Coagulation factor levels in neurosurgical patients with mild prolongation of prothrombin time: effect on plasma transfusion therapy.

Abstract

Neurosurgical patients often have mildly prolonged prothrombin time (PT) or international normalized ratio (INR). In the absence of liver disease this mild prolongation appears to be due to the use of very sensitive PT reagents. Therefore, the authors performed relevant coagulation factor assays to assess coagulopathy in such patients. They also compared plasma transfusion practices in their hospital before and after the study.
The authors tested 30 plasma specimens from 25 patients with an INR of 1.3-1.7 for coagulation factors II, VII, and VIII. They also evaluated plasma orders during the 5-month study period and compared them with similar poststudy periods following changes in plasma transfusion guidelines based on the study results.
At the time of plasma orders the median INR was 1.35 (range 1.3-1.7, normal reference range 0.9-1.2) with a corresponding median PT of 13.6 seconds (range 12.8-17.6 seconds). All partial thromboplastin times were normal (median 29.0 seconds, range 19.3-33.7 seconds). The median factor VII level was 57% (range 25%-124%), whereas the hemostatic levels recommended for major surgery are 15%-25%. Factors II and VIII levels were also within the hemostatic range (median 72% and 118%, respectively). Based on these scientific data, plasma transfusion guidelines were modified and resulted in a 75%-85% reduction in plasma orders for mildly prolonged INR over the next 2 years.
Neurosurgical patients with a mild prolongation of INR (up to 1.7) have hemostatically normal levels of important coagulation factors, and the authors recommend that plasma not be transfused to simply correct this abnormal laboratory value.

Full text

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J Neurosurg / Volume 114 / January 2011
J Neurosurg 114:3–7, 2011
3
3
H
thrombin, 3) the fibrinolytic system that controls the size
of thrombus and maintains vascular patency, and 4) the
cellular phase that includes platelets and endothelium. To
date, no single global test exists to assess these 4 compo-
nents of hemostasis. The in vitro coagulation tests, the PT
and PTT, were developed to identify the cause of bleed-
ing in a symptomatic bleeding patient; they have never
been shown to assess the risk of bleeding in a nonbleed-
ing patient.16,20,35
emostasis is a complex interaction among 1) the
fluid phase of procoagulants that generate throm-
bin, 2) the natural anticoagulants that regulate
Because different sensitivities of tissue thromboplas-
tin reagents account for the variability of PT, the INR
was introduced to monitor warfarin therapy. The INR
is a calculated value derived by the following formula:
(patient PT/mean normal PT)ISI, where ISI is a value as-
signed to the PT reagent when compared with a WHO
reference standard with an ISI of 1.0.31,43,44 The INR was
standardized on plasmas from patients on chronic war-
farin therapy that affects only VKD factors II, VII, IX,
and X. Use of the INR is therefore inappropriate in other
medical conditions in which clotting factors other than
VKD factors are affected.10 However, the INR is often
(mis)used in clinical practice to assess hemostasis in pa-
tients not receiving warfarin therapy; thus, patients with
mildly elevated INRs are reflexively transfused with FFP,
usually perioperatively.
In the past, less-sensitive thromboplastin reagents
(ISI > 2.0) caused a prolonged PT only when factor VII
Coagulation factor levels in neurosurgical patients with
mild prolongation of prothrombin time: effect on plasma
transfusion therapy
Clinical article
Karén Matevosyan, M.D.,1 Christopher MaDDen, M.D.,2 saMuel l. Barnett, M.D.,2
Joseph e. Beshay, M.D.,2 Cynthia rutherforD, M.D.,3 anD ravinDra saroDe, M.D.1
Departments of 1Pathology, 2Neurosurgery, and 3Internal Medicine, The University of Texas Southwestern
Medical Center, Dallas, Texas
Object. Neurosurgical patients often have mildly prolonged prothrombin time (PT) or international normalized
ratio (INR). In the absence of liver disease this mild prolongation appears to be due to the use of very sensitive PT
reagents. Therefore, the authors performed relevant coagulation factor assays to assess coagulopathy in such patients.
They also compared plasma transfusion practices in their hospital before and after the study.
Methods. The authors tested 30 plasma specimens from 25 patients with an INR of 1.3–1.7 for coagulation fac-
tors II, VII, and VIII. They also evaluated plasma orders during the 5-month study period and compared them with
similar poststudy periods following changes in plasma transfusion guidelines based on the study results.
Results. At the time of plasma orders the median INR was 1.35 (range 1.3–1.7, normal reference range 0.9–1.2)
with a corresponding median PT of 13.6 seconds (range 12.8–17.6 seconds). All partial thromboplastin times were
normal (median 29.0 seconds, range 19.3–33.7 seconds). The median factor VII level was 57% (range 25%–124%),
whereas the hemostatic levels recommended for major surgery are 15%–25%. Factors II and VIII levels were also
within the hemostatic range (median 72% and 118%, respectively). Based on these scientific data, plasma transfusion
guidelines were modified and resulted in a 75%–85% reduction in plasma orders for mildly prolonged INR over the
next 2 years.
Conclusions. Neurosurgical patients with a mild prolongation of INR (up to 1.7) have hemostatically normal
levels of important coagulation factors, and the authors recommend that plasma not be transfused to simply correct
this abnormal laboratory value. (DOI: 10.3171/2010.7.JNS091699)
Key WorDs      •      prothrombin time      •      international normalized ratio      •
coagulation factor      •      plasma      •      transfusion
Abbreviations used in this paper: FFP = fresh-frozen plasma; ICP
= intracranial pressure; INR = international normalized ratio; ISI =
international sensitivity index; PT = prothrombin time; PTT = partial
thromboplastin time; VKD = vitamin K–dependent.
See the corresponding editorial in this issue, pp 1–2.

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K. Matevosyan et al.
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J Neurosurg / Volume 114 / January 2011
was < 30%. With the older reagents, clinicians were ac-
customed to a PT value 1.5 times the normal value as in-
dicative of a significant coagulopathy such as that due to
disseminated intravascular coagulation, liver disease, or
therapeutic warfarin. Today, very sensitive thromboplas-
tin reagents (ISI approximately 0.9–1.2) are used for PT;
therefore, PT is prolonged even when factor VII values
are 40%–45%, well above the recommended hemostatic
level for surgical procedures, that is, 15%–25%.32 An INR
calculated with an ISI of 1.0 for a PT of 16.5 seconds is
only 1.5 compared with an INR of 2.1 when the reagent
ISI is 2.0. This PT value of 16.5 seconds (1.5 times nor-
mal) is believed by many clinicians to indicate coagul-
opathy. The result has most probably been an increase in
the number of plasma transfusions since the late 1990s
and can be primarily attributed to laboratorians’ failure
to educate clinicians as regards significant changes in PT
reagents.
The majority of transfusion-related deaths occur af-
ter the transfusion of a single unit of plasma. Yet each
year approximately 3 million plasma units are transfused
in the US despite the questionable effectiveness of this
therapy.7,13,14,25,26,42 Among the numerous potential adverse
complications of a plasma transfusion are transfusion-
associated circulatory overload, allergic reactions, and
transfusion-related acute lung injury, the number 1 cause
of transfusion-related death in the US.22,42
A mild elevation of PT is observed in many neuro-
surgical patients.3,6 Since there is a paucity of data on co-
agulation factor levels in patients with mild elevations of
PT or INR, we evaluated relevant clotting factors (II, VII,
and VIII) in neurosurgical patients. We also compared
the plasma transfusion practices in our hospital before
and after the study.
Methods
Patient Population
Thirty-one neurosurgical patients (trauma or elective)
with mildly elevated INRs (range 1.3–1.7, normal INR
0.9–1.2) were included in the study, which was conducted
at the Parkland Memorial Hospital in Dallas, Texas. The
local institutional review board approved the study.
Sample Collection
Within 8 hours of collection time, the coagulation
(PT and PTT) blood specimen (in 3.2% sodium citrate)
that triggered the request for plasma transfusions was
retrieved from the laboratory. Plasma was separated and
immediately frozen at −70°C pending further testing.
Factor Assays
Thirty plasma specimens from 25 patients were test-
ed for coagulation factors II, VII, and VIII on an auto-
mated coagulation analyzer (BCS, Dade Behring). Fac-
tor VII was selected because it affects PT (INR) and has
the shortest half-life (4–6 hours) of all VKD factors and
acts as an initiator of the coagulation cascade via the tis-
sue factor pathway. Factor II was selected because it is
the substrate for thrombin generation and has the longest
half-life (approximately 60 hours) of all VKD factors.33
Factor VIII was selected because it is an acute phase
reactant and elevated factor VIII level is a well-known
risk factor for thrombosis.39 Significantly increased factor
VIII levels are reflected in a shortened PTT. None of the
patients had evidence of liver disease.
Plasma Therapy
From the Transfusion Service’s computer information
system, we retrieved information on the number of plas-
ma units transfused for neurosurgery during the 5-month
study period; we also captured the PT, INR, and PTT val-
ues 24 hours after plasma transfusion to evaluate its ef-
fect. We instituted new plasma administration guidelines
based on study results and then compared plasma use in
neurosurgical patients with an INR of 1.3–1.6 during the
study period with plasma use during a similar 5-month
poststudy period. Plasma use was again evaluated at 1-
and 2-year intervals poststudy.
Results
Thirty-six samples were collected from 31 patients;
however, 6 samples from 6 patients were excluded from
the study because 2 patients were on warfarin and the
remaining 4 did not have neurosurgical diagnoses. Thus,
30 samples from 25 patients (5 patients had 2 separate
samples each during the hospital stay) were included in
the analysis. Table 1 shows patient demographics, and Ta-
ble 2 lists the PT, INR, and PTT results. The median INR
was 1.35 (range 1.3–1.7) with a corresponding median PT
of 13.6 seconds (range 12.8–17.6 seconds). All PTTs were
normal (median 29.0 seconds, range 19.3–33.7 seconds);
2 samples had shortened PTTs (19.3 and 20.9 seconds).
Factors II, VII, and VIII levels are also featured in
Table 2. All patients had factor VII ≥ 25%. Minimum val-
ues recommended for major surgery are 15%–25%.32 Fac-
tor II levels were also within the hemostatic range. Factor
VIII levels were elevated in 11 samples (164%–547%),
reflected by a PTT that was either short or at the lower
end of normal.
During the initial 5-month study period, 99 requests
for plasma transfusions for 69 patients with an INR of
1.3–1.7 were received in the Transfusion Service. A mean
of 3 U of plasma (median 2 U, range 1–7 U) were trans-
fused to 46 of 69 patients within the next 24 hours. Dur-
ing the 5 months after the implementation of new plasma
transfusion guidelines, the Transfusion Service received
only 15 requests for plasma for 14 patients with an INR of
1.3–1.7. Note, however, that only 2 of these patients were
transfused with plasma within the next 24 hours (1 patient
was status post–meningioma resection, and the other had
stable traumatic intracranial hemorrhage following a mo-
torcycle collision; neither of these 2 patients had active
bleeding or worsening of intracranial hemorrhage), and
12 did not receive transfusions. The mean and median
number of plasma units transfused was 2. The PT, INR,
and PTT at the time of a plasma request and 24 hours
posttransfusion are featured in Table 3. The INR values
did not significantly change over 24 hours in both groups

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J Neurosurg / Volume 114 / January 2011
Coagulation factors in patients with mild prolongation of INR
5
of patients (that is, those who were transfused with plas-
ma and those who were not) and did not show significant
statistical variation (p > 0.05).
Among 114 patients (study period and 5-month
follow-up period), 33 patients underwent red blood cell
transfusion (mean 2.9 ± 2 U, range 1–8 U) and 11 under-
went platelet transfusion (mean 1.5 ± 0.8 U, range 1–4 U)
during the 24 hours following plasma requests. In neuro-
surgical patients at our institution, the transfusion trigger
for red blood cells is a hemoglobin level ≤ 10 g/dl; and
for platelet transfusion, < 100 × 109/L. Two patients re-
ceived cryoprecipitate for hypofibrinogenemia; 1 patient
received one 10-pack dose, and one received two 10-pack
doses.
Discussion
Our study showed hemostatically normal levels of
important coagulation factors (II and VII) in patients
with a mild elevation of INR (within 1.5 times the mid-
normal range). These results support the observation that
there is no increase in the risk of bleeding in patients with
PT or INR values within 1.5–1.8 times the midnormal
range.17,23,28,36 In fact, many patients had elevated levels of
factor VIII, conferring a transient hypercoagulable state
despite the slightly prolonged INR. Moreover, there was
no significant change in PT, INR, or PTT after plasma
transfusions. Study results were presented during neuro-
surgery grand rounds. In the first 5 months after this pre-
sentation and the development of new plasma transfusion
guidelines, there was an 85% reduction in plasma transfu-
sion orders to correct mildly prolonged INR. During the
corresponding 5-month periods 1 and 2 years later, the
plasma requests for an INR of 1.3–1.6 remained low at
26% (26 requests over 5 months) and 15% (15 requests
over 5 months), respectively, compared with the study pe-
riod.
A recent retrospective study of ICP monitor place-
ment in severe head injury patients with mild abnormality
of the INR also showed no benefit of plasma therapy.11
In fact, the patients who received plasma therapy to cor-
rect the INR had significant delays (mean 19.2 hours) in
ICP monitor placement as compared with those who did
not get plasma (mean 8.8 hours, p < 0.002). Furthermore,
not all patients with a moderately prolonged INR (> 1.7)
had complete correction after receiving several units of
plasma, and ICP monitors were placed with INRs > 1.3
in these patients. The study did not show an increase in
the bleeding complication rates in patients with an INR
of 1.3–1.6 with or without plasma, and the authors con-
cluded that the data did not support plasma therapy for
an INR ≤ 1.6.11
Guidelines for plasma transfusion have been pub-
lished by the American Association of Blood Banks,40 the
British Committee for Standards in Haematology,1,9,18,29
and the College of American Pathologists,2 as well as for
pediatric patients.34 These consensus guidelines list only
a few clear-cut indications for plasma transfusion, includ-
ing the treatment of thrombotic thrombocytopenic pur-
pura,12,19,41 emergency reversal of vitamin K antagonists
(prothrombin complex concentrate containing all VKD
factors is the first choice), and treatment of bleeding due
to multiple factor deficiencies as seen with trauma, dis-
seminated intravascular coagulation, severe chronic liver
disease, and so forth.
Holland and Brooks21 demonstrated that FFP transfu-
sions in patients with an INR < 1.7 do not reliably reduce
the INR; in fact, they expose patients to unnecessary risk.
Even so, the use of FFP before procedures in patients with
an elevated INR appears to be quite common.46 The use
of plasma during the perioperative period has long been a
controversial subject. Several trials comparing prophylac-
tic plasma transfusion with other strategies were reported
in patients undergoing cardiopulmonary bypass sur-
gery. No studies have shown evidence of a perioperative
plasma transfusion benefit.38 Five trials have compared a
plasma group with a control group (no plasma) in patients
undergoing cardiopulmonary bypass surgery.5 Five addi-
tional trials compared prophylactic perioperative plasma
use with an artificial colloid solution such as Gelofusine,
hetastarch, or albumin.8,24,30,45 None of these trials con-
vincingly demonstrated that the prophylactic administra-
tion of a therapeutic dose of plasma reduced blood loss
and red blood cell transfusion. Similarly, retrospective
studies examining the ability of the PT or INR to predict
hemorrhage at the time of invasive procedures have failed
to show a correlation between the INR and hemorrhagic
outcomes.12,15,27 Perioperative bleeding has been correlat-
ed with surgical inexperience with the procedure.4,12,15,37
TABLE 1: Summary of characteristics in 25 patients in whom
plasma was obtained
CharacteristicValue
sex (M/F)
mean age (yrs)
diagnosis
intracerebral hemorrhage
subdural hematoma
epidural hematoma
closed head injury
intracranial tumor
traumatic vertebral fracture/dislocation
open skull fracture
traumatic pneumoencephalus
arteriovenous malformation
intractable seizures
altered mental status
22:3
43 ± 18
4
4
3
3
3
3
1
1
1
1
1
TABLE 2: Coagulation parameters in 30 plasma samples
ParameterMean ± SD (range)Median Normal Range
PT (sec)
INR
PTT (sec)
factor II (%)
factor VII (%)
factor VIII (%)
13.8 (12.8–17.6)
1.39 (1.3–1.7)
28.6 (19.3–33.7)
73 (40–107)
64 (25–124)
121 (43–547)
13.6
1.35
29.0
72
57
118
9–12.5
0.9–1.2
24.5–34.5
77–128
62–148
50–150

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K. Matevosyan et al.
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J Neurosurg / Volume 114 / January 2011
Conclusions
In summary, our data showed that patients with mild-
ly elevated INR (< 1.7) have hemostatically normal levels
of important coagulation factors. This revelation led to a
> 75% reduction in plasma therapy for such patients at our
institution. Therefore, we recommend that plasma should
not be transfused to neurosurgical patients to simply cor-
rect mild elevations in PT/INR.
Disclosure
The authors report no conflict of interest concerning the mate-
rials or methods used in this study or the findings specified in this
paper.
Author contributions to the study and manuscript preparation
include the following. Conception and design: Sarode, Madden,
Ruth erford. Acquisition of data: Sarode, Matevosyan, Madden,
Barnett. Analysis and interpretation of data: Sarode, Matevosyan,
Beshay. Drafting the article: Sarode, Matevosyan, Beshay. Critically
revising the article: Sarode, Madden, Barnett, Beshay, Rutherford.
Re viewed final version of the manuscript and approved it for
sub mission: all authors. Statistical analysis: Sarode, Matevosyan.
Ad ministrative/technical/material support: Sarode. Study supervi-
sion: Sarode, Matevosyan, Madden.
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TABLE 3: Values of PT, INR, and PTT at 2 different time periods
Study Period
before change in
guidelines
No. of Transfusion Requests
(no. of patients)
99 (69)
Procedure Performed (no. of
patients)
68 transfusions (46)
Time of TestingPT (sec) INRPTT (sec)
at request
in 24 hrs
at request
in 24 hrs
at request
in 24 hrs
at request
in 24 hrs
13.42
12.10
11.90
11.29
14.10
12.8
12.22
11.54
1.30
1.18
1.16
1.10
1.40
1.30
1.18
1.14
28.9
28.0
27.65
27.43
26.60
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27.4
26.99
31 nontransfusions (29)
after change in
guidelines
15 (14) 2 transfusions (2)
13 nontransfusions (12)

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Manuscript submitted November 11, 2009.
Accepted July 21, 2010.
Please include this information when citing this paper: published
online September 3, 2010; DOI: 10.3171/2010.7.JNS091699.
Address correspondence to: Ravindra Sarode, M.D., The Uni ver-
sity of Texas Southwestern Medical Center, 5323 Harry Hines Bou-
levard, CS3.114, Dallas, Texas 75390-9073. email: ravi.sarode@
utsouthwestern.edu.