferons

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7
Q

What makes up our First Line of Defence

A 
Skin 
Hair/*CILIA*
Saliva/tears
Mucous 
Stomach acids
Bile
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8
Q

What are the four signs of inflammation

A
  1. Redness
  2. Swelling
  3. Heat
  4. Pain*
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9
Q

What are the mediators of inflammation?

What are their functions?

A

Mediators include:

  • Prostaglandins
  • Leukotrienes
  • Bradykinins

Functions:

  • Vasodilation
  • Vascular Permeability
  • Recruitment of cells to the area of damage
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10
Q

What are the two main cells lines formed from pluripotent hematopoietic stem cells in the bone marrow?

A

Common Lymphoid Progenitor (CLP) and

Common Myeloid Progenitor (CMP)

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11
Q

What cells come from the CLP?

A

CLP: Common Lymphoid Progenitor

produce B cells, T cells, and NK cells released into the blood
which travel to the Lymph Nodes WHERE they would be activated and become Effector cells: Plasma cell
Activated T cell and
Activated NK cells

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12
Q

What are the cells that come from the CMP

A

CMP: Common Myeloid Progenitor

In the bone marrow it produces: Granulocyte/macrophage progenitor cells which in the blood produces the granulocytes: Neutrophils, Basophils, Eosinophils, unknown precursor of mast cells and monocytes

The later two produce in mast cells and macrophages respectively in the tissues

In the bone marrow it also produces Megakaryocyte and erythrocyte progenitor cells from which comes platelets and RBCs respectively.

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13
Q 
Dendritic Cells (DC)
Where would you find them 
What is their function
What do they release
A

Found at the site of any skin interface
They release Defensins* which are protein mediators that reduce the acceptance of different microbes in the area (i.e. staph aureus is a common microbe found on our skin that our body protects us from)

Activated function: antigen uptake in peripheral sites and antigen presentation

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14
Q

Neutrophils

A

These cells are apart of the innate immune system

Activated function: Phagocytosis and activation of bactericidal mechanisms

They are the FIRST to arrive at site of inflammation. And they release more cytokines to recruit more immune cells.

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15
Q

Macrophages

A

similar to neutrophils except they are also: professional antigen presenting cells (APCs)

They reside in tissues

Activated function: phagocytosis and activation of bactericidal mechanisms + APC fnx

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16
Q

Eosinophils

  • What do they contain
  • What are their main targets
A

Activated function: killing of antibody-coated parasites
- also involved in allergic and hypersensitivity reactions

part of the innate immune defense

Their granules contain large cyrstals called Major Basic Protein

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17
Q

Mast Cell

A

Activated function: release of granules containing histamine* and active agents

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18
Q

Basophil

- what do their granules contain?

A

rarest of leukocytes

granules: heparin, histamin and leukotrienes

play a role in hypersensitivity reactions.

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19
Q

Natural Killer Cells

A

Activated function: Releases lytic granules that kill some virus-infected cells

it is an INNATE immune cells EVEN though it stems from CLP cells
because they do NOT have B/T cell markers

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20
Q

What are the three different players in cell communication?

A
  1. Cell Surface Receptors (PRRs, TLRs)
  2. Cytokines (ILs)
  3. Chemokines (CXC, CC, C)
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21
Q

Cell Surface Receptors

A

These are Pattern Recognition Receptors (PRRs) some of which are termed Toll-Like Receptors

When they bind to their ligand (e.g. bacterial cell wall protein) the innate response is activated immediately.

Bacteria, viruses and parasites have conserved common structures/components that can be recognized by these receptors

activations –> rapid response to perceived danger. This response includes phagocytosis, release of chemokines and cytokines.

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22
Q

Examples of cell surface receptors on a macrophage

Activation of these receptors lead to the release of?

A 
mannose receptor 
glucan receptor 
LPS receptor (CD14) 
TLR
scavenger receptor

Activation releases:

  • cytokines
  • chemokines
  • lipid mediators

Macrophages also phagocytose the infected cell.

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23
Q

Examples of Ligands that bind to PPRs

A 
Peptidoglycan
Zymosan
dsRNA
LPS (gram neg bacteria) 
Flagellin
ssRNA
unmethylated DNA
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24
Q

Cytokines

A

these are proteins, secreted by cells, that affect the behaviour of nearby cells - which have cytokine specific receptors

cytokine binding tells the cells what to do through intracellular signalling pathways.

some examples include interleukines: IL which are a family of cytokines involved in the activation of responding cells, cell growth and differentiation, and induction of fever.

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25
Q

What are three cytokines released by macrophages that systemic effects?

A

recall these are professional APCs.

The three main ones are IL-1B, TNFa, IL-6

IL-1B:

  • activates vascular endothelium
  • activates lymphocytes
  • local tissue destruction
  • increases access of effector cells

systemic effects: Fever + production of IL-6

TNFa:
- activates vascular endothelium and increases vascular permeability–> increase of IgG, complement and increased fluid drainage to lymph nodes.

systemic effects: Fever, Shock

IL-6:

  • Lymphocyte activation
  • increased antibody production

systemic effects: Fever + induces acute-phase protein production

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26
Q

The Complement System

A

Is a series of proteins, found in plasma, that are involved in:

  • recognition of surface structures on pathogens,
  • inflammation,
  • activations of innate cells
  • killing
  • clearance of pathogens and products of inflammation from the body

ultimately preventing damage.

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27
Q

What are the three complement system pathways

A
  1. Classical: Antigen-AB complexes (pathogen surfaces)
  2. Lectin: Mannose-binding lectin or ficolin binding carbohydrates on pathogen surfaces
  3. Alternative: Pathogen surfaces

They all ultimately lead to C3 convertase which produce C3a, C5a: peptide mediators of inflammation, phagocyte recruitment

and C3b: binds to compliment receptors on phagocytes, leading to opsonization of pathogens and removal of immune complexes
which then lead to terminal complement components: which form membrane-attack complex, lysis of certain pathogens and cells.

so the three outcomes of the complement system are:

  • inflammation
  • opsonization of pathogens, - MAC
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28
Q

Timing of

innate vs early induced innate vs adaptive immune responses

A

Innate: 0-4 hours

Early induced Innate: 4-96 hours/4 days

Adaptive Immune: after 96 hours. leads to clonal expansion and differentiation to effector cells.

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29
Q

Systemic Inflammatory Response Syndrome (SIRS)

A

Uncontrolled inflammation leads to multiple organ involvement, especially lungs, kidneys, vasculature, liver and gut and a coagulopathy.

Diseases that show features of SIRS

  • bacterial sepsis (meningococemia)
  • pandemic influenza
  • SARS, COVID

In these diseases, infectious agents use cytokine storm as a sort of smoke screen to prevent orderly activation of both the innate and adaptive responses thus prolonging the time for replication and increasing the mortality in the hosts.

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30
Q

Patient related factors that influence CBC results

A
  • Activity
  • Stress
  • Altitude
  • Time of day
  • Medications
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31
Q

What does a total WBC count include?

A

all circulating, nucleated HEMATOPOIETIC cells with the exception of nucleated RBCs

WBC count used to diagnose and manage pts with hematologic and infectious diseases

also used to monitor pts using cytotoxic drugs, radiation therapy and some antimicrobial drugs.

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32
Q

WBC differential

A

the relative amounts of specific types of WBCs: neutrophils vs lymphocytes vs monocytes vs eosinophils vs basophils

too many or too little of a specific type of WBC can increase index of suspicion of infection, immune problem and conditions like leukemia.

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33
Q

Which is the most abundant WBC?

A

Neutrophils make up 50-60

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34
Q

Absolute vs Relative CBC

A

absolute count is considered more clinically valuable, it is a superior indicator of inflammation and infection.

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35
Q

Stages of Neutrophil development

A
  1. Metamyelocyte: the youngest neutrophil. Large nucleus, round or bean-shaped. abundant cytoplasm, pale blue
  2. Neutrophil band or stab: The nucleus is elongated and curved (horseshoe/S-shaped), cytoplasm is abundant, pink
  3. Segmented neutrophil: is a mature neutrophil, nucleus is separated in 2-5segments or lobes. cytoplasm is pale red.
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36
Q

Which are the largest WBC circulating in peripheral blood

A

Monocytes

they become macrophages when they reside in tissues

macrophages have different names depending on their tissue, i.e. Kupffer cells = macrophages that live in the liver

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37
Q

Mononuclear Phagocyte System

A

This system is used to describe the monocytes and macrophages because of their complex connection to the blood stream and tissue

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38
Q

When do Macrophages arrive at the site of injury

A

within 48 hours

usually the first cell to process and present antigen to lymphocytes

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39
Q

Lymphocytes

A

These are non-granulocytes responsible for immune responses to specific organisms

i.e. T cells and B cells

both produced in the bone marrow. T cell matures in thymus.

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40
Q

T cells

A

mature in the Thymus
responsible for cell-mediated immunity

it stimulates the B cell and triggers humoral/antibody mediated immunity

it has SEVERAL subtypes that can be divided into regulatory or effector cells!

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41
Q

B cells

A

Mature in the bone marrow

Is responsible for humoral antibody-mediated immunity

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42
Q

Neutrophilia

  • most common cause?
  • timeframe
  • type of disorder
  • associated with which other conditions?
A

Most commonly caused by: Acute Bacterial Infection

Timeline: Neutrophil counts will rise 4-6 hours after an invasion by microorganisms

This is a type of myeloproliferative disorder, and this type of disorder includes polycythemia vera and chronic myelocytic leukemia

high neutrophil count is also associated with

  • obesity
  • smokin
  • stress of surgery
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43
Q

Right vs left shift in neutrophils

A

Right shift: more mature neutrophils elevated
- pathologic conditions

Left shift: increased number of immature neutrophils released from the marrow

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44
Q

Neutropenia
- some causes

vs severe neutropenia

A

Count of less than 2,000 x 10e9/L

can occur with severe prolonged infections, or increased destruction of WBCs

consequence: inability to mount adequate defence when challenged

severe neutropenia: count less than 500 x 10e9/L
- predisposed to bacterial infection and opportunistic infections

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45
Q

Monocytosis

Absolute vs relative vs reactive absolute

A

Absolute Monocytosis: marker of myeloproliferative disorder (i.e. chronic myelomonocytic leukemia)

  • requires bone marrow examination and cytogenetic studies
  • hematology consultation needed

Relative Monocytosis: seen during recovery from drug-induced neutropenia
- does NOT require additional work-up

Reactive Absolute Monocytosis: Reflect chronic infectious, inflammatory, granulomatous processes, metastatic cancer, lymphoma, radiation therapy, and depression.

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46
Q

Lymphocytosis

Reactive Lymphocytosis vs B cell leukemia

A

Reactive Lymphocytosis with NORMAL appearing small lymphocyte morphology: viral etiology (e.g. mononucleosis, cytomegalovirus, measles)

B Cell Leukemia: (ALL or CLL)
merits a hematology consultation if clinical suspicion is present.

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47
Q

Eosinophilia

Triggers?

A
  • an increase in the eosinophil count

Triggers

  • occurs in response to parasitic infections
  • bronchoallergic reactions: asthma, allergic rhinitis, and hay fever
  • skin rashes
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48
Q

Basophilia

A

is the most uncommon cause of an elevated WBC

  • Should be suspected in patient with hypersensitivities
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49
Q

What is a normal process of aging

A

Lymphopenia

however NOT normal in children obviously. this maybe the only early sign of immune deficiency

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50
Q

How many litres of blood is there in an average human body?

How much of it is water vs proteins?

A

5-6 litres

90% water
7% proteins
2% organic compounds
1% inorganic salts

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51
Q

What is the ration of plasma vs cellular elements in blood?

A

55% plasma

45% cellular elements

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52
Q

Plasma vs Serum

A

acellular components
serum = plasma WITHOUT clotting factors

recall plasma makes up 55%

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53
Q

Buffy coat

A

consists of WBC and platelets, this is the 1%

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54
Q

Hematocrite

A

the percentage of blood by volume that consists of RBC

usually expressed as a decimal percentage from 0.000 to 1.000

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55
Q

The Erythrocyte

  • what is has vs lacks
  • shape
A

RBC
It is acidophilic- stains red with eosin

Lacks

  • Nucleus
  • Organelles

DOES have

  • membrane
  • Cytoskeleton
  • Enzymes
  • Hgb

it is a biconcave disc = increases SA

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56
Q

What is the lifespan of RBC
- how many cells replaced daily ?
where are they broken down?

A

100-120 days

1% replaced daily

broken down in cells of spleen and liver

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57
Q

What is Anemia?

What are the values to diagnose anemia?

A

Is when there is fewer than normal RBCs resulting in less Hgb

Men: Hgb less than 140 g/L
Women: Hgb less than 120 g/L

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58
Q

What is the entire structure of the RBC held together by?

A

the cytoskeleton*
depends on them to keep their shape

issues with cytoskeleton = diseases

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59
Q

List the 6 variations in RBCs

A

Microcytosis
Macrocytosis
Sickle cell shapes
Red cell fragments
Eccinocytes: spike cells, seens in renal insufficiency
Target cells: seen in hepatic insufficiency

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60
Q

What is Microcytosis

- common causes

A

smaller RBC size

Causes:
Iron Deficiency
Disorders of Hgb synthesis (i.e. thalasemmias)
Lead poisoning

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61
Q

What is Macrocytosis

- Common Causes

A

larger RBC size

Causes:

  • Vit B12 deficiency
  • Thyroid disease
  • Drug and alcohol effect
  • Disorders of the marrow (myelodysplasia)
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62
Q

The reticulocyte

  • too few vs too many vs normal in marked anemia
A

this is a young RBC, still has it’s nucleus/ribosomal TNA. they normally circulate in the peripheral blood. Often not included in the CBC, but important to check for RBC disorders.

too few: impaired production
too many: accelerated destructions
normal in anemia: impaired production (impaired compensation)

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63
Q

Which is the smallest cell in the blood?

A

Platelet.

* not REALLY considered a proper cell because it too has no nucleus

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64
Q

Which two blood cells don’t have a nucleus

A

RBC and platelets

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65
Q

Platelets

A

smallest “cell” in the blood
has no nucleus
comes from fragments of megakaryocytes of the bone marrow
filled with granules: serotonin and thromboxanes involved in clotting

it’s membrane has SEVERAL proteins to enable interaction with each other and with clotting factors

66
Q

What are the two leukocyte subtypes

A

Granulocytes

  • polymorphonuclear cells
  • neutrophils, eosinophils, basophils

Agranulocytes

  • mononuclear cells
  • monocytes and lymphocytes
67
Q

What are the two kinds of granules in a neutrophil

A

specific granules vs azurophilic granules

recall main mission of neutrophil is to phagocytose

68
Q

Where does hematopoeisis occur

child vs adult?

A

occurs in the bone marrow
fetus: yolk sac

infancy to childhood: entire skeleton participates (distal bones too), + the liver and spleen

adult: axial skeleton

69
Q

Two types of bone marrow

A

red: presense of blood and blood-forming cells
yellow: presence of a great number of adipose cells

70
Q

List some key players in hematopoiesis

A
  • Hematopoietic stem cell (HSC)
  • Pluripotent stem cell
  • bone marrow microenvironment
  • stroma
  • endothelial cells
    fibroblastoid cells
    miscroenvironment
71
Q

What are the stromal cells

A

Bone marrow stromal cells (BMSCs) usually refers toa group of multipotential, heterogenous members within the bone marrow that act as stem/progenitor cells of the bone tissue and are indirectly responsible for hematopoiesis.

they can become for example:

Macrophages
Fibroblasts
Endothelial cells

72
Q

Hematopoietic stem cells

- identified by which cell markers

A

capable of self renewal

cell markers: CD34, sca-1

73
Q

progenitor cells

some examples

A

not capable of indefinite self renewal
may not be capable of differentiating into ALL forms of blood cells as is the HSC

ex. Marrow progenitor cells: may differentiate into all forms of blood but cannot renew indefinitely

Common Myeloid progenitor (CMP)

  • Common megakaryocytic/erythroid progenitor
  • Common granulocyte/monocyte progenitor

Common Lymphoid Progenitor (CLP)

74
Q

erythropoiesis

  • controlled by which hormone?
  • factors that regulate it
  • timeframe
A

process of creating RBC/erythrocytes

hormone: erythropoetin [EPO] (made in the kidneys in response to low oxygen) which promotes it’s differentiation form one stage onto the next

starts as proerythroblast then becomes reticulocyte before a full RBC

regulated by rate of RBC destruction and tissue oxygen needs

timeframe: takes up to ONE week for EPO to reach bone marrow receptor and produce an effect. thus won’t be see in acute conditions.

75
Q

Platelet Production

- main player

A

Thrombopoietin (TPO)

produced in the liver (often seen thrombocytopenia in cirrhosis)
It is a megakaryocyte growth factor

76
Q

Hemoglobin (Hgb)

  • structure
  • function
  • production
A
  • made up of 4 polypeptide chains, each containing a heme group
  • each heme group can bind one oxygen molecule

Synthesis requires
- supply of iron
Normal production of protopophyrin and globin

77
Q

RBC production

  • lifespan
  • rate of destruction
  • How can you tell if RBC production is in a steady state?
A

lifespan: 100-120 days
destruction rate: 1%
Steady state: if normal erythroid/granulocytic ratio: 1/3 and based on the reticulocyte index

78
Q

what on a CBC tells you if pt has micro/macrocytosis?

A

MCV: Mean RBC Volume*: average size of RBC

microcytosis: <80
macrocytosis: >100

79
Q

Anemia

A

Occurs when there is an upset in the balance of RBC production and RBC destruction or loss (hemolysis)

80
Q

Polycythemia

A

Case of there being TOO MANY RBCs

81
Q

Approach to Anemia via CBC

MCV Finding: Microcytic

A
  1. Check Ferritin and Iron status
    a. Low: Iron deficiency anemia
    b. Normal: Thalassemia Hemoglobinopathy-> hemoglobin studies
    c. High: Anemia of chronic disease, Sideroblastic Anemia -> Bone marrow ringed sideroblasts
82
Q

Sideroblastic Anemia

A

Sideroblastic anemia is a group of blood disorders characterized by an impaired ability of the bone marrow to produce normal red blood cells . In this condition, the iron inside red blood cells is inadequately used to make hemoglobin, despite normal amounts of iron.

83
Q

Approach to Anemia via CBC

MCV Finding: Normocytic

A

Do Reticulocyte count

a. Low: aplasia anemia of chronic disease. Associated with high CRP and other cytokines
b. Normal: Acute blood loss
c. High: Hemolysis Chronic blood loss, associated with:
- high LDH
- high Bilirubin
- low haptoglobin
- can do a direct anti-globulin test

84
Q

Approach to Anemia via CBC

MCV Finding: Macrocytic

A

Do a blood smear morphology of neutrophils

a. No hypersegmented neutrophils

i. polychromasia -> reticulocytosis, associated with
- high LDH
- high bilirubin
- low haptoglobin
- direct anti globulin test
ii. Target cells -> Liver disease associated with
- high liver enzymes

b. Hypersegmented Neutrophils
Vit B12/Folate deficiency

85
Q

what is a particular sign that signals someone may have VITB12 deficiency

A

any problems walking, especially in the dark

because this deficiency can lead to neurologic issues

physical exam:

  • oral examination of the tongue
  • abdominal exam, R/O hepatosplenomegaly
  • Neurologic exam for loss of proprioception
86
Q

What tests should be ordered for someone with macrocytic anemia?

A
  • peripheral smear
  • liver panel (elevated liver enzymes)
  • reticulocyte count
  • serum folate/RBC folate
  • serum vit B12
87
Q

Megaloblastic anemia

  • investigative findings
  • consequences
  • either due to a. or b.
A

B12 or folic acid deficiency
results in defective hematopoiesis

Either due to

Pernicious Anemia: autoimmune destruction of parietal cells of the stomach. seen in up to 12% of the elderly population
( because parietal cells release instrinsic factor which is what enables absorption of b12)

other….
Nutritional
Malabsorption (due to conditions or diseases: celiac, crohn’s, parasitic infestation)

88
Q

Signs of Microcytic Anemia

A

deformed nail bed

fatigue

89
Q

Where is most of the total body iron stored?

A

Liver stores 70-90% of total body iron

so if you have liver issues, you may expect microcytic anemia maybe?
We did learn that cirrhosis is associated with thrombocytopenia because liver produces TPO

90
Q

Thalassemias

A

Absent or reduced produciton of globin chain = imbalance =
Excess globin chains precipitate within RBC, which makes them small, unstable, and die rapidly

two types: alpha or beta thalassemia

91
Q

Alpha Thalassemia Spectrum

A

you have different combinations of aa/aa
you can be missing one, two, three or all four
you can be missing 2, one on each side = trans, or 2, both from one side = cis

92
Q

In what population is thalassemia more common?

A

It is common in individuals of Mediterranean, Middle Eastern, Aftrican, South and Southeast Asian

93
Q

Alpha Thalassemia, diagnostic tests?

A
  1. Exclusion of iron deficiency and other hemogloinopathies. recall that thalassemia is a microcytic anemia present when Iron levels are NORMAL.
  2. Hb electropheresis is normal…
  3. DNA investigation. Must be done for prenatal samples for parents with alpha thalassemia trait.
    (can lead to fetal death from hypoxia)
94
Q

Beta Thalassemia

A
  • same principles as alpha thalassemia
  • different spectrums: minor, intermedia or major [would need blood transfusions to survive]

DIFFERENCE with alpha:
diagnosis is easily made with an abnormal hemoglobin electropheresis (will show elevated Hb A2)

No need for PCR testing for diagnosis

95
Q

What are the 4 etiologies of hemolytic anemia?

A
  1. Extra-corpuscular
  2. RBC membrane
  3. Enzyme defects (along the ring)
  4. Hemoglobin (in the biconcave center)

all these are relative to the RBC

96
Q

Extra-corpuscular hemolytic anemias

A

Autoimmune hemolytic anemia (AIHA): Immunoglobulin (IgG) mediated

diagnostic test: positive direct coombs test (types of hypersensitivities)

ex. heart valves (?)

97
Q

Red cell membrane hemolytic anemias

what are the two types?

A

There are two types:
Hereditary Elliptocytosis and
Hereditary spherocytosis

98
Q

Enzyme Defect Hemolytic Anemia

A

these are congenital

examples:
G6PD deficiency
PK deficiency

99
Q

Hemoglobinopathy and severe thalassemias Hemolytic Anemia

A

you’d have

  • unstable hemoglobins
  • congenital
  • may have family history
  • may have other clinical manifestations
100
Q

Sickle Cell Disease

A

Hemoglobinopathy hemolytic anemia (type 4)

Mutation of B-globin gene in RBC

  • diagnosed by a hemoglobin electropheresis
  • present form birth, sickled shape of RBC causes hemolysis, anemia, and vaso-occlusive = organ damage and PAIN crisis [pt will complain of limb pain]
  • this is the most common single gene disorder in the world
101
Q

What is the most common single gene disorder in the world?

A

sickle cell anemia

102
Q

What is polycythemia

A

Polycythemia refers to an increase in the number of red blood cells in the body. The extra cells cause the blood to be thicker, and this, in turn, increases the risk of other health issues, such as blood clots. Polycythemia can have different causes, each of which has its own treatment options

103
Q

The following signs could be indications of which RBC illness.

  • Facial plethora
  • red/purplish mucous membranes
  • no sign of cyanosis, normal O2 sat
  • marks of pruritus
  • spleen enlarged on exam
A

a lot of red, so think a lot of RBC = polycythemia

confirm that it is true polycythemia and not relative due to decrease in palsma volume (dehydration/diuretic invoked)

measure EPO level

104
Q

Types of Erythrocytosis

A

Relative and Absolute erythrocytosis

relative: water losses

absolute:
primary or secondary

105
Q

What are the two types of absolute erythrocytosis

A

Primary: independent of EPO
i.e. polycythemia (chronic erythroid leukemia)

Secondary: stimulated by EPO

a. appropriate: in cases of hypoxia
b. inappropriate: no hypoxia. indication of renal or liver cysts/tumours

106
Q

Polycythemia Vera

  • when to suspect
  • how to investigate it
  • treatment
A

suspect when: you have polycythemia INDEPENDENT of EPO
- it is compatible with a myeloprliferative disorder

investigate:
with JAK 2 blood tests
+/- Bone marrow aspirate and biopsy
refer to hematology

Treatment
- will need aspirin and phlebotomies to decrease his Hb back to normal and to avoid thrombotic risks

107
Q

What is the opposite of anemia?

A

polycythemia: too many RBCs

108
Q

In which anemia would occult bleeding be the cause?

A

microcytic anemia; presenting with Fe deficiency.

important to check for occult bleeding in GI tract, or menses

109
Q

Hemoglobin H disease

A

–/-a
on the severe spectrum of thalassemia disorders

presents as microcytic anemia with NORMAL iron levels.

110
Q

What are cis and trans thalassemias

A
  • a/-a = trans
  • -/aa = cis

both present as mildly anemic, microcytic anemia with NORMAL iron values

111
Q

-a/aa thalassemia means?

A

this person is only a carrier

will have a normal MCV

112
Q

What is the normal temperature range?

- When is our temperature the lowest vs highest?

A

35.3 - 3.7.7

lowest at 6am, highest at 4-6pm

113
Q

Average variation of body temperature is by how much?

what about for females after ovulation?

A

variation: 0.5 degrees

ovulating women: 0.6 degrees higher after ovulation

114
Q

Where is temperature measured to receive the best approximate?

  • how do oral readings compare?
A

Rectal and esophageal are the best approximations

oral temperature is about 0.6 degrees lower.

115
Q

Where is the control centre for body temperature?

A

several nuclei in the anterior hypothalamus

116
Q

What is the acute phase resposne?

A

It includes;
Fever
Neutrophilia
Change in serum proteins, hormones, intermediary metabolism
Sickness behaviour: lethargy, anorexia, loss of interest, hyperalgesia, sleep disturbance.

117
Q

Fever vs Hyperthermia?

A

Fever: increase in core temperature due to a change of the hypothalamic set point.
rarely over 41.1 degrees

Hyperthermia: is due to an overriding of the set point, temperature can be >41.5 degrees
aka hyperpyrexia

118
Q

What mechanisms do we use to increase our temperature to maintain core temperature in cold environments?

A
  1. vasoconstriction
  2. increased thermogenesis in brown fat. (important in new borns)
  3. piloerection
  4. shivering
  5. behavioural changes
119
Q

What mechanisms do we use to decrease our temperature to maintain core temperature in warm environments?

A
  1. Vasodilation
  2. Evaporation- insensible water loss, sweating
  3. Behavioural changes
120
Q

What are the different causes of fever?

A
  1. Infections – parasitic, bacterial, fungal, viral
  2. Tissue damage – myocardial infarction
  3. Inflammatory conditions – Kawasaki disease, rheumatic fever,
  4. Immune reactions eg transfusion reactions, drug fever
  5. Malignancy (malignant tumour?)
121
Q

What are the causes of hyperthermia?

A

Environmental heat and humidity
Exertion
Endocrine – thyrotoxicosis [too much thyroid hormone in you]
Drugs – anaesthetics
serotoninergic drugs 1e antidepressants

122
Q

Exogenous vs Endogenous pyrogens

A

Fever is induced by CYTOKINES, here is the back story:

  • It has been known for many years that bacterial products injected into animals produced fever., and they became known as EXOGENOUS pyrogens.
  • In the 1940’s, a protein was isolated from infected macrophages that would induce fever in experimental animals, and it was labelled ENDOGENOUS PYROGEN
  • Since then dozens of proteins that relay signals between cells of the immune system have been found and labelled CYTOKINES
123
Q

What is the pathogenesis of Fever?

A

Our immune cells recognize PAMPs (pathogen-associated molecular patterns) or DAMPs (Damage associated molecule patterns)

They use TLR (1-10) found on the cell surfaces and endosomes, which bind to LPS and other bacterial substances.

binding to TLR sets off a cascade of intracellular events, which results in release of pro-inflammatory cytokines

124
Q

What is secreted as a result of TLR activation?

A

pro-inflammatory mediators:
IL-1, TNFa which promotes secretion of IL6

these are the three systemic cytokines, as they lead to fever.

Knockout mice deficient in TNF or IL-1 have a decreased febrile response, those deficient in IL-6 lose the febrile response completely.

125
Q

What are the actions of IL1B, IL6, TNFa?

A
  1. Fever and malaise
  2. Acute phase proteins – c-reactive protein – binds to bacteria improves activation, activates complement
    - mannose-binding-lectin – also binds to pathogens and triggers complement
  3. Pulmonary surfactant proteins SP-A and SP-D
  4. Protein and energy mobilization
    - Migration of dendritic cells to lymph nodes
126
Q

Where do the three fever cytokines go and what do they trigger inorder to influence body temperature?

A
  • IL-1 and TNF –alpha stimulate production of IL6
  • These cytokines are carried in the bloodstream to the anterior hypothalamus, where they stimulate an increase in prostaglandins, especially PGE2.

Lesions in the hypothalamus will completely abrogate the response to LPS

  • Substances such as ASA which block PGE2 synthesis decrease the febrile response to LPS
  • Knockout mice which have lost the genes for PGE2 synthesizing enzymes or the PGE2 receptor do not produce fever with LPS
  • PGE2 is also produced peripherally, and this may account for the muscle aches and malaise which accompany fever.
127
Q

What happens with the activation of CVO?

A

CVO = circumventricular organs

ACTIVATION leads to:

  • Highly vascular
  • Fenestrated endothelium
  • Neural connections to other nuclei
  • Histochemical evidence of activation after injection of LPS
  • Damage to OVLT prevents fever after injection of LPS
  • Some microglia in the CVO’s express TLR’s and respond directly to LPS, even before peripheral production of cytokines
  • Endothelial cells throughout the brain can be activated by cytokines
128
Q

Which substance is the FINAL MEDIATOR of fever in the brain?

A

PROSTAGLANDIN E2
PEG2 causes fever when injected into the ventricle and the anterior hypothalamus

PGE2 can cross theblood-brain barrier and acts on EP3and perhaps EP1 receptors on thermosensitive neurons

This triggers the hypothalamus to elevate body temperature by promoting an increase in heat generation and a decrease in heat loss

The initial response thought to be mediated by ceramide release in neurons in the anterior hypothalamus

The late response is mediated by coordinate induction of COX-2 and microsomal PGE synthase-1 in the endothelium of blood vessels in the preoptic hypothalamic area to form PGE2GE2

129
Q

What are the two methods of heat production?

A
  1. Heat production
    Obligatory – produced by metabolic processes
    Facultative – produced by muscular activity
130
Q

What are the methods of heat loss?

A

Radiation – about 60% at rest
Evaporation – about 20% not active if relative humidity over 75%
Convection – about 20%

131
Q

How is heat lost during fever?

A

Increased blood flow to the skin.
Increased water loss through the skin and lungs
Behavioral changes

132
Q

What are the evolutionary benefits of continuing to produce fever?

A
  • Some bacteria and viruses reproduce more slowly at a temperature of 40
  • Increased temperature decreases the availability of iron, required by bacteria for growth.
  • Increased temperature may inhibit replication of some viruses
  • Almost every aspect of the innate and adaptive immune system is enhanced by fever-range temperature
  • “Sickness behavior” limits spread of infection
133
Q

How does fever put metabolic stress on the body?

A

Fever puts a metabolic stress on the body
O2 requirement and CO2 production
Water loss
Cerebral injury
Discomfort
Seizure activity?
Each degree C of temperature increase increases O2 requirement 11-13 % and heart rate 5-10%

134
Q

When should fever be treated?

A

Fever over 40 should be treated
Fever should be treated if the nervous system or cardiorespiratory system is compromised eg sepsis
Otherwise it should be treated to reduce discomfort.

135
Q

Fever Phobia

A

caregivers, pediatricians, ER nurses, a significant proportion believe fever is dangerous and can lead to seizures/brain damage.

HOWEVER:
Fever is a part of the normal inflammatory response
Fever may be beneficial
It may be dangerous where CNS or cardiovascular systems are compromised
It causes anxiety out of all proportion to the damage it does.
Treating fever is important to decrease discomfort and anxiety

136
Q

How would you respond to a toddler with fever?

why do new borns have fever more often?

A 
Does the child look well?
History of travel?
Any underlying conditions?
Are immunizations up to date?
Is the physical exam normal?

If not, the illness is almost certainly viral and no investigation is needed

Newborns are less able to localize infection
Severe bacterial infections: E. coli
Group b streptococcus
Listeria
First month 7% to 12.5% of febrile infants have a serious bacterial illness vs 1 – 3% of children 3 – 36 months

Serious viral infections: Herpes virus
Varicella-zoster
RSV

137
Q

Fever in old age

A

Infection is very likely because local defense mechanisms are impaired
Lungs
Urinary tract
Skin
However, fever can also be due to primary CNS damage
Pathogenesis poorly understood
hypoxia, ischemia
reperfusion
blood in the brain or CSF
Compression or damage to the anterior hypothalamus

138
Q

Neurologic Damage and Fever

A

Where there is brain injury, fever can exacerbate the injury
Accelerates toxic neurotransmitter release
Increases oxygen free radical production
Disrupts the blood-brain barrier

Even a 1 degree temperature increase in experimental animals can increase the zone of injury and worsen outcome

139
Q

At which temperature do you start to get irreversible damage?

A

Is this a fever?

This a heat stroke, a medical emergency

At temperatures > 42. irreversible damage begins to liver, brain, and vascular endothelium

Other scenarios: a child left in a car
elderly adult in a heat wave – estimated 8,000 excess deaths in the heat wave in Paris

140
Q

What are the predisposing factors leading to Heat Stoke?

A

Other illnesses, esp affecting ability to lose heat
Dehydration
Poor acclimatization
Medications: atropine
serotonin syndrome
malignant hyperthermia

141
Q

How do we conserve heat in fever?

A
  1. Blood is shunted away from the skin and extremities. This can raise temperature
  2. This leads to a sensation of cold which leads to behavioral changes – putting on more blankets, drinking hot liquids such as chicken soup
  3. Shivering. This can raise temperature rapidly
  4. Non-shivering thermogenesis takes place in brown fat, which is abundant in newborns but less important in adults.
142
Q

What are some examples of anti-pyretic drugs?

A

Non-steroidal anti-inflammatory drugs (NSAIDs)
Aspirin
Acetaminophen

143
Q

What are examples of endogenous pyrogens again?

A

Release ofcytokines such as IL-1β, IL-6,TNF-α, and interferons acting as endogenous pyrogens

144
Q

What is the effect of drugs that block PGE2/CO2

A

Drugs that block PEG2 decrease the febrile response.
Knockout mice deficient in COX-2 have a blunted febrile response.
COX-2 mRNA is increased in the hypothalamus during induced fever.
PEG2 activates neuronal circuits which activate the final response, but does not seem involved in normal thermoregulation

145
Q

How do NSAIDs work?

- what are their major actions?

A

They promote antipyretic effects by suppressing PGE2synthesis

It is PGE3, that triggers the hypothalamus to elevate body temperatures

Major Actions:

  • Analgesia (pain relief)
  • Anti-pyretic
  • Anti-inflammatory (except acetaminophen)
146
Q

Production and actions of prostaglandins and thromboxane

A
  1. membrane phopholipids - [phospholipase A2]-> arachidonic acid - [COX]->

a. Thromboxane: platelets, vascular SM cells
b. EP, prostaglandins: brain, kidney, vascular SM, platelets.

147
Q

Aspirin Major Actions

A
  1. Anti-pyretic action

Block the production of PGE2 to reset the hypothalamic temperature set point

  1. Anti-platelet/anti-thrombotic

Decreases platelet production of TXA2 by COX-1 to limit platelet aggregation and vasoconstriction

Can lead to BLEEDING

148
Q

Aspirin/NSAIDs

What are some adverse reactions

A
  • GASTROINTESTINAL
  • BLEEDING
  • EFFECTS ON
  • PREGNANCY
  • RENAL
  • ASPIRIN/other NSAID SENSITIVITY

All due to alteration of normal prostaglandin physiology
USE IS AVOIDED IN CHILDREN with viral illness

149
Q

What are sensitivity reactions?

A 
Non-immunologicaly mediated (caused by NSAID inhibition of COX pathway)
Signs and symptoms
            Rhinitis
            Nasal polyps
            Asthma
            Urticaria (hives)
            Laryngeal edema
            Bronchospasm
AVOID SALICYLATES/NSAIDs (advil)
ACETAMINOPHEN (tylenol) IS OK TO USE
150
Q

Over the counter names for the following drugs:

Salicylates
Acetaminophen
Ibuprophen

A

Salicylates: aspirin
Acetaminophen: tylenol
Ibuprophen: advil

151
Q

What are the adverse GI effects of NSAIDs?

What is the mechanism?

A

BLEEDING

ULCERATION

OBSTRUCTION

aspirin = salicylic acid, is an example of NSAIDs

MECHANISM:

LOSS of CYTOPROTECTIVE ACTIONS of GASTRIC PROSTAGLANDINS
Acid secretion is unabated
Decrease in protective mucus
Decrease in mucosal blood flow

152
Q

What are the risk factors for getting GI effects from NSAIDS/aspirin

A 
Age > 65 years
History of peptic ulcer or bleeding
Multiple NSAID use
High dose use
Alcohol
Anti-coagulant use
153
Q

NSAIDs on Gestation and Delivery

A

Antepartum and postpartum
Transfusion requirement is increased
Gestation is prolonged
Premature closure of the ductus

154
Q

Renal Prostaglandins Function

ultimate affect of NSAIDS due to their impact on kidneys?

A

Modulate Na, K and water excretion

NSAIDs (ibuprofen) block the above to reduce Na & K excretion and may cause INCREASE in BP & WEIGHT

155
Q

Aspiring Pharmacokinetics

- What is it’s half life?

A

It is DOSE DEPENDENT

Half life: 15 minutes

low dose: 2-3 hours
high dose: 12-15 hours

156
Q

What can result from an aspiring overdose?

A

Combined metabolic acidosis & respiratory alkalosis

157
Q

Compare Ibuprofen to aspirin

A

Also works through COX-1 and COX-2 inhibition HOWEVER,
COX inhibition is REVERSIBLE in ibuprophin. it is IRREVERSIBLE in aspiring.
and IBU is NOT used as an anti-platelet drug.

Adverse event profile is like aspirin
Great variability in individual response
Change to another NSAID
Not used as anti-platelet drugs

158
Q

Why does aspirin distinguish itself from other NSAIDs?

A

aspiring inhibits COX irreversibly** so the effects (i.e. anti-platelet) last the life time of the platelet.

vs the other NSAIDS inhibit cox reversibly and can be overcome by competitive agonist.

159
Q

Acetaminophen

A

Analgesic and anti-pyretic via inhibition of neuronal & vascular PGE2 generation

Weak anti-inflammatory & anti-platelet activity: failure to inhibit platelet TXA2 or inflammatory PGE2 synthesis

Little GI toxicity

Potentially hepatotoxic or nephrotoxic

160
Q

Acetaminophen Toxcitity

A

acetaminophen = tylenol

Hepatotoxic when dose >4 gm/day
Hepatotoxicity may occur @ doses <4gm/d following binge drinking 
Hepatic centrilobular necrosis
AST/ALT >1000 units
Treat with n-acetylcysteine orally
161
Q

All NSAIDs (including selective COX2 inhibitors) are

  • anti pyretic
  • analgesic
  • anti-inflammatory

EXCEPT:

A

Acetaminophen (tylenol)

has anti-pyretic and analgesic but no anti-inflammatory activity

Block F: Defence (9 decks)

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