(Circulation. 1999;99:1363-1369.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Recombinant Soluble Form of PSGL-1 Accelerates Thrombolysis and Prevents Reocclusion in a Porcine Model
From Preclinical R&D, Genetics Institute, Inc., Andover, Mass, and Charles River PharmServices, Southbridge, Mass (M.P.V.).
Correspondence to Anjali Kumar, PhD, Preclinical R&D, Genetics Institute, Inc., One Burtt Rd, Andover, MA 01810. E-mail akumar{at}genetics.com
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Abstract |
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Background—We investigated whether administration of a soluble recombinant P-selectin glycoprotein ligand-1 chimera (rPSGL-Ig) in conjunction with thrombolytic therapy would enhance thrombolysis by preventing ongoing interactions of leukocytes with platelets and the injured arterial wall.
Methods and Results—An occlusive thrombus was formed in an internal iliac artery of Yorkshire pigs by placement of a copper coil in the artery under fluoroscopic guidance. Pigs then received heparin and, 15 minutes later, either vehicle or rPSGL-Ig followed by infusion with 25 mg tissue plasminogen activator according to the 90-minute regimen. Blood flow through the artery was monitored by angiography and scored on a scale of 0 to 3. Lysis of the thrombus was accelerated by 70% in pigs treated with rPSGL-Ig 250 µg/kg compared with control (13.3±5.0 versus 44.4±13.3 minutes; n=9 each). Eight of 9 control pigs reoccluded in 13.8±16.9 minutes after the end of tissue plasminogen activator infusion, whereas no reocclusion was observed in 8 of 9 pigs in the rPSGL-Ig group. When the dose of rPSGL-Ig was increased to 500 µg/kg, time to lysis was shortened by 61% from control (18.0±8.4 versus 46.0±8.9 minutes). Reocclusion occurred in 6.0±15.2 minutes in control but not in any rPSGL-Ig–treated pig (n=5 each). In addition, near-normal flow (score 2 or 3) after thrombolysis was achieved 59% and 58% faster in the 2 rPSGL-Ig groups than in their respective controls.
Conclusions—Inhibition of leukocyte accumulation at the site of thrombosis with rPSGL-Ig may represent a safe therapeutic intervention that could be important in accelerating thrombolysis, achieving optimal reperfusion, and reducing incidence of acute reocclusion.
Key Words: thrombolysis • fibrinolysis • thrombosis • cell adhesion molecules • platelets • leukocytes
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The association of acute myocardial infarction with thrombus formation, frequently subsequent to plaque rupture,1 2 has made early thrombolytic therapy the standard of care for patients.3 Early initiation of thrombolytic therapy after the onset of symptoms reduces myocardial necrosis, preserves ventricular function, and decreases morbidity and mortality.4 5 6 However, with current thrombolytic therapy regimens, only
25% of all treated patients have timely, adequate, and
sustained coronary reperfusion.7 Hence, efforts
have been directed toward developing adjunctive therapies that can
enhance the thrombolytic effect of currently available
agents. Inhibitors of platelet
IIbß3 (GP IIb/IIIa)
integrin receptors have received much attention, and several
inhibitors have been studied in various models of
thrombolysis. Notably, the murine antiplatelet
antibody 7E3 in conjunction with tissue plasminogen
activator (tPA) was shown to accelerate
thrombolysis and prevent reocclusion in animal
studies.8 More recently, results presented from
the Thombolysis in Myocardial Infarction (TIMI) 14 clinical trial
suggest that combination of ReoPro (chimeric 7E3 Fab; abciximab)
with reduced doses of tPA or streptokinase enhanced
thrombolysis.9 However, significant
issues, such as bleeding and thrombocytopenia, still remain with
compounds of this class, especially in combination with heparin, and a
therapeutic with a better safety profile will be of value in the
clinic.
P-selectin is a membrane glycoprotein adhesion molecule
contained within platelet -granules10 11 and
Weibel-Palade bodies of endothelial
cells12 13 that is rapidly mobilized to the plasma
membrane on cell activation and granule secretion. It is a member of
the selectin family, which also includes E-selectin and L-selectin.
Selectins mediate rapid transient interactions of leukocytes
"rolling" on endothelial cells, generally believed
to be the prerequisite for firm adhesion and subsequent
extravasation.14 In addition, P-selectin mediates
adherence of activated platelets to leukocytes, such as
monocytes and neutrophils.15 16 The high-affinity
counterreceptor for P-selectin is a mucin-like
glycoprotein, P-selectin glycoprotein ligand-1
(PSGL-1), expressed on the surface of myeloid cells.17 18
Platelet-leukocyte interaction is of considerable
pathophysiological interest because it not only
serves to target both cell types to appropriate sites of inflammation
and/or hemostasis but also causes further functional alteration in both
cell types.
Platelet-leukocyte interactions, mediated by P-selectin, have been implicated in thrombus amplification and stabilization. In a key report by Palabrica et al,19 leukocyte accumulation and fibrin deposition in thrombi were found to be P-selectin–dependent. Adhesion of monocytes and platelets via P-selectin may cause tissue factor release from monocytes,20 which can initiate further coagulation and conversion of fibrinogen to fibrin. Interaction of platelets and neutrophils leads to the release of cathepsin G from neutrophils,21 which can damage endothelium and expose the subendothelial matrix and may attract further platelet adhesion.
Thrombi formed in the presence of an anti–P-selectin antibody lysed more rapidly on subsequent thrombolytic therapy in a cynomolgus monkey model, likely because of reduced fibrin content of the thrombi.22 In the present study, we investigated whether administration of a recombinant soluble PSGL-1 chimera (rPSGL-Ig) at the time of thrombolytic therapy would enhance fibrinolysis by preventing ongoing interactions of leukocytes with platelets and the injured arterial wall.
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Methods |
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rPSGL-Ig Chimera
PSGL-1 is the physiological ligand for P-selectin and binds P-selectin via an anionic amino-terminal peptide sequence.23 rPSGL-Ig is produced in Chinese hamster ovary cells, which have been engineered to coexpress the critical carbohydrate-modifying enzymes fucosyltransferase VII and core2 GlcNAc transferase.24 It comprises the first 47 amino acids from the N-terminal end of the extracellular domain of mature PSGL-1, fused at the "hinge" region of human IgG1. Two "hinge-proximal" amino acids at positions 234 and 237 within the IgGFc portion are mutated to alanine to reduce both complement activation and Fc receptor binding.25 This manipulation of the compound also gives it a long half-life,
11 days in 10-kg pigs (unpublished data, 1998).
This form of the molecule is a 10-fold more potent
inhibitor of P-selectin than E-selectin and an even weaker
inhibitor of L-selectin (unpublished data, 1997). It
inhibited P-selectin–mediated porcine platelet-neutrophil binding
(Dr Yahye Merhi, Montreal Heart Institute, unpublished data, 1998). The
formulation buffer for rPSGL-Ig consisted of 10 mmol/L histidine,
260 mmol/L glycine, 1% sucrose, and 0.005% Tween-80 with a pH of
6.6 at room temperature.
Animal Procedures
All animals used in this study were handled in compliance with
the Guide for the Care and Use of Laboratory Animals, 1996,
a publication of the National Research Council, National Academy Press,
Washington, DC. Experiments were performed in an American Association
for Accreditation of Laboratory Animal Care–approved laboratory
according to protocols that were reviewed and approved by the
Institutional Animal Care and Use Committee.
Induction of Arterial Thrombosis
Twenty-eight Yorkshire pigs (10 kg), male and female, were
anesthetized with tiletamine and zolazepam 6.6 mg/kg and
xylazine 4.4 mg/kg IM. Surgical anesthesia was maintained
by inhalation of 1.25% to 2.5% isoflurane (Inhalant
Isofluorane Vaporizer System, Ohio Medical Products). The animals
were allowed to respire on 1.5 to 2.5 L/min oxygen. Fluids and drugs
were administered via the marginal ear veins of both ears. A 5F
pediatric catheter (Cordis Corp) was introduced through the left
femoral vein into the inferior vena cava for blood
sampling. A 7F introducer (CR Bard) was placed in the left common
carotid artery and used to position a Teflon-coated guidewire (0.014
in) into the left or right internal iliac artery under fluoroscopic
guidance. A copper coil, made by wrapping a 26-gauge wire tightly
around a 20-gauge needle, was placed over the guidewire and directed
into the internal iliac artery with a 7F percutaneous
catheter (CR Bard). Once the coil was positioned, the guidewire was
removed and the catheter withdrawn into the abdominal aorta and used
for the injection of contrast medium (diatrizoate meglumine and
diatrizoate sodium; Mallinckrodt Medical) for arteriograms.
An occlusive thrombus was formed within minutes of placement of the copper coil, as judged by angiography. All animals were given 2000 U heparin IV, followed by an infusion of 1500 U/h in 0.9% saline to prevent clot extension. Heparin infusion was continued throughout the experiment and was adjusted to keep activated clotting time (measured every 15 minutes) at 2-fold to 3-fold of baseline.
Drug Administration and Flow Monitoring
After the thrombus had been aged for 15 minutes, an angiogram
was taken to confirm vascular occlusion. Animals then received a bolus
of either rPSGL-Ig 250 or 500 µg/kg IV or vehicle (rPSGL-Ig
formulation buffer) followed by human recombinant tPA (Activase;
Genentech, Inc). All pigs received 25 mg tPA at 1 mg/mL infused
intravenously over 90 minutes via a syringe pump (Harvard
Apparatus, Inc), with 10% of the dose delivered as an
initial bolus immediately after the rPSGL-Ig or vehicle bolus.
Arteriograms were taken every 10 minutes for up to 60 minutes after the
end of tPA infusion and were recorded for later playback and
confirmation of results. The times taken for lysis of the thrombus and
reocclusion of the artery were recorded. The experiment was
terminated at reocclusion or at 60 minutes after the end of tPA
infusion, whichever came first.
Scoring of Quality of Flow Reestablished
Blood flow reestablished past the thrombus in the copper coil on
treatment with rPSGL-Ig or vehicle and tPA was scored as 0, 1, 2, or 3,
with 0 indicating an occluded vessel and 3 indicating "normal"
flow. Time taken for reestablishment of "near-normal" flow (score
of 2 or 3) was compared.
Blood Sampling
Blood samples were obtained from the inferior vena
cava at baseline, before rPSGL-Ig/vehicle and tPA administration,
at reperfusion, and at termination for the following tests,
performed by Colorado Coagulation Consultants:
activated partial thromboplastin time, fibrinogen,
2-antiplasmin, plasminogen
activator inhibitor-1 (PAI-1) antigen, tPA
antigen, and tPA activity. Assays for other tests were not available
for porcine samples. In addition, for rPSGL-Ig–treated animals, blood
samples were drawn at baseline, 1 minute after drug administration, and
at termination to determine serum levels of rPSGL-Ig with an ELISA.
Data Analysis
Data are presented as mean±SD. Hypothesis testing for
differences in the means of control and rPSGL-Ig–treated groups was
performed with unpaired 2-tailed Student's t tests, and the
probability values were reported. Comparisons of the incidence of
reocclusion in the control and rPSGL-Ig groups and between the 2
rPSGL-Ig groups (250 and 500 µg/kg) were performed by test of
hypothesis on 2 proportions with the Z test and assuming
normal distribution. Statistical significance was judged at
P
0.05.
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Results |
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Time to Thrombolysis and Reocclusion
The first set of experiments was performed with a group of animals that received rPSGL-Ig 250 µg/kg and a corresponding control group that received the same volume of rPSGL-Ig formulation buffer (vehicle) just before tPA. In control pigs, lysis of the thrombus was achieved in 44.4±13.3 minutes (Figure 1A
). In
animals that were treated with rPSGL-Ig, flow was reestablished 70%
faster, after only 13.3±5.0 minutes (Figure 1A). On
thrombolysis, blood flow through the artery was graded
on a scale of 0 to 3. As shown in Figure 2, the time taken for reestablishment of
near-normal flow (score 2 or 3) was 59% faster in rPSGL-Ig–treated
pigs than in control pigs (23.8±16.9 versus 57.5±15.8 minutes).
Near-normal flow was not achieved in 1 animal in each group. In
addition, arteries in control pigs reoccluded in 13.8±16.9 minutes
after the end of tPA infusion for 8 of 9 pigs, whereas no reocclusion
was observed in the 1-hour observation period after the end of tPA
infusion in 8 of 9 pigs that received rPSGL-Ig 250 µg/kg in addition
to tPA (Table 1). Interestingly,
the 1 rPSGL-Ig–treated pig in which reocclusion did occur was the same
pig in which reestablishment of near-normal flow could not be achieved.
A series of angiograms from a representative control
and a pig treated with rPSGL-Ig 250 µg/kg is presented in
Figure 3.
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In the second set of experiments, the dose of rPSGL-Ig was increased to
500 µg/kg to see whether the characteristics of reestablished flow
could be further improved, and a corresponding control group was
studied. As shown in Figure 1B
, lysis of the thrombus in pigs
that received rPSGL-Ig was accelerated by 61% compared with control
(18.0±8.4 versus 46.0±8.9 minutes; Figure 2). Time taken for
reestablishment of near-normal flow (score 2 or 3) was 58% faster in
rPSGL-Ig–treated pigs than in control pigs (26.0±20.7 versus
62.5±22.2 minutes). Near-normal flow was not achieved in 1 animal in
the control group. Again, arteries in control animals reoccluded in
6.0±15.2 minutes after the end of tPA infusion in all 5 pigs in the
control group (Table 1). Reocclusion did not occur in the 1-hour
observation period in any of the 5 animals that received rPSGL-Ig.
The response in pigs treated with rPSGL-Ig 500 µg/kg was not significantly different from that in animals that received rPSGL-Ig 250 µg/kg in terms of acceleration of thrombolysis (61% versus 70%; P=0.21), incidence of reocclusion (1 of 9 versus 0 of 5), and time taken for reestablishment of near-normal flow (58% versus 59% faster; P=0.83). However, both groups of rPSGL-Ig–treated animals were significantly better than their respective controls.
Systemic Levels of Coagulation/Fibrinolytic Factors
Compared with baseline, high levels of tPA antigen and tPA
activity were measured in pigs after tPA administration, and the levels
were comparable in all control and rPSGL-Ig–treated groups. Selected
results are shown in Table 2. The
measures for the 2 control groups have been combined. No differences
were detected between control and rPSGL-Ig–treated groups or between
the 2 rPSGL-Ig groups. Plasma activated partial thromboplastin
time increased in all groups on administration of heparin. Fibrinogen
reduction was comparable in all groups, probably in relation to tPA
administration. Some reduction in
2-antiplasmin was seen in all groups. No
changes in PAI-1 antigen levels occurred. These data suggest that
rPSGL-Ig acts locally at the thrombus site and is not likely to
adversely affect the endogenous coagulation/fibrinolytic
system.
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Serum Concentrations of rPSGL-Ig
Serum concentrations of rPSGL-Ig were measured in samples from
rPSGL-Ig–treated pigs (Table 3). As
evidence of the long half-life of this compound, its concentrations
remain steady throughout the experiment.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Thrombolytic agents have been key in significantly advancing therapy of myocardial infarction; however, their benefits have been limited by the ability of currently available thrombolytic regimens to promptly restore optimal myocardial reperfusion in only
50% of patients.3 These
patients are those for whom grade 3 flow, as described by the TIMI
study group, is achieved within 90 minutes of treatment
administration.26 Of these, half of the patients go on to
experience recurrent ischemia (intermittent patency) or
complete vascular reocclusion within hours to days.3 7
Failure to reestablish adequate coronary tissue perfusion is
associated with a doubling in 30-day mortality, from 4% to
8%.27
Thrombosis/thrombolysis is a dynamic system in which
continuing platelet activation accompanied by the release of
thrombin, fibrinogen, and PAI-1 at the thrombus site leads to ongoing
thrombosis, which is directly linked to vascular reocclusion. In an
effort to improve currently available thrombolytic
therapy, the design of better thrombolytic agents, such
as variants of tPA, and the use of concurrent
thrombolytic therapy are being pursued. In this regard,
inhibitors of platelet
IIbß3 receptors have
recently received much attention and have been successful in the
clinic.9 The use of thrombolytic agents
carries some risk, such as hemorrhage, which is potentiated on
their combination with
IIbß3
inhibitors; hence, caution must be
exercised.28 29
Because ongoing interactions of activated platelets with
leukocytes via P-selectin influence fibrin deposition at the thrombus
site,19 we investigated whether inhibition of these
interactions would enhance the effect of thrombolytic
therapy. We assessed the effect of using rPSGL-Ig (P-selectin
antagonist) as an adjuvant to the
thrombolytic agent tPA in a porcine model of copper
coil–induced thrombosis. The thrombus formed within an intraluminal
copper coil is believed to be fibrin-rich, consisting of adherent
platelets bridged by a fibrin mesh and interspersed with
erythrocytes.30 Such thrombi have been shown to lyse on
thrombolytic therapy, yet reocclusion is frequent. In
fact, an IIbß3
antagonist (RGDY) was not effective in preventing
reocclusion of fibrin-rich thrombi.30 Continuing
platelet activation and fibrin accretion at the site of vascular
injury have previously been shown to precipitate
reocclusion.31 In this study, we show that treatment with
rPSGL-Ig at the time of thrombolytic therapy
accelerates thrombolysis and reestablishment of
near-normal flow and also prevents subsequent reocclusion despite the
continuing presence of the thrombogenic copper coil.
Platelets specifically recruit monocytes and neutrophils via their
surface expression of P-selectin for thrombus stabilization and
amplification.32 The release of tissue factor can occur on
platelet-monocyte adhesion via P-selectin20 or on
activated monocyte adhesion to endothelium or
fibrinogen via Mß2
(CD11b/CD18).33 34 Platelet-leukocyte interaction
leading to tissue factor release and subsequent fibrin deposition was
found to be P-selectin–dependent.19 In addition, thrombi
formed in the presence of a P-selectin antibody lyse more rapidly on
pharmacological thrombolysis, probably because of their
reduced fibrin content.22 The present work shows that
rPSGL-Ig, a form of the natural ligand for P-selectin, administered at
the time of thrombolytic therapy enhances
thrombolysis, most likely by inhibiting the continuing
adhesion of platelets to leukocytes, leading to fibrin accretion.
The colocalization of platelets and leukocytes in blood vessels and
possible functional consequences of this interaction have also been
reported in states such as myocardial infarction35 and
unstable angina36 and after
angioplasty.37 38
rPSGL-Ig appears to shift the balance in favor of thrombolysis by acting locally at the thrombus site, because no differences in systemic coagulation/fibrinolytic parameters were detected. Therefore, P-selectin antagonism is likely to be a safe approach, with no significant bleeding complications. In this regard, rPSGL-Ig did not prolong rat tail bleeding times when administered alone or in conjunction with aspirin, heparin, or both (unpublished data, 1998). Also, P-selectin–knockout mice were found to have bleeding times no different from those of wild-type mice.39 Administration of rPSGL-Ig caused little to no increase in susceptibility to bacterial infections in mice (unpublished data, 1998). This may be related to the fact that rPSGL-Ig is mainly a P-selectin antagonist, with weak binding properties to E- and L-selectin. In addition, because of the role of P-selectin in leukocyte recruitment to endothelium, P-selectin antagonism would have added anti-inflammatory benefit and protection from reperfusion injury. A selectin inhibitor administered as an adjunct to thrombolytic therapy was reported to reduce infarct size in a canine model of coronary thrombosis.40 Treatment with an anti–P-selectin antibody protected the feline heart in a model of myocardial ischemia and reperfusion injury.41 Finally, 2 anti–P-selectin antibodies decreased vein wall inflammation and thrombus formation in a baboon model of deep vein thrombosis.42
This work provides evidence that P-selectin antagonism is an effective approach to enhancing the effect of thrombolytic therapy. The physiological P-selectin ligand used in this work is a compound with a long half-life that has the added benefit of being administered as a bolus. rPSGL-Ig may represent a novel and safe therapeutic that could be important in accelerating thrombolysis, in promptly achieving optimal reperfusion, and in significantly reducing the incidence of acute reocclusion. Further clinical investigation of this compound is warranted.
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Acknowledgments |
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The authors wish to thank Robin Shearer and Kathryn Madden, Charles River PharmServices, for technical assistance. We are grateful to Dr Yahye Merhi, Montreal Heart Institute, for porcine platelet-neutrophil binding assays. We thank Dr Richard Rockar (Laboratory Animal Resources) for his input, Annamaria Paone (Assay Systems) for rPSGL-Ig measurements, Gregg Timony (Pharmacokinetics) for pharmacokinetic assessment of rPSGL-Ig, and Kristin Murray (Bioanalytical Sciences, Genetics Institute) for determining binding to selectins of rPSGL-Ig. Finally, we thank the PSGL-1 team at Genetics Institute, Inc.
Received June 25, 1998; revision received October 1, 1998; accepted October 26, 1998.
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