THE HASTENING OF COAGULATION OF BLOOD BY ADRENIN
The primary value of blood to the body must have been one of the
earliest observations of reasoning beings. When we consider the
variety of fundamental services which this circulating fluid
performs--the conveyance of food and oxygen to all the tissues,
the removal of waste, the delivery of the internal secretions,
the protection of the body against toxins and bacterial invasion,
and the distribution of heat from active to inactive regions--the
view of the ancient Hebrews that the “life of the flesh is in the
blood” is well justified. It is naturally of the utmost importance
that this precious fluid shall be safeguarded against loss. And its
property of turning to a jelly soon after escaping from its natural
channels assures a closure of the opening through which the escape
occurred, and thus protection of the body from further bleeding.
The slight evidence that adrenin hastens the clotting process has
already been hinted at. When we found that adrenin is set free in
pain and intense emotion, it seemed possible that there might exist
in the body an arrangement for making doubly sure the assurance
against loss of blood, a process that might nicely play its rôle
precisely when the greatest need for it would be likely to arise.
It was in 1903, while tracing in dogs the rise and fall of sugar
in the blood after administering adrenin, that Vosburgh and
Richards[94] first noted that simultaneously with the increase of
blood sugar there occurred more rapid coagulation. In some cases
the diminution was as much as four-fifths the coagulation time of
the control. Since this result was obtained by painting “adrenalin”
on the pancreas, as well as by injecting it into the abdominal
cavity, they concluded that “the phenomenon appears to be due to
the application of adrenalin to the pancreas.” Six years later,
during a study of the effect of adrenalin on internal hemorrhage,
Wiggers[95] examined incidentally the evidence presented by Vosburgh
and Richards, and after many tests on five dogs found “never the
slightest indication that adrenalin, either when injected or added
to the blood, appreciably hastened the coagulation process.” In 1911
von den Velden[3] reported that adrenin (about 0.007 milligram per
kilo of body weight) decreased the coagulation time in man about
one-half--an effect appearing 11 minutes after administration by
mouth, and 85 minutes after subcutaneous injection. He affirmed
also, but without describing the conditions or giving figures, that
adrenin decreases coagulation time _in vitro_. He did not attribute
the coagulative effect of adrenin in patients to this direct action
on the blood, however, but to vasoconstriction disturbing the normal
circulation and thereby the normal equilibrium between blood and
tissue. In consequence, the tissue juices with their coagulative
properties enter the blood, so he assumed. In support of this theory
he offered his observation that coagulation time is decreased after
the nasal mucosa has been rendered anemic by adrenin pledgets. Von
den Velden’s claim[96] for adrenin given by mouth was subjected to
a single test on man by Dale and Laidlaw,[97] but their result was
completely negative.
The importance of Vosburgh and Richards’ observation, the thoroughly
discordant testimony of later investigators, as well as the meager
and incidental nature of all the evidence that has been adduced
either for or against the acceleration of clotting by adrenin, made
desirable a further study of this matter. Especially was this further
study desirable because of the discharge of adrenin into the blood
in pain and emotional excitement. Accordingly, in 1914, H. Gray and
I[98] undertook an investigation of the question. In doing so we
employed cats as subjects. Usually they were quickly decerebrated
under ether, and then continuance of the drug became unnecessary.
Body temperature was maintained by means of an electric heating
pad. Respiration proceeded normally except in a few instances (in
which, presumably, there was hemorrhage into the medulla), when
artificial respiration had to be given.
The Graphic Method of Measuring the Coagulation Time
In order to avoid, so far as possible, the personal element in
determining when the blood was clotted, the blood was made to
record its own clotting. The instrument by means of which this
was done was the graphic coagulometer devised by W. L. Mendenhall
and myself,[99] and illustrated diagrammatically in Fig. 24. It
consists essentially of a light aluminum lever with the long arm
nearly counterpoised by a weight _W_. The long arm is prevented
from falling by a support _S_, and is prevented from rising by a
horizontal right-angled rod reaching over the lever at _R¹_ and
fixed into the block _B_ which turns on the axis _A_. Into the
same block is fixed the vertical rod _R²_. When this rod is moved
from the post _P¹_, against which it is held by the weight of the
horizontal rod _R¹_, towards the other post _P²_, the check on the
long arm of the lever is lifted, and if the short arm is heavier,
the long arm will then rise.
[Illustration: Figure 24.--Diagram of the graphic coagulometer.
The cannula at the right rests in a water bath not shown in this
diagram. For further description see text.]
The cannula _C_, into which the blood is received, is two centimeters
in total length and slightly more than two millimeters in internal
diameter. It is attached by a short piece of rubber tubing to the
tapered glass tube _T_, five centimeters long and five millimeters
in internal diameter. The upper end of this tube is surrounded by
another piece of rubber which supports the tube when it is slid
into the U-shaped support _U_, fixed directly below the end of the
short arm of the lever.
By drawing the cannulas from a single piece of glass tubing and
by making the distance from shoulder to upper end about twelve
millimeters, receptacles of fairly uniform capacity are assured.
All the dimensions, the reach of the rubber connection over the top
of the cannula (2-3 millimeters), the distance of the upper rubber
ring from the lower end of the glass chamber (4 centimeters), etc.,
were as nearly standard as possible.
A copper wire _D_, eight centimeters long and 0.6 millimeters in
diameter, bent above into a hook and below into a small ring slightly
less than two millimeters in diameter, is hung in a depression at
the end of the short arm of the lever. The small ring then rests
in the upper part of the cannula (see Fig. 24). The weight of the
copper wire makes the short arm of the lever heavier than the long
arm by 30 milligrams, when the delicate writing point is moving
over a lightly smoked drum. Half a dozen of these standard wires
are needed.
For accurate determination of the coagulation time Addis[100] has
defined the following conditions as essential:
1. The blood must always be obtained under the same conditions.
2. Estimates must all be made at the same temperature.
3. The blood must always come in contact with the same amount and
kind of foreign material.
4. The end point must be clear and definite and must always indicate
the same degree of coagulation.
The precautions taken to fulfill these conditions were as follows:
1. _Drawing the blood._--The blood was taken from the femoral
artery. The artery (usually the right) was laid bare in the groin
and freed from surrounding tissue. A narrow artery clip, with
each limb enclosed in soft rubber tubing (to prevent injury of
the tissues), and with its spring exerting gentle pressure, was
placed on the artery immediately below the deep femoral branch,
thus allowing no blood to stagnate above the clip. Between the clip
and a ligature applied about 1.5 centimeters below, an opening was
made. The blood was carefully milked out of the vessels between a
blunt dissector moved beneath, and a small forceps, twisted into
a pinch of absorbent cotton, moved above.
The cannula, cleaned in water, alcohol, and ether, was set in the
rubber connection of the glass tube; the point of the cannula was
then lubricated with vaseline and slipped into the artery. The
pressure of the clip on the artery was next very slightly released
and blood was allowed to flow into the cannula up to the lower
border of the rubber connection. Only a good-sized drop of blood
was needed. Sometimes the blood ran one or two millimeters above or
below, but without appreciably changing the result. Since the clip
was situated on the femoral immediately below a branch in which
the circulation persisted, _the blood received in the cannula was
always fresh from the moving stream_. As soon as the clip gripped the
artery again, the cannula was slipped out. A helper then promptly
milked the vessel in the manner described above, and covered it
with a pad of absorbent cotton smeared with vaseline to prevent
drying. Thereby blood was not permitted to stagnate; and when a new
sample was to be taken, the vessel was clean and ready for use.
The tip of the cannula was at once plugged by plunging it into a
flat mound of plasticine about three millimeters high. It was drawn
off sidewise lest the plasticine plug be pulled out again. One of
the copper wires _D_ was now slid into the tube and cannula, the
tube slipped into the U-support, and the wire lifted and hung on
the lever. This procedure, from the moment blood began to flow
until the wire was hung, consumed usually about twenty seconds.
2. _Uniform temperature._--Under the U-support was placed a large
water bath, in which the cannula and the tapering part of the tube
were submerged. A thermometer was fixed to the U-support so that
the bulb came near the cannula in the bath. The water was kept
within a degree of 25° C. This temperature was chosen for several
reasons: (a) The cannula has room temperature and rapidly cools the
small volume of blood that enters it. To heat blood and cannula to
body temperature would take time. A bath near room temperature,
therefore, seems preferable to one near body temperature. (b) The
test of clotting was conveniently made at intervals of a half-minute,
and if the clotting process were hastened by higher temperatures,
this interval would become relatively less exact. (c) A temperature
of 25° C. rather than lower was selected because, as Dale and
Laidlaw[101] have shown, the coagulation time is much slower for
a given change in temperature below 25° than for the same change
above. And with slowing of the process the end point, when the
determination depends on supporting a weight, is less likely to be
sharp. (d) The researches undertaken with use of this coagulometer
were concerned with factors hastening the process. For that reason
and for reason (b), a long rather than a short coagulation time
for normal conditions was desirable.
3. _Uniformity in the amount and kind of contact with foreign
surface._--The capacity of the cannulas was fairly uniform, as
stated above; the amount received in them was fairly constant; and
the wire hanging in the blood presented approximately the same
surface in different observations.
A further condition for insuring consistent treatment of the blood
in different cases was that of making the tests for coagulation
always at the same intervals. Below the writing point of the lever
was set an electromagnetic signal _E_, which recorded half-minutes.
At the moment a record was made by the signal (see first signal
mark, Fig. 25) the clip on the artery was opened, the blood taken,
and the process thus begun. In about 20 seconds the cannula was
suspended in the water bath and the wire was hanging on the lever.
At the next record by the signal and at every subsequent record the
vertical rod _R²_ was pushed with the index finger from post _P¹_
to post _P²_ and allowed to move back. This motion was uniform
and lasted about one second. The check _R¹_ on the long arm of
the lever was thus raised, and as the wire sank in the blood the
writing point rose, recording that coagulation had not taken place
(see Fig. 25).
[Illustration: Figure 25.--Record (reduced two-fifths) of five
successive tests of coagulation, with the animal in a uniform
condition. The lower line records intervals of 30 seconds. The
marks below the time record indicate the moments when the blood
samples were drawn.]
4. _Definite end point._--As soon as the blood clotted, the weight
of 30 milligrams was supported, and the failure of the lever to
rise to the former height in the regular time allowed, recorded
that the change had occurred.
Very rarely the swing of the lever would be checked for a moment
and would then begin to move rapidly, indicating that a strand
of fibrin had formed but not sufficiently strong to support the
weight, and that when the strand broke, the weight quickly sank in
the blood. If this occurred, the next record almost always was the
short line, which signified that the weight was well supported.
A very slight strand of fibrin was able to prevent the weight from
dropping, though at different times the amount of support differed,
as shown by the varying length of the final lines (compare first
and last series, Fig. 25). These variations are probably a rough
indication of the degree of coagulation. In our experiments, however,
the length of the final line was disregarded, and merely the fact
that the lever failed to swing through its usual distance was taken
as evidence of a clot, and the consequent short record was taken
as the end point.
As soon as this end point was registered, the tube, wire and cannula
were lifted out of the bath; the cannula was then separated from the
tube and pulled away from the wire. The clot was thus disclosed,
confirming the graphic record.
The method, at least when used at half-minute intervals, did not
reveal in all instances the same degree of clotting. Usually, when
the process was very rapid, the revealed clot was a thick jelly;
whereas, when the process was slow, a strand of fibrin or at most
a small amount of jelly was found. This difference in the _degree_
of coagulation introduced, of course, an element of inexactness.
In our experiments, however, this inexactness was unfavorable to
the result we were seeking for, i. e., the acceleration of the
process--because the jelly is a later stage than the fibrin strand;
and since we nevertheless obtained good evidence of acceleration, we
did not in these experiments attempt to determine more accurately
differences in the stage of the clotting process.
5. _Cleaning of apparatus._--After the wire was removed from the
tube, the clot attached to its ring-tip was carefully brushed away
under cool running water. Under the running water, also, a trimmed
feather was introduced into the cannula and the tube to push out the
plasticine and to wash out the blood. Wire, cannula and tube were
then dropped into a beaker receiving running hot water (about 80°
C.) and there allowed to remain for about five minutes. On removal
from this the parts were shaken free from water, passed through 95
per cent alcohol and again shaken free, passed through ether and
let dry.
By having a half-dozen cannulas and wires of standard size, it was
possible to save trouble by cleaning a number at one time.
Not infrequently the first few samples of blood taken from an animal
showed rapid or somewhat irregular rates of clotting. Some causes
for these initial variations will be presented in following pages.
The fairly uniform rate of clotting in any individual after the
initial stage, varied in twenty-one different animals from an average
of 3 to an average of 10.6 minutes, with a combined average of 5.9
minutes. The conditions for these variations among the individuals
have not been wholly determined.
The Effects of Subcutaneous Injections of Adrenin
The first observations were of this class.
Oct. 27. A cat weighing about 3 kilos was given 3 cubic centimeters
of adrenin 1:1,000, i. e., 1 milligram per kilo, under the skin. The
animal, in this instance, was kept in uniform ether anesthesia.
Following is a record showing when blood was taken, and the
coagulation time in each instance:
2.56--Injection made
.59--6 minutes
3.07--5.5 “
.13--5 “
.20--6.5 “
---
Average 5.7 minutes
3.27--3.5 minutes
.44--2 “
.55--2.5 “
4.07--3 “
.20--2 “
---
Average 2.6 minutes
4.44--6 minutes
5.00--4.5 “
5.50--5 “
---
Average 5.2 minutes
In this case the coagulation time remained at its usual level for
about 20 minutes after the subcutaneous injection.[*] Thereafter
for about an hour the coagulation time averaged 45 per cent of
its previous duration. And widely separated tests made during the
following hour indicated that approximately the initial rate of
clotting had been regained.
*[Footnote: This period is longer than is expected after the
subcutaneous injection of any drug. As will be shown later,
_strong_ doses of adrenin, if injected rapidly, may not at first
shorten the clotting process. Probably in some instances of
subcutaneous injection of these strong doses, the drug enters
the circulation more rapidly than in others and in consequence
coagulation is not at first accelerated.]
The rather long period (nearly 30 minutes), in the case just cited,
between the injection and the first appearance of rapid clotting was
not the rule. As the following figures show, the coagulation time
may become shortened quite promptly after subcutaneous injection.
Oct. 29. 3.30--5.5 minutes
.36--5.5 “
.44 Adrenin, 3 cubic centimeters, 1:1,000,
injected subcutaneously.
.46--5.5 minutes
.53--4 “
4.01--3.5 “
.08--3.5 “
.16--4.5 “
.23--5 “
.30--5.5 “
In this case nine minutes after the injection the change in the
rate of clotting had begun, and it continued more rapid for the
subsequent half-hour.
We did not attempt to find the minimal _subcutaneous_ dose which
would shorten clotting. A dose of 0.01 milligram per kilo, however,
has proved effective, as shown by the following figures:
Feb. 3. 11.34--10 minutes
.45-- 9 “
.50 to .52 Adrenin, 2.8 cubic centimeters, 1:100,000,
injected under skin of groin in cat weighing
2.8 kilos.
.55--10 minutes
12.06-- 7 “
.14-- 4 “
.19-- 5.5 “
.31-- 6 “
.37-- 7 “
.45-- 9 “
As will be shown later, the dose in this instance was ten times
the minimal effective _intravenous_ dose. On the basis of these
figures, less than a milligram of adrenin given subcutaneously
would be necessary to shorten clotting to a marked degree in a man
of average weight (70 kilograms).
Not many observations were made by us on the effects of adrenin
administered subcutaneously. The amount reaching the vascular
system and the rate of its entrance into the blood could be so much
more accurately controlled by intravenous than by subcutaneous
introduction that most of our attention was devoted to the latter
method.
The Effects of Intravenous Injections
In this procedure a glass cannula was fastened in one of the
external jugular veins and filled with the same solution as that to
be injected. A short rubber tube was attached and tightly clamped
close to the glass. Later, for the injection, the syringe needle
was inserted through the rubber and into the fluid in the cannula,
the clip on the vein was removed, and the injection made.
The solutions employed intravenously were adrenin 1:10,000, 1:50,000,
and 1:100,000, in distilled water.
The smallest amount which produced any change in clotting time was
0.1 cubic centimeter of a dilution of 1:100,000 in a cat weighing
two kilos, a dose of 0.0005 milligram per kilo. Four tests previous
to the injection averaged 5 minutes, and none was shorter than 4
minutes. Immediately after the injection the time was 2 minutes, but
at the next test the effect had disappeared. Doubling the dose in
the same cat--i. e., giving 0.2 cubic centimeter (0.001 milligram
per kilo)--shortened the coagulation time for about 40 minutes:
Dec. 23. 10.30--4 minutes
.35--4 “
.41--4 “
.46 Adrenin, 0.001 milligram per kilo.
.47--2.5 minutes
.50--3 “
.53--3.5 “
11.00--1.5 “
.05--1.5 “
.10--3 “
.15--2 “
.20--4 “
.26--4.5 “
.31--5 “
From 10.47, immediately after the second injection, till 11.20 the
average time for clotting was 2.5 minutes, whereas both before
and after this period the time was 4 minutes or longer. At 11.00
o’clock and 11.05, when the end point was reached in 1.5 minutes (a
reduction of 63 per cent), a thick jelly was found on examining the
cannula. The changes in clotting time in this case are represented
graphically in Fig. 26.
[Illustration: Figure 26.--Shortening of coagulation time after
injection of adrenin, 0.2 cubic centimeter, 1:100,000, (0.001
milligram per kilo), at 10:46. In this and following Figures a
scale for coagulation time is given in minutes at the left.]
In another case a dose of 0.0005 milligram per kilo failed to produce
any change, but 0.001 milligram per kilo (0.28 cubic centimeter
of adrenin, 1:100,000, given a cat weighing 2.8 kilos) brought a
sharp decline in the record, as follows:
Jan. 9. 11.32--6 minutes
.40--6 “
.47 Adrenin, 0.001 milligram per kilo.
.48--5.5 minutes
.55--4 “
12.00--5.5 “
.06--7 “
In these instances the animals were decerebrated. For decerebrate
cats, the least amount of adrenin, intravenously, needed to produce
shortening of coagulation time is approximately 0.001 milligram
per kilo.
In the above cases rapid clotting was manifest directly after
minute doses. Larger doses, however, may produce primarily not
faster clotting but slower, and that may be followed in turn by a
much shorter coagulation time. The figures below present such an
instance:
Nov. 25. 2.36--3 minutes
.40--3 “
.43 Adrenin, 0.5 cubic centimeter, 1:10,000.
.44--4 minutes
.49--3.5 “
.53--1.5 “
.55--1.5 “
.58--2 “
3.00--2.5 “
.03--1.5 “
.05--1.5 “
.07--2.5 “
.10--1.5 “
.14--1.5 “
.16--2.5 “
.19--3 “
.23--3 “
.30--3 “
This unexpected primary increase of coagulation time, lasting at
least six minutes, is in striking contrast to the later remarkable
shortening of the process from 3 to an average of 1.7 minutes for
more than 20 minutes (see Fig. 27, A).
[Illustration: Figure 27.--A, Primary lengthening followed by
shortening of the coagulation time when adrenin, 0.5 cubic
centimeter 1:10,000 (0.05 milligram), was injected slowly at 2:43.
B, Lengthening of the coagulation time without shortening when the
same dose was injected rapidly at 10:08.]
If a strong solution, i. e., 1:10,000, is injected rapidly, the
process may be prolonged as above, but not followed as above by
shortening, thus:
Nov. 28. 9.59--3 minutes
10.03--3 “
.08 Adrenin, 0.5 cubic centimeter, 1:10,000.
.10--3 minutes
.14--3.5 “
.18--3.5 “
.22--3.5 “
.26--3 “
.29--3 “
.33--3 “
There was in this case no decrease in coagulation time at any test
for a half-hour after the injection, but instead a lengthening (see
Fig. 27, B). Howell[102] has reported the interesting observation
that repeated massive doses of adrenin given to dogs may so greatly
retard coagulation that the animals may be said to be hemophilic.
These two instances show that on coagulation large doses have the
contrary effect to small, just as Hoskins[103] showed was true for
intestinal and Lyman and I[104] showed was true for arterial smooth
muscle.
In a few experiments the brain and the cord to midthorax were
destroyed through the orbit. Artificial respiration then maintained
the animal in uniform condition. Under these circumstances, adrenin
intravenously had more lasting effects than when given to the usual
decerebrate animals with intact cord. Fig. 28 illustrates such a
case. For thirty minutes before injection the clotting time averaged
5.4 minutes. Then, about ten minutes after one cubic centimeter
of adrenin, 1:50,000, had been slowly injected, clotting began
to quicken; during the next twenty minutes the average was 3.4
minutes, and during the following forty-five minutes the average
was 1.9 minutes--only 35 per cent as long as it had been before
the injection.
[Illustration: Figure 28.--Persistent shortening of the coagulation
time after injecting (in an animal with brain and upper cord
pithed) adrenin, 1 cubic centimeter, 1:50,000 (0.02 milligram),
at 11:01-02. The dash lines represent averages.]
In another case in which the brain and upper cord were similarly
destroyed, the clotting time, which for a half-hour had averaged 3.9
minutes, was reduced by one cubic centimeter of adrenin, 1:100,000,
to an average for the next hour and forty minutes of 2.3 minutes,
with 1.5 and 3 minutes as extremes. During the first forty minutes
of this period of one hour and forty minutes of rapid clotting all
of eight tests except two showed a coagulation time of 2 minutes or
less. The explanation of this persistent rapid clotting in animals
with spinal cord pithed is not yet clear.
As indicated in Figs. 26, 27 and 28, the records of coagulation show
oscillations. Some of these ups and downs are, of course, within
the limits of error of the method, but in our experience they have
occurred so characteristically after injection of adrenin, and so
often have appeared in a rough rhythm, that they have given the
impression of being real accompaniments of faster clotting. It
may be that two factors are operating, one tending to hasten, the
other to retard the process, and that the equilibrium disturbed by
adrenin is recovered only after interaction to and fro between the
two factors.
The oscillations in coagulation time after the injections suggest
that clotting might vary with changes in blood pressure, for that
also commonly oscillates after a dose of adrenin (see, e. g., Fig.
23). Simultaneous recording of blood pressure and determining
of coagulation time have revealed that each may vary without
corresponding variation in the other. Within ordinary limits,
therefore, changes of blood pressure do not change the rate of
clotting.
The Hastening of Coagulation by Adrenin Not a
Direct Effect on the Blood
As previously stated, von den Velden has contended that shortening
of coagulation time by adrenin is due to exudation of tissue juices
resulting from vasoconstriction. The amount of adrenin which
produces markedly faster clotting in the cat, is approximately 0.001
milligram per kilo. As Lyman and I[105] showed, however, this amount
when injected slowly, as in the present experiments, results in
brief vasodilation rather than vasoconstriction. Von den Velden’s
explanation can therefore not be applied to these experiments.
He has claimed, furthermore, that adrenin added to blood _in vitro_
makes it clot more rapidly, but, as already noted, he gives no
account of the conditions of his experiments and no figures. It is
impossible, therefore, to criticise them. His claim, however, is
contrary to Wiggers’s[106] earlier observations that blood with added
adrenin coagulated no more quickly than blood with an equal amount
of added physiological salt solution. Also contrary to this claim
are the following two experiments: (1) Ligatures were tied around
the aorta and inferior vena cava immediately above the diaphragm,
and thus the circulation was confined almost completely to the
anterior part of the animal. Indeed, since the posterior part ceases
to function in the absence of blood supply, the preparation may be
called an “anterior animal.” When such a preparation was made and
0.5 cubic centimeter of adrenin, 1:100,000 (half the usual dose,
because, roughly, half an animal), was injected slowly into one of
the jugulars, coagulation was not shortened. Whereas for a half-hour
before the injection the clotting time averaged 4.6 minutes, for an
hour thereafter the average was 5.3 minutes--a prolongation which
may have been due, not to any influence of adrenin, but to failure
of the blood to circulate through the intestines and liver.[107]
In another experiment after the gastro-intestinal canal and liver
had been removed from the animal, the average time for coagulation
during twenty-five minutes before injecting adrenin (0.23 cubic
centimeter, 1:100,000, in an animal weighing originally 2.3 kilos)
was 5.5 minutes, and during forty minutes after the injection it was
6.8 minutes, with no case shorter than 6 minutes. In the absence
of circulation through the abdominal viscera, therefore, adrenin
fails to shorten the clotting time. (2) The cannulas were filled
with adrenin, 1:1,000, and emptied just before being introduced into
the artery. The small amount of adrenin left on the walls was thus
automatically mixed with the drawn blood. Alternate observations
with these cannulas wet by adrenin and with the usual dry cannulas
showed no noteworthy distinction.
Feb. 19. 2.21--6 minutes, with usual cannula
.30--6.5 “ “ “ “
.36--6.5 “ “ adrenin “
.49--6 “ “ “ “
.56--7 “ “ usual “
3.04--6 “ “ adrenin “
The results of these experiments have made it impossible for us to
concede either of von den Velden’s claims, i. e., that clotting
occurs faster because adrenin is added to the blood, or because
adrenin by producing vasoconstriction causes tissues to exude
coagulant juices.
Vosburgh and Richards found that coagulation became more rapid
as the blood sugar increased. Conceivably faster clotting might
result from this higher percentage of blood sugar. Against this
assumption, however, is the fact that clotting is greatly accelerated
by 0.001 milligram adrenin per kilo of body weight, much less than
the dose necessary to increase the sugar content of the blood.[108]
And furthermore, when dextrose (3 cubic centimeters of a 10 per
cent solution) is added to the blood of an anterior animal, making
the blood sugar roughly 0.3 per cent, the coagulation time is not
markedly reduced. Adrenin appears to act, therefore, in some other
way than by increasing blood sugar.
Since adrenin makes the blood clot much faster than normally in the
intact animal, and fails to have this effect when the circulation
is confined to the anterior animal, the inference is justified that
in the small doses here employed adrenin produces its remarkable
effects, not directly on the blood itself, not through change in
the extensive neuro-muscular, bony, or surface tissues of the body,
but through some organ in the abdomen.
That exclusion of the liver from the bodily economy, by ligature
of its vessels or by phosphorus poisoning, will result in great
lengthening of the coagulation time has been clearly shown. The
liver, therefore, seems to furnish continuously to the blood a factor
in the clotting process which is being continuously destroyed in
the body. It is not unlikely that adrenin makes the blood clot
more rapidly by stimulating the liver to discharge this factor in
greater abundance. But proof for this suggestion has not yet been
established.
REFERENCES
[Footnote 94: Vosburgh and Richards: American Journal of Physiology,
1903, ix, p. 39.]
[Footnote 95: Wiggers: Archives of Internal Medicine, 1909, iii,
p. 152.]
[Footnote 96: Von den Velden: Münchener medizinische Wochenschrift,
1911, lviii, p. 187.]
[Footnote 97: Dale and Laidlaw: Journal of Pathology and
Bacteriology, 1912, xvi, p. 362.]
[Footnote 98: Cannon and Gray: American Journal of Physiology,
1914, xxxiv, p. 321.]
[Footnote 99: Cannon and Mendenhall: American Journal of Physiology,
1914, xxxiv, p. 225.]
[Footnote 100: Addis: Quarterly Journal of Experimental Physiology,
1908, i, p. 314.]
[Footnote 101: Dale and Laidlaw: _Loc. cit._, p. 359.]
[Footnote 102: Howell: American Journal of Physiology, 1914, xxxiii,
p. xiv.]
[Footnote 103: Hoskins: American Journal of Physiology, 1912, xxix,
p. 365.]
[Footnote 104: Cannon and Lyman: American Journal of Physiology,
1913, xxxi, p. 376.]
[Footnote 105: Cannon and Lyman: _Loc. cit._, p. 381.]
[Footnote 106: Wiggers: _Loc. cit._, p. 152.]
[Footnote 107: See Pawlow: Archiv für Physiologie, 1887, p. 458.
Bohr: Centralblatt für Physiologie, 1888, ii, p. 263. Meek: American
Journal of Physiology, 1912, xxx, p. 173. Gray and Lunt: _Ibid._,
1914, xxxiv, p. 332.]
[Footnote 108: Cannon: American Journal of Physiology, 1914, xxxiii,
p. 396.]