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Blood and Lymph > Week 8 > Flashcards

Week 8 Flashcards

1
Q

Blood group antigens

A

glycolipids (carbohydrates) found on surface of ALL body cells (including RBCs)

Terminal sugars confer antigenic specificity (A,B, or O)

ABO antigen found in nature → foreign one to you, you become immunized to it

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2
Q

Type A blood

A

AA or AO genotype

Glycosyl ABO transferase allele puts additional A sugar on H antigen

→ make anti-B ab

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3
Q

Type B blood

A

BB or BO genotype

Glycosyl Transferase ABO allele adds B sugar

→ make anti-A ab

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4
Q

Type AB blood

A

Glycosyl Transferase ABO allele adds both A and B antigens on their red cells

Rarest blood group

Universal recipients

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5
Q

Type O blood

A

OO genotype

No working ABO glycosyltransferase - only have basic core H antigen

Make anti A and B ab

Most useful as blood donors - can give to any phenotype

Populations tend to drift towards O blood type - A and B babies are at higher risk for hemolytic disease of the newborn

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6
Q

Bombay phenotype

A

Lack glycosyl transferase gene that puts final sugar onto core → no H antigen expression = little h

A, B and O are all incompatible (make antibody to A, B and O)

Type as O, but they are NOT O

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7
Q

Isohemagglutinins

A

ab we make to the foreign ABO antigens to us

Appear in blood around 3-6 months of age

IgM class (ab to pure carbohydrate antigen)

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8
Q

Rh antigens

Rh(D) positive?

A

Proteins D is most important one

Rh(D) positive = D dominant over d allele (DD or Dd)

92% of US blacks, 85% of US whites are RH+

DO NOT make antibody to it unless you are Rh(D)- and become immunized with Rh(D)+ red cells

Rh not ubiquitous in nature, so we don’t normally make ab to it

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9
Q

Electronic Crossmatch

A

telling which donor units are most compatible with recipient

-Identical or compatible at ABO and Rh

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10
Q

Major Crossmatch

what are you testing?
how are you testing it?
what do the results mean?

A

Are there abs in recipient’s plasma which can react with antigens in donor’s RBCs?

Mix plasma from recipient and red cells from donor in lab

Test for hemolysis or agglutination (ab to donor red cells)

None → compatible

YES → generalized complement-mediated hemolysis, free Hg deposited in kidneys → acute renal failure

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11
Q

Direct antiglobulin test

A

is there ab ALREADY on cells?

Tests cells coated with ab IN VIVO

Patient’s RBCs → mix with ab against human IgG

If IgG present on RBC surface → agglutinate

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12
Q

Indirect antiglobulin tests

A

-is there unexpected ab to RBC antigens in recipient plasma? Can be used to crossmatch recipient/donor more thoroughly

Donor RBCs + recipient plasma → wash, add antiglobulin

Detects ab that bound cells but didn’t agglutinate them initially

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13
Q

Heterophile antibody

A

Abs induced by external antigens that cross-react with self-antigens or another antigen

EX) Monospot test: ab in serum of patient with mono reacts with horse RBCs

EX) Syphilis: ab in serum of patient with syphilis, reacts with Treponema pallidum

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14
Q

Hemolytic disease of the newborn

A

Rh(D)+ babies of Rh(D)- mothers

Pregnancy with Rh(D)+ fetus → mom exposed to RhD from baby → makes ab

Only a problem for subsequent pregnancy with Rh(D)+ fetus

→ make ab that crosses placenta and destroys second fetuses RBCs → severe hemolysis in the newborn (high bili)

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15
Q

Mother becomes ______ with subsequent pregnancy with Rh(D)+ fetus which ___________

A

sensitized

boosts response (more severe hemolytic disease of the newborn)

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16
Q

How can you prevent hemolytic disease of the newborn?

A

Mom given IgG ab to Rh(D) at 28 wks and when mother delivers her first Rh(D)+ baby

Rh(D) ab opsonizes fetal RBCs → mom not immunized to Rh(D)+

Sweeping antigen out of mom before immunization occurs

Must receive RhIg each subsequent delivery

WILL NOT work if you are already immune to Rh(D)

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17
Q

ABO hemolytic disease

A

Typically:

  • Isohemagglutinins are IgM → DO NOT cross placenta
  • Anti-Rh abs are IgG → DO cross placenta
ABO hemolytic disease:
-Occasionally IgG isohemagglutinins made
-Especially prevalent in group O people
A or B fetuses of these women at risk of ABO hemolytic disease
-NO RhoGAM-like ab for this
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18
Q

Congenital diseases of bleeding/clotting (4)

A

Hemophilia A and B (Factor VIII and IX Deficiency)
Factor XI Deficiency
Factor VII Deficiency

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19
Q

Acquired diseases of bleeding/clotting (6)

A

1) Liver Disease
2) Vitamin K Deficiency (Warfarin Admin)
3) Disseminated Intravascular Coagulation (DIC)
4) Thrombosis
5) Lupus Anticoagulant
Familial 6) Hypercoagulable State (Thrombophilia)

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20
Q

Prothrombin time (PT) test measures ________ of which factors?

normal time?

A

procoagulant activity

factors 7, 10, 5, 2, and fibrinogen
[extrinsic pathway and common pathway]

normal = 9-12 secs

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21
Q

INR

A

international normalized ration - used to standardize PT time

normal INR = 1

specifically sensitive for vitamin K dependent factors (7, 10, 2)

measure of Warfarin

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22
Q

vitamin K dependent factors include… (4)

A

7, 10, 9 and 2

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23
Q

Warfarin, Vitamin K deficiency, and inadequate liver function can be measured by…

A

PT or INR

Warfarin (inhibits VitK dependent rxns)

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24
Q

Partia Thromboplastin Time (PTT) measures __________ of…

normal = ?

NOT affected by?
prolonged by?

A

Measures procoagulant activity of intrinsic and common pathway

NOT affected by deficiencies of Factor VII

Normal = 25-32 sec

Prolonged by anticoagulant drugs (heparin, fibrin split products), hemophilia
Monitors Heparin therapy

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25
Q

Thrombin time measures ________

sensitive to?
normal = ?

prolonged by?

A

measures procoagulant activity of fibrinogen

Sensitive to anticoag effect of heparin or fibrin split products

Normal = 12-18 secs

Prolonged with heparin contamination or fibrinogen deficiency

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26
Q

Bleeding time measures ____________

______ and _______ will prolong bleeding time

normal = ?

A

measures platelet-vessel interaction, number / function of platelets

Decrease in platelets (

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27
Q

PFA-100 (Platelet Function Analyzer)

A

In vitro bleeding time, determines platelet response to agonists

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28
Q

Hemophilia A is a deficiency in _______, and Hemophilia B is a deficiency in ________.

Hemophilia A and B are inherited _______

A

A –> Factor 8

B –> Factor 9

XR

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29
Q

Labs for hemophilia

normal _______ and ________

low ________

prolonged ________

A

normal PT, normal bleeding time

low factor 8 or 9

Prolonged PTT

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30
Q

Symptoms of hemophilia

Severe, mild, moderate, and carriers

A

Severe → spontaneous hemorrhage in joints, muscles, soft tissues, CNS

Moderate → usually need trauma for bleeding

Mild → only bleed after trauma
-Diagnosed after bad trauma or surgery

Carrier females with bleeding = symptomatic carriers

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31
Q

Treatment for hemophilia A and B

A

recombinant factor treatment given by IV 2-3 times a week

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32
Q

Factor 7 deficiency:

inheritance
presentation
labs

A

AR

Presents as postoperative hemorrhage

Labs: Protime (PT) significantly prolonged, normal PTT

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33
Q

Disseminated Intravascular Coagulation (DIC) caused by…

A

Massive trauma, hemorrhagic/septic shock, burns, acute leukemia, and drug reactions

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34
Q

DIC mechanism

A

→ intravascular deposition of fibrin → thrombosis of small/midsize vessels with organ failure

Depletion of platelets and coagulation factors (fibrinogen, platelets, Factor VIII, V) → bleeding

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35
Q

Lab results in DIC (6)

A

1) Very low fibrinogen level
2) Low platelets
3) PT least affected, prolonged (in contrast to liver disease)
4) Greatly prolonged PTT (low factor 8)
5) Prolonged TT
6) Increased fibrin split products (D-Dimer)

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36
Q

Coagulopathy and Liver Disease

A

Liver problem → deficiency in clotting factors (Factor V, vitamin K dependent Factors II, VII, IX, and X.

Very severe liver disease, fibrinogen low

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37
Q

Lab results for liver disease (5)

A

1) Prolonged PT (INR)
2) relatively less prolonged PTT (low IX and X)
3) if fibrinogen low → TT prolonged
4) Low platelets
5) Important to CHECK VITAMIN K DEFICIENCY

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38
Q

Lupus Anticoagulant

A

Common acquired abnormality → hypercoagulable state

THROMBOTIC TENDENCY (Deep vein thrombosis, pulmonary embolism, etc.)

Antiphospholipid Antibody Syndrome (APS): IgG ab anti phospholipid platelet membrane or endothelial cell

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39
Q

Lab tests/results for lupus anticoagulant (3)

A

Prolongs PTT, BUT DO NOT have bleeding tendency

Test specifically with Russell’s Viper Venom Test (dRVVT)

Tests for lupus anticoagulant

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40
Q

1:1 mixing study

A

Mix patient and control plasma 1:1 → assay PTT

IF PTT corrects → factor deficiency (because factor in control blood)

If acquired ab to factor 8 (lupus anticoagulant)→ PTT will NOT correct

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41
Q

Serum protein electrophoresis

A
  • Test function of humoral immune system
  • Cheap, easily quantified
  • Not very sensitive to small abnormalities
  • Can be done on urine, CSF and blood
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42
Q

What kind of serum protein electrophoresis will you see for:

1) Plasma Cell Myeloma
2) Hypo/Agammaglobulinemia
3) Polyclonal hypergammaglobulinemia

A

1) M spike in IgG
2) peaks are small
3) wider peak

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43
Q

Single radial immunodiffusion

A

Measures levels of individual immunoglobulin classes or subclasses

-must be a multivalent antigen that can form precipitate with an appropriate ab

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44
Q

Antinuclear antibodies (ANA)

How to test for their presence?

A

abs against autoantigens in the nucleus

1) Fix with agent that makes cell plasma membrane permeable so ab can penetrate
2) Wash and mix with labeled goat anti-human IgG

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45
Q

Immunofluorescence vs. immunohistochemistry

A

Immunofluorescence:
-Used to identify antibody in patient’s tissues (direct) or in their blood (indirect)

Immunohistochemistry:
-Uses final ab labeled with an enzyme that produces a brown/black product that can be observed and archived for a long time

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46
Q

throat swab smeared on slide, add fluorescent-labeled antibodies to known bacterial antigens

This is an example of a ________

A

direct immunofluorescence test

TEST FOR PRESENCE OF ANTIGEN

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47
Q

known bacteria placed on slide, add patient serum → label with fluorescent goat anti-human Ig

This is an example of a ________

A

indirect immunofluorescence

TEST FOR PRESENCE OF ANTIBODY

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48
Q

Passive agglutination

A

antigen-coated latex particles - test to detect ab

1) Couple antigens to RBCs or latex beads
2) → add dilutions of patient’s serum
3) Look for agglutination titer

EX) Used for RF which can agglutinate latex particles coated with IgG

Advantages: simple, cheap, anyone can do it

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49
Q

Reverse passive agglutination

A

Test to detect antigen

1) Latex beads coated with abs
2) Add bead to patient fluid of choice
3) If they agglutinate → antigen present

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50
Q

Simple Elisa

A

measures antibody

1) Antigen couple to a plate
2) Add test serum
3) If there is ab to antigen it will bind
4) Identified using enzyme-coupled antibody to expected serum antibody

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51
Q

Sandwich/Capture ELISA

6 steps

A

measures antigen

1) Use 2 different monoclonal abs to specific antigen of interest
2) Capture antibody: one ab on a plate so it’s stuck there
3) Add patient serum, Wash
4) Add second ab with enzyme coupled to it
5) Add colorless substrate that produces a colored product
6) Measure intensity of product color in a plate spectrophotometer

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52
Q

Measuring T cell number in lab - 2 ways

A

1) mAbs to CD3, CD4, or CD8 → count fluorescent cells under a microscope
2) Flow cytometry

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53
Q

Measuring T cell function in lab (6)

A

1) Skin test for Th1 activity - Best overall test to measure Th1 activity
2) Challenge DTH test
3) Mitogens (PHA or Con A) → stimulate T cells, observe proliferation or IL-2, IL-4, or IFNy production
4) Chest x-ray - look at thymus in infants
5) Lymphoid biopsy - check for suspected primary immunodeficiency
6) Killer cell assays

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54
Q

B cell function test in lab

A

serum protein electrophoresis

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55
Q

T cell function in clinic/ward

A

Rapid screen

EX) strep test, dipstick pregnancy test

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56
Q

Flow cytometry

A

measures number of B and T cells

  • Pump cells in suspension through orifice in single file
  • Cells bound to fluorescent-tagged antibody → quantify light emitted
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57
Q

Virchow’s Triad

A

1) Decreased blood flow (venous stasis)
2) Inflammation of or near the blood vessels (altered vessels)
3) Intrinsic alterations in the nature of the blood itself (altered coagulability)

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58
Q

Acute Iliofemoral Thrombosis of the Leg:

Symptoms? (3)

A

complete obstruction of venous outflow from an extremity

1) Extremely swollen
2) Blue
3) Painful

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59
Q

Composition of arterial thrombi vs. venous thrombi

A

Arterial = white thrombi

  • aggregated platelets
  • small amounts of fibrin
  • few red cells

Venous = red thrombi

  • large amounts of fibrin
  • numerous red cells
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60
Q

Arterial thrombi are formed under conditions of _________

Venous thrombi are formed under conditions of ________

A

high shear stress (vWF critical for platelet adhesion)

slow blood flow

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61
Q

Instigating factors of arterial thrombi (3)

A

ATHEROSCLEROSIS
HTN
turbulent blood flow at arterial branch points

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62
Q

Treatment of arterial thrombi

A

TIME is critical!

Acute:

1) Heparin → prevent further clot formation
2) tPA (fibrinolytic agent) → lyse existing clot

Long-Term:
1) Aspirin (inhibit COX) - ANTIPLATELET THERAPY

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63
Q

Instigating factors of venous thrombi

A

stasis, immobility, obesity, direct trauma, surgery, extrinsic compression, right-sided heart failure, presence of foreign body (IV, catheter)

Risk Factors: obesity, trauma, post-surgery, age, pregnancy

NOT HTN, hyperlipidemia → arterial problems

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64
Q

Pulmonary Embolus

A

part of thrombus breaks off and travels through major veins, past right heart, and into pulmonary artery circulation until it becomes lodged → prevents gas exchange → infarct

Signs/Symptoms: chest pain, dyspnea, anxiety, cough, syncope, cyanosis, chronic pulmonary HTN

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65
Q

Treatment of venous thrombosis

A

Anticoagulant therapy

1) Heparin - stops clot from getting bigger
2) Warfarin - prevent additional clots (slow to start working)

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66
Q

Clinical clues suggesting inherited hypercoaguable disorder (6)

A

1) First thrombosis age less than 50
2) Recurrent episodes of thrombosis
3) Family history of thrombosis
4) Thrombosis at unusual sites
5) Neonatal thrombosis
6) Thrombosis without apparent antecedent thrombogenic event (idiopathic)

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67
Q

D-Dimer Assay

A

Formed when cross-linked fibrin degraded by plasmin through fibrinolysis

Very sensitive but not specific

Positive D-dimer means further studies should be performed

high negative predictive value for DVT, but negative D-dimer rules out thrombosis

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68
Q

Venous ultrasound +/- US doppler is useful for diagnosing…

A

DVT in legs - 95% specificity and sensitivity

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69
Q

Spiral CT scan of chest and V/Q scan used to diagnose…

A

PE

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70
Q 
Antithrombin deficiency
(4)
A

1) Antithrombin inactivates thrombin, 10a, 9a, and 2a, so Antithrombin deficiency → hypercoagulable
2) AD - homozygotes fatal in utero
3) VENOUS thrombosis before age 50
4) Can cause heparin resistance - heparin is a cofactor of AT-III

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71
Q

Protein C deficiencies (3)

A

1) Protein C inactivates factors 5a and 8a to inhibit coagulation, VitK dependent
2) AD
3) Can be made worse by Warfarin therapy

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72
Q

Protein S deficiencies

A

1) VitK dependent, facilitates anticoagulant activity of activated protein C
2) Thrombosis in atypical areas
3) AD

73
Q

Factor V Leiden (4)

A

1) AD mutation of factor V gene → partial resistance to inactivation by proteolytic cleavage by protein C (NOT a deficiency)
2) Factor V Leiden inactivated 10x more slowly
3) Most common inherited predisposition to hypercoagulability in Caucasian populations
4) Increased coagulation AND decreased anticoagulation

74
Q

Prothrombin gene mutation

A

1) AD mutation in factor 2
2) Associated with VENOUS thrombosis
3) Very minor hypercoagulability
4) Causes elevated concentrations of plasma prothrombin

75
Q

Clinical features of anti-phospholipid antibody syndrome (3)

A

1) Increased risk for thrombosis, obstetric complications, and fetal death
2) Clots in veins and arteries, any vascular bed, any age or gender
3) Prolongs APTT - due to in vitro lab artifact (see Stabler’s lecture)

76
Q

Criteria for diagnosis in anti-phospholipid antibody syndrome

2 symptoms
4 blood tests

A

1) Vascular thrombosis
2) Complications of pregnancy

Labs:

1) Anticardiolipin antibodies (ACA)
2) Lupus anticoagulant
3) Beta2-glycoprotein-I antibodies
4) High titers for APab

77
Q

If you have…

  • 1 unprovoked event or provoked DVT
  • 2nd unprovoked event, Cancer, APLS, high-risk thrombophilia

Then you will be on anticoagulation therapy for how long?

A
  • 1 unprovoked event or provoked DVT –> 3 months of anticoagulation
  • 2nd unprovoked event, Cancer, APLS, high-risk thrombophilia –> indefinite anticoagulation
78
Q

Heparin mechanism of action (3)

A
  1. Heparin binds antithrombin III (serine protease inhibitor)→ increased rate of thrombin inactivation by 1000x
  2. Accelerates decay of 9a, 10a, and 12a by antithrombin III
  3. Heparin released by antithrombin and reused once thrombin binds complex (reversible binding to antithrombin)
79
Q

Heparin is used for (6)

A

*Venous thrombosis, *PE, MI, during/after coronary angioplasty, during surgery requiring cardiopulmonary bypass, kidney dialysis

80
Q

2 types of heparin

A
  1. unfractionated

2. Low molecular weight

81
Q

Type of heparin to use durin pregnancy

A

unfractionated

82
Q

Characteristics of unfractionated heparin (5)

A
  1. Binds antithrombin/thrombin complex
  2. Not absorbed from GI tract - must be given IV or IM
  3. Poor bioavailability, short half life → unpredictable dose response
  4. Requires hospital admission for careful monitoring - ONLY INPATIENT
  5. Does NOT cross placenta (can use during pregnancy)
83
Q

Mechanism of action of low molecular weight heparin

A

DO NOT inhibit thrombin by antithrombin

b. Selectively binds to and inactivates factor 10a by antithrombin
i. Only has 15 saccharide units, so cannot bind thrombin, only can inactivate factor 10a

84
Q

3 characteristics of low molecular weight heparin

A
  1. Given IM
  2. Longer half life, better bioavailability → more predictable dose response
  3. Requires less monitoring (OUTPATIENT treatment)
85
Q

3 complications of heparin therapy

A
  1. excessive bleeding
  2. heparin induce thrombocytopenia
  3. allergic reactions
86
Q

Treatment of hemorrhage due to heparin therapy

A

Stop use → anticoagulation effect disappears within hours

Can reverse life-threatening bleeding with protamine sulfate

87
Q

Heparin-Induced Thrombocytopenia

A

(Thrombosis)

  1. Platelet count decreases
  2. Abs to platelet factor 4/heparin complexes → platelets activated into prothrombotic state → venous thromboembolism, stroke, MI, arterial thrombosis
  3. Less likely with LMWH
88
Q

Allergic reactions to heparin are due to _____

A

chondroitin sulfate

contaminant in heparin supply

89
Q

Alternative anticoagulant therapies for thrombocytopenia:

A

Argatroban (Novastan) - small molecule inhibitor of thrombin

Lepirudin (Refludan) - recombinant form of hirudin anticoagulant from leeches → inhibits thrombin

90
Q

Advantages of new oral anticoagulants (3)

A

rapid onset of action, absence of food interactions, do not require monitoring

91
Q

Disadvantages of new oral anticoagulants (5)

A

contraindicated with kidney disease, greater GI bleeding, shorter half life (problem with compliance), cost, NO ANTIDOTE

92
Q

Pradaxa

A

for afib, approved in 2015 - thrombin inhibitor

93
Q

Eliquis

A

for afib approved in 2012 - factor Xa inhibitor

94
Q

Warfarin

A

Vitamin K analogue - inhibits enzymes that use vitamin K as a cofactor

1.Factor 2, 7, 9, 10 undergo vitamin K dependent gamma carboxylation of N-terminal glutamates → cannot bind calcium → non functional

95
Q

Warfarin is used for (4)

A

Venous thromboembolism, systemic embolism (pts with prosthetic heart valves or afib), stroke, recurrent infarction

96
Q

5 complications of warfarin

A

i. Hemorrhage
- Takes 24-48 hrs for reversal - coagulation factors must be resynthesized
- Can transfuse plasma to replace coagulation factors or Vit. K

ii. Cannot be used during pregnancy - crosses placenta
iii. Drug and food interactions
iv. Requires Monitoring - genetic variability in ability to metabolize Warfarin
v. Delayed onset of action

97
Q

Heparin onset of action

A

Rapid onset - Heparin acts quickly, but transitioned into an oral anticoagulant

98
Q

Warfarin onset of action

A

SLOW onset of action - must have turnover of factors before effective

99
Q

3 Fibrinolytic agents

A

I. t-PA (Tissue Plasminogen Activator): serine protease that binds fibrin, cleaves plasminogen → plasmin (degrades fibrin, degrades clot)

  • Used to dissolve clots in emergency setting
    ii. u-PA (Urokinase): converts plasminogen to plasmin (does NOT bind fibrin)
    iii. Streptokinase: non-enzymatic protein from B-hemolytic strep
  • Forms complex with plasminogen → activates it → converts to plasmin
100
Q

4 uses of fibrinolytic agents

A

i. Acute MI (in combo with ASA)
ii. Ischemic stroke (within 3 hrs after stroke)
iii. DVT (in combo with heparin/warfarin)
iv. PE

high risk agents (hemorrhage, systemic lytic state)

101
Q

3 types of antiplatelet agents

A
  1. Aspirin
  2. ADP receptor antagonists
  3. Gp IIb/IIIa inhibitors
102
Q

Aspirin

A

inhibit formation of platelet products

  1. Irreversibly inactivates COX1 → inhibit formation of thromboxane A2
  2. Effects last life of platelet (7-10 days)
  3. Used for prevention of AMI and stroke pts with atherosclerosis
103
Q

ADP receptor antagonists

A

prevent platelet aggregation (Plavix)

1.Block platelet activation by ADP
→ inhibits secretion of alpha granules, blocks expression of adhesion proteins GPIIb/IIIa

  1. Slow onset (5-7 days)
  2. Effects last for life span of platelet (7-10 days)
104
Q

Gp IIb/IIIa inhibitors

A

block adhesion proteins

  1. Block adhesion protein (integrin) on surface of platelets that is a receptor for fibrinogen → block platelet aggregation
  2. Given IV
  3. Before, during and after angioplasty
105
Q

Difference between HIV-seropositive and AIDS

A

HIV-Seropositive: people with antibody to HIV-1 virus

AIDS: once symptoms of opportunistic infections, Kaposi’s sarcoma, or Th (CD4+) cells fall below 200/uL

106
Q

Virus that causes AIDS (hard one, I know)

A

HIV-1

i. Lentivirus: Non-transforming retrovirus
1. RNA virus with no oncogene - copies its RNA into DNA (reverse transcriptase)
ii. DNA not being transcribed in host cell → latent until T cell is activated

107
Q

Origin of AIDS virus

A

i. Evolved from SIV in the 1940s in Zaire (Congo)

ii. First in US in 1978, in Africa in 1959

108
Q

Origin of current AIDS epidemic

A

Congo → rest of Africa → Caribbean → Europe → USA

109
Q

Approximate number of AIDS cases in USA and the world

A

i. USA: 1.1 million people living with AIDS in US (16% don’t know it)
1. 50,000 new cases a year
ii. World: 35 million people living with HIV in 2013
1. 36 million people have died from AIDS so far
2. 5th leading cause of death

110
Q

Two protective alleles to HIV

A
  1. People with two CCR DELTA32 alleles do NOT express any surface CCR5 → can become chronically infected with HIV but DO NOT become ill
    - “Long Term Survivors”
  2. HLA-B57:
    - “Elite Controllers” → become infected with HIV but did not progress to AIDS
    - Make effective CTL cells
111
Q

Pathogenesis of AIDS

A

i. HIV-1 is VERY antigenically variable
- Reverse transcriptase highly error prone → many variants of HIV
ii. Single exposure infection → Blood virus level peak at 6 weeks, Antibody to HIV peaks at 9 weeks → virus levels fall (but not to zero) = “Set Point”
- Set point determined by patient’s immune system
- Systemic infection between 6-9 weeks with loss of CD4 cells in gut mucosa, increased gut permeability

112
Q

HIV target cells (2)

A
  1. Dendritic cells

2. Th CD4+ cells

113
Q

HIV interaction with dendritic cells

A

a. Upon initial infection adheres to lectin on DC = DC-SIGN

b. Trojan horse → lymph nodes for Th cells

114
Q

HIV interactions with Th cells

A

Mode of entry of virus into cell:

i. HIV binds by its envelope glycoprotein gp120 to CD4 molecule on surface of Th cells
ii. → conformational change in gp120 and CD4 on cell surface
iii. → conformational change allows CD4 to bind co-receptor CCR5
iv. → gp41 binds cell membrane and allows fusion of virus with cell membrane
v. Binding to gp120/gp41 and conformational change creates hydrophobic region on T cell that allows virus to fuse with T cell membrane

Injects core into cell, activates reverse transcriptase

i.RNA → DNA → insert into nucleus of T cell with viral integrase

115
Q

HIV exit from cells

A

Viruses bud en masse from infected cell, tearing holes in membrane → cell dies

116
Q

Latency of HIV

A
  1. Seropositive without symptoms

2. Therapy can prevent next stages of disease progression

117
Q

Th1, Th2 and Tfh cells in HIV infections

A
  1. Th1: site of HIV infection
    - Orchestrates CTL killing - has molecules that bind GP120 → generates IL-2 → stimulates HIV transcription
  2. Tfh: site of HIV persistence in lymph node - harbors virus reservoir, has molecules that bind GP120, resides in lymph node follicles
    i. Suppress viral replication but can’t eliminate virus DNA from nuclei
    ii. When Tfh activated by its correct antigen → clone of virus producing cells
  3. Th2: has molecules that bind GP120, required for production of antibodies for antibody class switching required to stimulate antibody production
118
Q

3 Opportunistic infections common in AIDS patients

A
  1. Candida Albicans (yeast) - mouth, esophagus, rectum
    a. Fevers, night sweats, weight loss, fatigue
  2. TB: leading cause of death in people infected with HIV
  3. Malignancy (Kaposi sarcoma, Burkitt lymphoma)
119
Q

Late AIDS dementia complex:

A

due to brain cells infected with HIV (macrophages, microglia)

120
Q

Infections common in AIDS patients are primarily

A

Infections that require T cell mediated immunity

  1. Cytomegalovirus, hepatitis, HSV, VZV
  2. TB, Fungi (Candida albicans, pneumocystis jirovecii)
121
Q

Why do CD4 cells decline in AIDS patients

A

i. Virus able to replicate faster and longer than you can re-make CD4 cells
- Estimated that entire population of virus replaced daily, and CD4 cells every 3 days
- Eventually CD4 cells lost, unable to make them as fast
ii. Eventually can’t keep up, and CD4/CD8 ratio falls in blood
iii. → Immune system can no longer cope, opportunistic infection takes hold

122
Q

Ineffectiveness of antibody in HIV infection (2)

A
  1. When virus is replicating gp120/gp41 made early and inserted into cell plasma membrane → allows fusion of infected cell to nearby uninfected CD4 cells → syncytia
  2. Antibodies patient make are not protective but they do bind the virus and block attachment to and infection of Th cells
    - BUT neutralizing epitope on virus shielded by carbohydrate
123
Q

Lab diagnosis of AIDS

A
  1. Antibody measured by an ELISA, confirmed by Western Blot analysis
  2. Virus then sequenced to see what drugs it is susceptible to ($$)
  3. PCR identification of virus RNA
124
Q

6 treatments of HIV/AIDS

A

i. Reverse Transcriptase Inhibitors:

Nucleosides (NRTI): competitive inhibitors, chain terminators
Non-Nucleoside (NRTI): binds enzyme, changes conformation at catalytic site (common resistance mutation)

ii. Protease Inhibitors
iii. Fusion inhibitors
iv. CCR5 antagonist: blocks viral entry into CD4+ cells by changing conformation of CCR5 preventing engagement of gp120
v. Integrase inhibitor: blocks viral DNA insertion into cell DNA
vi. Antiretroviral Therapy (ART): two NRTIs and a third drug from a different class

125
Q

Problem with producing HIV vaccine

A

Need a vaccine that can preferentially stimulate Th1 cells and CTL

Currently vaccines best at inducing ab response - ab not protective

126
Q

Prospects for HIV vaccine

A

Broadly neutralizing antibodies (bnAb) can block infection by almost all HIV strains and mutant forms

Directed against gp120 that binds CD4

127
Q

6 challenges for HIV vaccine

A
  1. V(D)J of bnAb mutates very quickly and thus becomes ineffective at binding site on HIV
  2. Tremendous global genetic diversity of HIV
  3. Immense mutational capacity (evasion of T and B cell immunity)
  4. Latency in host genome - can’t be eliminated by antiretroviral drugs
  5. No known example of spontaneous immune clearance
  6. bnAbs have been found but are rare and take years to develop
128
Q

Basic process of blood collection

A

i. Volunteer donation
ii. Answer questions about current/past illnesses, surgery, travel, vaccination, high-risk behavior
iii. Call back with symptoms
iv. Abbreviated physical exam
v. Test hematocrit and platelet count
vi. Skin prep for phlebotomy (reduce bacterial contamination)

129
Q

6 components derived from blood donation

A
  1. whole blood
  2. packed red blood cells (PRBCs)
  3. Fres frozen plasma (FFP)
  4. Cryopreciptate
  5. Platelet concentrates
  6. Granulocyte (WBC) concentrates
130
Q

Whole blood

A
  1. Keep at 4-6 C for 35 days
  2. Hct is 36-40%
  3. Platelet / neutrophil function degenerate by 24-48 hrs of storage
  4. Red cells well maintained
  5. Loss of clotting factors more slowly
131
Q

Packed red blood cells (PRBCs):

A
  1. Keep at 4-6 C for 35 days or longer (42 days with special solutions)
  2. Hct is 70% without plasma
  3. RBCs only cell you want in there
    a. Can get some WBCs in there that you don’t want → use leukodepleted units
  4. Frozen/glycerolized RBC can last 10 years in freezer
132
Q

Fresh frozen plasma (FFP):

A
  1. Acellular product
  2. Keep at -18 C for one year
  3. > 80% all clotting and anti-coagulant proteins
    a. Contains all plasma proteins (procoagulant, anti-coagulant, complement proteins)
133
Q

Cryoprecipitate

A
  1. Made from fresh plasma frozen quickly at -80 C → sit for 18hrs at 4 C
  2. Cryoprecipitable proteins isolated and frozen at -18 C for one year
134
Q

Cryopreciptate contains (6)

A

a. Cryopreciptiable proteins
b. 80-100 U factor 8 per bag
c. vW Ag
d. Fibrinogen
e. Factor 13
f. Fibronectin

135
Q

Platelet concentrates

A

tx for pts with low count or poor function

  1. Random donor unit (RDUs) or Apheresis platelet concentrates
    a. Leukoreduced
    b. Stored at 22-24 C for 5-7 days in gas permeable bags
136
Q

Granulocyte concentrates

A
  1. Collected by apheresis
  2. No storage allowed
  3. Keep at room temp - transfuse within 8-12 hours
  4. Use for severe infections in neutropenic patients
137
Q

Blood groups

A

serologic determination of ABO and Rh(D) antigens of patients/donors

i. A: H antigen + fucose + N-acetylgalactosamine
ii. B: H antigen + fucose + D-galactose
iii. AB: H antigen + fucose + D-galactose + N-acetylgalactosamine
iv. O: H antigen + fucose
v. Rh alleles

138
Q

Indications for whole blood use

A

Massive transfusions to replace oxygen carrying capacity AND blood volume

ii. ABO, Rh(D) type specific
iii. Must be crossmatched

139
Q

Indications for packed red cells use

A

Transfused for oxygen carrying capacity: chronic anemia, acute blood loss

ii. ABO, Rh(D) type specific
iii. Must be crossmatched

140
Q

Indications for fresh frozen plasma use

A

Coagulopathy related procoagulant deficiency (DIC, liver failure, VitK deficiency)

ii. Use specific anticoags for inherited deficiencies
iii. ABO type specific
iv. No crossmatch

141
Q

Indications for platelet use

A

Bleeding associated with thrombocytopenia and/or platelet dysfunction

ii.ABO type specific or compatible

142
Q

Basic rules of blood administration (3)

A

1) Typed for ABO and Rh(D)
- Weak expression of D can be mistake for Rh-
2) Screened for antibodies other than ABO
3) Major Crossmatch

143
Q

Major crossmatch

A

Mix donor cells and recipients serum in vitro → evaluate for agglutination

  1. Add Coombs reagent to look for IgG or complement
  2. Remarkably reduces possibility of immediate hemolytic transfusion reactions
144
Q

What do you do in an urgent situation when a patient needs a transfusion

A
  1. Give O Rh(D) negative
    - For males and non-childbearing females can use O Rh(D)+
  2. Abbreviated testing of ABO and Rh(D) types and ab screen without crossmatch
145
Q

Infectious risks (7)

A

Syphilis, Hep A, Hep B, Hep C, HIV, WNV, CMV

146
Q

What is tested for when blood is collected? (3)

A

HIV, West Nile Virus, Hep C

147
Q

7 non infectious adverse events of transfusion reactions

A
  1. Febrile nonhemolytic transfusion reactions and mild allergic reactions
  2. Acute hemolytic transfusion reactions
  3. Delayed hemolytic reactions
  4. Anaphylactic reactions
  5. Dilutional coagulopathy
  6. GvH disease
  7. Iron overload
148
Q

Febrile nonhemolytic transfusion reactions and mild allergic reactions

A
  1. Caused by leukoagglutinins in recipient cytokines

2. TX: antipyretics, antihistamine

149
Q

Acute hemolytic transfusion reactions:

A

preformed alloantibodies and autoantibodies after infusing incompatible blood products (ABO) → intravascular hemolysis of transfused cells with activation of clotting (DIC)

1.Life threatening, severe → renal failure

150
Q

Delayed hemolytic reactions:

A

alloantibody production and slow destruction of transfused RBCs by extravascular hemolysis

151
Q

Anaphylactic reactions:

A

bronchospasm, airway response

1.TX: epinephrine, benadryl, steroids

152
Q

Dilutional Coagulopathy:

A

massive blood loss and transfusion with replacement of fluids or blood components - deficient clotting factors → Bleeding

TX: replace clotting factors or platelets

153
Q

Graft vs. Host Disease

A

lymphocytes from donor transfused in an immunoincompetent host

154
Q

Iron overload:

A

no physiologic mechanism to excrete excess iron

155
Q

Immune surveillance Theory

A

Theory that adaptive immune response evolved less for dealing with foreign substances than as a way of detecting changes in the body’s own cell surfaces

156
Q

Evidence for immune surveillance theory (4)

A

1) Immunodeficient/ Immunosuppressed people (particularly of T cells) have higher incidence of tumors (organ transplant, AIDS, chemo drugs)
2) Activated T cells in a tumor is a good prognostic sign
3) Spontaneous regression of some tumors
4) Paraneoplastic syndromes - symptoms at distant organ that doesn’t contain tumor cells

157
Q

3 steps of immunoediting

A

1) Elimination
2) Equilibrium
3) Escape

158
Q

Elimination step of immunoediting

A
  • elimination of most cells that get initiated by a mutagenic event via immune surveillance
  • Malignant clone recognized as abnormal by both innate and adaptive immune systems, and thus eliminated
159
Q

Equilibrium step of immunoediting

A
  • lymphocytes infiltrate tumor but do not fully destroy it
  • Remain in equilibrium until drop in host immune response - can occur for any number of reasons → further mutations accumulate and lead to reactivation
160
Q

Escape step of immunoediting

A

-tumor cells fight back

Examples:

1) Checkpoint inhibitory surface receptor ligands upregulated (CTLA-4 and PD1 receptors)
2) Immunosuppressive factors expressed by tumor cells (TGF-B)
3) Downregulate expression of MHC class I on tumor → less CTL recognition

161
Q

Tumor-Associated Antigens (TAA)

A

Antigens overexpressed or abnormally expressed by the tumor

-Driver or passenger mutations

162
Q

Tumor Rejection Antigens (TRA)

A

TAA recognized by T cells → destruction of tumor

small subset of TAAs

163
Q

Carcinoembryonic antigen (CEA)

A

Example of a TAA

  • Oncofetal antigen
  • Found in blood of patients with colon carcinoma and other cancers
  • Can test for CEA with high suspicion of colon cancer, to confirm complete excision, or to warn of recurrence
164
Q

Role of CTL cells in killing tumor cells - 3 steps

A

1) recognize TRA presented by MHC class I
2) CTL activated in nodes (not at tumor site) via interactions with APCs
3) Activated TRA-specific T cells leave lymph node and migrate to tumor → induce apoptosis via perforin (secretion-based) or Fas-mediated (transmembrane signaling) pathways

PROBLEM: tumors down regulate MHC class I receptors on their cells

165
Q

Role of Th1 cells in killing tumor cells

A

CD4+ cells recognize tumor antigens, make lymphokines and attract M1 macrophages

-Problem is tumor make themselves resistant to M1 and only susceptible to M2 macrophages which protect tumors

166
Q

NK cells have receptors for….

A

1) Stress markers –> NK killing
2) MHC class I –> suppress NK cells
3) Receptors for Fc for IgG –> ADCC killing

167
Q

Implications of tumor down regulation of MHC class I

A

Tumor cells downregulate MHC to avoid CTL → makes them NK targets

168
Q

PD-1

A
  • inhibitory receptor on T cell surface, engaged by PD-L1 on APC
  • Upregulated late in T cell activation
  • Keeps immune response in check
169
Q

CTLA-4

A

-Inhibitory receptor that appears on T cell surface that effectively turns off CTL

170
Q

_____ and _______ are over-expressed by tumor cells AND tumor infiltrating cells → turn off T cells that are present at tumor site!

A

PDL1 and CTLA-4 ligands

T cells there, just have their off buttons pushed

171
Q

BCG treatment

A
  • innocent bystander killing
  • Inject directly into tumor
  • Causes delayed-type hypersensitivity reaction to BCG
  • Tumor cells killed as innocent bystanders by M1 macrophages
  • Treatment of choice for superficial bladder carcinoma
172
Q

Nivolumap and Pembrolizumab are…

A

monoclonal antibodies against PD-1

173
Q

monoclonal antibodies against PD-1 act by…

A
  • bind PD-1 and prevent it from receiving inhibitory signal from PD-L1
  • Cover up off switch so tumor can’t push it
  • Not very toxic, and highly effective
174
Q

Ipilimumab

A

Monoclonal Abs against CTLA-4

  • effective, but toxic (big immune responses, including autoimmunity)
  • Prevent immune system from being turned off → autoimmunity
175
Q

Response to mAbs related to…

A

extent of PD-L1 expression on tumor associated cells (more PD-L1 = better response) AND directly correlated to number of tumor mutations

176
Q

Tumor-Infiltrating Lymphocytes

A

cells directly from tumor

Can be used in Autologous cell therapy

T cells expanded in culture → irradiate patient’s immune system → reintroduce T cells into the immune-depleted patient to kill remaining tumor cells

177
Q

Driver Mutation

A
  • activate oncogenes, inactivate tumor-suppressor genes
  • The reason the tumor grows
  • “Undruggable”
178
Q

Passenger Mutations

A

Greatly outnumber drivers

  • Not causative, but incidental to disorder that exists in transformed cells
  • “Neoantigens”
  • The more passenger mutations a tumor has the more likely it is to be well-controlled by therapies that relieve the CTL from “Checkpoint Blockade”
179
Q

Chimeric antigen receptor

A

Re-arms CTLs making them have higher affinity for MHC-peptide-TCR system

  • Light chain/heavy chain variable domain + transmembrane domain + T cell stimulatory domain
  • NO MHC RESTRICTION
  • Triggered via normal TCR-associated pathway to become fully-cytotoxic

Blood and Lymph (9 decks)

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