REVIEW ARTICLE

Treatment of coumarin-associated coagulopathy: a systematic

review and proposed treatment algorithms
F. DENTALI , * W. AGENO* and M. CROWTHER
*Department of Clinical Medicine, University of Insubria, Varese, Italy; and Department of Medicine, McMaster University, Hamilton, ON, Canada
To cite this article: Dentali F, Ageno W, Crowther M. Treatment of coumarin-associated coagulopathy: a systematic review and proposed
treatment algorithms. J Thromb Haemost 2006; 4: 185363.
Summary. Background: An excessive anticoagulant eect
because of coumarins is frequently encountered. Objective: To
review available literature on the management of warfarin-
associated coagulopathy and to propose evidence-based treat-
ment algorithms. Methods: Data sources were Medline and
Embase. Papers published between 1966 and December 2005
describing randomized trials or prospective cohort studies
evaluating treatments for coumarin-associated coagulopathy
were abstracted. Results: Low dose oral vitamin K rapidly and
reliably returns the international normalized ratio (INR) to the
usual therapeutic range in non-bleeding patients. Simple
withholding of acenocumarol results in rapid correction of its
anticoagulant eect. The impact of oral vitamin K on
phenprocumon-associated coagulopathy cannot be determined
from available literature. Intravenous vitamin K and coagula-
tion factors should be given to patients with major or life-
threatening hemorrhage. The optimal dose and type of
coagulation factor is not known. Conclusions: Vitamin K
therapy is an eective treatment for INR prolongation in
patients with coumarin-associated coagulopathy; coagulation
factor replacement is required, in addition, in patients with
major bleeding or with indication for immediate correction of
their INR. Clinical trials poweredtodetect dierences inrates of
bleeding and thrombosis are now required to determine if
vitamin K reduces the risk of bleeding without causing
thrombosis in non-bleeding patients with prolonged INR.
Keywords: anticoagulation, coagulation factor concentrates,
coumarins, vitamin K.
Introduction
Coumarins are effective for the prevention and treatment of
venous and arterial thrombosis but may cause bleeding
(especially if overdosed) or thrombosis (especially if under-
dosed). To minimize the risk of these complications, the
prothrombin time (PT) generally expressed as the interna-
tional normalized ratio (INR) to allow comparability among
centers is used to monitor the degree of coumarin-associated
anticoagulation. In most patients at risk of thrombosis,
achieving an INR of 2.03.0 minimizes bleeding risk while
producing an adequate antithrombotic effect. However, despite
monitoring and careful dose adjustment, anticoagulation
outside the desired reference interval with or without throm-
bosis or bleeding is frequently seen. An excessively elevated
INR independently predicts major bleeding; the risk of
bleeding approximately doubles for each single point of
increase in the INR above 3.0 and major bleeding occurs in
about 4% of patients who present with an INR of more than
6.0 who are treated with simple warfarin withdrawal [13].
The clinical management of patients who are receiving long-
term oral anticoagulant therapy (OAT) and who have supra-
therapeutic INR values with or without hemorrhage is a
frequently encountered and problematic clinical scenario.
Currently, it is estimated that almost 3 million people in the
USA are receiving long-term OAT; further, it is estimated that
up to 26 000 major bleeding episodes related to warfarin use
occur annually [4]. Guidelines on the clinical management of
patients with coumarin-associated coagulopathy have been
published by national and international societies such as the
American College of Chest Physicians and the Australian
Society of Thrombosis and Haemostasis [5,6], but recommen-
dations are based on very low levels of evidence.
A series of studies examining the treatment of coumarin-
associated coagulopathy have recently been published. In this
review we systematically review these studies; the results of our
searches are presented in two tables summarizing all available
evidence on the management of anticoagulated patients
requiring urgent or non-urgent reversal of anticoagulation.
We then use the results of the systematic review to generate
specic treatment recommendations.
Methods
A computer-assisted series of searches was performed to
identify all published trials. Studies were identied using
Medline (from 1966 to December 2005) and Embase (from
Correspondence: Walter Ageno, U.O. Medicina I, Ospedale di Circolo,
Viale Borri 57, 21100 Varese, Italy.
Tel.: +39 0332 278594; fax: +39 0332 278595; e-mail:
agewal@yahoo.com
Received 12 January 2006, accepted 27 March 2006
Journal of Thrombosis and Haemostasis, 4: 18531863
2006 International Society on Thrombosis and Haemostasis
1980 to December 2005) databases. All searches were carried
out without mapping search terms to subject headings. For
the rst search, terms included vitamin K, phylloquinone,
phytonadione, menadione, and excluded infant, newborn, fetus,
seizure or chemotherapy. For the second search, terms used
were plasma, fresh frozen plasma (FFP), cryosupernatant
plasma, coagulation concentrate, prothrombin complex concen-
trate (PCC), octaplex, FEIBA, recombinant factor VII
activated, rFVIIa or Novoseven. The results of these two
searches were combined (using the OR function), and then
combined with the results of the following search (using the
AND function). Terms used in the last search were warfarin,
acenocumarol, phenprocumon, phenprocoumon, vitamin K
antagonist, coumarin, or oral anticoagulant. The results of
the combined search were limited to human, and English
language. This strategy was rened by combining the results,
using the AND function, with the results of a search
including the terms treatment or intervention or correction.
The list of articles was manually reviewed by two authors
(M.C., F.D.). Papers whose titles or abstracts suggested they
presented either prospective cohort studies or randomized-
controlled trials (RCT) were selected for detailed review.
Additional papers meeting these inclusion criteria were
selected for review from the authors libraries, and from
review of the reference lists of those articles selected for
detailed review.
We excluded fromconsideration patients with elevated INRs
associated with coumarin therapy in the setting of procoagu-
lant disorders such as heparin-induced thrombocytopenia or
cancer-associated coagulopathy, as these require distinct man-
agement strategies beyond the scope of our review [7,8].
The treatment of patients with excessively prolonged INR
values depends fundamentally on the presence, severity and
location of bleeding, and on thrombotic risk. As a result, we
have chosen to present our review in two sections: Section 1
discusses patients who are not bleeding and Section 2 discusses
patients who are bleeding. Themes common to both patients
with and without bleeding include a thorough medical
assessment and discontinuation of anticoagulant treatment.
Results
Our search strategy produced 36 articles [944] which are
summarized in Tables 1 and 2. A formal combined statistical
analysis of these studies was not appropriate because of the
heterogeneity of methodology, interventions and outcome
assessments in the trials.
Section 1: management of the non-bleeding patient
The objectives of treatment for non-bleeding patients with an
excessively prolonged INRvalue is to reduce the likelihood that
the patient will develop bleeding complications by reducing the
duration of INR prolongation, while minimizing the risk of
thrombosis associated with a sub-therapeutic INR. Two main
treatment strategies are available: withholding coumarin alone,
or withholding coumarin and administering vitamin K. Athird
option, administering vitamin K and transfusion therapy of
coagulation factors (either in the form of FFP or coagulation
factor concentrates) should not be routinely used in non-
bleeding patients because it is expensive, potentially risky and
has not been demonstrated to be more effective than simple
administration of vitamin K. However, many physicians will
provide transfusion therapy to patients with an INR in excess
of 10 despite lack of evidence, and proof of the effectiveness of
oral vitamin K in this setting [45].
Withholding treatment Simply withholding coumarin and
allowing the INR to fall into the therapeutic range is the most
widely used approach to the treatment of patients with
warfarin-associated coagulopathy [46,47]. However, there is
evidence from a prospective cohort study of 114 patients that
this strategy is associated with a risk of major bleeding as high
as 9%in the 2 weeks after the elevated INRis detected [2]. This
observation suggests that simple warfarin withdrawal may be
unsafe because of a high risk of bleeding in the days following
anticoagulant withdrawal.
Vitamin K Observational studies suggest vitamin K is
infrequently used for the treatment of coumarin-associated
coagulopathy. Despite evidence for its efcacy, two North
American physician surveys found that about two-thirds of
physicians would not administer vitamin K to a non-bleeding
patient with an INR value above 8.5 [4,48]. Fully 25% of
physicians would not administer vitamin K even to a patient
considered to be at high risk for bleeding [48]. A variety of
vitamin Kpreparations are available for clinical use. In general,
phytonadione (vitamin K1, a plant-derived formof vitamin K)
has been used in clinical trials describing the utility of oral
vitamin K for the treatment of warfarin-associated
coagulopathy. Vitamin K2 (which is synthesized by bacteria)
and menadione have limited availability and have not been well
studied in clinical trials. Anaphylaxis has been described with
the intravenous (i.v.) administration of vitamin K1; most such
cases occurred with large doses of vitamin K being
administered rapidly and with little dilution. Modern
formulations of vitamin K for i.v. injection utilize solubilizers
that appear to be associated with a lower risk of anaphylaxis,
although accurate estimates of the true risk of anaphylaxis are
not available.
Intravenous vitamin K Three studies have compared different
doses of vitamin K administered intravenously in patients
presenting with warfarin-associated coagulopathy [9,11,23].
These studies concluded that a 0.5 mg i.v. dose was optimal if
the goal of therapy was to return the INR to the usual
therapeutic range. Intravenous vitamin K may cause
anaphylactoid reactions. Although frequently reported, and
likely more common in patients who receive large i.v. doses
administered rapidly, the true frequency of this complication is
about three per 10 000 doses administered, and it may be more
likely to occur if formulations containing polyethoxylated
1854 F. Dentali et al
2006 International Society on Thrombosis and Haemostasis
T
a
b
l
e
1
P
a
t
i
e
n
t
s
n
o
t
r
e
q
u
i
r
i
n
g
u
r
g
e
n
t
r
e
v
e
r
s
a
l
o
f
a
n
t
i
c
o
a
g
u
l
a
t
i
o
n
A
u
t
h
o
r
,
y
e
a
r
[
R
e
f
.
]
T
y
p
e
o
f
s
t
u
d
y
T
r
e
a
t
m
e
n
t
s
e
x
a
m
i
n
e
d
*
n
I
n
d
i
c
a
t
i
o
n
O
u
t
c
o
m
e
R
e
s
u
l
t
s
a
n
d
n
o
t
a
t
i
o
n
s
A
n
d
e
r
s
e
n
,
1
9
7
5
[
9
]
P
r
o
s
p
e
c
t
i
v
e
c
o
h
o
r
t
G
1
:
1
m
g
i
.
v
.
v
K
G
2
:
n
o
i
n
t
e
r
v
e
n
t
i
o
n
G
1
:
2
0
G
2
:
5
R
e
v
e
r
s
a
l
o
f
a
n
t
i
c
o
a
g
u
l
a
t
i
o
n
p
r
i
o
r
t
o
s
u
r
g
e
r
y
R
a
t
e
o
f
c
o
r
r
e
c
t
i
o
n
o
f
T
h
r
o
m
b
o
t
e
s
t
1
m
g
i
.
v
.
v
K
e

e
c
t
i
v
e
w
i
t
h
o
u
t
w
i
t
h
h
o
l
d
i
n
g
w
a
r
f
a
r
i
n
t
r
e
a
t
m
e
n
t
T
a
b
e
r
n
e
r
,
1
9
7
6
[
1
0
]
R
C
T
G
1
:
P
C
C
G
2
:
2
.
5
m
g
i
.
v
.
v
K
G
1
:
9
G
2
:
9
R
e
v
e
r
s
a
l
o
f
o
v
e
r
a
n
t
i
c
o
a
g
u
l
a
t
i
o
n
N
o
r
m
a
l
i
z
a
t
i
o
n
o
f
p
r
o
t
h
r
o
m
b
i
n
t
i
m
e
(
P
T
)
P
C
C
p
r
o
v
i
d
e
a
q
u
i
c
k
e
r
(
a
t
3
0
m
i
n
)
b
u
t
l
e
s
s
s
u
s
t
a
i
n
e
d
(
a
t
2
4
h
)
n
o
r
m
a
l
i
z
a
t
i
o
n
o
f
P
T
S
h
e
t
t
y
,
1
9
9
2
[
1
1
]
P
r
o
s
p
e
c
t
i
v
e
c
o
h
o
r
t
G
1
:
0
.
5
m
g
i
.
v
.
v
K
G
2
:
1
m
g
i
.
v
.
v
K
G
1
:
2
1
G
2
:
1
0
I
N
R
>
5
.
0
I
N
R
b
e
t
w
e
e
n
2
.
0
a
n
d
3
.
0
0
.
5
m
g
b
e
t
t
e
r
:
6
2
%
i
n
r
a
n
g
e
,
8
6
%
<
4
.
5
,
n
o
n
e
<
2
.
0
.
1
m
g
:
5
0
%
<
2
.
0
P
e
n
g
o
,
1
9
9
3
[
1
2
]
R
C
T
G
1
:
N
o
a
c
t
i
v
e
i
n
t
e
r
v
e
n
t
i
o
n
G
2
:
2
m
g
o
r
a
l
v
K
2
3
I
N
R
>
5
.
0
P
r
o
p
o
r
t
i
o
n
w
i
t
h
I
N
R
<
5
.
0
a
t
2
4
a
n
d
4
8
h
P
r
o
p
o
r
t
i
o
n
w
i
t
h
I
N
R
<
5
.
0
:
G
1
:
7
o
f
1
2
(
2
4
h
)
,
1
1
o
f
1
2
(
4
8
h
)
G
2
:
1
1
o
f
1
1
(
2
4
h
)
,
1
0
o
f
1
1
(
4
8
h
)
W
e
i
b
e
r
t
,
1
9
9
7
[
1
3
]
P
r
o
s
p
e
c
t
i
v
e
c
o
h
o
r
t
2
.
5
m
g
o
r
a
l
v
K
8
1
I
N
R
>
5
.
0
P
r
o
p
o
r
t
i
o
n
w
i
t
h
I
N
R
<
5
.
0
w
i
t
h
i
n
4
8
h
S
u
c
c
e
s
s
i
n
6
8
o
f
7
1
e
v
a
l
u
a
b
l
e
p
a
t
i
e
n
t
s
F
e
t
r
o
w
,
1
9
9
7
[
1
4
]
P
r
o
s
p
e
c
t
i
v
e
c
o
h
o
r
t
G
1
:
n
o
a
c
t
i
v
e
i
n
t
e
r
v
e
n
t
i
o
n
G
2
:
s
.
c
.
v
K
G
1
:
6
G
2
:
1
2
I
N
R
>
4
.
0
T
i
m
e
t
o
I
N
R
<
3
.
0
s
c
g
r
o
u
p
a
c
h
i
e
v
e
d
a
n
I
N
R
<
3
.
0
,
2
3
h
s
o
o
n
e
r
t
h
a
n
s
i
m
p
l
e
w
i
t
h
h
o
l
d
i
n
g
C
r
o
w
t
h
e
r
,
1
9
9
8
[
1
5
]
P
r
o
s
p
e
c
t
i
v
e
c
o
h
o
r
t
1
m
g
o
r
a
l
v
K
6
2
I
N
R
b
e
t
w
e
e
n
4
.
5
a
n
d
1
0
.
0
C
o
r
r
e
c
t
e
d
I
N
R
1
m
g
o
r
a
l
v
K
e

e
c
t
i
v
e
D
u
o
n
g
,
1
9
9
8
[
1
6
]
C
o
h
o
r
t
s
t
u
d
y
R
e
t
r
o
s
p
e
c
t
i
v
e
g
r
o
u
p
:
N
o
i
n
t
e
r
v
e
n
t
i
o
n
P
r
o
s
p
e
c
t
i
v
e
g
r
o
u
p
:
2
.
5
m
g
o
r
a
l
v
K
G
1
:
2
5
G
2
:
2
5
I
N
R
b
e
t
w
e
e
n
5
a
n
d
1
0
w
i
t
h
o
u
t
b
l
e
e
d
i
n
g
M
e
a
n
n
u
m
b
e
r
o
f
d
a
y
s
t
o
t
h
e
r
a
p
e
u
t
i
c
I
N
R
a
n
d
m
e
a
n
c
h
a
n
g
e
i
n
I
N
R
D
a
y
s
t
o
t
h
e
r
a
p
e
u
t
i
c
I
N
R
:
G
1
2
.
3
v
s
.
G
2
1
.
4
d
a
y
s
(
P
<
0
.
0
0
1
)
2
4
-
h
c
h
a
n
g
e
i
n
I
N
R
:
G
1
1
.
3
2
v
s
.
G
2
3
.
4
6
P
<
0
.
0
0
1
W
e
n
t
z
i
e
n
,
1
9
9
8
[
1
7
]
P
r
o
s
p
e
c
t
i
v
e
c
o
h
o
r
t
O
r
a
l
v
K
5
1
P
r
e
p
r
o
c
e
d
u
r
a
l
r
e
v
e
r
s
a
l
(
n

3
0
)
,
I
N
R
>
5
.
0
(
n

2
1
)
H
e
m
o
r
r
h
a
g
i
c
o
r
t
h
r
o
m
b
o
e
m
b
o
l
i
c
c
o
m
p
l
i
c
a
t
i
o
n
s
O
r
a
l
v
K
s
a
f
e
a
n
d
e

e
c
t
i
v
e
P
e
n
n
i
n
g
-
v
a
n
B
e
e
s
t
,
1
9
9
9
[
1
8
]
P
r
o
s
p
e
c
t
i
v
e
c
o
h
o
r
t
1

5
m
g
o
r
a
l
v
K
2
4
I
N
R
>
6
.
0
C
h
a
n
g
e
s
i
n
t
h
e
I
N
R
O
r
a
l
v
K
s
a
f
e
b
u
t
t
h
e
d
o
s
a
g
e
s
h
o
u
l
d
b
e
i
n
t
e
n
s
i

e
d
N
e
e
,
1
9
9
9
[
1
9
]
R
C
T
G
1
:
0
.
5

3
.
0
m
g
s
.
c
.
v
K
G
2
:
0
.
5

3
.
0
m
g
i
.
v
.
v
K
G
1
:
3
3
G
2
:
2
2
I
N
R
6
.
0

1
2
.
0
I
N
R
<
4
.
5
I
.
v
.
m
o
r
e
e

e
c
t
i
v
e
:
9
5
%
v
s
.
4
5
%
B
y
r
d
,
1
9
9
9
[
2
0
]
P
r
o
s
p
e
c
t
i
v
e
c
o
h
o
r
t
G
1
(
I
N
R
8
.
0

1
4
.
0
)
:
1
m
g
s
.
c
.
v
K
G
2

(
I
N
R
1
4
.
1

2
0
.
0
)
:
2
m
g
o
f
s
.
c
.
v
K
G
1
:
1
7
G
2
:
4
I
N
R
>
8
.
0
w
i
t
h
o
u
t
b
l
e
e
d
i
n
g
R
a
t
e
o
f
c
o
r
r
e
c
t
i
o
n
o
f
t
h
e
I
N
R
9
3
%
o
f
G
1
a
n
d
1
0
0
%
o
f
G
2
p
a
t
i
e
n
t
s
h
a
d
I
N
R
<
4
.
5
a
t
4
8
h
.
N
o
r
e
p
o
r
t
e
d
b
l
e
e
d
i
n
g
o
r
t
h
r
o
m
b
o
t
i
c
c
o
m
p
l
i
c
a
t
i
o
n
s
R
a
j
,
1
9
9
9
[
2
1
]
R
C
T
G
1
:
1
m
g
s
.
c
.
v
K
G
2
:
1
m
g
i
.
v
.
v
K
G
1
:
1
1
G
2
:
1
1
I
N
R
>
6
.
0
I
N
R
<
5
.
0
I
.
v
.
m
o
r
e
e

e
c
t
i
v
e
:
8
2
%
v
s
.
9
%
a
f
t
e
r
8
h
;
8
2
%
v
s
.
6
4
%
a
f
t
e
r
2
4
h
C
r
o
w
t
h
e
r
,
2
0
0
0
[
2
2
]
R
C
T
G
1
:
1
m
g
o
r
a
l
v
K
G
2
:
p
l
a
c
e
b
o
9
9
A
s
y
m
p
t
o
m
a
t
i
c
I
N
R
b
e
t
w
e
e
n
4
.
5
a
n
d
1
0
.
0
M
e
a
n
I
N
R
v
a
l
u
e
s
5
6
%
(
G
1
)
v
s
.
2
0
%
(
G
2
)
m
e
t
c
r
i
t
e
r
i
a
f
o
r
s
u
c
c
e
s
s
(
P
<
0
.
0
5
)
H
u
n
g
,
2
0
0
0
[
2
3
]
R
C
T
0
.
5
m
g
v
s
.
1
m
g
v
s
.
2
.
0
m
g
i
.
v
.
v
K
2
4
I
N
R
>
7
.
0
I
N
R
b
e
t
w
e
e
n
2
.
0
a
n
d
4
.
0
a
f
t
e
r
2
4
h
0
.
5
m
g
b
e
t
t
e
r
:
e
x
c
e
s
s
i
v
e
o
v
e
r
-
r
e
v
e
r
s
a
l
o
f
I
N
R
w
i
t
h
h
i
g
h
e
r
d
o
s
e
s
Treatment of coumarin-associated coagulopathy 1855
2006 International Society on Thrombosis and Haemostasis
T
a
b
l
e
1
(
C
o
n
t
i
n
u
e
d
)
A
u
t
h
o
r
,
y
e
a
r
[
R
e
f
.
]
T
y
p
e
o
f
s
t
u
d
y
T
r
e
a
t
m
e
n
t
s
e
x
a
m
i
n
e
d
*
n
I
n
d
i
c
a
t
i
o
n
O
u
t
c
o
m
e
R
e
s
u
l
t
s
a
n
d
n
o
t
a
t
i
o
n
s
P
a
t
e
l
,
2
0
0
0
[
2
4
]
R
C
T
G
1
:
2
.
5
m
g
o
r
a
l
v
K
G
2
:
p
l
a
c
e
b
o
3
0
I
N
R
b
e
t
w
e
e
n
6
.
0
a
n
d
1
0
.
0
T
i
m
e
t
o
r
e
a
c
h
I
N
R
<
4
.
0
O
r
a
l
v
K
s
i
g
n
i

c
a
n
t
l
y
r
e
d
u
c
e
d
t
i
m
e
t
o
a
c
h
i
e
v
e
I
N
R
<
4
.
0
W
a
t
s
o
n
,
2
0
0
1
[
2
5
]
P
r
o
s
p
e
c
t
i
v
e
c
o
h
o
r
t
3
O
r
a
l
a
n
d
1
i
.
v
.
v
K
p
r
e
p
a
r
a
t
i
o
n
s
6
4
R
e
q
u
i
r
e
d
n
o
n
-
u
r
g
e
n
t
c
o
r
r
e
c
t
i
o
n
o
f
a
p
r
o
l
o
n
g
e
d
I
N
R
C
h
a
n
g
e
s
i
n
t
h
e
I
N
R
a
n
d
l
e
v
e
l
s
o
f
v
i
t
a
m
i
n
K
-
d
e
p
e
n
d
e
n
t
c
l
o
t
t
i
n
g
f
a
c
t
o
r
s
I
.
v
.
v
K
p
r
o
d
u
c
e
d
a
h
i
g
h
e
r
p
r
o
p
o
r
t
i
o
n
o
f
I
N
R
<
4
.
0
a
t
4
a
n
d
2
4
h
a
f
t
e
r
a
d
m
i
n
i
s
t
r
a
t
i
o
n
F
o
n
d
e
v
i
l
a
,
2
0
0
1
[
2
6
]
R
C
T
A
l
l
p
a
t
i
e
n
t
s
h
e
l
d
O
A
C
;
h
a
l
f
r
e
c
e
i
v
e
d
1
m
g
o
f
o
r
a
l
v
K
1
0
9
I
N
R
>
6
.
0
w
i
t
h
o
u
t
m
a
j
o
r
b
l
e
e
d
i
n
g
P
r
o
p
o
r
t
i
o
n
o
f
p
a
t
i
e
n
t
s
w
i
t
h
I
N
R
2
.
0

4
.
0
,
a
n
d
p
r
o
p
o
r
t
i
o
n
w
i
t
h
I
N
R
<
2
.
0
W
i
t
h
v
K
,
I
N
R
f
e
l
l
f
r
o
m
8
.
4
t
o
3
.
3
c
f
8
.
1
t
o
2
.
5
(
P
<
0
.
0
0
1
)
.
M
o
r
e
v
K
p
a
t
i
e
n
t
s
h
a
d
I
N
R
v
a
l
u
e
s
<
2
.
0
(
P
<
0
.
0
0
1
)
P
e
n
d
r
y
,
2
0
0
1
[
2
7
]
P
r
o
s
p
e
c
t
i
v
e
c
o
h
o
r
t
1
m
g
o
r
a
l
v
K
3
0
I
N
R
o
f
m
o
r
e
t
h
a
n
8
.
0
C
h
a
n
g
e
s
i
n
t
h
e
I
N
R
O
r
a
l
v
K
s
a
f
e
A
g
e
n
o
,
2
0
0
2
[
2
8
]
R
C
T
G
1
:
1
m
g
o
r
a
l
v
K
G
2
:
p
l
a
c
e
b
o
G
1
:
3
0
G
2
:
3
0
I
N
R
m
o
r
e
t
h
a
n
4
.
5
M
e
a
n
I
N
R
v
a
l
u
e
s
c
o
r
r
e
c
t
e
d
O
r
a
l
v
K
r
e
s
u
l
t
s
i
n
m
o
r
e
o
v
e
r
-
r
e
v
e
r
s
a
l
o
f
I
N
R
t
h
a
n
s
i
m
p
l
y
w
i
t
h
h
o
l
d
i
n
g
a
c
e
n
o
c
u
m
a
r
o
l
C
r
o
w
t
h
e
r
,
2
0
0
2
[
2
9
]
R
C
T
G
1
:
O
r
a
l
v
k
(
1
m
g
)
G
2
:
s
.
c
.
v
K
(
1
m
g
)
5
1
A
s
y
m
p
t
o
m
a
t
i
c
I
N
R
v
a
l
u
e
s
b
e
t
w
e
e
n
4
.
5
a
n
d
1
0
.
0
P
r
o
p
o
r
t
i
o
n
o
f
p
a
t
i
e
n
t
s
w
i
t
h
I
N
R
v
a
l
u
e
s
b
e
t
w
e
e
n
1
.
8
a
n
d
3
.
2
6
0
%
(
G
1
)
v
s
.
2
4
%
(
G
2
)
m
e
t
c
r
i
t
e
r
i
a
f
o
r
s
u
c
c
e
s
s
(
P
<
0
.
0
5
)
L
u
b
e
t
s
k
y
,
2
0
0
3
[
3
0
]
R
C
T
G
1
:
2
.
5
o
r
a
l
v
K
G
2
:
0
.
5
m
g
i
.
v
.
v
K
G
3
:
5
m
g
o
r
a
l
v
K
G
4
:
1
m
g
i
.
v
.
v
K
G
1
:
2
3
G
2
:
2
3
G
3
:
8
G
4
:
9
I
N
R
6
.
0

1
0
(
G
1
a
n
d
G
2
)
,
I
N
R
>
1
0
(
G
3
a
n
d
G
4
)
I
N
R
a
t
2
4
a
n
d
4
8
h
I
.
v
.
v
K
c
a
u
s
e
d
a
m
o
r
e
r
a
p
i
d
f
a
l
l
i
n
t
h
e
I
N
R
,
b
u
t
a
b
s
o
l
u
t
e
I
N
R
w
a
s
s
i
m
i
l
a
r
,
i
r
r
e
s
p
e
c
t
i
v
e
o
f
t
r
e
a
t
m
e
n
t
,
a
t
2
4
h
P
o
l
i
,
2
0
0
3
[
3
1
]
P
r
o
s
p
e
c
t
i
v
e
c
o
h
o
r
t
2
m
g
o
r
a
l
v
K
1
2
7
I
N
R
>
7
.
2
C
h
a
n
g
e
s
i
n
t
h
e
I
N
R
O
r
a
l
v
K
s
a
f
e
a
n
d
e

e
c
t
i
v
e
i
n
p
a
t
i
e
n
t
s
o
n
t
r
e
a
t
m
e
n
t
w
i
t
h
w
a
r
f
a
r
i
n
.
P
t
o
n
t
r
e
a
t
m
e
n
t
w
i
t
h
a
c
e
n
o
c
u
m
a
r
o
l
w
e
r
e
e
x
p
o
s
e
d
t
o
u
n
d
e
r
-
c
o
a
g
u
l
a
t
i
o
n
A
g
e
n
o
,
2
0
0
5
[
3
2
]
R
C
T
G
1
:
1
m
g
o
r
a
l
v
K
G
2
:
p
l
a
c
e
b
o
G
1
:
2
9
G
2
:
3
0
I
N
R
6
.
0

1
2
.
0
w
i
t
h
o
u
t
b
l
e
e
d
i
n
g
i
n
p
a
t
i
e
n
t
s
w
i
t
h
m
e
c
h
a
n
i
c
a
l
v
a
l
v
e
s
N
u
m
b
e
r
o
f
p
a
t
i
e
n
t
s
w
i
t
h
I
N
R
v
a
l
u
e
s
b
e
t
w
e
e
n
2
.
3
a
n
d
3
.
7
1
3
(
G
1
)
v
s
.
4
(
G
2
)
m
e
t
o
u
t
c
o
m
e
(
P
<
0
.
0
0
1
)
v
K
,
v
i
t
a
m
i
n
K
;
G
1
,
g
r
o
u
p
1
;
G
2
,
g
r
o
u
p
2
;
G
3
,
g
r
o
u
p
3
;
G
4
,
g
r
o
u
p
4
;
s
.
c
.
,
s
u
b
c
u
t
a
n
e
o
u
s
;
i
.
v
.
,
i
n
t
r
a
v
e
n
o
u
s
;
R
C
T
,
r
a
n
d
o
m
i
z
e
d
c
l
i
n
i
c
a
l
t
r
i
a
l
;
I
N
R
,
i
n
t
e
r
n
a
t
i
o
n
a
l
n
o
r
m
a
l
i
z
e
d
r
a
t
i
o
;
P
C
C
,
p
r
o
t
h
r
o
m
b
i
n
c
o
m
p
l
e
x
c
o
n
c
e
n
t
r
a
t
e
;
O
A
C
o
r
a
l
a
n
t
i
c
o
a
g
u
l
a
n
t
s
;
F
F
P
,
f
r
e
s
h
f
r
o
z
e
n
p
l
a
s
m
a
;
c
f
,
c
o
m
p
a
r
e
d
w
i
t
h
.
*
U
n
l
e
s
s
o
t
h
e
r
w
i
s
e
n
o
t
e
d
,
w
a
r
f
a
r
i
n
w
a
s
t
e
m
p
o
r
a
r
i
l
y
w
i
t
h
h
e
l
d
i
n
a
l
l
c
a
s
e
s
.
1856 F. Dentali et al
2006 International Society on Thrombosis and Haemostasis
T
a
b
l
e
2
P
a
t
i
e
n
t
s
r
e
q
u
i
r
i
n
g
u
r
g
e
n
t
r
e
v
e
r
s
a
l
o
f
a
n
t
i
c
o
a
g
u
l
a
t
i
o
n
A
u
t
h
o
r
,
y
e
a
r
[
R
e
f
.
]
T
y
p
e
o
f
s
t
u
d
y
T
r
e
a
t
m
e
n
t
s
e
x
a
m
i
n
e
d
*
n
I
n
d
i
c
a
t
i
o
n
O
u
t
c
o
m
e
R
e
s
u
l
t
s
a
n
d
n
o
t
a
t
i
o
n
s
W
h
i
t
e
,
1
9
9
6
[
3
3
]
R
e
t
r
o
s
p
e
c
t
i
v
e
a
n
d
p
r
o
s
p
e
c
t
i
v
e
c
o
h
o
r
t
F
F
P
a
n
d
v
K
3
2
R
e
q
u
i
r
e
m
e
n
t
f
o
r
r
a
p
i
d
n
o
r
m
a
l
i
z
a
t
i
o
n
o
f
t
h
e
I
N
R
M
o
r
t
a
l
i
t
y
T
r
e
a
t
m
e
n
t
w
a
s
e

e
c
t
i
v
e
i
n
1
4
/
1
8
i
n
t
h
e
r
e
t
r
o
s
p
e
c
t
i
v
e
g
r
o
u
p
a
n
d
i
n
1
4
/
1
4
i
n
t
h
e
p
r
o
s
p
e
c
t
i
v
e
g
r
o
u
p
M
a
k
r
i
s
,
1
9
9
7
[
3
4
]
P
r
o
s
p
e
c
t
i
v
e
c
o
h
o
r
t
G
1
:
F
F
P
G
2
:
C
o
m
p
l
e
x
c
o
n
c
e
n
t
r
a
t
e
G
1
:
1
2
G
2
:
2
9
R
e
q
u
i
r
e
m
e
n
t
f
o
r
r
a
p
i
d
n
o
r
m
a
l
i
z
a
t
i
o
n
o
f
t
h
e
I
N
R
P
r
o
p
o
r
t
i
o
n
w
i
t
h
i
m
m
e
d
i
a
t
e
l
y
c
o
r
r
e
c
t
e
d
I
N
R
a
n
d
F
I
X
l
e
v
e
l
s
G
1
:
0
o
f
1
2
c
o
r
r
e
c
t
e
d
,
m
e
d
i
a
n
l
e
v
e
l
0
.
1
9
U
m
L
)
1
G
2
:
2
8
o
f
2
9
c
o
r
r
e
c
t
e
d
,
m
e
d
i
a
n
l
e
v
e
l
6
8
.
5
U
m
L
)
1
B
o
u
l
i
s
,
1
9
9
9
[
3
5
]
R
C
T
F
F
P
F
F
P
+
F
I
X
C
C
85
R
e
q
u
i
r
e
d
i
m
m
e
d
i
a
t
e
c
o
r
r
e
c
t
i
o
n
o
f
I
N
R
f
o
r
i
n
t
r
a
c
r
a
n
i
a
l
b
l
e
e
d
i
n
g
C
h
a
n
g
e
s
i
n
t
h
e
I
N
R
F
F
P
+
F
I
X
C
C
m
o
r
e
e

e
c
t
i
v
e
t
h
a
n
F
F
P
a
l
o
n
e
G
o
l
d
s
t
e
i
n
,
2
0
0
6
[
4
4
]
P
r
o
s
p
e
c
t
i
v
e
c
o
h
o
r
t
F
F
P
+
v
K
6
9
R
e
q
u
i
r
e
d
i
m
m
e
d
i
a
t
e
c
o
r
r
e
c
t
i
o
n
o
f
I
N
R
f
o
r
i
n
t
r
a
c
e
r
e
b
r
a
l
h
e
m
o
r
r
h
a
g
e
I
N
R
<
1
.
4
a
t
2
4
h
a
n
d
G
O
S
a
t
3
m
o
n
t
h
s
P
a
t
i
e
n
t
s
w
i
t
h
I
N
R
<
1
.
4
a
t
2
4
h
h
a
d
a
s
h
o
r
t
e
r
m
e
d
i
a
n
t
i
m
e
f
r
o
m
d
i
a
g
n
o
s
i
s
t
o

r
s
t
d
o
s
e
o
f
F
F
P
(
9
0
v
s
.
2
1
0
m
i
n
;
P

0
0
2
)
.
E
a
r
l
i
e
r
t
r
e
a
t
m
e
n
t
w
a
s
n
o
t
a
s
s
o
c
i
a
t
e
d
w
i
t
h
a
b
e
t
t
e
r
G
O
S
a
t
3
m
o
n
t
h
s
C
a
r
t
m
i
l
l
,
2
0
0
0
[
3
6
]
P
r
o
s
p
e
c
t
i
v
e
c
o
h
o
r
t
G
1
:
P
C
C
G
2
:
F
F
P
G
1
:
6
G
2
:
6
A
n
t
i
c
o
a
g
u
l
a
t
i
o
n
r
e
v
e
r
s
a
l
F
o
r
U
r
g
e
n
t
n
e
u
r
o
s
u
r
g
i
c
a
l
i
n
t
e
r
v
e
n
t
i
o
n
M
e
a
n
I
N
R
v
a
l
u
e
s
G
1
:
I
N
R
4
.
8
6
(
p
r
e
t
r
e
a
t
m
e
n
t
)
a
n
d
1
.
3
2
(
p
o
s
t
-
t
r
e
a
t
m
e
n
t
)
G
2
:
I
N
R
5
.
3
2
a
n
d
2
.
3
,
r
e
s
p
e
c
t
i
v
e
l
y
E
v
a
n
s
,
2
0
0
1
[
3
7
]
P
r
o
s
p
e
c
t
i
v
e
c
o
h
o
r
t
I
.
v
.
v
K
a
n
d
P
C
C
1
0
O
n
g
o
i
n
g
h
e
m
o
r
r
h
a
g
e
a
n
d
I
N
R
>
1
4
.
0
C
e
s
s
a
t
i
o
n
o
f
b
l
e
e
d
i
n
g
,
c
h
a
n
g
e
s
i
n
I
N
R
v
a
l
u
e
s
a
n
d
c
h
a
n
g
e
s
i
n
t
h
e
l
e
v
e
l
s
o
f
F
I
I
,
F
V
I
I
,
F
I
X
a
n
d
F
X
B
l
e
e
d
i
n
g
s
t
o
p
p
e
d
i
n
a
l
l
p
a
t
i
e
n
t
s
,
c
o
a
g
u
l
a
t
i
o
n
f
a
c
t
o
r
l
e
v
e
l
s
r
e
t
u
r
n
e
d
t
o
n
o
r
m
a
l
i
n
a
l
l
p
a
t
i
e
n
t
s
a
n
d
t
h
e
I
N
R
c
h
a
n
g
e
d
f
r
o
m
a
m
e
a
n
o
f
>
2
0
t
o
1
.
1
P
r
e
s
t
o
n
,
2
0
0
2
[
3
9
]
P
r
o
s
p
e
c
t
i
v
e
c
o
h
o
r
t
A
d
m
i
n
i
s
t
r
a
t
i
o
n
o
f
a
P
C
C
(
d
o
s
e
b
a
s
e
d
o
n
I
N
R
)
4
2
R
e
q
u
i
r
e
d
i
m
m
e
d
i
a
t
e
c
o
r
r
e
c
t
i
o
n
o
f
I
N
R
C
h
a
n
g
e
s
i
n
t
h
e
I
N
R
a
n
d
t
h
e
l
e
v
e
l
s
o
f
F
I
I
,
F
V
I
I
,
F
I
X
a
n
d
F
X
,
P
C
a
n
d
A
T
a
t
2
0
,
6
0
a
n
d
1
2
0
m
i
n
a
f
t
e
r
a
d
m
i
n
i
s
t
r
a
t
i
o
n
N
o
r
m
a
l
i
z
a
t
i
o
n
o
f
a
l
l
m
e
a
s
u
r
e
d
p
a
r
a
m
e
t
e
r
s
e
x
c
e
p
t
a
n
t
i
t
h
r
o
m
b
i
n
l
e
v
e
l
s
i
n
m
o
s
t
p
a
t
i
e
n
t
s
a
t
2
0
m
i
n
;
o
n
e
p
a
t
i
e
n
t
s
u

e
r
e
d
a
c
e
r
e
b
r
o
v
a
s
c
u
l
a
r
a
c
c
i
d
e
n
t
a
t
4
8
h
Y
a
s
a
k
a
,
2
0
0
2
[
4
0
]
P
r
o
s
p
e
c
t
i
v
e
c
o
h
o
r
t
G
1
:
P
C
C
+
v
K
G
2
:
P
C
C
G
3
:
v
K
G
1
:
1
1
G
2
:
2
G
3
:
4
R
e
q
u
i
r
e
d
i
m
m
e
d
i
a
t
e
c
o
r
r
e
c
t
i
o
n
o
f
I
N
R
C
h
a
n
g
e
s
i
n
t
h
e
I
N
R
P
C
C
s
a
n
d
v
K
m
o
r
e
e

e
c
t
i
v
e
t
h
a
n
P
C
C
s
a
l
o
n
e
a
n
d
v
K
a
l
o
n
e
L
u
b
e
t
s
k
y
,
2
0
0
4
[
4
2
]
P
r
o
s
p
e
c
t
i
v
e
c
o
h
o
r
t
P
C
C
2
0
R
e
q
u
i
r
e
d
i
m
m
e
d
i
a
t
e
C
o
r
r
e
c
t
i
o
n
o
f
I
N
R
f
o
r
b
l
e
e
d
i
n
g
o
r
u
r
g
e
n
t
s
u
r
g
i
c
a
l
p
r
o
c
e
d
u
r
e
C
h
a
n
g
e
s
i
n
t
h
e
I
N
R
,
c
o
a
g
u
l
a
t
i
o
n
f
a
c
t
o
r
s
l
e
v
e
l
s
,
s
a
f
e
t
y
a
n
d
t
o
l
e
r
a
b
i
l
i
t
y
R
a
p
i
d
d
e
c
l
i
n
e
o
f
I
N
R
w
i
t
h
i
n
1
0
m
i
n
a
f
t
e
r
P
C
C
a
d
m
i
n
i
s
t
r
a
t
i
o
n
.
G
o
o
d
c
o
r
r
e
l
a
t
i
o
n
b
e
t
w
e
e
n
c
o
a
g
u
l
a
t
i
o
n
f
a
c
t
o
r
s
a
n
d
I
N
R
.
G
o
o
d
s
a
f
e
t
y
a
n
d
t
o
l
e
r
a
b
i
l
i
t
y
Treatment of coumarin-associated coagulopathy 1857
2006 International Society on Thrombosis and Haemostasis
castor oil are used to maintain the vitamin K in solution [49].
To minimize the risk of anaphylactoid reactions, vitamin K
should be mixed in a minimum of 50 mL of i.v. uid and
administered, using an infusion pump, over a minimum of
30 min. Another concern is the potential to cause resistance to
coumarins. This complication has not been reported in
published studies in which patients received low-dose vitamin
K, irrespective of route [15,22,29,30].
Subcutaneous vitamin K Although widely used to treat
warfarin-associated coagulopathy [4,48], subcutaneous (s.c.)
vitamin K has unpredictable effects on lowering the INR. Nee
et al. [19] performed a RCT within which patients with INR
values between 6.0 and 20.0 received 0.5 or 3 mg of vitamin K
administered either s.c. or i.v. Twenty-four hours after vitamin
K, 45% of patients in the s.c. group had an INR < 4.5,
compared with 95%of patients in the i.v. group. Similarly, Raj
et al. [21] performed a single blind RCT that enrolled non-
bleeding patients with INRvalues > 6.0 to receive either 1 mg
of i.v. or s.c. vitamin K. At 8 h after vitamin K, 9%of patients
in the s.c. group, and 82% of patients in the i.v. group had an
INR < 5.0. At 24 h, these proportions were 64% and 82%,
respectively. These studies support the contention that if rapid
reductions in the INRare desired, i.v. vitamin Kis preferred to
s.c. vitamin K.
Oral vitamin K When used in doses of 12.5 mg, oral vitamin
K does not produce warfarin resistance, anaphylactoid
reactions, or skin reactions [15,22,27,29,31,50,51].
Furthermore, oral vitamin K simplies the out-of-hospital
management of asymptomatic warfarin-associated
coagulopathy because a healthcare visit is not needed at the
time of its administration.
The rst contemporary RCT of oral vitamin K was
performed by Pengo et al. [12]. Our group [22] randomized 92
patients with INR values of 4.510.0 to receive either 1 mg of
oral vitamin K, or placebo. Twenty-ve of 45 patients (56%)
who received vitamin K, and nine of 44 (20%) patients who
receivedplacebohadINRvalues of 1.83.2onthe dayfollowing
study drug administration (P 0.001 for comparison of
proportions between the two groups). Similar results were
reported by Patel et al. [27]. Our group has also performed a
RCT that demonstrated that low-dose oral vitamin K is more
effective than low-dose s.c. vitamin K[29]. Finally, in a RCTof
61patients withINRvalues of morethan6.0, Lubetskyet al. [30]
have recentlydemonstratedthat i.v. andoral vitaminKproduce
similar reductions in the INRvalue at 24 h, despite the fact that
the INRbegins tofall more quickly withi.v. vitaminK. Thus, in
this paper patients with INR values between 6.0 and 10.0 were
randomly allocated to receive 0.5 mg of i.v., or 2 mg of oral,
vitamin K. Six hours after vitamin K administration, 11 of 24
patients allocated to i.v. vitamin K, and 0 of 23 allocated to oral
therapy had an INR between 2.0 and 4.0 (P < 0.001).
However, by 24 h after presentation the INR values were
similar betweenthe twogroups (meanINR2.9 after i.v., and2.6
after oral vitamin K, respectively). More patients allocated to T
a
b
l
e
2
(
C
o
n
t
i
n
u
e
d
)
A
u
t
h
o
r
,
y
e
a
r
[
R
e
f
.
]
T
y
p
e
o
f
s
t
u
d
y
T
r
e
a
t
m
e
n
t
s
e
x
a
m
i
n
e
d
*
n
I
n
d
i
c
a
t
i
o
n
O
u
t
c
o
m
e
R
e
s
u
l
t
s
a
n
d
n
o
t
a
t
i
o
n
s
Y
a
s
a
k
a
,
2
0
0
5
[
4
3
]
P
r
o
s
p
e
c
t
i
v
e
c
o
h
o
r
t
P
C
C
+
-
V
K
4
2
R
e
q
u
i
r
e
d
i
m
m
e
d
i
a
t
e
c
o
r
r
e
c
t
i
o
n
o
f
I
N
R
C
h
a
n
g
e
s
i
n
t
h
e
I
N
R
,
t
h
r
o
m
b
o
e
m
b
o
l
i
c
c
o
m
p
l
i
c
a
t
i
o
n
s
5
0
0
I
U
o
f
P
C
C
s
c
o
r
r
e
c
t
s
o
f
I
N
R
b
e
l
o
w
5
.
0
b
u
t
w
e
r
e
i
n
a
d
e
q
u
a
t
e
w
h
e
n
I
N
R
i
s
5
.
0
o
r
m
o
r
e
.
N
o
t
h
r
o
m
b
o
e
m
b
o
l
i
c
c
o
m
p
l
i
c
a
t
i
o
n
s
D
e
v
e
r
a
s
,
2
0
0
2
[
3
8
]
P
r
o
s
p
e
c
t
i
v
e
c
o
h
o
r
t
R
e
c
o
m
b
i
n
a
n
t
F
V
I
I
a
c
o
n
c
e
n
t
r
a
t
e
1
3
I
m
m
e
d
i
a
t
e
r
e
v
e
r
s
a
l
o
f
w
a
r
f
a
r
i
n
-
i
n
d
u
c
e
d
a
n
t
i
c
o
a
g
u
l
a
t
i
o
n
P
T
-
I
N
R
R
e
c
o
m
b
i
n
a
n
t
F
V
I
I
a
p
r
o
d
u
c
e
d
s
a
f
e
a
n
d
r
a
p
i
d
r
e
v
e
r
s
a
l
S
o
r
e
n
s
e
n
,
2
0
0
3
[
4
1
]
P
r
o
s
p
e
c
t
i
v
e
c
o
h
o
r
t
R
e
c
o
m
b
i
n
a
n
t
F
V
I
I
a
c
o
n
c
e
n
t
r
a
t
e
7
R
e
q
u
i
r
e
d
i
m
m
e
d
i
a
t
e
c
o
r
r
e
c
t
i
o
n
o
f
I
N
R
C
h
a
n
g
e
s
i
n
t
h
e
I
N
R
a
n
d
s
u
b
j
e
c
t
i
v
e
e
v
a
l
u
a
t
i
o
n
o
f
h
e
m
o
s
t
a
s
i
s
d
u
r
i
n
g
a
n
d
a
f
t
e
r
t
h
e
s
u
r
g
i
c
a
l
p
r
o
c
e
d
u
r
e
S
i
x
p
a
t
i
e
n
t
s
u
n
d
e
r
w
e
n
t
d
r
a
i
n
a
g
e
o
f
t
h
e
C
N
S
h
e
m
a
t
o
m
a
a
n
d
a
l
l
p
a
t
i
e
n
t
s
s
u
r
v
i
v
e
d
v
K
,
v
i
t
a
m
i
n
K
;
G
1
,
g
r
o
u
p
1
;
G
2
,
g
r
o
u
p
2
;
G
3
,
g
r
o
u
p
3
;
R
C
T
,
r
a
n
d
o
m
i
z
e
d
c
l
i
n
i
c
a
l
t
r
i
a
l
;
I
N
R
,
i
n
t
e
r
n
a
t
i
o
n
a
l
n
o
r
m
a
l
i
z
e
d
r
a
t
i
o
;
P
C
C
,
p
r
o
t
h
r
o
m
b
i
n
c
o
m
p
l
e
x
c
o
n
c
e
n
t
r
a
t
e
;
O
A
C
o
r
a
l
a
n
t
i
c
o
a
g
u
l
a
n
t
s
;
F
F
P
,
f
r
e
s
h
f
r
o
z
e
n
p
l
a
s
m
a
;
c
f
,
c
o
m
p
a
r
e
d
w
i
t
h
;
r
V
I
I
a
,
r
e
c
o
m
b
i
n
a
n
t
f
a
c
t
o
r
V
I
I
a
;
F
I
X
C
C
,
f
a
c
t
o
r
I
X
c
o
m
p
l
e
x
c
o
n
c
e
n
t
r
a
t
e
;
P
C
,
p
r
o
t
e
i
n
C
;
A
T
,
a
n
t
i
t
h
r
o
m
b
i
n
;
C
N
S
,
c
e
r
e
b
r
a
l
n
e
r
v
o
u
s
s
y
s
t
e
m
;
G
O
S
,
G
l
a
s
g
o
w
o
u
t
c
o
m
e
s
c
a
l
e
.
*
W
a
r
f
a
r
i
n
w
a
s
t
e
m
p
o
r
a
r
i
l
y
w
i
t
h
h
e
l
d
i
n
a
l
l
c
a
s
e
s
.
1858 F. Dentali et al
2006 International Society on Thrombosis and Haemostasis
i.v. (7) than oral (2) vitamin K were over-reversed, as indicated
by an INR value < 2.0 at 24 h (P 0.08).
In some countries there is no readily available form of oral
vitamin K. In these countries the i.v. form of vitamin K can be
mixed with orange juice, to mask its unpleasant avor, and
administered by mouth. We have used this strategy successfully
in a series of studies [15,22,29]. In other areas, the smallest dose
of vitamin Kavailable is 5 mg; this dose may over-reverse some
patients, suggesting that half a tablet (2.5 mg) may be a more
appropriate dose. Physicians may consider keeping a supply of
vitamin Kin their ofces as vitamin Kmay not be immediately
available through pharmacies outside hospitals. In some cases,
patients with particularly difcult to control INR values may
benet from keeping a small supply of vitamin K at home to
facilitate its administration when they are discovered to have a
prolonged INR value.
No studies have directly compared the efcacy of differing
doses of oral vitamin K. A recent cumulative analysis of the
available literature does suggest, however, that the optimal
dose of oral vitamin K is 11.25 mg for patients with INR
values between 4.510.0, and 2.5 mg for patients with INR
values of more than 10.0 [52].
Dierent approaches with dierent oral anticoagu-
lants There is compelling evidence suggesting that low-dose
oral vitamin K is an effective treatment for warfarin-induced
coagulopathy. However, other oral anticoagulants, including
acenocumarol or phenprocumon, are widely used outside
North America for the prevention of thrombosis.
Acenocumarol has a much shorter half-life than warfarin.
Our group compared the effect of withholding acenocumarol
and administering 1 mg oral vitamin K by simply withholding
acenocumarol in asymptomatic patients presenting with INR
values between 4.5 and 10.0 [28]. We found that vitamin K
over-reversed many patients, suggesting that simple withdrawal
is the preferred treatment for acenocumarol-induced
coagulopathy. These results are consistent with those
observed by Fondevila et al. [26]. To our knowledge there is
only one contemporary study of the effectiveness of vitamin K
for the treatment of excessive anticoagulation because of
phenprocoumon [18]. In this study, lowdoses of oral vitamin K
were effective only in some patients presenting with INR > 6,
suggesting that treatment should be intensied. Furthermore,
given the very long half-life of phenprocoumon, INR levels
should be carefully monitored to verify if a new administration
of vitamin Kis necessary. However, no rmconclusions can be
drawn from this study, thus additional studies on the role of
oral vitamin K in the management of patients presenting with
phenprocoumon-associated coagulopathy are required.
Patients with mechanical heart valves Management of the
non-bleeding patient with mechanical heart valves (MHV) is
problematic. Patients with MHV(particularly those with mitral
valves or older valves in the aortic position) are at high risk of
systemic embolism, and it may be prudent to reserve oral
vitamin K for those patients with INRs of more than 6.0. Our
group has recently published a RCT in which we compared the
effect of withholding warfarin and administering 1 mg oral
vitamin K with simply withholding warfarin in asymptomatic
patients with MHV presenting with INR values between 6.0
and 12.0 [32]. Compared with placebo, 1 mg of oral vitamin K
more commonly returned prolonged INR values to near-
therapeutic range within 1 day (P < 0.001). Furthermore,
there was no signicant difference between the two groups in
the proportion of patients with INRvalues < 1.8, and none of
the patients in the study experienced a thrombotic or bleeding
event during follow-up. However, because of the small sample
and to the short-term follow up of the study, inferences on
thromboembolic and bleeding complications associated with
the administration of small doses of vitamin K are of limited
value.
Section 2: management of the bleeding patient
The management of patients who bleed while receiving
coumarins must be individualized and depends on the severity
and location of the hemorrhage and the INR when bleeding
occurs. For patients who have relatively minor bleeding from
an accessible site, such as epistaxis or wound bleeding, local
compression with or without a reduction or discontinuation of
coumarins may sufce. Patients with severe hemorrhage or
hemorrhage into a critical organ require more aggressive
management, including correction of the bleeding lesion,
discontinuation of their anticoagulant, administration of
vitamin K and either FFP or PCCs with the goal of rapidly
normalizing the INR.
Vitamin K All patients with major bleeding as a result of
coumarin therapy should receive i.v. vitamin K and
coagulation factor replacement. Intravenously administered
vitamin Kworks more rapidly than either oral or s.c. vitamin K
[19,21,30]. Reduction of the INR begins within 2 h [30], and a
correction to within the normal range is generally achieved
within 24 h if hepatic function is normal and if a sufciently
large dose is given; low-dose vitamin K (0.51 mg) without
coagulation factor replacement is inappropriate if the goal of
therapy is normalization of the INR within 12. Thus, for
example, Shetty and colleagues [11] compared doses of 0.5 mg
and 1 mg administered i.v. and found that the INR did not
reliably normalize by 24 h with either dose.
Coagulation factors In North America, plasma remains the
most widely used coagulation factor replacement product for
urgent reversal of coumarin anticoagulation [4]. The usual dose
of plasma is 15 mL kg
)1
, that is, about 34 units of plasma in
the average-sized adult [53,54]. A lower dose (58 mL kg
)1
)
may be appropriate when urgent reversal of a therapeutic
(rather than supratherapeutic) INR is required [55]. However,
FFP may be a potential carrier of infective agents and its use is
associated with an increased risk of volume overload.
Furthermore, FFP usually takes a prolonged period of time
to thaw and administer.
Treatment of coumarin-associated coagulopathy 1859
2006 International Society on Thrombosis and Haemostasis
For patients with life-threatening hemorrhage the use of
PCCs may be preferable to plasma, if readily available. In a
study conducted on patients who were bleeding because of
warfarin overdosage, Makris et al. [34] demonstrated that
clotting factor concentrates, given in a dose of 2550 U kg
)1
(based on factor [F] IXunits), corrected an elevated INRmore
effectively than did FFP. A more recent study [37] examined
the efcacy of PCCs given as a single dose of 30 U kg
)1
(i.v.
injection over 1015 min) for 10 patients who required urgent
reversal of warfarin overdose because of bleeding and greatly
elevated INR values (median INR, > 20; range, 8.9 > 20).
Patients also received 5 mg i.v. vitamin K. All INR values
measured 30 min postinfusion were 1.3 or less (median, 1.1),
and the median INR remained at 1.1 at 24 h. Yasakaet al. [40]
compared the use of either PCCs and vitamin Kwith the use of
vitamin K or PCCs alone in 17 patients with major hemorrha-
gic complication during warfarin treatment. When PCCs were
administered without vitamin K there was a rapid normaliza-
tion of the INR with a rebound increase 1224 h later; this
rebound increase in the INRis routinely seen when coagulation
factor replacement is not accompanied by vitamin K, and is
because of the fact that the half-life of warfarin far exceeds the
half-life of the administered coagulation factor complexes.
Recently, Yasaka et al. [43] published an analysis of the efcacy
of different doses of PCCs for the treatment of elevated INR
values in patients with major hemorrhagic complications of
anticoagulant treatment or who required invasive procedures.
They found that 500 IU of the PCCs were sufcient for rapid
correction of INR values below 5.0 but that they were
inadequate in patients with INR values of 5.0 or more.
Cartmill et al. [36] performed a prospective study in which the
utility of PCCs was compared with FFP in patients requiring
neurosurgical intervention as a result of warfarin-associated
hemorrhage. Patients receiving PCCs had a more rapid and
more complete reversal of their over-anticoagulation, although
it was unclear whether patients who received PCCs had an
improved clinical outcome.
Three major issues have limited the use of PCCs in
patients presenting with life-threatening hemorrhage. The
rst is the fear of thrombotic complications, which have been
reported to occur after its administration, particularly in
patients with severe liver disease [56]. The second is the
limited availability of these products, and the third is the lack
of knowledge on the part of treating physicians. Further-
more, in patients receiving PCCs, the risk of transmission of
infective agents is still present, although extremely low. A
new solvent/detergent-treated and nanoltered PCC was used
in a recent study of 20 anticoagulated patients who
experienced a major bleeding complication or who needed
an emergency surgical procedure [42]. In these patients INR
declined to near normal values 10 min after administration of
this PCC and remained low for several hours; however the
study was too small to examine the true safety and efcacy
of this compound. Unfortunately, the paucity of adequate
data does not allow a direct comparison among different
PCCs.
Recent interest has focused on the use of recombinant
FVIIa (rFVIIa) for the treatment of warfarin-associated
coagulopathy. rFVIIa effectively corrects the INR in healthy
human volunteers receiving acenocumarol [57]. In a pros-
pective cohort study of 13 patients who were excessively
anticoagulated with warfarin, rFVIIa rapidly corrected pro-
longed INR values [38]. Sorensen et al. [41] investigated the
effect of rFVIIa in seven anticoagulated patients presenting
with central nervous system (CNS) bleeding emergencies.
Pretreatment INRs ranged from 1.7 to 6.6, and 10 min after
a single dose of rFVIIa (1040 lg kg
)1
) all INRs were under
1.5. Six patients underwent drainage of the CNS hematoma
and all patients survived. rFVIIa appears to be relatively safe.
Indeed in a recent systematic review only 2% of patients
treated with rFVIIa experienced a thrombotic complication
[58]. However, routine use of rFVIIa should be avoided until
better quality evidence supporting its effectiveness becomes
available as most of thromboembolic complications occur
when rFVIIa is used for unlabelled indication such as urgent
reversal of anticoagulation [59]. rFVIIa should always be
given in concert with i.v. vitamin K because it has a half-life
of < 60 min [60]. Sequential administration of rFVIIa will
therefore be required in patients with coumarin-associated
coagulopathy until vitamin K is able to reduce the INR to
the normal range.
Finally, in a small randomized trial Boulis et al. [35]
evaluated the use of FFP supplemented with FIX complex
concentrate (FIXCC) compared to use of FFP alone in the
management of 13 anticoagulated patients with warfarin-
related intracranial hemorrhage. Use of FIXCC signicantly
reduced the time to correct INR, and the rate of INR
correction was signicantly higher in patients using FIXCC.
Furthermore, the volume of FFP required for INR correction
was signicantly higher in patients randomized to FFP alone,
resulting in more frequent complications because of uid
overload, although the effect of FIXCC on mortality was
unclear.
Cryoprecipitate contains very small amounts of the vitamin
K-dependent coagulation factor levels, and as such should not
administered to patients with warfarin-associated coagulopa-
thy, unless a co-incident coagulopathy is present as character-
ized by reduced levels of brinogen.
Some patients will not have a reduction in their INR values
after administration of vitamin K with or without coagulation
factor supplementation. Such patients should be suspected to
harbor either unexpected liver disease, a coagulation factor
inhibitor, or have an alternative coagulopathy. Therefore, a
careful assessment for such conditions is warranted in patients
who do not respond; in many cases a satisfactory response is
only achieved after their underlying condition is corrected
(where possible).
Patients with mechanical heart valves Patients with
MHV who are bleeding should be treated as any other
bleeding patient; of particular note it is likely that the
risk of death from major hemorrhage far exceeds the risk
1860 F. Dentali et al
2006 International Society on Thrombosis and Haemostasis
of death from stroke or systemic embolism when warfarin
is temporarily interrupted at the time of a bleeding event
[33].
Conclusions
As there are currently no published data that support the
hypothesis that a rapid return of a prolonged INR to the
desired range is associated with a reduction in bleeding events,
our recommendations (Table 3) are based on studies that use
the elevated INRas a surrogate marker for the risk of bleeding.
In summary, we believe that there is sufcient evidence to
recommend the routine use of low-dose oral vitamin K in
patients presenting with warfarin-associated coagulopathy, but
not in patients presenting with acenocumarol-associated coag-
ulopathy. Data on phenprocoumon-associated coagulopathy
are insufcient to draw denitive conclusions.
Evidence on treatment of patients who present with an
elevated INR value and who have major bleeding are based
mainly on uncontrolled or controlled but not randomized
series of patients. Treatment includes withholding oral
anticoagulants, administering i.v. vitamin K, and transfusion
of coagulation factor concentrates. The source of the
bleeding, and the cause of the prolongation of the INR
should be sought, and corrected. Our recommendations are
summarized in Table 4.
Warfarin-associated coagulopathy is commonly encoun-
tered and is associated with bleeding. Optimal treatment,
including the use of oral vitamin K in the asymptomatic
patient, and i.v. vitamin K in concert with coagulation
factors in the bleeding patient, should reduce the morbidity
associated with this condition. However, large randomized
studies within which the usefulness of these interventions is
measured by clinical events, including bleeding and throm-
bosis, are required.
Acknowledgements
Crowther is a Career Investigator of the Heart and Stroke
Foundation of Canada.
Disclosure of Conict of Interests
The authors state that they have no conict of interest.
References
1 Oden A, Fahlen M. Oral anticoagulation and risk of death: a medical
record linkage study. BMJ 2002; 325: 10735.
2 Hylek EM, Chang YC, Skates SJ, Hughes RA, Singer DE. Prospective
study of the outcomes of ambulatory patients with excessive warfarin
anticoagulation. Arch Intern Med 2000; 160: 161217.
3 Landefeld CS, Rosenblatt MW, Goldman L. Bleeding in outpatients
treated with warfarin: relation to the prothrombin time and important
remediable lesions. Am J Med 1989; 87: 1539.
4 Libby EN, Garcia DA. A survey of oral vitamin K use by anticoag-
ulation clinics. Arch Intern Med 2002; 162: 18936.
5 Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek H. The
pharmacology and management of the vitamin k antagonists: the
seven ACCP conference on antithrombotic and thrombolitic therapy.
Chest 2004; 126: 20433.
6 Baker RI, Coughlin PB, Gallus AS, Harper PL, Salem HH, Wood
EM; Warfarin Reversal Consensus Group. Warfarin reversal: con-
sensus guidelines, on behalf of the Australasian Society of Thrombosis
and Haemostasis. Med J Aust 2004; 181: 4927.
7 Warkentin T, Greinacher A. Heparin-induced thrombocytopenia:
recognition, treatment, and prevention: the seven ACCP conference
on antithrombotic and thrombolitic therapy. Chest 2004; 126: 31137.
8 Warkentin TE. Current agents for the treatment of patients with
heparin-induced thrombocytopenia. Curr Opin Pulm Med 2002;
8: 40512.
Table 3 Suggested treatment strategies for various International Nor-
malized Ratio (INR) values in asymptomatic patients receiving warfarin
administered to achieve a target INR of 2.03.0
INR 4.510.0* 1. Withhold warfarin
2. Administer 1 mg oral vitamin K
3. Reintroduce warfarin at a lower dose
on the following day
4. Recheck INR in 672 h
5. Identify, and where possible, remedy the
cause of the elevated INR
OR
1. Withhold warfarin
2. Recheck INR in 2448 h
INR > 10 1. Withhold warfarin
2. Administer 2.55.0 mg of oral vitamin K
3. Recheck INR in 24 h
OR
1. Withhold warfarin
2. Administer 0.51.0 mg of i.v. vitamin K
3. Recheck INR in 24 h
*INR 6.010.0 may be a more appropriate range for patients with
mechanical heart valves.
Table 4 Suggested treatment strategies for bleeding patients
Major but non-life-threatening
bleeding with any
increase in INR
1. Withhold oral anticoagulant
treatment
2. Administer i.v. vitamin K
(110 mg), with higher doses in
patients with more prolonged
INR values
3. Consider administration of
coagulation factors using com-
plex concentrates or plasma
4. Treat remediable causes of
hemorrhage
5. Provide medical support, inclu-
ding transfusion of red blood
cells or platelets, as required
Life-threatening bleeding
with any increase in INR
1. Withhold oral anticoagulant
treatment
2. Replace coagulation factors
using complex concentrates or
plasma
3. Administer i.v. vitamin K
(510 mg)
4. Treat remediable causes of
hemorrhage
5. Provide medical support, inclu-
ding transfusion of red blood
cells or platelets, as required
Treatment of coumarin-associated coagulopathy 1861
2006 International Society on Thrombosis and Haemostasis
9 Andersen P, Godal HC. Predictable reduction in anticoagulant activity
of warfarin by small amounts of vitamin K. Acta Med Scand 1975; 198:
26970.
10 Taberner DA, Thomson JM, Poller L. Comparison of prothrombin
complex concentrate and vitamin K1 in oralanticoagulant reversal.
BMJ 1976; 2: 835.
11 Shetty HG, Backhouse G, Bentley DP, Routledge PA. Eective
reversal of warfarin-induced excessive anticoagulation with low dose
vitamin K1. Thromb Haemost 1992; 67: 1315.
12 Pengo V, Banzato A, Garelli E, Zasso A, Biasiolo A. Reversal of
excessive eect of regular anticoagulation: low oral dose of phytona-
dione (vitamin K1) compared with warfarin discontinuation. Blood
Coagul Fibrinolysis 1993; 4: 73941.
13 Weibert RT, Le DT, Kayser SR, Rapaport SI. Correction of excessive
anticoagulation with low-dose oral vitamin K1. Ann Intern Med 1997;
126: 95962.
14 Fetrow CW, Overlock T, Le L. Antagonism of warfarin-induced
hypoprothrombinemia with use of low-dose subcutaneous vitamin K1.
J Clin Pharmacol 1997; 37: 7517.
15 Crowther MA, Donovan D, Harrison L, McGinnis J, Ginsberg J.
Low-dose oral vitamin K reliably reverses over-anticoagulation due to
warfarin. Thromb Haemost 1998; 79: 11168.
16 Duong TM, Plowman BK, Morreale AP, Janetzky K. Retrospective
and prospective analyses of the treatment of overanticoagulated pa-
tients. Pharmacotherapy 1998; 18: 126470.
17 Wentzien TH, OReilly RA, Kearns PJ. Prospective evaluation of
anticoagulant reversal with oral vitamin K1 while continuing warfarin
therapy unchanged. Chest 1998; 114: 154650.
18 Penning-van Beest FJA, Rosendaal FR, Grobbee DE, van Meegen E,
Stricker BHC. Course of the international Normalized Ratio in
response to oral vitamin K1 in patients overanticoagulated with
phenprocoumon. Br J Haematol 1999; 104: 2415.
19 Nee R, Doppenschmidt D, Donovan DJ, Andrews TC. Intravenous
vs. subcutaneous vitamin K1 in reversing excessive oral anticoagula-
tion. Am J Cardiol 1999; 83: 2868.
20 Byrd DC, Stephens MA, Hamann GL, Dorko C. Subcutaneous
phytonadione for reversal of warfarin-induced elevation of the Inter-
national Normalized Ratio. AmJ Health Syst Pharm1999; 56: 23125.
21 Raj G, Kumar R, McKinney WP. Time course of reversal of anti-
coagulant eect of warfarin by intravenous and subcutaneous phyto-
nadione. Arch Intern Med 1999; 159: 27214.
22 Crowther MA, Julian J, Douketis JD, Kovacs M, Biagoni L, Schnurr
T, McGinnis J, Gent M, Hirsh J, Ginsberg J. Treatment of warfarin-
associated coagulopathy with oral vitamin K: a randomized clinical
trial. Lancet 2000; 356: 15513.
23 Hung A, Singh S, Tait RC. A prospective randomized study to
determine the optimal dose of intravenous vitamin K in reversal of
over-warfarinization. Br J Haematol 2000; 109: 5379.
24 Patel RJ, Witt DM, Saseen JJ, Tillman DJ, Wilkinson DS. Random-
ized, placebo-controlled trial of oral phytonadione for excessive anti-
coagulation. Pharmacotherapy 2000; 20: 115966.
25 Watson HG, Baglin T, Laidlaw SL, Makris M, Preston FE. A com-
parison of the ecacy and rate of response to oral and intravenous
Vitamin K in reversal of over-anticoagulation with warfarin. Br
J Haematol 2001; 115: 1459.
26 Fondevila CG, Grosso SH, Santarelli MT, Pinto MD. Reversal of
excessive oral anticoagulation with a low oral dose of vitamin K1
compared with acenocoumarine discontinuation. A prospective,
randomized, open study. Blood Coagul Fibrinol 2001; 12: 916.
27 Pendry K, Bhavnani M, Shwe K. The use of oral vitamin K for
reversal of over-warfarinization. Br J Haematol 2001; 113: 83940.
28 Ageno W, Crowther M, Steidl L, Ultori C, Mera V, Dentali F,
Squizzato A, Marchesi C, Venco A. Low dose oral vitamin K to
reverse acenocoumarol-induced coagulopathy: a randomized con-
trolled trial. Thromb Haemost 2002; 88: 4851.
29 Crowther MA, Douketis JD, Schnurr T, Steidl L, Mera V, Ultori C,
Venco A, Ageno W. Oral vitamin k lowers the international normal-
ized ratio more rapidly than subcutaneous vitamin k in the treatment
of warfarin-associated coagulopathy. A randomized, controlled trial.
Ann Intern Med 2002; 137: 2514.
30 Lubetsky A, Yonath H, Olchovsky D, Loebstein R, Halkin H, Ezra D.
Comparison of oral vs. intravenous phytonadione (vitamin K1) in
patients with excessive anticoagulation: a prospective randomized
controlled study. Arch Intern Med 2003; 163: 246973.
31 Poli D, Antonucci E, Lombardi A, Gensini GF, Abbate R, Prisco D.
Safety and eectiveness of low dose oral vitamin K1 administration in
asymptomatic out-patients on warfarin or acenocoumarol with
excessive anticoagulation. Haematologica 2003; 88: 2378.
32 Ageno W, Garcia D, Silingardi M, Galli M, Crowther M. A rand-
omized trial comparing 1 mg of oral vitamin K with no treatment in
the management of warfarin-associated coagulopathy in patients with
mechanical heart valves. J Am Coll Cardiol 2005; 16: 7323.
33 White RH, Mckittrick T, Takakuwa J, Callahan C, McDonnel M,
Fihn S. Management and prognosis of life threatening bleeding during
warfarin therapy. Arch Intern Med 1996; 156: 11971201.
34 Makris M, Greaves M, Phillips WS, Kitchen S, Rosendaal FR, Preston
EF. Emergency oral anticoagulant reversal: the relative ecacy of
infusions of fresh frozen plasma and clotting factor concentrate on
correction of the coagulopathy. Thromb Haemost 1997; 77: 47780.
35 Boulis NM, Bobek MP, Schmaier A, Ho JT. Use of factor IX
complex in warfarin-related intracranial hemorrhage. Neurosurgery
1999; 45: 11138.
36 Cartmill M, Dolan G, Byrne JL, Byrne PO. Prothrombin complex
concentrate for oral anticoagulant reversal in neurosurgical emergen-
cies. Br J Neurosurg 2000; 14: 45861.
37 Evans G, Luddington R, Baglin T. Beriplex P/N reverses severe war-
farin-induced overanticoagulation immediately and completely in
patients presenting with major bleeding. Br J Haematol 2001; 115: 998
1001.
38 Deveras RA, Kessler CM. Reversal of warfarin-induced excessive
anticoagulation with recombinant human factor VIIa concentrate.
Ann Intern Med 2002; 137: 8848.
39 Preston FE, LaidlawST, Sampson B, Kitchen S. Rapid reversal of oral
anticoagulation with warfarin by a prothrombin complex concentrate
(Beriplex): ecacy and safety in 42 patients. Br J Haematol 2002; 116:
61924.
40 Yasaka M, Sakata T, Minematsu K, Naritomi H. Correction of INR
by prothrombin complex concentrate and vitamin K in patients with
warfarin related hemorrhagic complication. Thromb Res 2002; 108:
2530.
41 Sorensen B, Johansen P, Nielsen GL, Sorensen JC, Ingerslev J.
Reversal of the International Normalized Ratio with recombinant
activated factor VII in central nervous systembleeding during warfarin
thromboprophylaxis: clinical and biochemical aspects. Blood Coagul
Fibrinol 2003; 14: 46972.
42 Lubetsky A, Homan R, Zimlichman R, Eldor A, Zvi J, Kostenko V,
Brenner B. Ecacy and safety of a prothrombin complex concentrate
(Octaplex) for rapid reversal of oral anticoagulation. Thromb Res 2004;
113: 3718.
43 Yasaka M, Sakata T, Naritomi H, Minematsu K, Optimal dose of
prothrombin complex concentrate for acute reversal of oral anti-
coagulation. Thromb Res 2005; 115: 4559.
44 Goldstein JN, Thomas SH, Frontiero V, Joseph A, Engel C, Snider R,
Smith EE, Greenberg SM, Rosand J. Timing of fresh frozen plasma
administration and rapid correction of coagulopathy in warfarin-
related intracerebral hemorrhage. Stroke 2006; 37: 1515.
45 Gunther KE, Conway G, Leibach L, Crowther MA. Low-dose oral
vitamin K is safe and eective for outpatient management of patients
with an INR > 10. Thromb Res 2004; 113: 2059.
46 Glover JJ, Morrill GB. Conservative treatment of overanticoagulated
patients. Chest 1995; 108: 98790.
47 Lousberg TR, Witt DM, Beall DG, Carter BL, Malone DC. Evalua-
tion of excessive anticoagulation in a group model health maintenance
organization. Arch Intern Med 1998; 158: 52834.
2006 International Society on Thrombosis and Haemostasis
1862 F. Dentali et al
48 Wilson SE, Douketis JD, Crowther MA. Treatment of warfarin-
associated coagulopathy: a physician survey. Chest 2001; 120: 19726.
49 Riegert-Johnson DL, Volcheck GW. The incidence of anaphylaxis
following intravenous phytonadione (vitamin K1): a 5-year retro-
spective review. Ann Allergy Asthma Immunol 2002; 89: 4006.
50 Harrell CC, Kline SS. Oral vitamin K1: an option to reduce warfarins
activity. Ann Pharmacother 1995; 29: 122832.
51 White RH, Minton SM, Andya D, Hutchinson R. Temporary reversal
of anticoagulation using oral vitamin K. J Thromb Thrombolysis 2000;
10: 149.
52 Wilson SE, Watson HG, Crowther MA. Low-dose oral vitamin K for
management of asymptomatic patients with elevated INRs: a reviewof
the literature. CMAJ 2004; 170: 8214.
53 Baglin T. Management of warfarin (coumarin) overdose. Blood Rev
1998; 12: 918.
54 Contreras M, Ala FA, Greaves M, Jones J, Levin M, Machin SJ,
Morgan C, Murphy W, Napier JA, Thomson AR. Guidelines for the
use of fresh frozen plasma. British Committee for Standards in Hae-
matology, Working Party of the Blood Transfusion Task Force.
[Comment]. Transfus Med 1992; 2: 5763.
55 Report of the Expert Working Group. Guidelines for red blood cell
and plasma transfusion for adults and children. CMAJ 1997; 156:
S1S24.
56 Hellstern P. Production and composition of prothrombin complex
concentrates: correlation between composition and therapeutic e-
ciency. Thromb Res 1999; 95: S712.
57 Erhardtsen E, Nony P, Dechavanne M, Ffrench P, Boissel JP, Hedner
U. The eect of recombinant factor VIIa (NovoSeven) in healthy
volunteers receiving acenocoumarol to an International Normalized
Ratio above 2.0. Blood Coagul Fibrinolysis 1998; 9: 7418.
58 Levi M, Peters M, Buller HR. Ecacy and safety of recombinant
factor VIIa for treatment of severe bleeding: a systematic review. Crit
Care Med 2005; 33: 88390.
59 OConnell KA, Wood JJ, Wise RP, Lozier JN, Braun MM.
Thromboembolic adverse events after use of recombinant human
coagulation factor VIIa. JAMA 2006; 295: 2938.
60 Mathijssen NC, Masereeuw R, Verbeek K, Lavergne JM, Costa JM,
van Heerde WL, Novakova IR. Prophylactic eect of recombinant
factor VIIa in factor VII decient patients. Br J Haematol 2004; 125:
4949.
2006 International Society on Thrombosis and Haemostasis
Treatment of coumarin-associated coagulopathy 1863