(Circulation. 1997;96:761-768.)
© 1997 American Heart Association, Inc.
Articles |
Clearance of Tissue Plasminogen Activator (TPA) and TPA/Plasminogen Activator Inhibitor Type 1 (PAI-1) Complex
Relationship to Elevated TPA Antigen in Patients With High PAI-1 Activity Levels
From the Department of Laboratory Medicine (W.L.C., P.H.), University of Washington, Seattle; the Laboratory of Hematology (M.C.A., M.F.A., I.J.-V.), CJF INSERM, Marseille, France; and the Department of Diabetology and Nutrition CHU Timone (P.V.), Marseille, France.
Correspondence to Wayne L. Chandler, MD, Department of Laboratory Medicine, Box 357110, University of Washington, Seattle, WA 98195-7110. E-mail chandler{at}mail.labmed.washington.edu
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Abstract |
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Background To evaluate the effect of plasminogen activator inhibitor type 1 (PAI-1) levels on the clearance of total tissue plasminogen activator (TPA) antigen, we studied the clearance of active TPA and TPA/PAI-1 complex in subjects with low (181±109 pmol/L; n=7) and high (1166±322 pmol/L; n=4) baseline active PAI-1.
Methods and Results A 5-µg/kg bolus of TPA was infused
over a 15-second period followed by measurement of TPA activity, TPA
antigen, TPA/PAI-1, TPA/C1 inhibitor, PAI-1 activity, and
PAI-1 antigen over a 4-hour period. 
-Phase clearance of total TPA
antigen was faster in subjects with low PAI-1 (t1/2 of
3.5±0.7 minutes) versus high PAI-1 (t1/2 of 5.3±0.9
minutes) (P=.006). Clearance of all factors was best fit by
a two-compartment pharmacokinetic model based on a computer-simulated
human circulatory system. The average hepatic clearance fraction in the
two-compartment model was greater for active TPA (89±10%,
t1/2 of 2.4±0.3 minutes) than for TPA/PAI-1 complex
(48±17%, t1/2 of 5.0±1.8 minutes)
(P=.0006).
Conclusions Plasma clearance of active TPA was faster than clearance of TPA/PAI-1 complex. High levels of active PAI-1 converted more TPA into TPA/PAI-1 complex, effectively slowing the clearance of total TPA antigen and explaining in part why high levels of PAI-1 activity are associated with increases in total TPA antigen.
Key Words: plasminogen activators • hepatic clearance • plasma
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Introduction |
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The fibrinolytic system plays an important role in regulating the removal of thrombi from the vascular system. Fibrinolysis in the vascular bed is initiated by TPA, an enzyme that converts plasminogen to plasmin on the fibrin surface. The concentration of active TPA in blood is regulated by the rate of secretion of TPA, the inhibition of TPA by PAI-1 and other inhibitors, and the hepatic clearance of TPA.1 2 3 Epidemiological studies have shown that reduced blood fibrinolytic activity4 and elevated plasma PAI-1 activity,5 6 PAI-1 antigen,5 and TPA antigen5 7 8 9 10 are associated with an increased risk of myocardial infarction. One consistent finding in many studies has been a strong association between elevated PAI-1 activity or antigen and elevated levels of total TPA antigen.11 12 13 14 TPA exists in several forms in blood, including free active TPA and TPA bound to PAI-1 and other inhibitors.15 16 17 18 19 20 In plasma, PAI-1 forms stable stoichiometric complexes with TPA.21 As PAI-1 levels rise in blood, the fraction of TPA in the active form falls and TPA/PAI-1 complex levels rise.13 22 If TPA/PAI-1 complex were cleared from the blood more slowly than active TPA, then total TPA levels would tend to rise when PAI-1 was increased. The purpose of the present study was to determine the rate of clearance of active TPA versus TPA/PAI-1 complex and to evaluate the effect of elevated PAI-1 levels on the relationship between total TPA antigen and PAI-1 activity.
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Methods |
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Human Subjects
The study was performed in the Center of Clinical Pharmacology and Therapeutic Evaluation. The local ethics committee approved the investigation. Eleven healthy volunteers (7 men and 4 women) aged 37.8±10.7 years (range, 21 to 51 years) and weighing 81.2±26.3 kg (range, 51 to 127 kg) were studied. Subjects were selected according to their plasma PAI-1 levels. Seven had low PAI-1 activity (181±109 pmol/L; 4 men, 3 women) and 4 had high PAI-1 activity (1166±322 pmol/L; 3 men, 1 woman). None of the subjects were taking medication.
TPA Infusion and Blood Sample Protocol
Before TPA infusion, subjects refrained from smoking or drinking
caffeine-containing beverages for 48 hours, fasted for 12 hours, and
rested (in a sitting or supine position) for 30 minutes. A 5-µg/kg
bolus of recombinant TPA (Actilyse, Boehringer Ingelheim) was
infused intravenously over a 15-second period at 8
AM. A light breakfast was served 2 hours after the
injection. Blood was collected from the arm oppo-site the infusion
site via an antecubital catheter. The blood collections were taken just
before TPA infusion and 0.5, 1, 2, 4, 8, 12, 15, 20, 30, 45, 60, 90,
120, 180, and 240 minutes after the bolus injection. After the first 2
mL of blood was discarded, 5 mL of blood was drawn into citrate
supplemented with platelet-stabilizing agents (Diatube, Stago) to
reduce PAI-1 antigen release from platelets, 5 mL was drawn into
acidified citrate (Stabilyte, Biopool) to stabilize active TPA, and 5
mL was drawn into citrate containing PPACK at a final concentration of
100 µmol/L (Calbiochem) to block in vitro formation of complexes
between TPA and its inhibitors.23 All samples
were immediately centrifuged at 1800g for 30 minutes
at 4°C, separated into aliquots, and frozen at -80°C until
analyzed.
Assay Methods
TPA activity was measured in acidic citrate plasma by use of an
amidolytic method (BIA TPA, Chromogenix). Total TPA antigen assays
measure the total amount of TPA in blood, including free and complexed
TPA. Total TPA antigen was measured in acidic citrate plasma, total
PAI-1 antigen was measured in citrate plasma containing platelet
inhibitors, and TPA/PAI-1 complex antigen was measured in
PPACK plasma using enzyme immunoassays as previously described
(Stago).22 TPA/C1-I antigen was measured in PPACK plasma
by a modification of the method of Huisman et al24 with
the use of microtiter plates coated with monoclonal anti–human TPA
F(ab')2 fragments and sheep polyclonal anti–human C1-I
F(ab')2 fragments conjugated to peroxidase (The Binding
Site). PAI-1 activity was measured in acidic citrate plasma by use of a
back-titration method (Spectrolyse/PL, Biopool). C1-I antigen was
measured in PPACK plasma by use of an enzyme immunoassay (The Binding
Site).
Clearance Models
Three methods were used to evaluate the clearance of different
forms of TPA: (1) determination of the half-life of total TPA from 2 to
12 minutes after TPA infusion in patients with low and high PAI-1
activity; (2) a single-compartment circulatory model with TPA infusion
into the plasma compartment followed by first-order elimination of all
factors by the liver; and (3) a two-compartment circulatory model with
TPA infusion into plasma compartment, first-order elimination of all
factors by the liver, and first-order transfer of active TPA and
TPA/PAI-1 complex to and from separate second compartments (Fig 1
). Two-compartment models are used to evaluate
clearance of factors that show an - and ß-phase of clearance as
described previously for TPA.25 The circulatory model is
described in more detail below.
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Model Circulatory System
The model circulatory system consists of a
cardiopulmonary circulation that distributes blood flow into
coronary, cerebral, upper-extremity, splanchnic, renal,
lower-extremity, and "other" circulations (Fig 2).1 2 Estimates of resting total blood
volume, plasma volume, and cardiac output were based on height, weight,
and resting hematocrit as previously described.26 27
Estimated resting blood volumes and blood flows for different organs
were determined as previously described.1 2 28 29
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The fibrinolytic system of the model contains active TPA, active PAI-1,
C1-I, TPA/PAI-1 complex, and TPA/C1-I complex. The molar concentrations
of these proteins are regulated by four processes: (1) in vivo
secretion of TPA and PAI-1, (2) infusion of exogenous TPA, (3)
inhibition of TPA by PAI-1 and C1-I forming their respective complexes,
and (4) hepatic clearance of all factors. Total TPA is assumed to be
equal to active TPA plus TPA/PAI-1 plus TPA/C1-I. Total PAI-1 is
equivalent to active PAI-1 plus TPA/PAI-1 complex. Total PAI-1 in the
simulation underestimated total PAI-1 antigen in plasma by a small
amount because latent PAI-1 was not accounted for. Two other proteins
(2-antiplasmin and 2-macroglobulin) that
slowly inhibit TPA have been reported; these inhibitors
were not included in the model because their role was felt to be
negligible compared with PAI-1 and C1-I.
TPA is primarily secreted from vascular endothelial cells.30 The majority of the endothelium is located in small vessels and capillaries.29 TPA secretion in the simulation is simplified by assuming that (1) TPA is secreted only by vascular endothelial cells, (2) all vascular endothelium is located in the capillary beds, and (3) TPA secretion is the same in all capillary beds.
There may be several sources for PAI-1 in blood. Liver has been shown to secrete PAI-1 in vivo and in vitro.31 32 33 Endothelial cells in culture secrete PAI-1, but they do not appear to secrete PAI-1 in vivo except during the acute-phase response.11 13 22 28 34 35 Recent studies have indicated that adipose tissue, particularly in the abdominal region, may also be a source of plasma PAI-1.36 37 38 39 40 Separate simulations were run with secretion of PAI-1 either from the liver or from systemic capillary beds, which model endothelial secretion or secretion from adipose tissue, respectively. Because there were no significant changes in the measured concentration of C1-I during the infusion of TPA, the concentration of C1-I was held constant in the model at baseline levels.
In large arteries and veins, the ratio of endothelial cell surface area to blood volume is low. It was assumed that no secretion of TPA or other factors occurred in large vessels and that the only changes in concentration were due to the reaction between TPA and either PAI-1 or C1-I.1 A second-order rate constant of 3.7x107 mol/L-1·s-1 was used for the reaction between one-chain TPA and PAI-1.3 41 42 The rate constant for the reaction between one-chain TPA and C1-I was adjusted to produce the best fit between measured and simulated levels of TPA/C1-I complex.
Depending on the specific model used, changes in concentration in the
capillary beds may occur due to secretion of TPA or PAI-1, the
inhibition reactions with PAI-1 and C1-I, and transfer of active TPA
and TPA/PAI-1 complex to a second compartment. In the liver sinusoids,
changes in concentration occur due to the secretion of active PAI-1,
the reaction between TPA and its inhibitors, and the
clearance of the appropriate fraction of each factor as the blood flows
into the hepatic veins. In the single-compartment clearance model, TPA
is infused into the upper-extremity vein of the model, followed by
clearance through the liver. The rate of clearance from plasma for all
factors is directly proportional to liver blood
flow.43
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). It is assumed
that transfer to these second compartments occurred primarily in the
capillary beds. Huisman et al24 reported a half-life of 4.2 minutes for the clearance of TPA/C1-I complex. The hepatic extraction fraction for TPA/C1-I was adjusted to produce a half-life of 4.2 minutes in the simulation. Due to the low levels of TPA/C1-I, only single-compartment hepatic clearance was modeled for this complex.
Cardiac output in the simulation was set to the estimated value for each subject. Baseline TPA and PAI-1 secretion rates were estimated as previously described.1 2 If a circadian decrease in TPA or PAI-1 was noted between the baseline and 4-hour sample points, TPA and PAI-1 secretion rates were adjusted to produce a linear decrease in TPA and PAI-1 to match the measured levels. The same dose of TPA given to the subject was infused into the upper-extremity vein of the model over a 15-second period. Hepatic extraction fractions and second-compartment microconstants were adjusted to minimize the sum of weighted squared errors between measured and simulated levels of active TPA, total TPA, TPA/PAI-1, and total PAI-1 from 2 minutes to 30 minutes after infusion of TPA.1 PAI-1 activity measurements were not used in the model because it was difficult to accurately measure PAI-1 activity during the TPA infusion.
The simulation was run on a Macintosh Quadra 700 (Apple Computers) using THINK Pascal 4.0 (Symantec). Complete details of the circulatory model, including a copy of the source code for the program, are available from the authors at no charge.
Statistical Evaluation
Group distributions are presented as the mean±SD.
Comparisons within groups used repeated measures ANOVA and the Tukey
honestly significant difference test; comparisons between groups used
between-group ANOVA. Statistica/Mac software (Stat-Soft) was used for
all statistical calculations.
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Results |
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Effects of Bolus Infusion of TPA
At baseline, before infusion of TPA, four subjects had high levels of active PAI-1 (1166±322 pmol/L) whereas the remaining seven subjects had low levels of active PAI-1 (181±109 pmol/L; P=.00002). Fig 3
shows the effect of a bolus infusion of 5 µg/kg
TPA in the low– and high–PAI-1 groups. Total TPA, active TPA, and
TPA/PAI-1 complex levels peaked by 2 minutes, followed by a continuous
decrease in the level of all three factors. TPA/C1-I levels increased
20% to 30% after bolus TPA infusion in both groups then fell at a
rate similar to TPA/PAI-1 complex. Both low– and high–PAI-1 groups
showed a drop in active PAI-1 and total PAI-1 antigen after infusion of
TPA. In the high–PAI-1 group, PAI-1 antigen levels fell from a
baseline of 1406±477 to 730±328 pmol/L 15 minutes after infusion of
TPA (P=.0002); slowly rose again, peaking at 60 to 90
minutes; then progressively decreased, following the usual PAI-1
circadian rhythm.
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Clearance of TPA
Total TPA antigen peaked by 2 minutes in all subjects at levels
that were not significantly different in the low–PAI-1 group
(1294±329 pmol/L) versus the high–PAI-1 group (1299±288 pmol/L),
indicating that both groups started clearance with the same peak level
of total TPA. The simple -phase half-life of total TPA antigen from
2 to 12 minutes after TPA infusion was significantly longer in subjects
with high PAI-1 (5.3±0.9 minutes) versus low PAI-1 (3.5±0.7 minutes;
P=.006). At 30 minutes, total TPA antigen levels continued
to be elevated in the high–PAI-1 group (258±72 pmol/L) versus the
low–PAI-1 group (103±42 pmol/L; P=.009). Active TPA also
peaked by 2 minutes in all subjects but fell faster in the high–PAI-1
group because of increased formation of TPA/PAI-1 complex.
As seen in Fig 3, total TPA clearance was characterized by an initial
rapid -phase followed by a slower ß-phase in both the low– and
high–PAI-1 groups. Using a computer simulation of the human
circulatory system, we studied two models of clearance: a
single-compartment model with all clearance through the liver
(-phase only) and separate two-compartment models (Fig 1) for active
TPA and TPA/PAI-1 complex (- and ß-phases).
Fig 4 shows the effect of single-compartment versus
two-compartment clearance models on the fit between measured and
simulated levels of active TPA, TPA/PAI-1 complex, total TPA, and total
PAI-1 in one subject with high PAI-1 activity. As can be seen, the
single-compartment model based on hepatic clearance tended to
overestimate TPA/PAI-1 complex levels soon after the bolus infusion was
completed while underestimating total TPA and TPA/PAI-1 complex at 30
minutes. Addition of the second compartment had the effect of rapid
transport or binding of TPA, lowering the concentration soon after
infusion, followed by slow release later. The model predicted that the
ß-phase of clearance noted in the original data above was essentially
due to this slow release from the second compartment. The
Table gives the average hepatic extraction fractions,
second-compartment microconstants, and total squared errors for the
one- and two-compartment models. The two-compartment model produced a
better fit between simulated and measured levels of active and
complexed TPA in both the high– and low–PAI-1 groups. Overall, the
average total squared error was 64% lower in the two-compartment
versus the one-compartment model (P=.016). The best fit in
both the one- and two-compartment models occurred when active TPA was
cleared faster by the liver than was TPA/PAI-1 complex. In the
two-compartment model, the estimated hepatic-clearance half-lives were
2.4±0.3 minutes for active TPA versus 5.0±1.8 minutes for TPA/PAI-1
complex (P=.0036).
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Two subjects had high transfer rates for essentially all of the
second-compartment constants. Their data tended to skew the averages
shown in the Table toward higher values. The predicted rate of transfer
from the blood to the second compartment for active TPA
(K2) ranged from 3 to 28 h-1, with
a median rate of 6 h-1, whereas the transfer
rate for TPA/PAI-1 complex (K4) ranged from 4 to 22
h-1, with a median rate of 12
h-1. The predicted rate of transfer from the
second compartment to the blood for active TPA (K-2)
ranged from 4 to 72 h-1, with a median rate of
16 h-1, whereas the transfer rate for
TPA/PAI-1 complex (K-4) also ranged from 4 to 72
h-1, with a median rate of 7
h-1. There were no significant differences in
the second-compartment microconstants for active TPA versus TPA/PAI-1
complex.
The source of PAI-1 secretion is still controversial; endothelium, hepatocytes, and adipocytes have all been suggested as sources of PAI-1 in plasma. To determine whether different sites for PAI-1 secretion might affect the clearance model, we compared (1) PAI-1 secretion from the liver versus (2) secretion from the systemic capillary beds, modeling a mixture of endothelial and adipose tissue secretion. The overall errors, hepatic extraction fractions, and second-compartment microconstants were not significantly different in the liver versus capillary models of PAI-1 secretion.
The model also provided a rough indication of the rate of active PAI-1
clearance by the liver. The model predicted hepatic extraction
fractions for active PAI-1 ranging from 5% to 
20%, with a mean of
10%. Finally, the model predicted two different second-order rate
constants for the reaction between TPA and C1-I. The rate constant for
TPA secreted by endothelium in vivo (based on baseline
levels of TPA/C1-I) was predicted to be 519
mol/L-1·s-1, but
the rate constant for C1-I reacting with infused TPA was 23
mol/L-1·s-1.
Effect on Total TPA Levels
To evaluate the effect of slower TPA/PAI-1 clearance on total TPA
levels, we ran steady-state clearance simulations using the circulatory
model with hepatic extraction fractions set to the average values for
the two-compartment model in the Table: 89% for active TPA and 48%
for TPA/PAI-1 complex. The simulation was allowed to run with TPA and
PAI-1 secretion held constant until steady-state levels of all factors
were reached. This simulated baseline levels of these factors in vivo.
Fig 5 shows the effect of using progressively higher
baseline PAI-1 secretion rates while holding the TPA secretion rate the
same for all simulations. As baseline PAI-1 increased, more secreted
TPA was converted into TPA/PAI-1, which in turn was cleared more
slowly, resulting in an increase in the total TPA level. The model
predicted that an increase in active plasma PAI-1 from 6 to 50 ng/mL
would increase total TPA antigen from 10 to 16 ng/mL with no change in
TPA secretion.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The purpose of this study was to determine the rate of clearance of active TPA versus TPA/PAI-1 complex and to evaluate the effect of increased PAI-1 levels on total TPA antigen in plasma. First, we evaluated the simple
-phase clearance of total TPA in seven subjects
with low PAI-1 and four with high PAI-1 activity. We found that total
TPA was cleared more slowly in subjects with high PAI-1. Most prior
studies used radiolabeled TPA or measurements of TPA antigen to
determine total TPA clearance.25 43 44 Using these
methods, determination of clearance rates for individual forms of TPA
was not possible. Where clearances of both active and total TPA were
measured, active TPA was cleared faster than total TPA, but the
contribution of hepatic clearance versus inhibitors to the
overall clearance of active TPA was not
determined.45 46
The use of a circulatory model of TPA regulation allowed us to
track the bolus infusion of TPA, the reaction between TPA and PAI-1
forming TPA/PAI-1 complex, and the hepatic clearance of active and
complexed TPA. By fitting the computer model to measured levels of
these factors, we estimated that 89% of active TPA was removed from
the plasma as it flowed through the liver versus only 48% for
TPA/PAI-1 complex. These clearance fractions were equivalent to
half-lives of 2.4 minutes for active TPA and 5.0 minutes for TPA/PAI-1
complex. Brommer et al32 reported similar findings using
direct measurements of TPA activity and total TPA antigen in the
hepatic artery versus the hepatic vein. They reported that the liver
clears 71% of TPA activity (half-life of 2.9 minutes) while
clearing 39% of total TPA antigen (half-life of 5.3 minutes). Because
most TPA in resting samples is in the form of TPA/PAI-1 complex,
Brommer et al suggested that complexed TPA was cleared more slowly than
free TPA.
Other studies using perfused rat liver systems reported faster
clearance of purified TPA/PAI-1 complex (-phase half-life of 9.7
minutes) versus free TPA (-phase half-life of 20.1
minutes).47 Perfused rat liver systems show half-lives for
TPA clearance that are 20-fold longer than in the intact rat
(-phase half-life of 1 minute), even though the liver is the major
clearance organ.48 It is possible either that rat
clearance is different from human clearance or that clearance in
isolated rat livers differs from clearance in the intact animal.
This difference in clearance rates for active versus complexed TPA in
humans may have important clinical implications. Recent work has shown
that increased levels of total TPA antigen and elevated levels of PAI-1
activity or PAI-1 antigen are associated with an increased risk of
arterial thrombosis leading to myocardial
infarction.5 6 7 8 9 10 High total TPA antigen as a risk factor
seems counterintuitive, and a number of explanations have been
suggested, including increased secretion and
endothelial injury.9 10 Differences in
clearance may provide another explanation. Higher levels of PAI-1 in
blood convert a greater fraction of the secreted TPA in TPA/PAI-1
complex (Fig 5). Because TPA/PAI-1 is cleared more slowly than active
TPA, the total level of TPA rises even though TPA activity is falling.
Thus, elevated total TPA antigen is in part a surrogate measure of high
PAI-1 activity.
Prior studies25 44 have reported that clearance of total
TPA in humans is biphasic, with - and ß-phase half-lives of 4
and 30 minutes, respectively. This same biphasic pattern was seen in
our data (Fig 3). We found that active TPA, TPA/PAI-1, and total TPA
clearance were best fit using a two-compartment circulatory model with
elimination from the central or plasma compartment. The ß-phase of
clearance could be explained by the slow release of active TPA and
TPA/PAI-1 complex from the second compartment into the plasma. The
circulatory model directly estimated microconstants for the transfer of
active TPA and TPA/PAI-1 complex to and from the second compartment
(Table). In two subjects, the model predicted much higher
second-compartment transfer rates than in the remaining subjects; this
skewed the average results shown in the Table toward higher values.
Whereas the hepatic extraction fraction for active TPA was greater than
that for TPA/PAI-1, there were no significant differences in the
second-compartment microconstants for active versus complexed TPA.
Although this may indicate that a single second-compartment mechanism
operates for both active and complexed TPA, it is more likely that the
current data set and second-compartment model were not adequate to
accurately simulate the true mechanism of the second compartment.
TPA clearance by the liver involves at least two pathways: the mannose receptor on liver endothelial cells and Kupffer cells and the LRP receptor on parenchymal cells.49 Recent work suggests that the mannose receptor primarily binds free TPA, whereas the LRP receptor binds free and complexed TPA but clears complexed TPA more quickly. Clearance by the LRP receptor alone would predict faster clearance of complex compared with active TPA. It may be the combination of the two clearance mechanisms, mannose and LRP receptors, in vivo that results in faster active TPA clearance.
It is interesting to speculate on the composition of the second compartment for active and complexed TPA. One possibility is receptors such as annexin II, an endothelial cell receptor that binds active TPA or endothelial cell TPA-binding proteoglycans.50 51 52 Clearance receptors might also act as a second compartment, but the rate of endocytosis is so fast it is unlikely they would release a significant amount of TPA once bound. For a receptor to act as a second compartment, it must have a high-enough density, an appropriate binding constant, and slow internalization, allowing the release of bound TPA.
Active TPA is also removed from the blood by reaction with
inhibitors. As expected, all subjects showed decreases in
PAI-1 activity and increases in TPA/PAI-1 complex immediately after the
infusion of TPA. What was not expected was that total PAI-1 antigen was
also decreased by infusion of TPA. This suggests that TPA/PAI-1 complex
is cleared more quickly by the liver than is active PAI-1. Wing et
al47 report similar findings for a isolated perfused rat
liver model. The circulatory model indicated hepatic extraction
fractions for active PAI-1 ranging from 5% to 20%, with a mean of
10%. This was similar to the 20±10% hepatic extraction fraction
reported by Brommer et al for active PAI-1.32
The principal inhibitor of TPA is PAI-1, but C1-I also plays a role.1 18 24 Subjects in the present study had on average 27±12 pmol/L TPA/C1-I complex at baseline. TPA/C1-I levels rose 20% to 30% during TPA infusion, followed by rapid clearance. The average half-life for TPA/PAI-1 complex of 5.0±1.8 minutes was similar to the half-life of 4.2 minutes reported by Huisman et al24 for TPA/C1-I complex. This may indicate a similar clearance mechanism for all TPA/inhibitor complexes, possibly through the LRP receptor.
As in our previous study,1 the circulatory model
indicated that the in vivo reaction rate between TPA and C1-I was
faster than the rate measured in vitro. The model predicted that C1-I
reacts with TPA secreted from endothelium with a rate
constant >500
mol/L-1·s-1. The
predicted rate for the in vivo reaction between C1-I and infused TPA
was 23
mol/L-1·s-1.
Huisman et al24 reported an in vitro rate constant for the
reaction between TPA and C1-I of 5
mol/L-1·s-1. This
suggests that endothelium or some other cell surface
may in some way accelerate the reaction between TPA and C1-I in
vivo.
In summary, we found that active TPA was cleared from the blood more quickly than TPA/PAI-1 complex and that the clearance profile for active TPA, TPA/PAI-1 complex, and total TPA antigen was best fit by a two-compartment mechanism. The slower clearance of TPA/PAI-1 complex may explain in part the higher levels of total TPA antigen seen in patients with high levels of PAI-1 activity.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by grants from the Institut National de la Santé et de la Recherche Médicale, from the Ministère de l'Education Nationale, de l'Enseignement Supérieur et de la Recherche, and from Boehringer Ingelheim. The authors are very grateful to Prof D. Collen and Prof R. Lijnen (Center for Molecular and Vascular Biology, Leuven, Belgium) for helpful advice. The authors also wish to thank Dr O. Blin (Center of Clinical Pharmacology and Therapeutic Evaluation, CHU Timone, Marseille, France) for his skillful assistance and J. Ansaldi for excellent technical work.
Received October 28, 1996; revision received February 3, 1997; accepted February 16, 1997.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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3. Chandler WL. A kinetic model of the circulatory regulation of tissue plasminogen activator. Thromb Haemost. 1991;66:321-322.
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