Topic 3 Flashcards
Protamine-
A ____ ____ protein that’s ___% arginine
polycationic polypeptide
67%
-Derived from salmon sperm
Protamine-
Strongly ____ with numerous _____ charges
alkaline
positive
Protamine-
Two active sites. Binds with heparin to form a
stable salt precipitate
Protamine-
Neither heparin or protamine have an
anticoagulant effect once conjoined
Protamine-
Produces mild
anticoagulant effect independent of heparin
Heparin-Protamine Clearance
Reticuloendothelial System
Reticuloendothelial System (RES)=
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
Reticuloendothelial System is now known as the
Mono-nuclear Phagocyte System (MPS)
Other Protamine Uses
- Neutral Protamine Hagedorn insulin (NPH)
- Protamine-Zinc insulin (PZI)
- Exploration into antineoplastic uses since it inhibits neovascularization
- Possible future gene therapy uses involving viruses
No viable ______ to protamine exists (yet)!
alternative
Anticoagulation Effect of Protamine-
Effect becomes clinically significant at doses
3 times amount needed for heparin neutralization
Anticoagulation Effect of Protamine-
Anticoagulant effect clinically significant only when
large amounts of protamine given
Anticoagulation Effect of Protamine-
Seems to be caused by
inhibition of platelet-induced aggregation by the heparin-protamine complex
Recent evidence demonstrates protamine has ___ ____ effect on platelet aggregation; it makes platelets ____ ______ to the “triggers” released by other platelets (such as ADP, thromboxane)
no direct
less sensitive/insensitive
Anticoagulant effect seen at excess protamine doses of
6 to 15 mg/kg
Most patients should tolerate an excess protamine dose of
1 to 2 mg/kg without adverse effects on hemostasis
Protamine overdose can cause
platelet dysfunction which can last for several hours
lower doses of protamine tend to cause
less chest tube drainage
provides for higher platelet counts
“more” normalized clotting times
The dose of protamine necessary to neutralize heparin is different—often significantly different–
in vitro as compared to in vivo
Both heparin and protamine are biologic preparations and vary widely in
potency
Since heparin is continuously metabolized, the required dose of protamine
decreases over time
Calculation of Protamine Dose methods:
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 during the case or based on initial heparin loading dose
Fixed Dose advantages
Simple
Does not rely on ACT
“It’s a really easy protocol to write”
Fixed Dose disadvantages
Variability of heparin half-life so could give too much or too little
Heparin ACT Dose-Response Curve=
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
Heparin ACT Dose-Response Curve advantages
Easy to use
More accurate protamine dose – less protamine given; Decreased blood product requirements
Heparin ACT Dose-Response Curve disadvantages
You gotta do math…
Relies on ACT (No fixed correlation between ACT and heparin concentrations , i.e. other factors affect ACT)
Heparin Concentration method advantages
Consistently results in lower protamine dose versus ACT response curve
Heparin Concentration method disadvantages
- 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)
Protamine Titration=
- 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
Protamine Titration advantages
Usually give less protamine than fixed dose
Less post operative bleeding
Less exposure to blood products
Absence of heparin rebound
Protamine Titration disadvantages
Estimation of patient’s blood volume
Variability of heparin and protamine preparations
Heparin neutralization 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)
- Can be ameliorated by giving protamine intra-arterial
Your Nemesis=
Histamine
-Basophils/Mast cells
Specific Histamine receptors cause (6)-
- 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
Cromolyn sodium=
mast cell membrane stabilizer and helps prevent mast cell degranulation before its occurrence
Adverse Reactions to Protamine
REACTION CLASSIFICATION I
Type IIa =
- True anaphylaxis- IgE mediated. Anamnestic
- Decreased SVR, PA, LA, RA pressures +/- bronchospasm
- ~50% of IDDM patients taking NPH insulin have anti-protamine IgE
Adverse Reactions to Protamine
REACTION CLASSIFICATION I
Type IIb =
- Immediate Anaphylactoid- No IgE involvement
- Mediated by thromboxane
- leads to pulmonary vasoconstriction & bronchoconstriction
Adverse Reactions to Protamine
REACTION CLASSIFICATION I
Type IIc =
- Delayed Anaphylactoid
- Increased post-0p pulmonary edema
- Also related to complement activation with histamine/thromboxane/”others” release
Adverse Reactions to Protamine
REACTION CLASSIFICATION I
Type III =
- 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
Adverse Reactions to Protamine
REACTION CLASSIFICATION II
Type A =
Pharmacologic histamine release
Adverse Reactions to Protamine
REACTION CLASSIFICATION II
Type B =
True anaphylaxis (IgE mediated)
Adverse Reactions to Protamine
REACTION CLASSIFICATION II
Type C =
Anaphylactoid thromboxane release
Pulmonary vasoconstriction
Bronchoconstriction
Risk Factors=
- Fish Allergy (up to 27% of general population)
2. Antibody development (5%) from prior exposure
Potential Risk of True Allergic Response-
Prior reaction to protamine risk increase
189 fold increase
Potential Risk of True Allergic Response-
Allergy to fish risk increase
24.5 fold increase
Potential Risk of True Allergic Response-
Exposure to NPH insulin risk increase
8.2 fold increase
Potential Risk of True Allergic Response-
Allergy to any drug risk increase
3 fold increase
Potential Risk of True Allergic Response-
Prior exposure to protamine risk increase
No increase
Rate of Administration
Studies suggest no faster than 5 mg/minute although 15 mg/minute might be more common
Alternatives to protamine= (6)
- Allow heparin to be metabolized
- Platelet concentrates
- Hexadimethrine
- Heparinase I
- Lactoferrin
- Heparin-Removal Devices
Platelet concentrates=
- Platelet factor 4 (PF4) released from activated platelets combines with and neutralizes protamine
- Platelet concentrates do not restore coagulation following bypass
Hexadimethrine=
- 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
