Report on Therapy

Colloidally Suspended Phytonadione in

Bishydroxycoumarin-Induced
Hypoprothrombinemia*
MILTON SHOSHKES, M.D., EDWIN L. ROTHFELD, M.D. and MARTIN JACOBS, M.D.

Newark, New Jersey

T
HE WIDER CLINICAL application of hypopro- forty-eight adults who previously had been receiving
thrombinemia-inducing anticoagulants has anticoagulant therapy with bishydroxycoumarin (Di-
increased the need for a readily available anti- cumarol@) for actual or threatened thromboembolic
phenomena. Forty of this group were hospitalized
dote. At present, phytonadione (or oil soluble
for acute myocardial infarctions, five for acute
vitamin K1) is accepted as an effective antidote
coronary insufficiency, two for acute pulmonary in-
to such drug-induced hypoprothrombinemia.V
farction and one for priapism. Blood prothrombin
It is administered orally in doses ranging from times were determined daily. The administration of
10 to 50 mg., or parenterally as an oil in water bishydroxycoumarin was discontinued the day before
emulsion administered intravenously, usually testing, usually after the prothrombin time had been
in a 50 mg. dose. This oil emulsion has definite stabilized for several weeks at twenty-three seconds
disadvantages, however. The stability of the (50 per cent) or more. On the morning of the day of
emulsion may he broken by freezing or by testing, determination of the prothrombin time was
mixing with numerous types of parenteral done just prior to the administration of colloidally
suspended Kit and two, four, six, eight and twenty-
medicaments. Moreover, prolonged storage
four hours thereafter. The initial prothrombin time
under less than ideal conditions is not recom-
in all subjects successfully tested was twenty-three
mended. The preparation must I)e diluted
seconds or higher. Eight subjects were used as con-
before it can be injected intravenously: yet trols. Each dosage a Id route was tested in a separate
despite such precautions, near syncopal and group of ten patients. The series included the ad-
syncopal episodes sometimes follow. ministration of 10 mg. of the vitamin intravenously,
A water soluble salt of phytonadione, dihy- intramuscularly or subcutaneously, plus one other
drovitamin K, hiphosphate, recently was in- group given 5 mg. intravenously. The vitamin also
vestigated in this laboratory in the hope that it was used for the emergency treatment of single bleed-
would be an improvement over the emulsion. ing episodes in nine subjects (four of whom were
also included in the series given 10 mg. intra-
However, it proved to be a far less potent
venously). Seven subjects were given 10 mg. of
antidote under clinical conditions3 More re-
phytonadione intravenously; one received the first
cently, a microsuspension of vitamin K1 has
5 mg. intravenously followed by 10 mg. the following
been made available. The oil soluble vitamin day; and one subject received 10 mg. subcutaneously.
is in colloidal dispersion and is a clear amber Oxalated blood was used throughout and the pro-
fluid without visible particles containing 10 mg. thrombin times were determined by the Link-Shapiro
per cc. of vitamin K1 in an isotonic solution with modification of the Quick method, using SoluPlastin
benzyl alcohol as a preservative.
t AquaMephytcn,@ kindly supplied by Nathaniel
S. Ritter, M.D., of the Department of Medical Research,
METHOD
Research Laboratories, Merck Sharp & Dohme, Inc.,
The studies were performed successfully upon Rahway, New Jersey.

* From the Department of Medicine, Beth Israel Hospital, Newark, N. J. Aided by a grant from Merck, Sharp &
Dohme, Inc., to the Research Foundation of the Beth Israel Hospital.

72 THE AMERICAN JOURNAL OF CARDIOLOGY

 Vitamin K1 in Hypoprothrombincmia 73

(solution of thromboplajtin derived from fresh brain TABLE *

and lung tissue). Response of Bishydroxycoumarin-Induced Hypopro-

thrombinemia to Parenterally Administered Colloidally
RESULTS Suspended Phytonadione (Vitamin KI)

Table I charts the results after the parenteral

Mean
administration of 10 mg. intravenously, intra- Time Minimum ~~aximum
muscularly and subcutaneously and 5 mg. intra- Observed Fall Fall Fall
(hours) (seconds) (seconds) / (m-k)
venously. The individual control prothrombin
time in seconds was used as the baseline value;
deviations from this value were averaged as Control (ei,yht subjects)
mean positive or negative values. For example,
a fall in prothrombin time of five seconds is
recorded as -5 and a rise of eight seconds as
+8. The bishydroxycoumarin was discon-
tinued for twenty-four hours prior to testing;
therefore, a moderate fall in the prothrombin
times over the succeeding twenty-four hours
70 mg. Giurn Intraurnously (ten subjects)
after the last dose of anticoagulant is to he
expected in the control series of eight subjects.
In this trial, the mean fall after twenty-four 2 14
4 24 9 12 ~ 38
hours was ten seconds. A potent vitamin K1 6 29 10 12 42
should accelerate significantly this fall toward 8 27 5 42
normal levels. 24 24 5 40
The 10 mg. intravenous dose was effective in
reducing the elevated prothrombin times. A 70 m,p-.Gioen Intramuscular/y(ten subjects)
positive and statistically significant effect was
noted two hours after injection, becoming maxi-
mum in four to six hours. P values of over 2.5
were found with each determination. How-
ever, this same dose when given intramuscularly
was far less effective, requiring eight hours to
begin to accelerate the fall of prothrombin time
10 mg. Giwn Subr~ctanrously(/en subjects)
over the control values. These depressions
were intermediate between those observed for I
2 0 ~ 8
the control and 10 mg. intravenous dose, and
4 1 ;~ i 0 11
were maximum by the twenty-four hour ob- 6 : 7
servation. However, no statistical significance 8 13 ~ 4 (+I 12
could be confirmed for these trials, despite this 24 12 ~ 8 1 / 23
apparent trend. The 10 mg. dose given sub-
cutaneously and the 5 mg. dose given intra- 5 mg. Giurn Intravenously (ten subjects)
venously showed no demonstrable effect over
the control observations.
Despite the accelerated return to normal limits
noted after givinp- 10 mg. intravenously and in-
tramuscularly, four subjects of the former group
and five of the latter group had prothrombin
values of less than 50 per cent of normal twenty-
four hours after the administration of vitamin Effect on Patients with Bleeding: Table II

K, confirming a definite persistence of anti- summarizes the data on those subjects treated
coagulant effect. All of the subjects given 10 for bleeding. Fortunately, no catastrophic
mg. of the drug intravenously had a fall in hemorrhage occurred during these observations;
their prothrombin times. Three of those given gross hematuria was the most frequent hemor-
the drug intramuscularly, however, had no fall rhagic complication treated. All seven patients
whatsoever over the twenty-four hours of oh- given the 10 mg. intravenously and the one
servation. patient given 10 mg. subcutaneously responded

JULY 1961
74 Shoshkes, Rothfeld and ,Jacobs

TABLE II demonstrated by the excellent clinical response

Response of Bleeding Phenomena to Parenterally Ad- of the bleeding episodes treated (Table II).
ministered Colloidally Suspended Phytonadione
All seven of the subjects who received 10 mg.
intravenously and the one who received 10 mg.
Time of subcutaneously responded rapidly and without
Dose Bleeding Bleeding
Route
Phenomena
a recurrence of the bleeding. However, this
(mg. 1 Control
(hours) small series should not give a sense of false
confidence. Again, it should be emphasized
10 Intravenous Gross 12 that four of the subjects who were given 10 mg.
hematuria intravenously did not reach a therapeutically
10 Intravenous Gross 6 safe prothrombin time level of 50 per cent or
hematuria more even twenty-four hours after this dose was
10 Intravenous Gross 8
hematuria
given. The intramuscular or subcutaneous
10 Intravenous Gross 18 routes offer an even less predictable assurance of
hematuria success, although it appears that the intra-
10 Intravenous Gross 9 muscular route may be utilized if a vein cannot
hematuria
be entered. In the therapy of catastrophic and
10 Intravenous Rectal 12
10 Intravenous Pleural 24 life-threatening hemorrhage, one must still be
10 Subcutaneous Gross 6 prepared for failure. If, after an adequate trial
hematuria of vitamin K1 therapy, the prothrombin time
5 Intravenous Gross Jncontrolled ; fails to show a recovery one must then resort to
hematuria responded
transfusions of fresh blood to restore a normal
to 10 mg.
intra- coagulation mechanism and to reduce the ele-
venously vated prothrombin time.

SUMMARY

well and within twenty-four hours or less. A study of the effectiveness of a phytonadione
The single subject given 5 mg. intravenously (vitamin K1) colloidal suspension in reducing
for gross hematuria did not stop bleeding. His the elevated prothrombin times of bishydroxy-
prothrombin time at the onset of bleeding was coumarin-treated patients was performed. Pro-
sixty-five seconds; twenty-four hours after this thrombin times were studied two, four, six,
injection it was forty-five seconds, with the eight and twenty-four hours after the adminis-
brisk bleeding unchecked. He then was given tering to groups of ten patients each, of 10 mg.
10 mg. intravenously with an excellent response of the phytonadione intravenously, intramus-
within twenty-four hours. cularly and subcutaneously, as well as after
Aduerse Reactions: No untoward reactions administering 5 mg. intravenously.
ascribable to the vitamin K1 were experienced The 10 mg. dose given intravenously showed a
in any of these subjects. No special or unusual statistically significant acceleration of the return
precautions were taken for its parenteral of the elevated prothrombin times toward
administration. It was given undiluted by all normal as compared to a control group of eight
routes and no objective reactions were observed; patients similarly studied. This effect was ob-
there were no unusual patient complaints. served at two hours and was greatest four hours
One patient died of a presumed pulmonary after the vitamin was given. The 10 mg. sub-
embolus six hours after receiving 10 mg. intra- cutaneous dose and the 5 mg. intravenous dose
venously. Another patient sustained an ex- failed to accelerate the return of the prothrom-
tension of his myocardial infarction twenty-four bin times toward normal. The 10 mg. dose
hours after receiving a 10 mg. intramuscular given intramuscularly showed some effect after
dose. These episodes probably had no relation twenty-four hours, but this could not be proved
to the medication used, as they are frequent statistically significant. Using the 50 per cent
complications of the presenting illnesses under prothrombin time value as the index of a return
treatment. to a normal coagulation mechanism, four out of
the group of ten patients given 10 mg. intra-
COMMENTS venously failed to reach this value.
The of the
effectiveness low dosage levels Nine bleeding episodes secondary to bishy-
with hits newer preparation of phytonadione is droxycoumarin therapy were treated. Seven

THE AMERICANJOURNAL OF CARDIOLOGY

 Vitamin K1 in Hypoprothrombinemia 75

patients receiving 10 mg. intravenously and one 2. NEWCOMB, T. F. Current concepts in therapy:
anticoagulants. ~Vew Englnnd J. Med., 260: 545,
who received 10 mg. subcutaneously stopped
1959.
their bleeding in six to twenty-four hours after
3. SHOSHKES, M. and TAMI, M. Dihydrovitamin Kt
treatment. The one patient who received 5 biphosphate in bishydroxycoumarin-induced hypo-
mg. intravenously continued to bleed until a prothrombinemia. J. Lab. B Ctin. Med., 46:
second dose of 10 mg. was given intravenously. 21, 1960.
4. SHOSHKES, M. and PERELMAN, A. J. Vitamin K1 in
REFERENCES treatment of bishydroxycoumarin-induced hypo-
1. Council on Pharmacy and Chemistry: New and prothrombinemia: comparison of intravenous and
Nonofficial Remedies, p. 505. Philadelphia, 1956. intramuscular administration. J.4.M..4., 161 :
J. B. Lippincott Co. 1145, 1956.

JULY 1961