© 1999 American Heart Association, Inc.
Thrombosis |
Inhibition of Tissue Factor Pathway During Intermittent Pneumatic Compression
A Possible Mechanism for Antithrombotic Effect
From the Department of Medicine, The Sol Sherry Thrombosis Research Center (V.D.C., L.S., A.K.R.), and the Departments of Surgery (A.J.C., R.H.), and Physiology (J.P.G.), Temple University School of Medicine, Philadelphia, Pa.
Correspondence to A. Koneti Rao, MD, Division of Hematology and Thromboembolic Diseases, Temple University School of Medicine, 3400 N Broad Street, OMS 300, Philadelphia, PA 19140. E-mail koneti{at}astro.ocis.temple.edu
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Abstract |
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Abstract—Intermittent pneumatic compression (IPC) devices are an effective prophylaxis against lower extremity deep vein thrombosis. Their antithrombotic effect has been attributed to a reduction in venous stasis and enhanced fibrinolysis. The initiating mechanism for blood coagulation is the tissue factor (TF) dependent pathway, which is inhibited by tissue factor pathway inhibitor (TFPI). We have investigated the effect of IPC on the TF pathway in 6 normal subjects and 6 patients with postthrombotic venous disease undergoing IPC for 120 minutes; all subjects were studied with each of 5 IPC devices. In normal subjects and patients, plasma factor VIIa (FVIIa) activity (the activated form of factor VII [FVII]) declined from mean values ranging 51 to 65 and 50 to 53 mU/mL before IPC with different devices to 10 to 13 and 20 to 22 mU/mL at 180 minutes, respectively (P<0.001 for all groups). FVII antigen levels were unchanged. Plasma TFPI (P<0.001) rose from mean baseline values ranging 69 to 79 and 57 to 61 ng/mL to 76 to 123 and 71 to 79 ng/mL at 180 minutes in normal subjects and patients, respectively (P<0.001 for all groups). Plasma prothrombin fragment F1.2 levels showed minimal changes. There was an inverse relationship between TFPI and FVIIa in normal subjects (r=-0.31, P=0.001) and patients (r=-0.37, P<0.001). IPC results in an increase in plasma TFPI and decline in FVIIa. Inhibition of TF pathway, the initiating mechanism of blood coagulation, is a possible mechanism for the antithrombotic effect of IPC.
Key Words: intermittent pneumatic compression • tissue factor pathway • factor VIIa • tissue factor pathway inhibitor • factor VII
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Introduction |
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Intermittent pneumatic compression (IPC) is an established nonpharmacological method of prophylaxis against deep vein thrombosis.1 The mechanisms for the antithrombotic effects of IPC are unclear and generally considered to be due to reduction of venous stasis in the lower extremities and stimulation of endogenous fibrinolytic mechanisms.1 2 3 4 However, the effects of IPC on the early events of blood coagulation are unknown. The initiating mechanism of blood coagulation is the tissue factor (TF)–dependent pathway, which is regulated primarily by the tissue factor pathway inhibitor (TFPI), a Kunitz type inhibitor circulating in plasma.5 6 7 This pathway is initiated when factor VIIa (FVIIa, the activated form of FVII) is exposed to its cofactor, tissue factor (TF), leading to formation of TF-FVIIa complex, which proteolytically activates factor X (FX) and factor IX (FIX).5 6 7 TFPI inhibits FXa directly and the TF-FVIIa complex in the presence of FXa.5 6 7 8 Thus TFPI is a key natural anticoagulant that functions at the initial steps of blood coagulation.5 6 7 Although a thromboembolic disease secondary to an inherited TFPI deficiency is yet to be recognized, there is evidence in rabbits suggesting that TFPI protects against thrombosis after exposure of blood to TF9 10 and decreases mortality in Escherichia coli-induced shock in baboons.11 Plasma TFPI levels are elevated after intravenous administration of heparin.12 13 It has been suggested that TFPI contributes to the anticoagulant properties of heparin14 and that heparin-releasable pool of TFPI may be of physiological importance.13 Plasma TFPI levels increase after exercise15 and in several disease states.13
Because of the increasing recognition of TFPI as a major modulator of the TF pathway and the existence of TFPI pools that can be potentially mobilized, we postulated that the antithrombotic effects of IPC may be related to modulation of the TF-mediated pathway of blood coagulation. In this study, we report our findings in 6 normal subjects and 6 patients with a history of venous thrombotic disease subjected to IPC using 5 separate devices.
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Methods |
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Six normal subjects (4 males, 2 females; mean age 46 years, range 25 to 68 years) and 6 patients (4 males, 2 females; mean age 48 years, range, 31 to 66 years) with postthrombotic chronic venous insufficiency were studied during IPC with each of 5 different devices. The patients had a history of proximal deep vein thrombosis and evidence of recanalization and thickened venous walls on venous duplex studies They were matched by sex and age to the normal subjects. Two of the patients were on oral anticoagulants at the time of the studies. These patients were studied to determine whether presence of underlying chronic venous disease impacts on the response to IPC. Blood samples were also obtained from 3 normal subjects who were handled in an identical manner to the study subjects but were not subjected to IPC. All studies were performed after approval by the institutional review board and each participant signed an informed consent.
Devices
Five external compression devices were studied in random
sequence; these included thigh-length sequential compression sleeves
(TSQ, SCD Kendall Health Care Products Company); calf-length
sequential compression sleeves (CSQ, SCD Kendall Healthcare
Products Company); thigh length single chamber garments DVT30 (TSC,
Flowtron Huntleigh Healthcare); calf length single chamber garments
(CSC, Flowtron Huntleigh Health Care); and Plexipulse foot pump (FP,
NuTech). Two of these are applied to the calf region (CSQ, CSC), 2
extend to the thigh region (TSQ, TSC), and 1 (FP) is applied only to
the foot. Each volunteer rested in a supine position for at least 15
minutes before studies with each device. The devices were applied for
120 minutes as per manufacturer’s instructions.
Each volunteer was studied at the same time of day with an interval of at least 7 days between studies. Blood samples were drawn from antecubital vein, without application of a tourniquet, into one-tenth volume of 3.8% sodium citrate. They were obtained at baseline, 60, 120, and 180 minutes after start of IPC. Plasma was harvested by centrifugation at 2500g for 20 minutes within 30 minutes of collection. Plasma was stored as aliquots at -80°C.
Assays
Factor VIIa was measured using recombinant soluble tissue factor
with a commercially available kit (Diagnostica
Stago).16 FVII antigen levels were measured using an
enzyme linked immunoassay (Diagnostica Stago) and expressed
as a percentage of the value in pooled normal plasma. TFPI antigen was
measured using Imubind total TFPI ELISA kit from American
Diagnostica Inc.17 This assay measures both
free TFPI, lipoprotein associated TFPI, and complexes of TFPI with FXa
and TF-FVIIa. Prothrombin fragment F1.2 levels were measured using an
ELISA (Behring Diagnostic Inc). Antithrombin activity was
measured using a chromogenic substrate S-2238 (Pharmacia
Hepar) and bovine thrombin (Armour Pharmaceutical Co).18
The antithrombin activity is expressed as a percent of activity in
pooled normal plasma.
Statistical Analysis
Data are presented as means±standard error of mean.
Data from each plasma protein measurements were analyzed
separately using a logarithmic transformation of the data. A 3-factor
factorial design was used with repeated measures on the third factor,
the sample time. The factors were as follows: treatment groups (normals
and patients), intermittent compression devices (5 different ones), and
sample times (0, 60, 120, and 180 minutes). An ANOVA for repeated
measures with fixed effects was used for each
analysis.19 The Greenhouse-Geisser epsilon was
used to adjust for multi-sample asphericity in the significance tests
of within-subject effects.20 After tests on main effects,
multiple comparisons, vertical (between treatment groups) and
horizontal (between sample times), were carried out using the
Dunn-Bonferroni procedure adjusted for repeated measures maintaining an
experiment-wise alpha level of 0.05.19 A MANOVA was
carried out utilizing a linear combination of the data from the 4
plasma proteins and using the same repeated measures design.
Hotelling’s T2 statistic was calculated for the
treatment group, pressure devices, and sample times
effect.21 Significance levels were measured at 
0.05
throughout. Pearson product-moment correlations between plasma
proteins were computed separately for patient and control groups. The
significance level for each correlation coefficient was based on a
2-tailed test at the P=0.05 level.22
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Results |
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Changes in Plasma Levels of Factor VII, TFPI, Prothrombin Fragment F1.2, and Antithrombin
There were no significant differences between the 2 groups in the baseline values of any of the proteins measured. FVIIa levels declined significantly (P<0.001) during IPC in both normal subjects and patients (Figure 1A
) and with each
device. The levels at 60, 120, and 180 minutes were lower compared with
baseline levels in both groups. There was a significant
(P<0.001) difference in FVIIa levels over time between the
2 groups; the 180 minutes levels were lower in the normal subjects
(P<0.05) (18% to 24% of baseline values) compared with
patients (40% to 43%) (P<0.05). There were no significant
differences between the devices in either group.
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) and calf length (
) sequential
compression sleeves; thigh length (•) and calf length (
) single
chamber garments; and foot pump (
). There is a decline
(P<0.001) in FVIIa during intermittent pneumatic
compression in both normal subjects and patients and with each of the
devices used.
Factor VII antigen levels reflect total circulating FVII in plasma.
Although the ANOVA revealed a significant time effect
(P=0.006), the multiple comparisons indicated no
consistent pattern across time in either group for FVII antigen
(Figure 1B
). In normal individuals a small increase
(P<0.05) was observed at 60 and 120 minutes over basal
levels during IPC using 1 device (TSC) but not others. The FVII antigen
levels were significantly higher in the patients compared with normal
subjects (P=0.002); significant differences were found
between groups during IPC with 2 devices (CSQ, TSQ).
Plasma TFPI levels rose in both normal subjects and patients
(P<0.001) (Figure 2A). TFPI
levels were higher (P<0.05) relative to baseline at 180
minutes in both groups with all devices and at 120 minutes in normal
subjects with all devices, except TSC. The mean levels at 180 minutes
ranged from 126% to 204% of basal in normal subjects and 125% to
133% in patients. TFPI levels during IPC were higher in normal
subjects compared with patients (P<0.001). There were
significant differences (P<0.05) between the groups at 60
minutes for CSC, 120 minutes for TSQ, and 180 minutes for FP and CSQ.
No significant differences were observed between devices in normal
subjects or patients.
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The ANOVA for repeated measures indicated a significant change over
time (P=0.002) in plasma F1.2 levels and differences between
the normal subjects and patients (P<0.001) (Figure 2B). Although there was an increasing trend over time for
several devices in normal subjects, the changes in F1.2 were not
significant. Normal subjects had higher F1.2 levels than patients but
this could not be confirmed by multiple comparisons. No significant
differences were observed between devices.
Results of a multivariate analysis combining data from the 4 plasma protein measurements (FVIIa, FVII antigen, TFPI, and F1.2) reinforced the between groups differences found on the univariate analyses (not shown).
No significant differences were observed either over time or between groups in plasma antithrombin activity (not shown). FVIIa, FVII antigen, and TFPI levels were also measured in sequential samples from 3 normal subjects who were handled in an identical manner to the study subjects but not subjected to IPC devices. No significant changes were observed over 180 minutes
Relationships Between Changes in FVII, TFPI, and F1.2
To understand the nature of the changes occurring in plasma during
IPC we explored the relationships between the plasma levels of the
proteins measured. The relationships were analyzed separately
for the normal subjects and patients using pooled data from all the
devices. No relationship was observed in either group between FVII
antigen and FVIIa levels. There was an inverse relationship in both
groups between plasma TFPI and FVIIa (Figure 3) (normal subjects: r=-0.31,
P=0.001; patients: r=-0.37,
P<0.001). An inverse but weaker relationship was also
observed between TFPI and FVII antigen levels in normal subjects
(r=-0.23; P=0.012) but not patients. There was a
direct relationship between F1.2 and TFPI levels that was observed in
normal subjects (r=0.37; P=0.001) (Figure 4) but not in patients. Of particular
interest was a direct relationship in normal subjects between plasma
TFPI and F1.2 levels even when only baseline data were examined
(r=0.56, P=0.002) (Figure 4) suggesting a
stimulatory effect of thrombin generation on TFPI release into
plasma.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The major findings in this study are that IPC induces a rise in plasma levels of TFPI, the principal regulator of the TF pathway of blood coagulation, with a concomitant decrease in plasma FVIIa, the activated form of FVII, in both normal subjects and patients with venous disease. An inverse relationship was observed (Figure 3
) between plasma TFPI levels and FVIIa levels. Although the
number of normal subjects and patients studied is small, each subject
was studied with each of 5 different IPC devices with a uniformly
consistent trend. Circulating blood normally contains picomolar
concentrations of FVIIa,16 which could trigger the initial
FVIIa-TF catalyzed activation of factors X and IX when blood is exposed
to extravascular tissue factor and thereby initiate blood coagulation.
The observed increase in TFPI with a decrease in FVIIa suggests that
IPC induces an inhibition of the earliest events in the activation of
blood coagulation by the TF pathway. TFPI is synthesized primarily in
the endothelial cells.22 There are at
least 3 distinct pools of TFPI in vivo.7 The largest pool
(~80% to 85%) remains associated with the
endothelial surface.7 The plasma pool
constitutes 10% and 80% of this circulates associated with
lipoproteins.23 24 Approximately 3% of total TFPI is
present in the platelet pool. The pool associated with the
vascular endothelium is released into the plasma by
heparin.12 13 The heparin-releasable pool may constitute
the major pool responsible for the anticoagulant effect of
TFPI.25 We postulate that the observed increase in plasma
TFPI levels after IPC originates from the endothelial
cells and may result from the following 2 mechanisms: by displacement
from endothelial surface (as occurs after heparin
infusion)12 13 and secretion from the intracellular
stores. This would lead to an increase in plasma of full-length
carrier-free TFPI, which is a more efficient anticoagulant than the
C-terminally truncated and lipoprotein bound TFPI in
plasma.26 27 Although plasma levels of free TFPI were not
measured in our study, this would imply that the increase in TFPI
anticoagulant activity would be higher than that reflected by increase
in the total plasma TFPI levels observed in our subjects.
Our studies show a striking decline in FVIIa levels during IPC (Figure 1) without a concomitant change in FVII antigen (Figure 2). FVIIa cannot be neutralized effectively unless it is bound
to TF,5 6 7 and the 2 plasma proteinase
inhibitors that inhibit FVIIa-TF catalytic activity are
TFPI5 6 7 and antithrombin.28 29 30 31 No changes
were observed in plasma antithrombin levels in our subjects. The
inverse relationship between FVIIa levels and TFPI (Figure 3) in
both groups of subjects suggests a role of TFPI in the decline in
FVIIa. TFPI inhibits FVIIa by a mechanism that requires
FXa,5 6 7 8 and the rate-limiting step for the inactivation
of FVIIa-TF appears to be the initial formation of TFPI-FXa
complex.32 The small "idling" amounts of FXa that are
continuously produced under basal conditions even in normal
individuals6 may fulfill this requirement. It has been
suggested33 that plasma TFPI levels are regulated by
constant low levels of FXa activation that occurs under basal
conditions.6 Our findings are in line with this
hypothesis. In our studies, there was a correlation between plasma F1.2
(a product of the action of FXa on prothrombin) and TFPI levels in
normal subjects (Figure 4). Indeed, a relatively strong
relationship was observed even in baseline plasma samples from normal
subjects (r=0.56, P=0.002) (Figure 4).
Moreover, IPC may induce minimal localized activation of the TF pathway
(possibly via activation of monocytes or endothelial
cells) leading to some additional FXa and thrombin generation and
endothelial release of TFPI. Thrombin can rapidly
release TFPI from endothelial
sources.34 Although plasma F1.2 levels were not
markedly elevated in our studies (Figure 2), a localized and
limited thrombin generation that is rapidly controlled may not result
in a discernible increase in peripheral plasma levels. The
hypothesis that a low level generation of FXa and thrombin lead to
coagulation inhibitory mechanisms via TFPI is supported by
previous observations that infusion of low levels of thrombin leads to
an anticoagulant effect.35 Lastly, the specific mechanisms
by which IPC induces a release of TFPI or causes a decline in FVIIa
remain to be defined, and it is conceivable that they are unrelated and
due to mechanisms other than those postulated above.
There were differences between normal subjects and patients in some of
the measurements. Plasma TFPI levels during IPC were lower
(P<0.001) in the patients (Figure 2), suggesting
that presence of underlying postthrombotic venous disease may blunt the
increase in TFPI levels. This may be related to chronic
endothelial dysfunction with impaired TFPI synthesis
and secretion or to chronic depletion of the
endothelial pool of TFPI, similar to that observed
after administration of heparin.36 Consistent
with the diminished TFPI, the FVIIa levels were significantly higher at
120 and 180 minutes in the patients, although baseline levels were
comparable in the 2 groups (Figure 1). FVII antigen levels were
slightly higher in patients, and this has been observed in patients
with vascular diseases.37 38 Overall, the differences
between patients and normal subjects, in the rise in TFPI and decline
in FVIIa, may suggest a diminished antithrombotic effect of IPC in
patients with severe venous disease. Lastly, our studies failed to
detect major differences between the effects of different devices,
possibly related to the small number of subjects. Further studies in a
larger number of subjects are needed to clarify the involved mechanisms
and differences between devices.
In summary, our studies demonstrate that IPC results in an increase in plasma TFPI and a decrease in FVIIa levels indicating inhibition of TF-dependent pathway. We postulate that IPC induces release of TFPI from endothelial TFPI pool. Inhibition of the TF pathway, the major physiological initiating mechanism of blood coagulation, may be an important mechanism for the antithrombotic effect of intermittent pneumatic compression.
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Acknowledgments |
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A.K.R. is the recipient of an Academic Award in Vascular Disease (NHLBI, KL 07 H102658). This study was supported in part by NIH General Clinical Research Grant RR00349 and Research Grants from Huntleigh Healthcare, Inc, Manalapan, NJ and NuTech, San Antonio, TX. The excellent secretarial assistance of JoAnn M. Hamilton is gratefully acknowledged.
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Footnotes |
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This study has been previously published in abstract form (Blood. 1996;88:625a) and presented at the annual meeting of the American Society for Hematology, Orlando, FL, in December 1996.
Received February 19, 1999; accepted May 19, 1999.
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