test 7 part 2 Flashcards
Protamine
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)
What is the Reticuloendothelial System (RES)?
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)
Neutral Protamine Hagedorn insulin (NPH)
- makes it more stable
- makes shelf life longer
Protamine-Zinc insulin (PZI)
- makes it more stable
- protamine makes things more stable
other alternatives for reversal?
No viable alternative to protamine exists (yet)!
Anticoagulation Effect of Protamine
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
Calculation of Protamine Dose
Anticoagulant effect of given dose of heparin varies greatly between patients
Weight-based dosing versus heparin concentration versus heparin activity
methods of trying to figure out how much protamine to give
Fixed dose
ACT/heparin dose-response curve
Heparin concentrations
Protamine titration
Fixed Dose
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
ADVANTAGES of fixed dose
Simple; Does not rely on ACT
DISADVANTAGES of fixed dose
Variability of heparin half-life so could give too much or too little
Heparin ACT Dose-Response Curve
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
ADVANTAGES of Heparin ACT Dose-Response Curve
Easy to use; More accurate protamine dose – less protamine given; Decreased blood product requirements
DISADVANTAGES of Heparin ACT Dose-Response Curve
Relies on ACT (No fixed correlation between ACT and heparin concentrations, i.e. other factors affect ACT)
Heparin Concentration
Not easy to determine directly – several methods available but all must be done in the laboratory
ADVANTAGES of Heparin Concentration
Results in lower protamine dose versus ACT response curve
DISADVANTAGES of Heparin Concentration
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)
Protamine Titration
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
Advantages of Protamine Titration
Usually give less protamine than fixed dose
Less post operative bleeding
Less exposure to blood products
Absence of heparin rebound
Disadvantages of Protamine Titration
Estimation of patient’s blood volume
Variability of heparin and protamine preparations
Use same protamine source for determinations
Protamine complications
Heparin-Protamine complex activates the complement cascade via the classical pathway
Allergic reactions
Pulmonary hypertension
Transient systemic hypotension in most patients
Adverse Reactions to Protamine : REACTION CLASSIFICATION I
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
Adverse Reactions to Protamine : REACTION CLASSIFICATION II
Type A
Pharmacologic histamine release
Type B
True anaphylaxis (IgE mediated)
Type C
Anaphylactoid thromboxane release; Pulmonary vasoconstriction; Bronchoconstriction
Protamine Reactions:
Pharmacologic Release
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)
Risk Factors
o Fish Allergy (up to 27% of general population?)
o Post Vasectomy (?)
o Antibody development (5%) from prior exposure
Potential Risk of True Allergic Response
- Prior reaction to protamine = 189 fold increase
- Prior exposure to protamine = No increase
Rate of Administration
Studies suggest no faster than 5 mg/minute although 15 mg/minute might be more common
Alternatives to protamine
Allow heparin to be metabolized
Platelet concentrates
Hexadimethrine (problems with renal toxicity)
