© 1995 American Heart Association, Inc.
Articles |
Suppression of Plasma-Activated Factor VII Levels by Warfarin Therapy
From the National Cardiovascular Center, Clinical Laboratory (T.S., Y.K., T. Matsuyama) and Research Institute (H.K., T. Miyata), Fujishirodai, Suita; Hyogo Prefectural Awaji Hospital (K.K., T. Matsuo), Sumoto; and the Awaji-Hokutan Public Clinic (K.K.), Ikuha, Japan.
Correspondence to Toshiyuki Miyata, PhD, National Cardiovascular Center Research Institute, Fujishirodai 5, Suita 565, Japan.
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Abstract |
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Abstract To investigate the effect of warfarin treatment on the early phase of tissue factor–induced coagulation, we measured plasma-activated factor VII (factor VIIa) levels by a direct fluorogenic assay in 74 cardiovascular disease patients on long-term oral anticoagulation. We divided the patients into three groups based on the international normalized ratio (INR). In the patients with INR ranges of <1.7 and 1.7 to 2.5, factor VIIa levels were 42% and 61% lower, respectively, than in age- and sex-matched controls. Factor VII coagulant activity (factor VIIc), factor VII antigen (factor VIIag), protein C, and factor X levels were also reduced to a similar extent in both groups. However, in patients with an INR >2.5, the factor VIIa level was not decreased compared with that at an INR of 1.7 to 2.5, although the factor VIIc, factor VIIag, factor X, and protein C levels were all decreased further. Although the precise relation between the reduction of factor VIIa levels and the increase of INR requires appropriately designed long-term clinical trials, our data suggest that an INR range of 1.7 to 2.5 is sufficient for the suppression of factor VIIa. During the long-term follow-up of three patients with congenital antithrombin III or protein C deficiency, the factor VIIa level was more responsive to changes in the warfarin dose than the INR, and there were generally no corresponding changes of the thrombin–antithrombin III complex (TAT) level. However, one patient showed a transient marked increase of factor VIIa during the discontinuation of warfarin that was accompanied by an increase in TAT. Based on these findings, factor VIIa could be useful for monitoring both hypercoagulable and hypocoagulable states.
Key Words: warfarin • activated factor VII • oral anticoagulant • international normalized ratio (INR) • prothrombin time
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Introduction |
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Warfarin is commonly used for the primary or secondary prevention of venous and arterial thromboembolism,1 so establishment of its minimum effective dose is clinically important. Low-dose warfarin is reported to be useful for several clinical indications,2 3 and the pilot study of low-dose warfarin in primary prevention in high-risk men has been reported.4 The international normalized ratio (INR), which is obtained from the prothrombin time (PT) determined by using a highly sensitive thromboplastin, is recommended for monitoring the intensity of anticoagulation.5 An INR range of 2.0 to 2.25 has been reported to be safe and effective in patients with tissue heart valve replacement.6 An INR range of 1.7 to 2.5 would be associated with a lower bleeding risk than more intensive warfarin treatment and would thus require less frequent laboratory monitoring.7 The incidence of coronary artery disease (CAD) and deep vein thrombosis in the Japanese is markedly lower than in Westerners,8 so that the risk of bleeding with anticoagulation may be a more serious problem for the Japanese.
Factor VII is a plasma vitamin K–dependent glycoprotein that
plays an important role in the initiation of tissue factor–induced
coagulation.9 A large prospective study has shown a
relation between factor VII coagulant activity (factor VIIc) and
the incidence of CAD. An increase of 1 SD in the factor VIIc level
(
25% increase) results in a 62% increase in the incidence of CAD
after 5 years.10 An increase of the factor VIIc level is
also related to cardiovascular disease in the Japanese
population.11 12 13 14 Warfarin reduces the plasma level of
factor VIIc as well as other vitamin K–dependent
factors,15 16 17 and a fixed low dose of warfarin (1 mg/d)
significantly reduces factor VIIc levels without affecting
PT.18
In vitro, factor VII is converted to two-chain active factor VIIa by various coagulation proteases, including factor Xa, factor IXa, factor XIIa, thrombin, and factor VIIa. Trace levels of circulating factor VIIa (0.5% to 1% of the total factor VII antigen [factor VIIag] level) have been reported to be present in normal plasma.19 20 21 Factor VIIa is thought to catalyze the initial activation of factor VII in complex with a cell-surface procoagulant protein, tissue factor, under pathological conditions. Thus, plasma factor VIIa activity may be a better marker for the early phase of tissue factor–induced coagulation than factor VIIc or factor VIIag. Morrissey et al20 report a coagulation assay for factor VIIa using transmembrane- and cytoplasmic domain–free soluble tissue factor. They suggest that measuring factor VIIa levels might be useful for monitoring the warfarin dose in patients on oral anticoagulation. We modified this assay and subsequently demonstrated that plasma factor VIIa levels showed a more significant increase than factor VIIc and VIIag levels in patients with cardiovascular disease or diabetes mellitus.21 22
In the present study, we measured plasma factor VIIa levels in patients with cardiovascular disease who were receiving long-term warfarin treatment and compared them with the levels of factor VIIc, factor VIIag, other vitamin K–dependent factors, protein C, and factor X. We also investigated the relation between the plasma levels of factor VIIa and thrombin–antithrombin complexes (TAT), a marker of thrombin generation, in patients with congenital antithrombin III or protein C deficiency who were on warfarin treatment.
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Methods |
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Patient Population
We studied 74 patients on long-term warfarin therapy (44 men: age, 60.3±9.7 years; 30 women: age, 56.5±13.4 years), including 18 patients with cerebral embolism, 40 patients with mitral or aortic valve replacement, and 16 patients with acute carotid occlusion producing transient ischemic attacks or stroke. Two patients with antithrombin III deficiency and one patient with protein C deficiency were referred by the National Cardiovascular Center. Seventy-four healthy control subjects matched for age and sex (36 men: age, 57.4±6.4 years; 38 women: age, 59.6±5.2 years) were selected from participants in routine annual check-ups. The control subjects all showed normal results in routine laboratory tests, had no intercurrent illnesses, and were not receiving any medical treatment.
Collection and Processing of Blood Samples
Blood was collected into siliconized glass vacuum tubes (Nipuro)
containing sodium citrate and was centrifuged at 4500g for 5
minutes at room temperature. Aliquots of platelet-poor plasma were
stored at -70°C until use.
Assay Procedure
The plasma factor VIIa level was measured directly by our
fluorogenic assay method by using recombinant soluble tissue factor
expressed in yeast and purified23 as
described.21 Reaction times were converted to factor VIIa
concentrations in nanograms per milliliter by comparison with a
standard curve produced by serial dilution of purified plasma factor
VIIa, which was kindly provided by Dr Tomohiro Nakagaki of the
Chemo-Sero-Therapeutic Research Institute, Kumamoto, Japan. The plasma
factor VIIa level was also expressed as a percentage of the activity in
the sex- and age-matched control group.
PT was measured with human placental thromboplastin (Thromborel S; Behringwerke) and an automated coagulometer (KC-10; Ammelung GmbH). The International Sensitivity Index of this reagent (lot No. 505507C) was 1.09. The intensity of oral anticoagulation was expressed as the INR. Factor VIIc was measured with a chromogenic assay autoanalyzer (Behring Chromotimer, Behringwerke AG) by using a human placental calcified thromboplastin reagent (Chromoquick, Behringwerke AG) and factor VII–deficient plasma as described.21 Factor VIIag was determined with an enzyme-linked immunosorbent assay (ELISA) kit (Diagnostica Stago). Protein C amidolytic activity was measured using S-2366 (KabiVitrum AB) as the substrate and Agkistrodon contortrix venom (Protac, Pentapharm) as the activator for protein C.24 Factor X was determined by a chromogenic assay by using Testzyme FX (Chromogenix AB). TAT was assayed by using a commercial ELISA kit (Enzygnost TAT, Behringwerke AG). The levels of factor VIIc, factor VIIag, protein C, and factor X were expressed as a percentage of the levels in commercially available standard human plasma (Behringwerke AG). In our laboratory, the interassay (intra-assay) coefficients of variation of the assays of factor VIIa, PT, factor VIIc, factor VIIag, protein C, and factor X are 4.2% (1.3%), 2.5% (0.4%), 2.8% (1.5%), 4.4% (4.2%), 1.5% (1.2%), and 2.3% (1.9%), respectively.
Statistical Analysis
Data are shown as mean±SD. ANOVA and the Mann- Whitney
U test were used for comparison of the mean values in the
various groups, and P<.02 was taken to indicate
significance in the U test. Pearson's correlation
coefficients for the different variables were calculated, and
P<.01 was taken to indicate significance. The paired
t test was used for the comparison of the changes of the
values within the same subjects in Fig 1
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Results |
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Plasma Factor VIIa Levels in Patients on Warfarin
We measured the plasma levels of factors VIIa, VIIc, and VIIag, protein C, and factor X in 74 cardiovascular disease patients maintained on long-term warfarin therapy for cerebral embolism, mitral or aortic valve replacement, and acute carotid occlusion with transient ischemic attacks or stroke. The overall mean INR was 2.11 (range, 1.15 to 4.29) and the mean levels (and range) of each parameter were as follows: factor VIIa, 1.18 ng/mL (0.29 to 4.17 ng/mL); factor VIIc, 48.2% (23.3% to 96.0%); factor VIIag, 62.6% (13% to 152%); protein C, 49.0% (16.9% to 86.7%); and factor X, 42.8% (9.8% to 75.4%). The levels of factors VIIa and VIIc in the age- and sex-matched control subjects were 2.69±0.78 ng/mL and 120±25%, respectively.
We classified the patients into three groups based on the INR range
(group I, <1.7; group II, 1.7 to 2.5; and group III, >2.5). The
plasma levels of factors VIIa, VIIc, and VIIag, protein C, and factor X
in each group are shown in the Table. The factor VIIa
level in group I (INR, <1.7) was significantly lower than that in the
control group (1.56±0.52 versus 2.69±0.78 ng/mL, respectively;
P<.0001). The factor VIIa level was 42% lower than in
control subjects, which was similar to that of factor VIIc. In group II
(INR, 1.7 to 2.5), the factor VIIa level was further decreased along
with decreases in factor VIIc, factor VIIag, protein C, and factor X.
Factor VIIa was 61% lower than in control subjects, again similar to
that of factor VIIc. However, the factor VIIa level in group III (INR,
>2.5) was not significantly different from that in group II, although
the levels of factor VIIc, factor VIIag, protein C, and factor X were
further decreased along with the INR.
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The Table
also shows the specific activity (factor VIIc/factor VIIag
ratio) of plasma factor VII in the three groups. The activity was 78%
to 85% of normal, a finding consistent with the level of 78% in a
previous report.25 These data suggest the presence of
nonfunctional or partially functional molecules of the factor in the
blood of individuals undergoing drug therapy and suggest that intensive
warfarin treatment mainly decreases the protein level but not the
specific activity.
To perform more detailed comparisons, we measured factor VIIa levels
and other parameters two through seven times during 2 months in each
patient on warfarin treatment. Ten patients showed INR changes from
group I (INR, <1.7) to group II (INR, 1.7 to 2.5) or vice versa, and
18 patients showed changes from group II to group III (INR, >2.5) or
vice versa (Fig 1). The factor VIIa levels in INR <1.7 were
significantly higher than those in INR 1.7 to 2.5 (P=.0006;
data not shown). The factor VIIa level in INR 1.7 to 2.5 in each
patient was not significantly different from that in INR >2.5
(P=.1585; Fig 1), although the levels of factor VIIc, factor
VIIag, protein C, and factor X were decreased significantly along with
the INR (P<.0001 for each; data not shown).
Fig 2 shows the relation of INR to factors VIIa,
VIIc, and VIIag, and protein C. INR showed a negative correlation with
the levels of factors VIIc and VIIag and protein C
(r=-.748, -.584, and -.777, respectively). The factor X
level was also negatively correlated with INR (r=-.740,
P<.0001; data not shown). However, the negative correlation
between factor VIIa and INR was very weak (r=-.240,
P=.039; Fig 2A). Two of the 74 patients showed high factor
VIIa levels compared with the INR (above the mean+2 SD of the
factor VIIa/INR ratio in all 74 subjects) (Fig 2A, closed circles).
However, the factor VIIc and VIIag levels of both patients were normal
and did not distinguish these two patients from the others (Fig 2B and 2C).
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indicates patients with a high factor VIIa level compared with the INR
(ie, above the mean+2 SD of the factor VIIa/INR ratio in all 74
subjects).
Patients With Antithrombin III or Protein C Deficiency on
Warfarin
We performed a detailed investigation of the sequential changes in
the levels of factor VIIa and TAT in three patients with a history of
recurrent venous thrombosis (Fig 3A through 3C). Day 1
was defined as the date of blood collection for the study.
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Subject 1 was a 57-year-old woman with congenital heterozygous
antithrombin III deficiency (Fig 3A). She had suffered from severe
recurrent deep vein thrombosis and was being treated with 5 mg warfarin
daily. When she ceased taking it, occlusion of the abdominal aorta
occurred and she was hospitalized. Warfarin treatment was not restarted
in order to perform intravenous digital subtraction angiography. The
factor VIIa and TAT levels increased transiently after digital
subtraction angiography, from 1.74 to 8.46 ng/mL and 5.2 to 17.7 ng/mL,
respectively, indicating thrombin generation along with factor VIIa
formation, while the INR did not change significantly (Fig 3A). The
relation between the injection of contrast medium and the transient
increase of factor VIIa and TAT levels was not clear. Restarting her
warfarin treatment decreased the TAT and factor VIIa levels. However,
the TAT level remained above the normal range, and the factor VIIa
level was not decreased in comparison to that on day 1.
Subject 2 was a 52-year-old man with congenital heterozygous
antithrombin III deficiency (Fig 3B) who suffered from deep vein
thrombosis. He had been treated with 5 mg warfarin daily after
hospitalization. Warfarin was discontinued from day 7 through day 14,
resulting in an increase of factor VIIa to 1.6 ng/mL and a decrease of
the INR to 1.0. Subsequent restarting of warfarin treatment resulted in
a rapid decrease of factor VIIa and a slow increase of the INR,
confirming the previous finding by Morrisey et al20 that
factor VIIa levels decrease faster than the INR increases on warfarin
therapy. During this period, TAT levels were within the normal
range.
Finally, Fig 3C shows a 24-year-old man with congenital heterozygous
abnormal protein C deficiency (type II deficiency) who first developed
venous thrombosis at the age of 19. He had a C-to-A exchange at
nucleotide position 1387, leading to an amino acid substitution of
Arg
Ser at position -1 (T. Miyata et al, unpublished data, 1994).
Warfarin treatment was started on day 8, and the dose was changed as
shown in Fig 3C. The factor VIIa level decreased rapidly and reached
its nadir on day 11. The factor VIIa level more rapidly reflected a
change in dosage of warfarin than the INR, since an increase of the INR
was delayed in a manner similar to that observed in patient 2. Minor
changes of the factor VIIa level were not accompanied by changes of the
TAT level, which stayed within the normal range.
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Discussion |
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An increased factor VIIc level is known to be a risk factor for CAD,9 so the reduction of factor VIIc using warfarin has been tried as primary preventive therapy. An INR of 1.5 achieved by oral anticoagulation has been reported to reduce the factor VIIc level from a pretreatment value of
115% to 70%.4 An
epidemiological study has shown that individuals with a 70% factor
VIIc level have a low risk of CAD.10 More recently,
treatment with a fixed low dose of warfarin (1 mg/d) has been reported
to significantly reduce the factor VIIc level from 136% to
125%.18 At this warfarin dose, PT was prolonged but
stayed within the normal range. The present study assessed the effect of warfarin treatment on the early phase of tissue factor–induced coagulation. We measured PT and plasma factor VIIa levels in 74 cardiovascular disease patients on long-term warfarin treatment. Warfarin therapy is usually monitored by one-stage PT, which provides an estimate of the functional activity of factor VII, factor X, and prothrombin. This assay uses various concentrations of animal or human tissue thromboplastin to activate the extrinsic coagulation cascade and thereby convert prothrombin to thrombin under arbitrary in vitro conditions. We used the INR instead of PT because uncertainty about the sensitivity of commercially available thromboplastin makes the INR preferable for interlaboratory comparison. The possibility of using factor VIIa to monitor patients on warfarin was first suggested by Morrissey et al.20 However, precise comparison of factor VIIa levels with the INR and the levels of factor VIIc and other vitamin K–dependent factors was not performed by Morrissey's group.
The levels of prothrombin fragment 1+2 in patients on warfarin
treatment with an INR range of 1.3 to 1.6 are reported to be suppressed
to 49% of those in untreated control subjects,7 and
another study has indicated4 that an INR of 1.5 produces a
45% reduction of the factor VIIc level. This low factor VIIc level is
associated with a low risk of CAD. In the present study, warfarin
treatment at a similar intensity (INR, <1.7) caused a 42% lower
factor VIIa level than in control subjects. When the factor VIIc level
was expressed as a percentage of the activity in an age- and
sex-matched control group (120.1±24.9%), factor VIIc was 45% lower
than in control subjects (Table). Thus, in this INR range, both the
factor VIIa and factor VIIc levels and subsequent prothrombin
activation are comparably reduced.
When the INR ranges from 1.7 to 2.5, the levels of vitamin K–dependent coagulation factors and prothrombin fragment 1+2 have been reported to be reduced to about 20% to 50% of normal.17 Using this INR range, an 86% reduction in the incidence of embolic stroke was obtained in patients with nonrheumatic atrial fibrillation.3 With the INR range of 1.7 to 2.5 used in our study, factor VIIa levels were 61% lower than in control subjects, and factor VIIc levels were 54% lower than those in our control group, again indicating the similar low level of vitamin K–dependent coagulation factors and prothrombin fragment 1+2.
Unexpectedly, in our patients with an INR >2.5, factor VIIa levels
showed little difference from those in patients with an INR of 1.7 to
2.5 (1.02 and 1.05 ng/mL, respectively), although the levels of factor
VIIc, factor VIIag, protein C, and factor X were further decreased
along with the increased INR (Table). Furthermore, this observation was
confirmed by comparison in individuals whose INR changed from 1.7 to
2.5 to >2.5 (Fig 1). The changes of factor VIIa levels in those
patients were not significant (P=.1585). Although the
precise relation between the reduction of factor VIIa level and the
increase of INR requires appropriately designed long-term clinical
trials, our data suggest that an INR range of 1.7 to 2.5 is sufficient
for the suppression of factor VIIa. This discrepancy between the
changes of factor VIIa and other vitamin K–dependent factors during
intensive warfarin treatment suggests that factor VIIa generation
and/or metabolism occur by different mechanisms from those operating
for factor VIIc, factor VIIag, protein C, and factor X. We have
reported21 that plasma factor VIIa levels do not correlate
with indirect measures of hepatic protein synthesis because the
correlation of factor VIIa levels with cholinesterase and triglyceride
levels was not statistically significant. Thus, the data described here
may support the speculation that plasma factor VIIa is partially
produced outside the liver.
Morrissey et al20 report that factor VIIa and PT levels
were negatively correlated, although a statistical evaluation was not
done. We confirmed their findings and also showed that the negative
correlation between factor VIIa and INR is statistically weak
(r=-.240), while the correlation of INR with the levels of
factor VIIc, factor VIIag, and protein C was strong
(r=-.748, -.584, and -.777, respectively; Fig 2). The
interassay coefficient of variation for the factor VIIa assay was
4.2%, which was not much different from those of the other assays,
indicating that the weak correlation between factor VIIa and INR was
not attributable to the assay variation. The weak correlation between
factor VIIa and INR would be attributable to our finding that factor
VIIa levels did not change much as the INR increased from 1.7 to 2.5 to
>2.5. Therefore, factor VIIa may be an independent marker for
monitoring the effectiveness of warfarin treatment.
We also measured the levels of factor VIIa and TAT as well as the INR
in patients with congenital antithrombin III or protein C deficiency on
warfarin treatment (Fig 3). We confirmed previous findings by Morrissey
et al20 that the factor VIIa level decreased faster
(within 1 week) than the INR increased with a change in warfarin
dosage. Because a full antithrombotic effect is not demonstrable until
7 to 10 days after the start of oral anticoagulation,26 it
is likely that a change of only factor VIIc and factor VIIa activity is
not sufficient to alter the risk of thrombosis. The concentrations of
vitamin K–dependent factors are not equally depressed during long-term
oral anticoagulation, with factor X being the lowest, prothrombin
showing an intermediate value, and factors VII and IX being the
highest.27 Another study has shown that oral
anticoagulants reduce factor VIIc and protein C activity more rapidly
than factor X activity.16 These findings may explain the
rapid changes of factor VIIa with the alteration of the warfarin
dose.
The usefulness of new assays allowing the detection of hemostatic activation has recently been evaluated. These assays include the determination of prothrombin fragment 1+2 and the determination of TAT complexes. Oral anticoagulation at conventional levels is reported to decrease prothrombin fragments 1+2 to far below the normal range17 while TAT remains normal.28 Therefore, TAT seems to be an insensitive assay for detecting the response to oral anticoagulation. In our long-term follow-up of three patients, the TAT levels remained within the normal range, except for one reading in patient 1, and this exceptional result was associated with an increase in the factor VIIa level. Factor VIIa levels are increased by aging and cardiovascular disease.21 These states are known to be associated with hypercoagulability, so an increased factor VIIa level appears to reflect a hypercoagulable state. It seems reasonable to infer from in vitro studies that plasma factor VIIa serves a priming function in the tissue factor–mediated triggering of the clotting cascade.8 29 30 Based on these findings, use of the factor VIIa level could have several advantages for monitoring both hypercoagulable and hypocoagulable states.
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Acknowledgments |
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We thank Dr Tomohiro Nakagaki of the Chemo-Sero-Therapeutic Research Institute, Kumamoto, Japan, for providing human plasma factor VIIa.
Received April 5, 1994; accepted October 12, 1994.
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