the heparin preparation, and the ac

[REVJEWAIRTSCII tual coagulation system used for

the testing. No constant relation
ship could be established between
the quantities of protamine required
for neutralization of a given number
of units of heparin. This appeared
to be owing to differences in ac
companying materials in both pro
Protamine -
antagonist to heparin tamine and heparin preparations
and to the fact that the ability of
protamine to combine with heparin
L. B. Jaques, m.a., ph.d., f.r.s.c, Saskatoon, Sask. was not related specifically to those
groups in heparin responsible for
its anticoagulant activity.6
Summary: Protamine is used fective. Our studies demonstrated Today it is still difficult to es
for titration of heparin in vitro two uses for this
property of pro tablish a relationship between milli
for diagnosis of hemorrhagic tamine. The first8 was neutralization grams of protamine and units of
states and for neutralization of of the anticoagulant action of hepa heparin, essentially for the same
heparin in vivo to terminate rin in blood samples, both to de reasons, but in particular because
heparinization. The protamine monstrate the presence of heparin of the considerable variability found
equivalent varies with the heparin in blood and to measure the amount in heparin preparations commer
preparation, conditions of of heparin in the sample. It was cially available and the difficulties
testing and, in vivo, with the known as protamine titration and in standardizing them in terms
amount of heparin present in the has since been widely used by hema- of international units. In recent
circulation. The latter depends tologists and others. Since an excess studies79 we have conducted chem
on time after administration and of protamine shows anticoagulant ical analyses on a number of com
the hemodynamic and metabolic properties when added to blood mercial heparin preparations and
state of the patient. Protamine, samples, the minimal amount of have found a great variation in
when injected rapidly, will release protamine required to bring the many chemical parameters. Further
histamine and agglutinate clotting time to a normal value pro more, no correlations were found
platelets. Bleeding (spontaneous vides a measure of the amount of between activity on biological po
hemorrhage) demonstrates heparin present in the blood sample. tency tests in vitro or in vivo and
a multiple breakdown of hemostatic The second use of protamine, as any chemical parameter. It is there
mechanisms due to surgical stress, demonstrated by Jaques, Charles fore not surprising that Lowary et
drugs, exposure of the blood and Best,4 was to reduce hypo- al found a similar variation in pro
to foreign surfaces, etc. Simple coagulability due to heparin by its tamine neutralization. To discuss
rules for the amount of protamine injection into the circulation, known the equivalence of protamine to
required for an individual patient as protamine neutralization. heparin in terms of milligrams per
based on clinical judgement will be In order to titrate heparin with mg. as compared to units per mg.
satisfactory in most cases. When protamine in vitro or to neutralize requires a value for units per mg.
hemostasis is not achieved, it must heparin in vivo, it is necessary to of heparin. The crystalline hydrated
be appreciated that heparin and know the equivalence of protamine barium sait has a well documented
protamine are only part of a and heparin. However, we originally value of 100 units/mg. Removal of
complex deteriorating situation. observed that the value of the factor water and barium results in a value
for this equivalence can be changed of 156 units/mg. Current heparin
Protamine has long been used in both in vitro and in vivo and this preparations show a wide range of
conjunction with heparin therapy. is confirmed by the recent report values, from 60 to 180 units/mg.
At the suggestion of Professor C. of Lowary er of of a study of neu Heparin is supplied for clinical use
H. Best, in 1937 I undertook a tralization in vitro and in vivo in bottled solutions containing a
study on the practical use of pro which demonstrated "a significant specific number of units as deter
tamine as a heparin antagonist, difference in the neutralization of mined by biological assay (several
after the demonstrations by A. different types of sodium heparin by different official assay methods
Fischer1 that basic proteins could protamine sulfate". exist). The actual weight of heparin
hinder the anticoagulant activity of used will vary with manufacturer,
heparin and by Chargaff and Olson2 In vitro equivalence of batch, assay procedure, etc. To con
that protamine was particularly ef- sider 100 units as equivalent to 1
protamine and heparin mg. of heparin is convenient, but
Our early studies demonstrated that the figure so obtained will not give
l. b. jaques, W.S. Lindsay Professor,
in vitro the number of milligrams the actual weight of heparin used.
College of Medicine, University of of protamine required to neutralize The considerable variability in
Saskatchewan
exactiy 1 mg. of heparin depended heparin preparations is in part re
Reprint requests to: Dr. L. B. Jaques, upon the particular protamine prep lated to difficulties in standardiza-
Hemostasis-Thrombosis Research Unit,
Dept. of Physiology, University of aration (source, method of extrac- tion because of problems in bio
Saskatchewan, Saskatoon, Sask. tion, accompanying materials, etc), logical assay of heparin. It has been
C.M.A. JOURNAL/MAY 19, 1973/VOL. 108 1291
widely assumed that comparison of
the anticoagulant activity of one
heparin preparation with a standard
heparin on blood or plasma is
sufficient. However, Jaques and
Charles10 showed that the relative
activity of heparins from different
sources, even when prepared in
the same manner as the crystalline
barium salts, varied with different
coagulation assay systems. Evid-
ently this is because heparin prep-
parations have different activities
with respect to various stages of
blood coagulation. The importance
of this phenomenon has been em
phasized recently by the interna
tional collaborative study of the
assay of heparin. Thirteen labora
tories studied coded heparin prep
arations supplied by the WHO
Laboratory for International Stand
ards.11 This study demonstrated that
while all the assay methods give
very similar values for any heparin
preparation when tested blind
against itself, large discrepancies
appear when two heparin prepara
tions are compared blind. This is
because the preparations exhibit
different relative activities with
changes in substrate plasma, etc.
These discrepancies can be as great
as 40% with the same assay pro
cedure (e.g. the USP .assay) when
different batches of substrate (in
this case sheep plasma) are used.
The US Pharmacopoeia describes
procedures for standardizing pro
tamine for use with insulin and with
heparin. However, with such varia
tion in relative activity of heparin
preparations in different test sys
tems, a figure for the neutralization
equivalent in mg. of protamine thus
standardized per 100 units of hepa
rin must be considered with some
reserve, particularly when USP
heparin standard, which contains a
large amount of diluent, is used.
The protamine titration
for heparin
Shortening of a prolonged clotting
time on addition of protamine is
usually an adequate demonstration
of the presence of heparin in the
blood sample. However, since in heparin in blood State in body fluids
vitro it is easy to add amounts of
0 2 u./ml.
protamine sufficiently large to in
> 2 u./ml.
crease the clotting time, it is neces
sary to determine the minimal
> 7 u./ml.
amount of protamine required to
shorten the clotting time to normal
Adapted from references 10 and 11
1292 C.M.A. JOURNAL/MAY 19, 1973/VOL. 108
values. To be able to express this as
equivalent heparin, it is necessary to
titrate in normal blood a known
heparin preparation with the prota
mine to be used. Further, the test is
only valid with respect to the pa
tient's plasma if normal levels of the
different components of blood co
agulation are present and if the
plasma does not contain protamine
or abnormal amounts of mucopoly-
saccharides. Protamine combines
with mucopolysaccharides, nucleic
acids and fibrinogen. Fibrinogen
split products, identified as anti
coagulants12 occurring in blood in
the intravascular coagulation syn
drome, may contribute to a titration
value for protamine.
Distribution and fate of
heparin in vivo
When protamine is used to neutral
ize heparin in the circulation, the
immediate question is how much
heparin is present. This requires a
knowledge of how much heparin
has been injected, the period of
time since the injection, the dis
tribution of heparin in body com-
partments, and the functional status
of the kidneys, reticulo-endothelial
system and other organs involved
in removing heparin from the cir
culation. To assume that the amount
of heparin present is the amount
injected divided by the total blood
volume may give a figure in error
by several orders of magnitude.
As indicated in Table I, heparin
in the circulation is disposed of in
various ways, depending on whether
it is associated with plasma protein
or is "free". At concentrations up
to 2 units/ml. blood, the heparin
appears to be attached to plasma
proteins in connection with the
coagulation system.18 In agreement
with this is Estes' calculation14 that
the relative volume of distribution
of heparin in man for median doses
of 2 mg./kg. is 57 mg./kg. or close
Table I
Relation of heparin concentration in the blood and mode of removal
Concentration of
Associated with plasma proteins Desulfated Inorganic S04
Not associated with plasma
proteins. Enters tissue spaces, Uroheparin Uroheparin
lymph.
Part taken up by macrophages,
endothelium, etc.
to the plasma volume. With higher
concentrations in the blood (larger
single intravenous doses), some
heparin is not bound and passes
into tissue spaces and appears in
the lymph. Some is taken up by
macrophages in the reticulo-endo
thelial system and some by endo
thelium. At blood concentrations
above 7 units/ml., unchanged
heparin is excreted by the kidney.
Partially degraded heparin (uro-
heparin) is also found in the urine.
However, for heparin attached to
plasma protein, destruction involves
removal of sulfate and its excretion
as inorganic sulfate. Hence removal
of heparin from the circulation is
not effected by a single route; this
is an added safety factor in its use.
Estes found a plasma half-life of
1.5 hours for heparin in man with a
dose of 2 mg./kg. Olsson, Lagergen
and Ek15 found that the plasma half-
life of heparin increases with in
creasing dosage. Further, Solandt
and Best16 demonstrated that the
effect of heparin on platelets per
sisted longer than the hypocoag-
ulability but that this effect can also
be reversed with protamine. Estes
has similarly found that the plasma
half-life for heparin is not the same
when measured by different coagu
lation tests.
The amount of heparin present in
the circulation can be determined
by various tests .
clotting time
(increased), protamine titration,
partial thromboplastin time (in
creased), thrombin clotting time,
and extraction followed by measure
ment in colorimetric or anticoagu
lant tests. Tests based on blood
coagulation are, in general, speedy
but they require that the coagula
tion system be essentially normal.
Hence, while such tests are very
successful in the control of long-
term intravenous heparin therapy,17
they are less successful in surgical
patients suddenly developing a
complex hemostatic defect.
Metabolic Renal
route excretion
Unchanged heparin
Heparin and hemostasis the result of combined defects of
While we were developing heparin hemostasis, identification of its
causes is not simple. Cessation of
for clinical use in 1934 we were
told by colleagues that this was a not hemorrhage by a treatment does
waste of time since patients (cer identify the cause of the hem
orrhage, since the direct action of
tainly surgical patients) who re the treatment (e.g. protamine in a
ceived heparin would bleed to death.
The universal administration of heparinized the patient) may have only
suspended
heparin to patients without the oc diate hemorrhagic effect of the imme
currence of spontaneous hemor agent (stress) by
rhage, even during major operations, neutralizing an accessory variable
is evidence that this is not the case. (heparin).
Another useful way of picturing
Hemorrhage associated with the hemostasis is as the algebraic sum
administration of heparin means of the effectiveness of hemostatic
that hemostasis has been deranged mechanisms
blood
by several factors simultaneously.18 platelets, vascular response
.
Toxicity of protamine
In 1949 I
reported studies on the
toxicity of intravenous protamine in
animals.18 In confirmation of the
report of Thompson,19 I found that
protamine causes a pronounced fall
in blood pressure in the anesthet-
ized dog and causes cardiovascular
collapse in other animal species.
Many of the actions observed were
histamine-like. These effects could
be reduced by injecting the pro
tamine slowly. Protamine toxicity
in part appears to be due to its
action as a histamine-liberator and

coagulation, possibly in part as a histamine

Extensive experimental and clinical relation to in .

hemodynamic forces .
simulator. Protamine in combining
observations are summarized in flow and blood with heparin in mast cells will dis-
Table II. pressure, i.e. the
hemostatic balance. place histamine and/or serotonin.
Spontaneous hemorrhage has Experience with relatively large
multiple causation. A single agent Hemostatic efficiency = doses of protamine after overdosage
producing a single disruption in Coagulation + Platelets + Vessel wall with heparin suggests that prota
hemostasis does not result in spon Blood pressure mine first combines with exogenous
taneous hemorrhage. Blood coagu heparin in the circulation and that
lation has been suspended in normal If the mechanisms in the numerator only when there is protamine in
subjects by excessive doses of anti are all impaired, even though not excess of the amount required for
coagulants in combination without sufficient singly to cause bleeding, combination are the mast cells af
spontaneous hemorrhage. Sponta hemostasis is seriously impaired. fected. This is a further reason for
neous hemorrhage occurs when, in Thus, in a patient with stress and limiting protamine dosage to that
addition to suspension of coagula some degree of thrombocytopenia equivalent to the heparin in the
tion, there is interference with plate and/or other impairment of plate circulation. Ellison, Ominsky and
let function or with the vascular let function, bleeding can occur Wollman20 reported that intravenous
component of hemostasis, either by with a small amount of heparin in injections in eight volunteers of mul
the presence of disease or by stress. the circulation and cease with its tiple doses of protamine totalling
Since spontaneous hemorrhage is removal. 800 mg./70 kg. produced the ty
Table II
pical symptoms of histamine release
Occurrence of spontaneous hemorrhage
itching/flushing, fatigue/malaise,
nausea/vomiting, headache, hyper
Components of hemostasis: (1) blood coagulation ventilation and temperature eleva
(2) platelets tion. All exhibited itching/flushing,
(3) vascular wall while only one showed hyperventila
Treatments and conditions lowering hemostatic efficiency of components tion and temperature elevation. The
Group 1: (a) anticoagulants (dicumarol, phenylindanedione, heparin) intensity of symptoms increased as
(b) deficiencies of coagulation factors as in hemophilia, disseminated intra the dose was increased. Adverse
vascular coagulation, etc. effects seen on the electrocardio
Group (a) thrombocytopenia
2: gram appear related to histamine re
lease. Gourin, Streisan and Stuckey21
(b) drugs affecting platelet function, such as acetylsalicylic acid, reserpine, observed in dogs an increase in
etc.
Group 3: (a) stress: frost-bite, hypertonic intraperitoneal saline, operation, restraint, coronary sinus blood flow and de
subcutaneous physiological saline daily, electroshock, insulin convulsions, crease in peripheral resistance.
LSD, anesthetics and depressants As the difficulties with protamine
(b) changes in the adrenopituitary axis: ACTH, STH, salicylates, histamine, are largely those associated with
adrenalin, desoxycorticosterone, adrenalectomy defective hemostasis, it is surprising
(c) local pathology: inflammation, bacterial toxins, tumours, etc. that little attention has been paid
to the observation18 that protamine
Spontaneous hemorrhage results (+)}rom combinations of treatments caused marked platelet clumping
Treatment with disappearance of platelets both
Group 1 Group 2 Group 3 in vivo and ex vivo and that the
Treatment {Group 21 + + hypotension produced in dogs ap
Group + +
Group 3 + + peared to be related to the produc
Spontaneous hemorrhage does not result from two treatments which produce a single tion of thrombocytopenia. Throm
defect in hemostasis. It results from a combination of treatments, producing
defects. multiple bocytopenia produced by protamine
can contribute to the difficulties in
Spontaneous hemorrhage (breakdown of hemostasis) has multiple causes controlling bleeding at operation,
C.M.A. JOURNAL/MAY 19, 1973/VOL. 108 1293
 ALDOAET
(methyldopa, MERCK SHARP & DOHME Std.)
while the release of serotonin, etc.
by the disintegrating platelet masses
of protamine must usually involve
more than the minimal prolonga-
in the pulmonary microcirculation tion of clotting produced by the
INDICATIONS: Sustained moderate through severe will embarrass the pulmonary cir-
hypertension. protamine. Raby and ServelleTM re-
DOSAGE SUMMARY: Start usually with 250 mg. two or
three times daily during the first 48 hours; thereafter adjust culation. ported three cases in which hypo-
at intervals of not less than two days according to the
patient's response. Maximal recommended daily dosage is Occasionally, by mistake, hepa- coagulability and difficulty in pro-
3.0 g. of methyldopa. In the presence of impaired. renal
function smaller doses may be needed. rin is given in gross overdosage. ducing surgical hemostasis were due
Syncope in older patients has been related to an increased to excess protamine; coagulability
sensitivity in those patients with advanced arteriosclerotic
vascular disease and may be avoided by reducing the dose.
There is a tendency to administer
Tolerance may occur occasionally between the second immediately a corresponding over- and hemostasis were normalized
and third month after initiating therapy. Effectiveness can
frequently be restored by increasing the dose or adding a dosage of protamine. However, after the injection of heparin.
thiazide.
CONTRAINDICATIONS: Active hepatic disease such as
acute hepatitis and active cirrhosis; known sensitivity to
while suspension of blood coagula- On the other hand, it has been
methyidopa; cases of mild or labile hypertension respon-
sive to mild sedation or thiazides alone; pheochromocy-
bility (in the absence of any other observed that after neutralization
toma; pregnancy. Use cautiously if there is a history of liver
disease or dysfunction.
hemostatic defect) is relatively of heparin in the circulation by
PRECAUTIONS: Acquired hemolytic anemia has occurred
rarely. Hemoglobin and/or hematocrit determinations
harmless, this is certainly not the protamine following the institution
should be performed when anemia is suspected. If anemia
is present, determine if hemolysis is present. Discontinue
case for protamine. The same hypo- of extracorporeal circulation for
drug if hemolytic anemia is evident. Discontinuation and/or tension caused by rapid injection of open-heart surgery, later blood
corticosteroid treatment has brought about prompt remis-
sion of anemia.
A positive direct Coombs test has been reported in some
protamine in dogs has been pro- samples are incoagulable. Frick and
patients on continued therapy with methyldopa, the exact
mechanism and significance of which is not established.
duced in man by too zealous use Brbgli25 have reproduced this
Incidence has varied from 10 to 20%. If a positive test is to
develop it usually does within 12 months following start of
of protamine as an antidote. Hence phenomenon by neutralizing hepa-
therapy. Reversal of positive test occurs within weeks to
months after discontinuation of the drug. Prior knowledge
protamine should be used in this rin with protamine in normal in-
of this reaction will aid in cross matching blood for trans-
fusion. This may result in incompatible minor cross match.
situation only when there are speci- dividuals, in blood from the heart-
!f the indirect Coombs test is negative, transfusion with
otherwise compatible blood may be carried out. If positive,
fic symptoms to indicate that the lung machine, and in decalcified
advisability of transfusion should be determined by a
hematologist or expert in transfusion problems.
heparin overdosage must be coun- plasma. They find it is due to the
Reversible leukopenia with primary effect on granulocytes
has been seen rarely. Rare cases of clinical agranulocy-
teracted and then with great care. protaminase known to be present
tosis have been reported. Granulocyte and leukocyte counts
returned promptly to normal on discontinuance of drug.
The demonstration by Gore et al" in blood and also that this effect
Occasionally fever has occurred within the first three
of pulmonary arteritis produced in is not seen if protamine chloride is
weeks of therapy, sometimes associated with eosinophilia
or abnormalities in one or more liver function tests. Liver
rabbits by the injection of prota- used instead of protamine sulfate.
biopsies in several patients with liver dysfunction showed a
microscopic focal necrosis compatible with drug hyper- mine suggests that such injections There has been wide variation
sensitivity. Determine liver function, leukocyte and dif-
ferential blood counts at intervals during the first six to may also be responsible for pro- in the amount of protamine re-
eight weeks of therapy or whenever unexplained fever may
occur. Discontinue if fever occurs in absence of infection. longed pathological change. commended for clinical neutraliza-
Methyidopa may potentiate action of other antihyperten-
sive drugs. Follow patients carefully to detect side reac- tion of heparin. A ratio of 1 or 2
tions or unusual manifestations of drug idiosyncrasy.
Fluorescence in urine samples at same wave lengths as
Protamine dosage for heparin mg. of protamine sulfate for each
catecholamines may be reported as urinary cate-
cholamines. This will interfere with the diagnosis of
neutralization in vivo 100 USP units of exogenous sodium
pheochromocytoma. Methyidopa will not serve as a diag-
nostic test for pheochromocytoma.
Usage In Pregnancy: Because clinical experience and fol-
According to Berger, Ramaswany heparin is widely accepted and a
low-up studies in pregnancy have been limited, the use of
methyidopa when pregnancy is present or suspected re-
and Ryan,' excessive bleeding is commonly used figure is 1.3 mg.
quires that the benefits of the drug be weighed against the one of the unsolved problems of of protamine for each 100 units of
possible hazards to the fetus.
ADVERSE REACTIONS: Cardioascular: Angina pectoris
may be aggravated; reduce dosage if symptoms of or-
open-heart surgery. Because a suf- heparin. Osborn"6 suggested, when
thostatic hypotension occur; bradycardia occurs occa-
sionally. Neurological: Symptoms associated with effective
ficiently large excess of protamine using 300 units of heparin/kg., giv-
lowering of blood pressure occasionally seen include dizzi-
ness, lightheadedness, and symptoms of cerebrovascular
can be added to blood in vitro to ing 5 mg. protamine/kg. of body
insufficiency. Sedation, usually transient, seen during initial
therapy or when dose is increased. Similarly, headache,
exert an anticoagulant effect and weight in 50 ml. of 5 % glucose
asthenia, or weakness may be noted as early, but transient
symptoms. Rarely reported: paresthesias, parkinsonism,
cause the protamine test for hepa- over 10 minutes, followed in one
psychic disturbances including nightmares, reversible mild
psychoses or depression, and a single case of bilateral
rin to appear negative despite its hour by a further 1 to 2 mg./kg.
Bell's palsy. Gastrointestinal: Occasional reactions gener-
ally relieved by decrease in dosage: mild dryness of the
presence, it has been assumed this Castaneda27 advised that instead of
mouth and gastrointestinal symptoms including distention,
constipation, flatus, and diarrhea; rarely, nausea and vomi-
is also the case when protamine is using protamine, reliance be placed
ting. Hematological: Positive direct Coombs test, acquired
hemolytic anemia, leukopenia and rare cases of throm- used for neutralization of heparin on spontaneous return to a normal
bocytopenia. Toxic and Allergic: Occasional drug related
fever and abnormal liver function studies, and a rise in in vivo. The minimum amount of coagulation mechanism. Berger,
BUN. Rarely, mild and reversible jaundice, skin rash, sore
tongue or "black tongue". Endocrine and Metabolic: protamine required in vitro to in- Ramaswany and Ryan23 reported
Rarely, breast enlargement, lactation and impotence;
weight gain and edema which may be relieved by adminis- crease the clotting time is approx- improved hemostasis with lower
tering a thiazide diuretic. If edema progresses or signs of
pulmonary congestion appear, discontinue drug. Miscel- imately 0.02 mg./ml. of blood and doses of protamine; a single dose of
laneous: Occasionally nasal stuffiness, mild arthralgia and
myalgia; rarely, darkening of urine after voiding. five times this (0.1 mg./ml. requir- 0.5 to 0.66 mg./kg. was used for
Full Information on dosage, contraindications, precau-
tions, adverse reactions and references Is available on ing a dose of 700 mg./70 kg. body each 100 USP units of heparin,
request
HOW SUPPLIED weight) is required to produce a with additional small amounts (25
Film Coated Tablets 'ALDOMET'* are yellow, film-coated,
biconvex-shaped tablets, with the MSD symbol engraved marked prolongation."' Ellison, to 50 mg.) if required.
on one side, and are supplied as follows:
Ca 8737-each tablet containing 125 mg. of methyldopa, Ominsky and Wollman"0 have ex- Since, as indicated previously,
supplied in bottles of 100 and 500 tablets.
Ca 3290-each tablet containing 250 mg. of methyidopa, amined the effects of overdoses of there are many variables that will
supplied in bottles of 50 and 500 tablets.
Ca 8733-each tablet containing 500 mg. of methyidopa, protamine in both patients and vo- affect the length of time heparin
supplied in bottles of 50 and 250 tablets. lunteers. Repeated doses in volun- remains in the circulation, it would
teers of 200 mg./70 kg. (up to 800 seem preferable to determine the
(MC-856) ^ C mg. total) caused only a transitory amount of protamine required for
increase of the Lee-White coagula- the individual patient by a prota-
tion time from 6.7 to 9.4 minutes mine titration. As adapted by
O MERCK with no change in the partial throm- Perkins et alY8 the procedure can
I SHARP
I& DOllME CANADA LIMITED boplastin time. Hence difficulties be conducted in the operating room.
A Leader in Cardiovascular Medicine due to bleeding after the injection Hawksley'9 reported that in 27 cases
C.M.A. JOURNAL/MAY 19, 1973/VOL. 108 1295
in which this was done, the amount and the time interval from its ad- neutralize heparin after extensive
of protamine required was less than ministration, but depends markedly and prolonged operations, no simple
would be given by rule-of-thumb on the absolute concentrations rule of protamine-heparin equiva-
dosages. However, one limitation is reached in the blood and the hemo- lence will suffice to ensure that
that, for technical reasons, the pro- dynamic and metabolic condition of hemostasis will always be instantly
tamine titration does not detect the patient. Direct determination achieved. When hemostasis is not
traces of heparin. Yet traces of in vitro in the operating room of effected it is essential to appreciate
heparin (as indicated in discussing the amount of protamine required the many contributing factors and
the hemostatic balance) will have to neutralize the heparin present assess their significance for the
an unfavourable effect in the pres- in the patient's blood can provide patient.
ence of a lowering of other hemo- an equivalence figure applicable to
static parameters. Rothnie and Kin- the patient. (In addition, it may Resume
month30 found such traces were demonstrate the presence of such
responsible for the postoperative problems as rapid fibrinolysis.) Be- La protamine, antagoniste de l'he-
oozing both in the experimental cause of the variability in heparin parine
animal and in man after open-heart preparations (probably related to La protamine est employee pour
surgery. To detect traces of heparin, difficulties of standardization), fig- titrer l'heparine in vitro dans le
they used the thrombin clotting time ures for the heparin equivalent of diagnostic des diatheses hemorra-
with toluidine blue as heparin anta- protamine preparations are of lim- giques et pour neutraliser l'h'parine
gonist and injected additional pro- ited value. Therefore, it is wiser, in vivo, en vue de mettre fin a
tamine as indicated. when a titration on the blood is not l'heparinisation. La dose de pro-
done, to depend on a rule-of-thumb tamine varie avec la preparation
Conclusions dosage such as not more than 1.0 d'heparine utilisee, les conditions
mg./100 USP units of heparin. This particulieres de l'essai et in vivo,
Protamine is still the chief agent is to be injected slowly in divided avec la quantite d'heparine presente
available for neutralizing heparin. doses, stopping the injection when dans le sang circulant. Ce dernier
Applied to the titration of the anti- hemostasis is achieved. The amount facteur est fonction du laps de
coagulant action of heparin in vitro, should be reduced in proportion to temps ecoule depuis l'administra-
it provides a useful means of diag- the time which has elapsed since tion de l'heparine et de l'etat hemo-
nosis of hemorrhagic states. The the last heparin administration (by dynamique et metabolique du
amount of heparin present in the about 1 mg./min. for the average malade. Injectee rapidement, la
circulation is related to total dosage patient). In using protamine to protamine lib ere de 1'histamine et
agglutine les plaquettes. Le saigne-
ment (hemorragie spontanee) signe
une alteration des mecanismes de
l'hemostase provoquee par une
agression chirurgicale, la prise de
medicaments, le contact du sang
avec des corps etrangers, etc. Dans
la majorite des cas, des regles tres
simples, basees sur le jugement cli-
nique, permettent de connaitre la
dose de protamine necessaire a un
malade donne. Si l'hemostase n'est
pas realisee, il faudra songer que
l'heparine et son antagoniste la pro-
tamine peuvent n'etre, dans le cas
en question, qu'une partie d'une
situation pathologique complexe.

References
1. FISCHER A: Die Bindung von Hepa-
rin an Eiweiss. Biochem Zeit 278:
133, 1935
UROSTOMY BAGS 2. CHARGAFF E. OLSON KB: Studies on
the chemistry of blood coagulation.
by Hollister VI. Studies on the action of heparin
and other anticoagulants. The in-
A simple yet effective method of meeting the special needs of fluence of protamine on the anti-
ureterostomy and ileal conduit patients. Easy to apply, easy to coagulant effect in vivo. J Biol
Chem 122: 153, 1937
drain. Made of odor-barrier film and available with Karaya Seal 3. WATERS ET, MARROWITZ J, JAQUES
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