Blood, 15 April 2003, Vol. 101, No. 8, pp. 3002-3007
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Distinct dose-dependent effects of plasmin and TPA on
coagulation and hemorrhage
Daphne Stewart,
Mansze Kong,
Valery Novokhatny,
Gary Jesmok, and
Victor J. Marder
From the Vascular Medicine Program, Los Angeles
Orthopaedic Hospital, The David Geffen School of Medicine at UCLA,
University of California Los Angeles, CA; and Department of
Pharmacology, Bayer Corporation, Research Triangle Park, NC.
 |
Abstract |
All thrombolytic agents in current clinical usage are plasminogen
activators. Although effective, plasminogen activators uniformly increase the risk of bleeding complications, especially intracranial hemorrhage, and no laboratory test is applicable to avoid such bleeding. We report results of a randomized, blinded, dose-ranging comparison of tissue-type plasminogen activator (TPA) with a
direct-acting thrombolytic agent, plasmin, in an animal model of
fibrinolytic hemorrhage. This study focuses on the role of plasma
coagulation factors in hemostatic competence. Plasmin at 4-fold,
6-fold, and 8-fold the thrombolytic dose (1 mg/kg) induced a
dose-dependent effect on coagulation, depleting antiplasmin activity
completely, then degrading fibrinogen and factor VIII. However, even
with complete consumption of antiplasmin and decreases in fibrinogen and factor VIII to 20% of initial activity, excessive bleeding did not
occur. Bleeding occurred only at 8-fold the thrombolytic dose, on
complete depletion of fibrinogen and factor VIII, manifest as prolonged
primary bleeding, but with minimal effect on stable hemostatic sites.
Although TPA had minimal effect on coagulation, hemostasis was
disrupted in a dose-dependent manner, even at 25% of the thrombolytic
dose (1 mg/kg), manifest as rebleeding from hemostatically stable ear
puncture sites. Plasmin degrades plasma fibrinogen and factor VIII in a
dose-dependent manner, but it does not disrupt hemostasis until
clotting factors are completely depleted, at an 8-fold higher dose than
is needed for thrombolysis. Plasmin has a 6-fold margin of safety, in
contrast with TPA, which causes hemorrhage at thrombolytic dosages.
(Blood. 2003;101:3002-3007)
© 2003 by The American Society of Hematology.
| |
Introduction |
Thrombolytic therapy with plasminogen activators is
a highly effective modality for achieving both vascular reperfusion and clinical benefit in patients with arterial occlusions, for example, acute myocardial infarction, peripheral arterial occlusion, and ischemic stroke.1 However, such therapy is unfortunately
accompanied by a significant risk of intracranial hemorrhage (ICH),
which occurs in 1% to 2% of patients who receive continuous treatment for 2 to 24 hours.2,3 ICH is especially prevalent in
patients who are older and smaller, those who are hypertensive or have a history of transient ischemic attack or stroke, and those treated with tissue plasminogen activator (TPA).4,5 Patients
treated for ischemic stroke are especially prone to symptomatic or
lethal ICH, with an occurrence of 10% to 16% after receiving TPA or
streptokinase (SK), about 10-fold greater than in patients who receive
only anticoagulation.6 To date, the use of every effective
thrombolytic agent causes this adverse outcome, and even newly approved
TPA mutants7,8 or reduced-dosage regimens of
TPA9 share this risk for ICH.
We recently reported on an alternative to plasminogen activator-type
thrombolytic agents, namely, plasmin, a direct fibrinolytic enzyme that
does not require plasminogen to achieve thrombolysis.10 First tested for efficacy more than 40 years ago, plasmin was ineffective when administered by the intravenous route11
because it was neutralized by plasma antiplasmin.12
However, our regional administration of plasmin by catheter directly to
the thrombus avoids antiplasmin neutralization, and rabbit arterial and
venous thrombolysis models clearly document thrombolytic activity of plasmin.10,13 In addition, our studies show a significant
advantage of plasmin over TPA in its safety from fibrinolytic
hemorrhage.10 Thrombolytic doses of plasmin (2 or 4 mg/kg)
did not cause bleeding, whereas thrombolytic doses of TPA (1 or 2 mg/kg) induced fibrinolytic hemorrhage.10 Our explanation
for safety using plasmin is that antiplasmin neutralizes plasmin that
appears in the circulation, whereas TPA circulates, binds to hemostatic
plugs at sites of vascular injury, degrades fibrin, and induces fresh
hemorrhage.10
Although plasmin clearly shows safety from bleeding with therapeutic
(thrombolytic) dosages, important questions still remain regarding its
pharmacophysiology. For example, does a higher dosage of plasmin
consume antiplasmin, thereby allowing free plasmin to circulate,
degrade clotting factors, and induce hemorrhage? If so, our hypothesis
regarding the mode of action of plasmin would be strengthened. In
addition, such results would indicate that laboratory monitoring of
antiplasmin could provide a useful predictive marker for bleeding.
Because there is no currently applicable laboratory assay available for
predicting hemorrhage in a patient receiving a plasminogen activator,
such a monitoring tool for thrombolytic therapy with plasmin would
represent a unique advantage for its use. Further, does bleeding follow
antiplasmin consumption or does bleeding occur only after further
consumption of clotting factors such as fibrinogen and factor VIII?
Observations regarding these laboratory end points could provide
insights for the pathophysiology of plasmin-induced bleeding and for
its prevention.
Accordingly, this study uses an animal model of fibrinolytic
hemorrhage14 to evaluate escalating dosages of plasmin,
above the 2-mg/kg dose that dissolves experimental
thrombi,13 to determine if a threshold dose for bleeding
exists and if such bleeding can be predicted or at least explained by
changes in blood coagulation or fibrinolytic parameters. As control,
and to test what dose of TPA can be administered without inducing
bleeding, TPA at progressively lower doses, below that which is optimal
for thrombolysis (1 mg/kg),13 were compared for bleeding
manifestations and for blood coagulation parameters.
| |
Materials and methods |
Human plasminogen was purified from plasma by affinity
chromatography on lysine-Sepharose 4B (Amersham Pharmacia, Uppsala, Sweden),15,16 eluted with 0.1 M glycine and 0.03 M lysine
at pH 3.0, and stabilized by addition of 
-aminocaproic acid (EACA; 0.02 M final concentration). After adjustment to pH 7.5, the
plasminogen was activated to plasmin with a 100:1 molar ratio of
plasminogen to streptokinase (American Diagnostica, Greenwich, CT) in
0.05 M glycine, 0.015 M L-lysine, 0.01 M EACA, and 10%
glycerol. After 16 hours at 4°C, activation was stopped with sodium
chloride and EACA, final concentrations 0.5 M and 0.25 M, respectively.
The pH was adjusted to 8.5 and SK-activated plasminogen was applied to
a benzamidine-Sepharose 6B (Amersham Pharmacia Biotech, Piscataway, NJ) column equilibrated with 0.05 M Tris
(tris(hydroxymethyl)aminomethane), 0.5 M sodium chloride, 0.25 M EACA buffer at pH 8.5. Plasmin was eluted with 1.0 M EACA, pH 7.5, and SK was removed by octyl-Sepharose 4 FF (Amersham Pharmacia)
chromatography at pH 3.4 after equilibration with 0.1 M glycine, 0.03 M
lysine. Polyacrylamide gel electrophoretic analysis with sodium dodecyl
sulfate (SDS-PAGE) showed a single nonreduced band and bands
corresponding to heavy and light chains under reduced conditions. Final
preparations showed N-terminal lysine, contained 18 to 23 caseinolytic
U/mg17 and were not contaminated by SK, as measured by
enzyme-linked immunosorbent assay (ELISA).
The experimental system for assessing fibrinolytic hemorrhage used the
rabbit ear puncture model based on the "rebleed
phenomenon."14,18 The experimental protocol was approved
by the Animal Care and Use Committee at Los Angeles Orthopaedic
Hospital. Thirty New Zealand white rabbits (Hazelton Research Products,
Denver, PA) weighing 3.5 to 4.5 kg were assigned to 6 treatment groups
in a randomized, prospective manner. Following these observations, baseline measurements were obtained in an additional group of 5 rabbits, which received saline only, in an open, unblinded manner.
Animals were anesthetized with 40 mg/kg ketamine HCl (Phoenix
Pharmaceuticals, St Joseph, MO) and 5 mg/kg xylazine (Phoenix Pharmaceuticals; 2.7-3.25 mL total volume) by intramuscular injection. After anesthesia was achieved, the skin of both ears and the neck was
shaved and a depilatory (Nair; Sally Hansen Division, Del Laboratory,
Farmingdale, NY) was applied to the ears. The left external jugular
vein was exposed surgically, catheterized with a 30-cm 7F 3-lumen
catheter (Braun, Bethlehem, PA), and attached to syringes containing
saline, anesthesia mixture, and experimental infusion. Anesthesia was
maintained by intermittent injections of the ketamine HCI/xylazine
mixture every 3 to 10 minutes as required. Primary bleeding times were
determined after full-thickness punctures (3.5 mm width) of the ear
with a number 11 surgical blade (Feather Safety Razor, Medical
Division, Osaka, Japan), at 30 and 10 minutes and immediately
prior to initiation of TPA or plasmin infusion. The duration of
bleeding was measured by absorption of blood onto 11-cm circular filter
paper discs (Whatman International, Maidstone, United Kingdom) at
30-second intervals. Thrombolytic was administered by continuous pump
infusion (Sage Instruments, Orion Research, Boston, MA) of a 10-mL
sample over 50 to 55 minutes. Each rabbit received 1 of 30 coded
samples, prospectively randomized and blinded to the observer,
containing TPA (Genentech, South San Francisco, CA; 1, 2, or 4 mg) or
human plasmin (16, 24, or 32 mg). Plasmin used in these experiments had
a pH of 3.7 prior to infusion. All infusates were prepared at Bayer
Corporation, stored at 
80°C, then thawed at 32°C just before
infusion. After initiation of the infusion, ear bleeding times were
performed at 10, 30, 60, 70, 120, and 180 minutes. During the 3-hour
observation interval after initiation of infusion, all lesions were
monitored for renewed bleeding. No infused animal died prior to being
killed at 180 minutes with intravenous sodium pentobarbital (48 mg/2
mL, Kentosol injection; Med-Pharmex, Pomona, CA). Figure
1 illustrates the experimental plan,
showing the times for ear puncture bleeding times (arrow) and blood
samples (*) relative to agent or saline infusion.
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| Figure 1.
Schematic representation of the experimental design.
Diagram shows the bleeding times (arrows) and blood samples (*)
relative to the 50- to 60-minute infusion of plasmin or TPA. Infusions
into rabbits (4 kg body weight) were performed in a randomized, blinded
manner, using coded vials containing plasmin (16, 24, or 32 mg) or TPA
(1, 2, or 4 mg) in a total volume of 10 mL. Data were pooled by group
for statistical analysis, without knowledge of treatment. Control
infusions of 10 mL saline to 5 animals were performed in an open-label
manner at the end of the study.
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Blood samples were obtained at 30 minutes and immediately prior to the
start of infusion, and at 10, 60, 70, 90, 120, and 180 minutes after
the start. Blood (4.5 mL) was collected on citrate anticoagulant (0.5 mL, 0.25 M sodium citrate) through a dedicated lumen of the external
jugular vein catheter and kept at 4°C until the end of each
experiment. After centrifugation at 3000g at 4°C for 30 minutes, plasma was tested immediately for factor VIII activity,
fibrinogen concentration, and functional antiplasmin activity according
to established procedures.19-21
Data were grouped according to coded samples and analyzed without
knowledge of the specific agent infused by 
2 and by
t test or repeated measure analysis of variance (ANOVA) comparison of means.
| |
Results |
Figure 2 schematically illustrates
the ear puncture primary bleeding times (PBTs) and rebleeding episodes
for animals that received TPA (0.25, 0.5, or 1.0 mg/kg) or plasmin (4, 6, or 8 mg/kg).
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| Figure 2.
Schematic representation of bleeding.
Bleeding is diagramed before, during, and after infusion of
plasmin (left) or TPA (right) to groups of 5 rabbits. PBTs were
performed on cohorts of 5 animals at 30 minutes, 10 minutes, and 0 minutes before infusion and at 10, 30, 60, 70, 90, 120, and 180 minutes
after the start of infusion. The vertical shaded rectangle represents
the infusion period from 0 to 55 to 60 minutes. The heavy lines
indicate when bleeding occurred, either the primary bleeding times
shown at the extreme left margin of each line, or renewed bleeding at
these same sites over the 180-minute observation period. Intervals of
stable hemostasis are indicated by the light horizontal
lines.
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Five animals that were infused with saline control showed no change in
PBT, mean of 50 tests 2.25 ± 0.4 minutes (not shown). TPA at 1 mg/kg
showed a nonsignificant prolongation of the PBT during infusion
(8.2 ± 20.0 versus 2.3 ± 0.9; P = .26), with return to pretreatment values after infusion (Table
1). Plasmin at 4 mg/kg had no
effect on PBT; at 6 mg/kg, the posttreatment PBT was slightly
prolonged. At 8 mg/kg, plasmin strikingly prolonged the PBT, but
only after the infusion was completed (25.5 ± 41.0 minutes).
Ear puncture sites were continuously scrutinized for renewed bleeding
for a maximum of 180 minutes. All 10 rabbits infused with TPA at 1 or
0.5 mg/kg and 4 of the 5 rabbits receiving only 0.25 mg/kg showed
renewed bleeding from previously stable ear puncture sites at 36%,
30% and 12%, respectively, of 50 sites. None of the animals exposed
to plasmin at 4 mg/kg or 6 mg/kg manifested rebleeding. Rebleeding from
stable hemostatic sites occurred in 3 of 5 rabbits that received
plasmin at 8 mg/kg, at 16% of the ear puncture sites.
Figure 3 shows the absolute total
duration of bleeding for each rabbit. Bleeding for more than 50 minutes
occurred more often at higher doses of TPA, in 1 of 5, 3 of 5, and 4 of
5 rabbits receiving TPA at 0.25, 0.5, and 1 mg/kg, respectively,
suggesting a dose-dependent pattern of bleeding. Plasmin caused
excessive bleeding only at the highest dose (3 of 5 animals),
suggesting a distinctive threshold, rather than a dose-dependent,
pattern of bleeding.
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| Figure 3.
Total bleeding induced by TPA or plasmin.
Results shown for 5 animals that received 0.25, 0.5, or 1 mg/kg
TPA (left panel) or 4, 6, or 8 mg/kg of plasmin (right panel). Total
bleeding is calculated for individual animals as the sum of bleeding
detected from all 10 puncture sites (Figure 2).
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The mean duration of bleeding at each ear puncture site, induced
before, during, or after infusion of TPA or plasmin, is shown in Figure
4. TPA disrupted hemostasis at sites
induced prior to or during infusion, with no effect at sites induced
after the infusion (60 minutes and thereafter). By contrast, plasmin
had no effect on preinfusion ear puncture sites or on those induced early (10 minutes) into the infusion. Rather, plasmin caused bleeding from puncture sites induced toward the end (30 minutes) and after the infusion.
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| Figure 4.
Total bleeding induced by TPA or plasmin.
Total bleeding induced by TPA (1 mg/kg) or plasmin (8 mg/kg)
relative to the time during which agent was infused. Results are
expressed as mean of 5 animals for either treatment group. The
preinfusion ear puncture bleeding times were performed at 30, 10,
and 0 minutes before starting TPA or plasmin. During the 55- to
60-minute infusions, ear punctures were induced at 10 and 30 minutes;
postinfusion bleeding times were performed at 60, 70, 90, and 120 minutes. TPA ( ) caused increased bleeding from the sites induced
before or during infusion, most evident at the 10-minute site, whereas
plasmin ( ) caused bleeding from midpoint of infusion and at all
subsequent ear puncture sites. Results for bleeding at 180 minutes are
not shown because experiments were terminated just after these
observations.
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To assess whether blood coagulation contributed to these patterns of
bleeding, antiplasmin, factor VIII, and fibrinogen were monitored over
the course of each experiment (Figure 5).
TPA caused minimal changes in antiplasmin activity or fibrinogen and
only a mild decrease in factor VIII to 60% of initial concentration. There was no difference in coagulation factor concentration at TPA
doses between 0.25 mg/kg and 1 mg/kg. Results with plasmin were
different, showing a dose-dependent decrease in all 3 laboratory parameters, reaching nadir levels at the end of infusion (60 minutes). Antiplasmin activity produced apparent negative nadir values, probably
reflecting the presence of catalytically active plasmin entrapped in
2-macroglobulin.22
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| Figure 5.
Concentrations of plasma antiplasmin, factor VIII, and
fibrinogen.
Plasma antiplasmin (top), factor VIII (middle), and fibrinogen
concentrations (bottom) in animals exposed to TPA (open symbols) or
plasmin (solid symbols) over the course of the 180-minute observation.
Mean results for each cohort of 5 animals expressed as percent of
pretreatment value at 30 minutes, normalized to 100%. Data are
corrected for results obtained with saline alone, which was associated
with a 5% decrease in all results during the 60-minute infusion and
with a 10% decrease in values of samples obtained from 60 to 180 minutes. Results for TPA were not different at dosages of 0.25 mg/kg
( ), 0.5 mg/kg ( ), or 1.0 mg/kg ( ). Plasmin showed a
dose-dependent decrease in all 3 assays on exposure to increasing
dosages of 4 mg/kg ( ), 6 mg/kg (), and 8 mg/kg ( ).
Antiplasmin activity was fully depleted with plasmin at 6 mg/kg, a dose
that decreased fibrinogen and factor VIII to 20% to 30% of initial
activity. Only at a dose of 8 mg/kg did plasmin cause depletion of
fibrinogen and factor VIII to levels at or below the lower limit of
quantification.
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The disparate dose-dependent effects of TPA and plasmin on coagulation
and bleeding are shown in Figure 6.
Progressively higher doses of TPA showed no dose-dependent effect on
fibrinogen, but did show a stepwise increase in bleeding
(P = .051 and P = .055, respectively, for 1 mg/kg and 0.5 mg/kg versus 0.25 mg/kg). On the contrary, plasmin caused
a dose-dependent decrease in fibrinogen concentration, but a threshold
effect on hemostasis, excessive bleeding occurring only at the highest
dose. Excessive bleeding with TPA occurred despite maintenance of
fibrinogen concentrations above 150 mg/dL, whereas plasmin at 4 or 6 mg/kg decreased the fibrinogen concentration to 100 mg/dL without
causing bleeding. Plasmin caused bleeding only when the
fibrinogen concentration was less than the lower limit of
quantification (25 mg/dL). The timing of the nadir fibrinogen values
caused by plasmin (8 mg/kg; Figure 5) coincided with the time that ear
punctures showed prolonged bleeding, near to or after the end of
infusion (Figure 2).
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| Figure 6.
Fibrinogen concentrations compared with total bleeding.
Nadir fibrinogen concentrations (top) are compared with total
bleeding (bottom) in animals receiving TPA or plasmin. Control values
for nadir fibrinogen concentrations, at 0 mg/kg of plasmin or TPA, were
determined in plasma samples obtained before infusion (at 30 and 0 minutes). Control values for total bleeding were determined in the 5 rabbits that received saline (mean of 50 determinations, 2.25 ± 0.4
minutes). Decrease in plasma fibrinogen concentration with plasmin was
dose-dependent and more profound than with TPA, which did not alter the
fibrinogen concentration significantly from the pretreatment level.
Nevertheless, TPA induced bleeding in a stepwise manner at increasing
dosages, unrelated to the plasma fibrinogen concentration. Plasmin did
not induce excessive bleeding at 4 or 6 mg/kg. At a plasmin dose of 8 mg/kg, the nadir fibrinogen concentration dropped below the lower limit
of quantification, in association with the appearance of excessive
bleeding.
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| |
Discussion |
This study clearly distinguishes between TPA and plasmin relative
to the relationship of plasma coagulation factors with bleeding. TPA
caused bleeding regardless of the plasma concentration of antiplasmin,
fibrinogen, or factor VIII (Figure 6), consistent with prior
observations that show minimal effect of TPA on
coagulation23 and no predictive value of laboratory
coagulation assays for a bleeding event caused by
TPA.2,24-26 By contrast, plasmin caused no excessive
bleeding when fibrinogen and factor VIII were present, but
induced excessive bleeding when the factors were absent (below the
limit of quantification). Thus, for the first time, a clear profile of
plasma coagulation assays is linked to protection from bleeding on
administration of a thrombolytic agent, albeit only with plasmin.
In addition to these different effects on coagulation, plasmin and TPA
exhibited markedly different patterns of bleeding. First, TPA caused
bleeding at therapeutic dosage13 and even at 25% of this
amount; plasmin caused no bleeding except at supratherapeutic (8-fold)
dosages. Second, TPA caused bleeding in a dose-dependent manner,
increasing progressively with incremental doses between 0.25 mg/kg and
1 mg/kg, whereas plasmin showed normal hemostasis at doses of 2 mg/kg,10 4 mg/kg, or 6 mg/kg and excessive bleeding only
at the threshold dose of 8 mg/kg (Figure 6). Third, TPA caused bleeding
only during administration, whereas plasmin (at 8 mg/kg only) caused
bleeding toward the end and after termination of infusion (Figure 4).
Fourth, TPA caused rebleeding, that is, renewed oozing from previously
stable ear puncture sites, whereas plasmin mostly affected primary
hemostasis (Figure 2).
The distinct effects of plasmin and TPA on coagulation and bleeding can
be explained by their biochemical properties. TPA avidly binds to
fibrin on thrombi and at vascular injury sites, where its enzymatic
activity is physiologically focused, but causes only limited
degradation of plasma coagulation factors.27-29 The dose-dependent nature of TPA bleeding reflects progressively higher local accumulations on hemostatic plugs, thus inducing bleeding from
stable ear puncture sites, even from those incurred before the TPA
infusion was started. In patients, this effect is indirectly reflected
by the correlation of blood TPA concentration with bleeding risk.30 Once the TPA infusion is terminated, the agent is
rapidly cleared31 and at these dosages, newly induced,
postinfusion trauma sites do not bleed excessively (Figure 4).
The effects of plasmin can now be explained as follows. Plasmin is
rapidly neutralized by antiplasmin32 and is thus prevented from circulating and binding to fibrin of hemostatic plugs. Thus, stable ear puncture sites are immune from disruption by infused plasmin. However, we show that at a high enough dose of plasmin (8 mg/kg), antiplasmin activity was depleted and plasmin-sensitive substrates in blood such as fibrinogen and factor VIII were degraded in
a dose-dependent manner (Figure 6). When fibrinogen and factor VIII
were completely depleted, a threshold of hemostatic protection was
breached, allowing bleeding to occur (Figure 6). Such bleeding was
observed only toward the end and after plasmin infusion (Figure 2). So
long as fibrinogen and factor VIII concentrations remained below the
lower limit of quantification (Figure 5), bleeding continued for the
ensuing 120-minute observation period (Figure 2).
There are clinical implications for our observations regarding the
safety, efficacy, and monitoring of thrombolytic therapy using plasmin.
As to efficacy, plasmin would not be applicable for systemic
administration, such as in patients with acute myocardial infarction,
because safe dosages of the agent would be neutralized by antiplasmin.
However, regional administration of plasmin such as in patients with
thrombosed arteriovenous shunts, arterial graft occlusions, deep vein
thrombosis, or coronary artery thrombosis after failed percutaneous
intervention, should be achievable without the risk of ICH that
accompanies regional use of TPA, urokinase, or
staphylokinase.33-35 Because the dose of plasmin that
causes excessive bleeding was more than 6-fold greater (Figure 6) than the effective thrombolytic dose,13 additional dosages of
plasmin could be infused locally to maximize thrombolytic efficacy.
This potential of safe administration of supratherapeutic amounts of plasmin contrasts with the situation using plasminogen activators, where even reduced dosages are associated with bleeding36
and higher doses of TPA-type agents proportionately increase bleeding risk.2
Our concept of plasmin use for thrombolysis, namely, regional infusion
for efficacy and dose selection that preserves coagulation for safety,
contrasts with the approach used by Nagai et al37 and by
Lapchak et al38 using microplasmin in experimental embolic stroke. These studies used systemic (intravenous) rather than regional
(intra-arterial) infusion with the objective of depleting, rather than
preserving, antiplasmin activity. The authors conclude that neurologic
improvement with microplasmin was achieved without increased risk for
parenchymal hemorrhage,38 but because the rate of
hemorrhage with placebo was much higher than in historical controls,39 the safety of this approach requires
further study.
Our results indicate that the threshold pattern of plasmin-induced
bleeding occurred only on complete depletion of clotting factors, thus
providing a unique circumstance for laboratory monitoring of treatment.
In this scenario, plasmin treatment could be monitored and judged as
safe from excessive bleeding so long as significant amounts of clotting
factors are present. Such monitoring is not feasible for TPA
administration, because changes in clotting factor concentration do not
correlate with bleeding complications.26
In conclusion, we have compared plasmin with TPA in a randomized and
blinded study in an established rabbit model of fibrinolytic hemorrhage. The data provide insights into rational dose selection of
plasmin and the role of plasma coagulation for hemostatic safety during
plasmin infusion.
| |
Footnotes |
Submitted August 20, 2002; accepted November 11, 2002.
Prepublished online as Blood First Edition Paper, November
21, 2002; DOI 10.1182/blood-2002-08-2546.
Supported by research funding provided by the Los Angeles
Orthopaedic Foundation and by a research grant from Bayer Corporation to Los Angeles Orthopaedic Hospital.
V.N. and G.J. are employed by the company whose thrombolytic agent
(plasmin) was studied in the present work.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Victor J. Marder, Los Angeles Orthopaedic
Hospital/UCLA, 2400 South Flower St, Los Angeles, CA 90007; e-mail:
vmarder{at}laoh.ucla.edu.
| |
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Abstract
Introduction
