Topic 3

Question 1

Protamine-

A ____ ____ protein that’s ___% arginine

Answer 1

polycationic polypeptide
67%
-Derived from salmon sperm

Question 2

Protamine-

Strongly ____ with numerous _____ charges

Answer 2

alkaline

positive

Question 3

Protamine-

Two active sites. Binds with heparin to form a

Answer 3

stable salt precipitate

Question 4

Protamine-

Neither heparin or protamine have an

Answer 4

anticoagulant effect once conjoined

Question 5

Protamine-

Produces mild

Answer 5

anticoagulant effect independent of heparin

Question 6

Heparin-Protamine Clearance

Answer 6

Reticuloendothelial System

Question 7

Reticuloendothelial System (RES)=

Answer 7

Consists of monocytes, macrophages, tissue histiocytes and Kupffer cells located in the liver, spleen, and lymph nodes

• Responsible for clearing “stuff”
• Kind of a “diffuse” part of the immune system

Question 8

Reticuloendothelial System is now known as the

Answer 8

Mono-nuclear Phagocyte System (MPS)

Question 9

Other Protamine Uses

Answer 9

1. Neutral Protamine Hagedorn insulin (NPH)
2. Protamine-Zinc insulin (PZI)
3. Exploration into antineoplastic uses since it inhibits neovascularization
4. Possible future gene therapy uses involving viruses

Question 10

No viable ______ to protamine exists (yet)!

Answer 10

alternative

Question 11

Anticoagulation Effect of Protamine-

Effect becomes clinically significant at doses

Answer 11

3 times amount needed for heparin neutralization

Question 12

Anticoagulation Effect of Protamine-

Anticoagulant effect clinically significant only when

Answer 12

large amounts of protamine given

Question 13

Anticoagulation Effect of Protamine-

Seems to be caused by

Answer 13

inhibition of platelet-induced aggregation by the heparin-protamine complex

Question 14

Recent evidence demonstrates protamine has ___ ____ effect on platelet aggregation; it makes platelets ____ ______ to the “triggers” released by other platelets (such as ADP, thromboxane)

Answer 14

no direct

less sensitive/insensitive

Question 15

Anticoagulant effect seen at excess protamine doses of

Answer 15

6 to 15 mg/kg

Question 16

Most patients should tolerate an excess protamine dose of

Answer 16

1 to 2 mg/kg without adverse effects on hemostasis

Question 17

Protamine overdose can cause

Answer 17

platelet dysfunction which can last for several hours

Question 18

lower doses of protamine tend to cause

Answer 18

less chest tube drainage
provides for higher platelet counts
“more” normalized clotting times

Question 19

The dose of protamine necessary to neutralize heparin is different—often significantly different–

Answer 19

in vitro as compared to in vivo

Question 20

Both heparin and protamine are biologic preparations and vary widely in

Answer 20

potency

Question 21

Since heparin is continuously metabolized, the required dose of protamine

Answer 21

decreases over time

Question 22

Calculation of Protamine Dose methods:

Answer 22

Fixed dose
ACT/heparin dose-response curve
Heparin concentrations
Protamine titration

Question 23

Fixed Dose=

Answer 23

Give fixed amount of protamine for each unit of heparin that was given

• Usually 1 to 1.3 mg of protamine per 100 units of heparin
• Usually based on total amount of heparin given during the case or based on initial heparin loading dose

Question 24

Fixed Dose advantages

Answer 24

Simple
Does not rely on ACT
“It’s a really easy protocol to write”

Question 25

Fixed Dose disadvantages

Answer 25

Variability of heparin half-life so could give too much or too little

Question 26

Heparin ACT Dose-Response Curve=

Answer 26

``` Plot pre and post heparin ACT Determine slope of curve Measure ACT after termination of bypass Calculate total heparin load -Protamine dose is usually 1.3 mgs per 100 units of total heparin load ```

Question 27

Heparin ACT Dose-Response Curve advantages

Answer 27

Easy to use | More accurate protamine dose – less protamine given; Decreased blood product requirements

Question 28

Heparin ACT Dose-Response Curve disadvantages

Answer 28

You gotta do math… | Relies on ACT (No fixed correlation between ACT and heparin concentrations , i.e. other factors affect ACT)

Question 29

Heparin Concentration method advantages

Answer 29

Consistently results in lower protamine dose versus ACT response curve

Question 30

Heparin Concentration method disadvantages

Answer 30

- Takes time to determine - Requires estimate of patient plasma volume - Not always good correlations between heparin concentrations and clotting times - Because of time requirement, protamine dose may not reflect actual heparin concentration when given (heparin continued to be metabolized)

Question 31

Protamine Titration=

Answer 31

- Tubes of various dilutions of a protamine solution - Fixed volume of heparinized whole blood added - Tube with lowest concentration resulting in the shortest clotting time represents best neutralization of heparin - Actual protamine dose calculated-neutralization ratio

Question 32

Protamine Titration advantages

Answer 32

Usually give less protamine than fixed dose Less post operative bleeding Less exposure to blood products Absence of heparin rebound

Question 33

Protamine Titration disadvantages

Answer 33

Estimation of patient’s blood volume | Variability of heparin and protamine preparations

Question 34

Heparin neutralization complications

Answer 34

1. Heparin-Protamine complex activates the complement cascade via the classical pathway 2. Allergic reactions 3. Pulmonary hypertension 4. Transient systemic hypotension in most patients

Question 35

Adverse Reactions to Protamine REACTION CLASSIFICATION I Type I =

Answer 35

- Mild hypotension due to histamine release (Rapid infusion) | - Can be ameliorated by giving protamine intra-arterial

Question 36

Your Nemesis=

Answer 36

Histamine | -Basophils/Mast cells

Question 37

Specific Histamine receptors cause (6)-

Answer 37

- Increase sensitivity to pain and itching - Dilation of arterioles and precapillary sphincters - Increased HR (both direct and reflex effect) - Most critters experience bronchoconstriction - Increase GI motility - Wheals and flares

Question 38

Cromolyn sodium=

Answer 38

mast cell membrane stabilizer and helps prevent mast cell degranulation before its occurrence

Question 39

Adverse Reactions to Protamine REACTION CLASSIFICATION I Type IIa =

Answer 39

- True anaphylaxis- IgE mediated. Anamnestic - Decreased SVR, PA, LA, RA pressures +/- bronchospasm - ~50% of IDDM patients taking NPH insulin have anti-protamine IgE

Question 40

Adverse Reactions to Protamine REACTION CLASSIFICATION I Type IIb =

Answer 40

- Immediate Anaphylactoid- No IgE involvement - Mediated by thromboxane - leads to pulmonary vasoconstriction & bronchoconstriction

Question 41

Adverse Reactions to Protamine REACTION CLASSIFICATION I Type IIc =

Answer 41

- Delayed Anaphylactoid - Increased post-0p pulmonary edema - Also related to complement activation with histamine/thromboxane/”others” release

Question 42

Adverse Reactions to Protamine REACTION CLASSIFICATION I Type III =

Answer 42

- Occurs in 0.6% of adult cardiac surgical patients - Catastrophic pulmonary vasoconstriction (IgG/complement-mediated) - Noncardiogenic pulmonary edema - Intense vasoconstriction seems to be thromboxane-mediated - No long-term negative sequelae

Question 43

Adverse Reactions to Protamine REACTION CLASSIFICATION II Type A =

Answer 43

Pharmacologic histamine release

Question 44

Adverse Reactions to Protamine REACTION CLASSIFICATION II Type B =

Answer 44

True anaphylaxis (IgE mediated)

Question 45

Adverse Reactions to Protamine REACTION CLASSIFICATION II Type C =

Answer 45

Anaphylactoid thromboxane release Pulmonary vasoconstriction Bronchoconstriction

Question 46

Risk Factors=

Answer 46

1. Fish Allergy (up to 27% of general population) | 2. Antibody development (5%) from prior exposure

Question 47

Potential Risk of True Allergic Response- | Prior reaction to protamine risk increase

Answer 47

189 fold increase

Question 48

Potential Risk of True Allergic Response- | Allergy to fish risk increase

Answer 48

24.5 fold increase

Question 49

Potential Risk of True Allergic Response- | Exposure to NPH insulin risk increase

Answer 49

8.2 fold increase

Question 50

Potential Risk of True Allergic Response- | Allergy to any drug risk increase

Answer 50

3 fold increase

Question 51

Potential Risk of True Allergic Response- | Prior exposure to protamine risk increase

Answer 51

No increase

Question 52

Rate of Administration

Answer 52

Studies suggest no faster than 5 mg/minute although 15 mg/minute might be more common

Question 53

Alternatives to protamine= (6)

Answer 53

1. Allow heparin to be metabolized 2. Platelet concentrates 3. Hexadimethrine 4. Heparinase I 5. Lactoferrin 6. Heparin-Removal Devices

Question 54

Platelet concentrates=

Answer 54

- Platelet factor 4 (PF4) released from activated platelets combines with and neutralizes protamine - Platelet concentrates do not restore coagulation following bypass

Question 55

Hexadimethrine=

Answer 55

- Synthetic polycation – not easy to get in US - Problems with renal toxicity - Use can avoid true allergic reactions due to protamine - Still can produce pulmonary vasoconstriction if given too quickly