Heparin Neutralization- Exam 1

Question 1

Protamine

Answer 1

A polycationic polypeptide protein
67% arginine
Derived from salmon sperm (now recombinant technologY)
strongly alkaline with numerous positive charges
2 active sites
binds with heparin to form stable salt precipitate
Mild anticoagulant effect independent of heparin

Question 2

Fate of heparin-protamine

Answer 2

partially metabolized and eliminated
gradually lysed back into heparin and protamine theorized as possible heparin-rebound since heparin has longer half life than protamine
Current theory: reticuloendotehlial system

Question 3

Reticuloendothelial System

Answer 3

Diffuse part of immune system
Monocytes, macrophages, tissue histocytes, Kupffer cells in liver, spleen, lymph nodes
clearing “stuff”
Now called Mononuclear Phagocyte System (MPS)

Question 4

Other Protamine Uses

Answer 4

Neutral Protamine Hagedorn Insulin (NPH)
Protamin-Zinc insulin (PZI)
Explore into antineoplastic uses since it inhibits neovasculization
gene therapy involving viruses

Question 5

Antineoplastic

Answer 5

growth of new blood cells in tumors

Question 6

Anticoagulant effect of protamine

Answer 6

clinically significant at doses 3x amt needed for heparin neutralization
Caused by inhibition of platelet-induced aggregation by heparin-protamin complex (recently: makes platelets less sensitive to triggers released by other paltelets)
Effect seen when excess protamine doses are 6-15 mg/kg
Patients should tolerate excess of 1-2 mg/kg with adverse effects

Question 7

Methods for Protamine Dosing

Answer 7

Fixed Dose
ACT/heparin dose-response curve
heparin concentrations
protamine titrations

Question 8

Fixed Dose

Answer 8

Give fixed amt (usually 1 to 1.3 mg of protamine per 100units of heparin)

Simple, doesnt rely on ACT
But variability of heparin half-life so not always accurate

Question 9

Heparin ACT Dose Response Curve

Answer 9

Plot pre-heparin ACT
Plot post-heparin ACT
plot curve-determine slope
measure act after bypass
calculate total heparin load
Protamine 1.3 mg per 100 units heparin

easy to use, more accurate, less protamine given
decreased blood products
relies on act, and you have to do math

Question 10

Heparin Concentrations

Answer 10

Requires Lab
lower protamine doses vs act response curve
test takes time
requires estimate of plasma volume
because of the time requirement heparin on board may change

Question 11

Protamine Titration

Answer 11

Tubes of various dilutions of protamine solution
fixed vol of heparinized whole blood added to each
tube with lowest concentration resulting in shortest clotting time represents best neutralization ratio

less protamine than fixed, less post op bleeding, less blood products, absence of heparin rebound
Estimation of patient’s blood volume, variability of heparin and protamine preparations (use same protamine source for determinations)

Question 12

Protamine Complications

Answer 12

Hep-Pro complex activates complement cascade
allergic rxns
pulmonary htn
transient systemic hypotension in most patients

Question 13

Type I Protamine Rxn

Answer 13

Mild hypotension due to histamine release (rapid infusion)
give protamin intra-arterial/intra-aortic
Problem is mast cells in lungs

Question 14

Histamine

Answer 14

Basophils/mast Cells
Histamine receptors:
increase sensitivity to pain and itching
dilation of arterioles and precap sphincters
increased HR (direct and reflex effect)
bronchoconstriction 
GI motility
Wheals and flares

Question 15

Cromolyn sodium

Answer 15

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

Question 16

Type IIa Protamine Rxn

Answer 16

Anaphylaxis
IgE mediated
Anamnestic (body primed so 2nd rxn worse)
SVR, PA, LA and RA pressures +/- bronchospasm
50% IDDM patients taking NPH insulin have anti protamine IgE
Risks: BPH, post vasectomy, but not supported by good data

Question 17

Type IIb Protamine Rxn

Answer 17

Immediate Anaphylactoid
No IgE
Mediated by thromboxane, leads to pulmonary vasoconstriction and bronchoconstriction

Question 18

Type IIc Protamine Rxn

Answer 18

Delayed Anaphylactoid Rxn
increased post op edema
complement activation
histamine/thromboxane/other release

Question 19

Type III Protamine Rxn

Answer 19

0.6% adult cardiac surgical patients
Catastrophic pulmonary vasoconstriction (IgG/compelemnt mediated); noncardiogenic pulmonary edema
intense vasoconstriction seems to be thromboxane mediated
no long-term negative effects

Question 20

Protamine Rxn Classificiation II

Answer 20

Type A: Pharmacologic histamine release
Type B: true anaphylaxis (IgE mediate)
Type C: Anaphylactoid thromboxane release: pulmonary vasoconstriction; bronchoconstriction

Question 21

Risk Factors for Protamine Rxn

Answer 21

Fish Allergy (27% general population)
Post vasectomy
antibody development 5% from prior exposure (reop, dialysis, neutral protamine hagedorn insulin- extends duration of action to 24 hrs)

Question 22

Rate of Administration of Protamine

Answer 22

No faster than 5 mg/min althought 15 mg/min more common

Question 23

Protamine Alternatives

Answer 23

Platelet Concentrates
Hexadimethrine
Heparinase I
lactoferrin
Heparin-Removal devices
Intra-aortic protamine injections

Question 24

Platelet Concentrates

Answer 24

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

Question 25

Hexadimethrine

Answer 25

Synthetic polycation- not easy to get in US
problems with renal toxicity
use can avoid true allergic reactions due to protamine
still can produce pulmomonary vasoconstrictions if given too quickly

Question 26

Heparinase I

Answer 26

failed in clinical trials

Question 27

Lactoferrin

Answer 27

demonstreated modest neutralizing capacity