test 7 part 2

Question 1

Protamine

Answer 1

 A polycationic polypeptide protein that’s 67% arginine
 Derived from salmon sperm (now made via recombinant technology) patients illergic to fish
 Strongly alkaline with numerous positive charges
 Two active sites
 Binds with heparin ionically to form a stable salt precipitate
 Produces mild anticoagulant effect independent of heparin **
 Neither heparin or protamine have an anticoagulant effect once conjoined
 Heparin-Protamine complex cleared by Reticuloendothelial System (RES)

Question 2

What is the Reticuloendothelial System (RES)?

Answer 2

 Part of the immune system
 Consists of:
 Monocytes (intravascular and when they move out of the blood vessels they turn into macrophages)
 Macrophages (take stuff up)
 In Spleen and lymph nodes
 Kupffer cells
 In Liver
 Responsible for clearing “stuff”
*Now referred to as the Mono-nuclear Phagocyte System (MPS)

Question 3

Neutral Protamine Hagedorn insulin (NPH)

Answer 3

• makes it more stable

- makes shelf life longer

Question 4

Protamine-Zinc insulin (PZI)

Answer 4

• makes it more stable

- protamine makes things more stable

Question 5

other alternatives for reversal?

Answer 5

No viable alternative to protamine exists (yet)!

Question 6

Anticoagulation Effect of Protamine

Answer 6

 Most patients should tolerate an excess dose of 1 to 2 mg/kg without adverse effects on hemostasis
 Overdose can cause platelet dysfunction which can last for several hours

Question 7

Calculation of Protamine Dose

Answer 7

 Anticoagulant effect of given dose of heparin varies greatly between patients
 Weight-based dosing versus heparin concentration versus heparin activity

Question 8

methods of trying to figure out how much protamine to give

Answer 8

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

Question 9

Fixed Dose

Answer 9

 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

Question 10

ADVANTAGES of fixed dose

Answer 10

 Simple; Does not rely on ACT

Question 11

DISADVANTAGES of fixed dose

Answer 11

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

Question 12

Heparin ACT Dose-Response Curve

Answer 12

 Plot pre-heparin ACT
 Plot post-heparin ACT
 Plot curve – 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 13

ADVANTAGES of Heparin ACT Dose-Response Curve

Answer 13

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

Question 14

DISADVANTAGES of Heparin ACT Dose-Response Curve

Answer 14

 Relies on ACT (No fixed correlation between ACT and heparin concentrations, i.e. other factors affect ACT)

Question 15

Heparin Concentration

Answer 15

 Not easy to determine directly – several methods available but all must be done in the laboratory

Question 16

ADVANTAGES of Heparin Concentration

Answer 16

 Results in lower protamine dose versus ACT response curve

Question 17

DISADVANTAGES of Heparin Concentration

Answer 17

 Takes time to determine (if test is even available)
 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 18

Protamine Titration

Answer 18

 Tubes of various dilutions of a protamine solution
 Fixed volume of heparinized whole blood added to each tube
 Tube with lowest concentration resulting in the shortest clotting time represents best neutralization of heparin
 Actual protamine dose calculated based on assumed neutralization ratio

Question 19

Advantages of Protamine Titration

Answer 19

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

Question 20

Disadvantages of Protamine Titration

Answer 20

 Estimation of patient’s blood volume
 Variability of heparin and protamine preparations
 Use same protamine source for determinations

Question 21

Protamine complications

Answer 21

 Heparin-Protamine complex activates the complement cascade via the classical pathway
 Allergic reactions
 Pulmonary hypertension
 Transient systemic hypotension in most patients

Question 22

Adverse Reactions to Protamine : REACTION CLASSIFICATION I

Answer 22

Type I
 Mild hypotension due to histamine release (Rapid infusion)
Type IIa:
 True anaphylaxis; IgE mediated
Type IIb
 Immediate anaphylactoid; No IgE
Type IIc
 Delayed anaphylactoid; Increased pulmonary edema
Type III (Occurs in 0.6% of adult cardiac surgical
patients)
 Catastrophic pulmonary vasoconstriction (IgG/complement mediated); Noncardiogenic pulmonary edema

Question 23

Adverse Reactions to Protamine : REACTION CLASSIFICATION II

Answer 23

 Type A
 Pharmacologic histamine release
 Type B
 True anaphylaxis (IgE mediated)
 Type C
 Anaphylactoid thromboxane release; Pulmonary vasoconstriction; Bronchoconstriction

Question 24

Protamine Reactions:

Pharmacologic Release

Answer 24

 Protamine causes histamine release with rapid infusion
 Shows to be released from degranulating mast cells (in the lungs)
 Independent of heparin-protamine complexes
 Protamine alone causes
 Found greater degree of hypotension and greater histamine levels
 Given on right side of heart (goes straight to the lungs and they release histamine)
 Lower when given on the left side of the heart (ie. Intra-aortic)

Question 25

Risk Factors

Answer 25

o Fish Allergy (up to 27% of general population?)
o Post Vasectomy (?)
o Antibody development (5%) from prior exposure

Question 26

Potential Risk of True Allergic Response

Answer 26

• Prior reaction to protamine = 189 fold increase

- Prior exposure to protamine = No increase

Question 27

Rate of Administration

Answer 27

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

Question 28

Alternatives to protamine

Answer 28

 Allow heparin to be metabolized
 Platelet concentrates
 Hexadimethrine (problems with renal toxicity)