heparin neutralization Flashcards
protamine
A polycationic polypeptide protein (what does this
mean) that’s 67% arginine Derived from salmon sperm (now made via recombinant
technology)
Strongly alkaline with numerous positive charges
protamine rxn with heparin
Two active sites
Binds with heparin to form a stable salt precipitate
Neither heparin or protamine have an anticoagulant effect once conjoined
Produces mild anticoagulant effect independent of heparin
Heparin-Protamine Clearance
Surprisingly, the metabolic “fate” of the heparin- protamine complex is unclear
It might be partially metabolized and eliminated
It might be gradually lysed back into heparin and protamine which has been theorized as a possible “heparin rebound” mechanism since heparin has a longer half-life than protamine
Current theory is it’s cleared by the Reticuloendothelial System
What the heck is the Reticuloendothelial System (RES)?
What the heck is the Reticuloendothelial System (RES)?
Kind of a “diffuse” part of the immune system
Consists of monocytes, macrophages (what’s the difference?), tissue histiocytes (what the heck are these) and Kupffer cells located in the liver, spleen, and lymph nodes
Responsible for clearing “stuff” *Now referred to as the Mono-
nuclear Phagocyte System (MPS)
Other Protamine Uses
Neutral Protamine Hagedorn insulin (NPH)
Protamine-Zinc insulin (PZI)
xploration into antineoplastic uses since it inhibits neovascularization
Possible future gene therapy uses involving viruses
No viable alternative to
protamine exists (yet)!
Anticoagulation Effect of Protamine
Debate about clinical significance and required dosage for effect
Effect becomes clinically significant at doses 3 times amount needed for heparin neutralization (1)
Anticoagulant effect clinically significant only when large amounts of protamine given (2)
Perkins et al. Neutralization of heparin in vivo with protamine. J Lab Clin Med 1956;48:223-226. Ellison et al. Is protamine a clinically significant anticoagulant? Anesthesiology 1971;35:621-629.
Anticoagulant effect seems to be caused by inhibition of platelet-induced aggregation by the heparin- protamine complex (3).
Recent evidence demonstrates protamine has no direct effect on platelet aggregation; it makes platelets less sensitive/insensitive to the “triggers” released by other platelets (such as ADP, thromboxane, etc….remember those?)
So one angry little platelet has increased difficulty getting the whole platelet crowd in a roar.
Anticoagulant effect seen at excess protamine doses of 6 to 15 mg/kg (4)…maybe…sort of…”-ish”.
Most patients should (may/maybe not?) tolerate an excess dose
f 1 to 2 mg/kg without adverse effects on hemostasis
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, and “more”
normalized clotting times.
It is difficult to move this topic from the realm of PerfList argument into the realm of evidence-based practice for several reasons:
1) The dose of protamine necessary to neutralize heparin is different—often significantly different– in vitro as compared to in vivo
2) Both heparin and protamine are biologic preparations and vary widely in potency
3) Since heparin is continuously metabolized, the required dose of protamine decreases over time…any measurement gives historical results
Calculation of Protamine Dose
Anticoagulant effect of given dose of heparin varies greatly between patients
Weight-based dosing versus heparin concentration versus heparin activity
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 ADVANTAGES Simple; Does not rely on ACT “It’s a really easy protocol to write”
DISADVANTAGES
Variability of heparin half-life so could give too much or too little
Heparin ACT Dose-Response Curv
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, BUT…
ADVANTAGES Easy to use; More accurate protamine dose – less protamine given;
Decreased blood product requirements
DISADVANTAGES
Yougottadomath…
ReliesonACT(NofixedcorrelationbetweenACTandheparin 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 (new methods are being researched which may be portable)
ADVANTAGES Consistently results in lower protamine dose versus ACT response
curve (what might THAT mean?) DISADVANTAGES
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)
ALMOST CERTAINLY more accurate, simple, P.O.C heparin concentration tests will become available during your careers
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
Assume it takes 1.1 mg of protamine to neutralize 100 units of heparin; This tells you how much heparin is in the tube; With an estimated patient blood volume you can estimate the total heparin load
Protamine Titration
ADVANTAGES
Usually give less protamine than fixed dose; Less post operative bleeding; Less exposure to blood products; Absence of heparin rebound
DISADVANTAGES
Estimation of patient’s blood volume; Variability of heparin and protamine preparations (use same protamine source for determinations)
Complications
Heparin-Protamine complex activates the complement cascade via the classical pathway
Allergic reactions Pulmonary hypertension Transient systemic hypotension in most patients
REACTION CLASSIFICATION I Type I
Mild hypotension due to histamine release (Rapid infusion) Can be ameliorated by giving protamine intra-arterial (intra-aortic)…what does THAT suggest to you?
Your Nemesis, Histamine
Basophils/Mast cells
Specific Histamine receptors in critter:
Increase sensitivity to pain and itching
Dilation of arterioles and precapillary sphincters
Increased HR (both direct and reflex effect)
Most critters experience bronchoconstriction (lagomorphs excepted, Kristen)
GI motility (oops!) Wheals and flares
What to do, what to do…
*Cromolyn sodium is a mast cell membrane stabilizer and helps prevent mast cell degranulation before its occurrence
REACTION CLASSIFICATION I
Type IIa:
Trueanaphylaxis;IgEmediated.Anamnestic decrease SVR, PA, LA, & RA pressures +/- bronchospasm
~50% of IDDM patients taking NPH insulin have anti- protamine IgE
Some commonly-accepted risk associations (BPH, post- vasectomy) are NOT supported by good data (yet) but are belief-based “facts”
REACTION CLASSIFICATION I
Type IIb:
ImmediateAnaphylactoid;NoIgEinvolvement
Mediated by thromboxane; leads to pulmonary vasoconstriction & bronchoconstriction
REACTION CLASSIFICATION I Type IIc:
Delayed Anaphylactoid; Increased post-0p pulmonary edema
Also related to complement activation with histamine/thromboxane/”others” release
REACTION CLASSIFICATION I
Type III:
Occurs in 0.6% of adult cardiac surgical
patients
Catastrophicpulmonaryvasoconstriction (IgG/complement-mediated); Noncardiogenic pulmonary edema
Intensevasoconstrictionseemstobethromboxane- mediated
No long-term negative sequelae (if patient lives!)
REACTION CLASSIFICATION II TypeA
Pharmacologic histamine release
REACTION CLASSIFICATION II Type B
True anaphylaxis (IgE mediated)
REACTION CLASSIFICATION II Type
Anaphylactoid thromboxane release; Pulmonary vasoconstriction; Bronchoconstriction
Risk Factors
Fish Allergy (up to 27% of general population?) Post Vasectomy (?); but this seems to happen mostly
in men…
Antibody development (5%) from prior exposure • Re-op patients • Dialysis patients • Neutral protamine Hagedorn (NPH) Insulin preparation
• Addition of protamine extends duration of action to 24 hours
• Heparin/ProtamineinCathlab
Risk Increase
Prior reaction to protamine
189 fold
allergy to fish
24.5 fold increase
Exposure to NPH insulin
8.2 fold increase
allergy to any drug
3 fold increase
prior exposure to protamine
no increase
Protamine added to regular insulin
Neutral Protamine Hagedorn insulin
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
alternatives to protamine Platelet concentrates
Platelet factor 4 (PF4) released from activated platelets combines with and neutralizes protamine
Platelet concentrates do not restore coagulation following bypass Recombinant form failed clinical trials
alternatives to protamine 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
alternatives to protamine Other
HeparinaseI:failedinclinicaltrials Lactoferrin: Demonstrated modest neutralizing capacity Heparin-RemovalDevices intraaortic protamine injections
