© 2000 American Heart Association, Inc.
Molecular Medicine |
Immunoneutralization of Glycoprotein Ib
Attenuates Endotoxin-Induced Interactions of Platelets and Leukocytes With Rat Venular Endothelium In Vivo
From the Departments of Biochemistry (Y. Ishimura, M.S.) and Medicine (Y. Ikeda) and Blood Center (M.H.), School of Medicine, Keio University, Tokyo; the Department of Obstetrics and Gynecology, Ehime University School of Medicine, Ehime (T.K., M.I.); and the Pharmaceutical Frontier Research Laboratories, JT Inc, Yokohama, Kanagawa (T.T., S.S.), Japan.
Correspondence to Makoto Suematsu, MD, PhD, Associate Professor, Department of Biochemistry, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail msuem{at}mc.med.keio.ac.jp
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Abstract |
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Abstract—This study aimed to examine molecular mechanisms for endotoxin-induced adhesive changes in platelets in vivo. Platelets labeled with carboxyfluorescein diacetate succinimidyl ester were visualized in rat mesenteric venules through intravital microscopy assisted by a high-speed fluorescence video imager at 1000 frames per second or by a normal-speed intensifier under monitoring of erythrocyte velocity. Leukocyte rolling was examined by normal-speed transmission video images. The velocity of platelets traveling along the centerline of venules followed that of erythrocytes, whereas that measured at the periendothelial space was significantly smaller than the erythrocyte velocity; a majority of these cells exhibited transient but notable rolling with endothelium. Administration of endotoxin increased the density of periendothelial platelets and reduced the rolling velocities of platelets and leukocytes in venules: All events were attenuated by anti–rat P-selectin monoclonal antibody s789G or by anti–human glycoprotein (GP) Ib
monoclonal antibody
GUR83/35, which blocks ristocetin-induced aggregation of rat
platelets. Isolated rat platelets injected into
endotoxin-pretreated rats were able to roll on the venules. This event
was attenuated by pretreatment of platelets in vitro with GUR83/35
but not with s789G, suggesting involvement of
endothelial P-selectin and platelet GP Ib in the
endotoxin-induced responses. Furthermore, isolated human platelets
showed similar rolling interactions with endotoxin-preexposed rat
venules, and pretreatment of the platelets with GUR83/35, but not
with s789G, significantly reduced such interactions. Our results
provide the first evidence for involvement of GP Ib in
endotoxin-induced microvascular rolling of platelets and
leukocytes, and this system serves as a potentially useful tool to
examine GP Ib–associated function of human platelets in
vivo.
Key Words: platelets • endothelial cells • P-selectin • shear stress • endotoxin
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Introduction |
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Under physiological conditions, platelets are thought to circulate in close contact with microvascular endothelial cells without adhering to their surface. The cells have been thought to neither adhere to the site of injury nor undergo activation until these cells are exposed to platelet-activating subendothelial substances such as collagen.1 On the initial adhesive process, platelets can release varied mediators and activate other platelets.2 Once the first layer of adhered platelets forms the stable thrombogenic surface, growth of the hemostatic plug occurs dependently on the mediator-elicited platelet-to-platelet interactions.2 These 2 events represent adhesion and aggregation of platelets, respectively.
Detailed knowledge of the density or velocity distribution of
platelets flowing along the periendothelial space
in vivo could help us understand mechanisms for the initial process of
thrombogenesis and subsequent inflammatory responses involving
leukocyte adhesion for several aspects: First, determination of the
density of platelets in the local area allows us to estimate the
rate of local platelet delivery. Second, analyses of
velocity distribution of the periendothelial
platelets make it possible to estimate alterations in adhesive
force between platelets and endothelial cells under
disease conditions and thus provide important information on changes in
their adhesivity under flow conditions. Third, considering the presence
of varied adhesion molecules on platelets that might bind to ligand
molecules on the surface of leukocytes, the density of platelets in
the periendothelial space could determine venular
leukocyte recruitment in acute inflammatory processes.3 4
However, little knowledge of the behavior of individual platelets
circulating close to the periendothelial space has been
available because of technical difficulties in visualizing these cells
in a reliable manner. We applied intravital ultrahigh-speed intensified
microscopy assisted by carboxyfluorescein diacetate
succinimidyl ester, a fluorochrome that can stain platelets
intravitally. The present results provide evidence that under
disease conditions such as endotoxemia, circulating platelets
display the periendothelial rolling in postcapillary
venules through mechanisms involving endothelial
P-selectin and glycoprotein (GP) Ib on platelets and
help leukocyte rolling and adhesion in vivo.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our study protocol was approved by the Animal Care and Utilization Committee of Keio University School of Medicine. Male Wistar rats were anesthetized for intravital microscopy of mesenteric microvessels in vivo5 6 7 8 and treated with an intravenous injection of carboxyfluorescein diacetate succinimidyl ester, a nonfluorescent precursor taken up into platelets and partly into leukocytes, forming a stable fluorochrome, carboxyfluorescein succinimidyl ester (CFSE), in the cells.5 6 CFSE-labeled platelets were visualized through multifunctional intravital fluorescence microscopy as described previously.5 7 Advantages of the present approach compared with previous methods for platelet visualization are described in the online-only Materials and Methods (see http://www.circresaha.org). Six main protocols were used: Rats in group 1 were intravenously perfused with physiological saline as a vehicle for 30 minutes. In group 2, rats were injected with lipopolysaccharide (LPS, O111B4; 1.0 mg · kg-1 · h-1 IV for 30 minutes) according to the previous experimental model of endotoxemia.9 Animals in groups 3 and 4 were pretreated with new monoclonal antibodies (mAbs) against rat P-selectin s789G and s84F. Rats in groups 5 and 6 were pretreated with anti–human GP Ib
mAbs, GUR83/35 and WGA3. GUR83/35
is reported to recognize a conformation-specific epitope between
residues 1 and 302 of GP Ib and to block the binding of von
Willebrand factor to human platelets in the presence of
ristocetin, whereas WGA3 binds to the same region but does not block
the ristocetin-induced aggregation of platelets.10 11
These mAbs were injected at 1.5 mg/kg IV 5 minutes before the start of
the LPS infusion. Individual erythrocytes and platelets were
visualized through an ultrahigh-speed intensified video microscope.
This system allowed us to visualize platelets and erythrocytes at
1000 frames per second for 1 second under epi-illumination and
transillumination, respectively. Velocities of individual platelets
were normalized by dividing the values by the regional erythrocyte
velocity in the centerline or the periendothelial
region, with the result designated as the relative platelet
velocity (VP/VR) in each
region. This value serves as a semiquantitative index of the adhesion
energy between platelets and endothelial cells. We
examined differences in circulating platelet counts and the density
of platelets between the periendothelial and
centerline regions of microvessels as shown in previous studies using
acridine red–assisted intravital microscopy.12 The
normalized densities of CFSE-positive platelets in the centerline
(DPC) and periendothelial
(DPE) regions were defined as described in the
online-only Materials and Methods (see http://www.circresaha.org). The
relative rolling velocity of leukocytes
(VW/VR) and the density of
adherent cells were determined separately with normal-speed
transmission video images as described elsewhere.5 7 In
other experiments, isolated rat and human platelets were injected
intravenously into rats undergoing 30-minute exposure to
the LPS infusion, and their behavior in venules was examined with a
silicon-intensified target (SIT) camera.8 Function of
isolated platelets was examined with a laser-scattering
platelet aggregometer. Anti–P-selectin mAbs were generated, and
their ability to block P-selectin–mediated cell adhesion in vitro was
characterized. Differences among groups were examined by 1-way ANOVA
with Fisher’s multiple comparison test. An expanded Materials and Methods section is available online at http://www.circresaha.org.
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Results |
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Individual Platelets Labeled With CFSE
Figure 1
illustrates the effects of
in vivo fluorescence labeling with CFSE on platelet
aggregation. As seen in Figures 1A and 1B, the distribution of
rat platelets on a culture dish corresponded to that of the cells
tagged with fluorescence, whereas not all platelets were
able to be visualized under the same optical conditions as used for
intravital microscopy. As depicted in Figure 1C, platelets
labeled or unlabeled with CFSE were equally activated and
displayed similar extents of microaggregate formation in response to
ristocetin and ADP. Peak signal intensities indicating small and large
aggregates and peak percentage values of light transmission (%T)
elicited by ADP were not statistically different between the groups
(Table 1). Furthermore, time to observe
these peak values did not differ significantly. Circulating counts of
platelets were not different between the animals treated or
untreated with CFSE (data not shown). Collectively, the present
method for labeling of platelets allowed us to observe individual
platelets through fluorescence microscopy without notable
alterations in platelet functions in vitro.
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Millisecond Interactions of Platelets With Microvascular
Endothelium
As shown in Figure 2A, videorecording at 1000 frames per second under
transillumination allowed us to visualize individual erythrocytes
packed in microvessels and recognized as granular patterns of images.
Regional velocities of single erythrocytes in venules were
analyzed by tracing movement of each cell per unit frame with a
frame-by-frame analysis, as shown in Figure 3. At this recording rate,
CFSE-labeled platelets can be visualized, but their exact
localization inside the vessels could hardly be identified because of
their rapidity of movement, as seen in Figure 2B. Conversely,
their frame-by-frame reproduction by replaying at 30 frames per
second allowed us to visualize individual platelets as pinpoint
dots and to trace movement of these cells along vessel walls. As seen
in serial fluorographs with 20- or 40-ms intervals in Figures 2C
through 2H, a single platelet moving in the
periendothelial space of the venule exhibited quite
heterogeneous changes in its velocity. The distance of
movement per unit time in 1 cell (arrows) differed greatly from that in
another cell (asterisks), indicating a heterogeneity in
velocities among different platelets.
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Spatial and Temporal Alterations in Erythrocyte Velocity in
Microvessels
On the basis of the frame-by-frame analysis of
transillumination images, we examined temporal and spatial profiles of
the erythrocyte velocity in postcapillary venules. As seen in Figure 3A
, showing the velocity of single erythrocytes (z
axis) as a function of time (x axis) and position
(y axis) of measurements, the velocity measured in the
venular centerline region did not fluctuate greatly. The velocity of
erythrocytes flowing in venules was greater in the centerline region
than in the periendothelial region. This observation
led us to hypothesize that the heterogeneity of
movement of platelets in the periendothelial region
illustrated in Figure 2 could result from transient adhesive
interactions of the cells with the endothelial surface
rather than from local changes in erythrocyte velocities. To test this
hypothesis, we examined alterations in the relative velocity of
individual platelets versus erythrocyte velocity
(VP/VR) in venules of the
control rats. As shown in 3B, the
VP/VR values of a single
platelet flowing at the centerline of venules was almost constant,
at 
100%, in venules. Conversely, the velocity of platelets
flowing in the periendothelial regions exhibited a
fluctuating pattern: The
VP/VR values of these
platelets occasionally became as low as 50% of the local
erythrocyte velocity, suggesting the presence of adhesive interactions
between the periendothelial platelets and
microvascular endothelium.
Such a baseline level of the platelet-endothelium
interactions was enhanced by treatment of rats with LPS. Figure 3C illustrated histograms showing distribution of the
VP/VR values in the
periendothelial space of venules. In the controls, the
periendothelial platelet velocity varied greatly
among different cells, whereas the mean VP value
was 92% of the mean VR value, and 50% of
the cells exhibited a velocity <90% of the regional erythrocyte
velocity. At 30 minutes after the start of the LPS administration,
venular wall shear rates did not change significantly, but the
VP/VR histogram exhibited a
marked shift to the left side. Under the present experimental
conditions, venular wall shear rates in the LPS-untreated and -treated
rats were 486±39 s-1 and 476±52
s-1 (mean±SD of 7 experiments), respectively,
showing no statistical difference. These results suggest that LPS
increases the adhesion energy between periendothelial
platelets and venular endothelium in vivo.
P-Selectin–Mediated Microvascular Rolling of Platelets in
LPS-Treated Rats
We determined the effects of mAbs against P-selectin and GP Ib
and then applied them to the in vivo systems. Figure 4A illustrates the effects of the
anti–rat P-selectin mAbs on the intercellular adhesion between the
P-selectin–expressing transfectant and HL-60 cells. The mAb s789G, but
not s84F, dose-dependently attenuated the cell adhesion, indicating
that the former mAb serves as a reagent to block leukocyte adhesion.
Figure 4B depicted effects of anti–human GP Ib mAbs on
ristocetin-induced aggregation of rat platelets. As seen, GUR83/35,
but not WGA3, significantly suppressed ristocetin-induced responses of
rat cells, indicating that the former mAb can be used to block the rat
GP Ib–mediated events.
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P<0.05 vs data in the WGA3-treated platelets. C,
Inhibitory effects of these mAbs on LPS-induced changes in
the circulating number of platelets (PLT),
DPE/DPC, and VP/VR.
*P<0.05 vs control values. The values indicate mean+SEM
of 6 different rats in all groups.
Figure 4C shows LPS-induced alterations in circulating
platelet counts and density
(DPE/DPC) and velocity
(VP/VR) of
periendothelial platelets in venules and depicts
the effects of the aforementioned mAbs against P-selectin or GP Ib
on these parameters. Administration of LPS significantly
reduced the number of platelets in peripheral blood
samples. Conversely, the
DPE/DPC values exhibited an
20% elevation on the administration of LPS. The LPS-induced
elevation of the periendothelial platelet density
coincided with a marked reduction of the mean
VP/VR values, indicating an
increasing adhesivity between the platelets and
endothelial cells. Collectively, the LPS-induced
thrombocytopenic changes appeared to occur concurrently with
margination of circulating platelets to the
periendothelial space. Pretreatment with s789G but not
with s84F significantly attenuated the LPS-induced changes in these
platelet parameters, suggesting that P-selectin
mediates the LPS-induced microvascular margination of platelets.
Most importantly, pretreatment with the mAb GUR83/35 but not with WGA3
elicited similar inhibitory effects on the LPS-induced
changes, suggesting that functional blockade of GP Ib on circulating
platelets cancels platelet-endothelium
interactions in LPS-exposed venules. Conversely, the administration of
1 of the 2 mAbs to the LPS-untreated rats did not evoke alterations in
these parameters (data not shown).
Another important event observed during the administration of LPS was a
reduction of the rolling velocity of leukocytes in venules. As seen in
Table 2, the administration of LPS
induced an 60% reduction of the
VW/VR. Pretreatment with
s789G abolished the LPS-elicited alterations, suggesting involvement of
P-selectin in leukocyte rolling in the stimulated venules, which was in
good agreement with previous studies.3 8 The LPS-elicited
reduction of the rolling velocity was also attenuated significantly by
pretreatment with GUR83/35, suggesting that functional blockade of GP
Ib attenuates the LPS-induced elevation of adhesion energy. The LPS
infusion also elicited a marked increase in the density of adherent
leukocytes that was attenuated by pretreatment with s789G. The blockade
of GP Ib by GUR83/35 also attenuated the LPS-induced venular
leukocyte adhesion significantly, although its effect was smaller than
that of s789G. Collectively, these results suggest that the
platelet adhesion molecule GP Ib is a determinant involved in
mechanisms for the LPS-induced microvascular leukocyte recruitment.
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Role of GP Ib in Rolling of Rat and Human Platelets in
LPS-Pretreated Venules
Observations shown in Figure 4 led us to further examine
the roles of P-selectin and GP Ib in the LPS-induced interactions
between platelets and venular endothelium. To that
effect, differences in adhesivity of isolated rat platelets
pretreated or not treated with mAbs against these adhesion molecules
were examined in LPS-pretreated rats under observation with an SIT
camera. Once injected, the platelets displayed a transient adhesion
and rolling, and some cells exhibited stationary adhesion to the
venular endothelium (Figure 5). A subpopulation of the
platelets flowing at the periendothelial space
often attached to rolling leukocytes and made them slow down further.
Formation of leukocyte-platelet complex was seen occasionally. As
summarized in Figure 5, right, CFSE-labeled platelet rolling
on venules was enhanced by pretreatment with LPS. When the isolated
platelets were pretreated with the mAb s789G, their adhesive
responses were not greatly changed. By contrast, pretreatment of the
isolated platelets with GUR83/35 almost abolished their adhesion to
the LPS-preexposed venules. These results showed that blockade of
constitutively expressed GP Ib on platelets is involved in
mechanisms through which this mAb administered in vivo attenuated the
LPS-induced platelet interactions with the
endothelium.
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This observation tempted us to examine whether human platelets
could utilize GP Ib–mediated mechanisms to adhere to rat venular
endothelium in vivo. As seen in Figure 6A, the platelets administered into
the LPS-treated rats exhibited rolling with greater frequency than
those administered into the untreated controls over the whole ranges of
the velocities. The population of the slow rollers with velocities
<0.2 mm/s became markedly elevated in the LPS-treated group. As
shown in Figure 6B, in vitro pretreatment of human platelets
with the mAb GUR83/35, but not with WGA3, significantly attenuated such
adhesive changes observed in vivo. Thus, the present findings
demonstrated that human platelets exogenously administered into the
rat vascular system are able to roll on microvascular
endothelium through GP Ib–mediated mechanisms.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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High-speed microfluorography allowed us to show that platelets not only can traverse through the centerline region of microvessels in a free-flowing manner but also can move along the periendothelial region and display notable interactions with the endothelial surface at millisecond intervals even under unstimulated, ordinary conditions. Such interactions of platelets are distinct from the slow rolling behavior observed only in a subpopulation of platelets that has been detected by normal-speed videomicroscopy.13 14 Although this varied among individual cells, a majority of periendothelial platelets displayed rapid but detectable attachment to the endothelium, and some of them exhibited a velocity <50% of the erythrocyte velocity measured in situ. Such interactions of platelets were markedly enhanced by LPS treatment. The present data indicate that unstimulated platelets are able to roll on the LPS-preexposed venules and suggest a crucial role of P-selectin expressed at the side of the stimulated endothelium, as also shown in previous reports using different experimental models.14 15 Moreover, this adhesion molecule appears to be involved in the LPS-induced shift of platelet distribution toward the periendothelial space. However, we were unable to address molecular determinants for the baseline adhesive interactions of platelets with the unstimulated venules: Inasmuch as the s789G pretreatment did not alter the baseline platelet interactions in vivo, the role of P-selectin in vivo appeared to be small or none.
Most importantly, the present study provided a novel insight into
mechanisms for platelet adhesion mediated by GP Ib in vivo. Two
parameters were significantly altered by LPS through
mechanisms involving GP Ib: increases in the adhesion energy of
platelets to venular endothelium and the density of
the cells traveling along the periendothelial space.
Because 1 of the mAbs s789G and GUR83/35 at the present dose
sufficiently attenuated the LPS-induced changes in these platelet
parameters, the interaction between P-selectin expressed on
the LPS-stimulated venular endothelium and GP Ib on
platelets appears to play a role in the adhesive responses of
platelets. This notion is fully supported by recent studies in
vitro showing that GP Ib serves as a platelet counterreceptor
for P-selectin.16
Another important event observed under GP Ib immunoneutralization is
downregulation of LPS-induced venular leukocyte rolling and adhesion:
Several different patterns of platelet-leukocyte interactions were
observed in the LPS-treated microvessels. First, as also shown
elsewhere,3 17 circulating platelets adhere to the
surface of leukocytes and thereby help them slow down to roll and
adhere. Second, platelets moving along the
periendothelial space may by chance collide with
leukocytes rolling directly along venular endothelium
and help them slow down further for stationary adhesion. The GP
Ib–mediated elevation of the periendothelial
platelet density and increase in the adhesion energy to the
LPS-exposed venules could enhance both of these mechanisms for
intercellular interactions and secondarily activate leukocyte
adhesivity. Detailed molecular mechanisms for the GP Ib–mediated
direct interactions between platelets and leukocytes in vivo (eg,
L-selectin) and involvement of plasma factors reacting with GP Ib (eg,
von Willebrand factor) should be examined
further.18 19
Finally, our study revealed that the rat system serves as a potentially
useful tool to examine GP Ib–associated function of human
platelets in vivo, in that they can utilize GP Ib to roll in a
manner similar to that of rat platelets on the stimulated
microvascular endothelial cells. GP Ib has been known
to play important roles in a variety of functional alterations of
platelets in vitro, such as shear-dependent
aggregation19 and adhesion to immobilized von
Willebrand factor under flow conditions in
vitro.20 In humans, conversely, there are genetic
disorders of this adhesion molecule, such as Bernard-Soulier
syndrome21 or cases of heightened platelet aggregation
by ristocetin.10 22 However, a
pathophysiological link of such in vitro events to
actual behavior of functionally impaired platelets in vivo is
largely unknown because of lack of the intravital system to examine
human platelet functions. Determination of impaired adhesive
properties of human platelets collected from disease patients
deserves further studies to understand the whole mechanisms for
platelet-dependent hemostatic and thrombotic disorders from
microvascular viewpoints, and such studies are under way in our
laboratories.
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Acknowledgments |
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This work was supported by Advanced Medical Technology in Health Sciences Research Grants from Ministry of Health and Welfare and in part by Keio Medical Science Fund.
Received January 31, 2000; accepted March 29, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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R. Gotoh, J.-i. Suzuki, H. Kosuge, T. Kakuta, S. Sakamoto, M. Yoshida, and M. Isobe E-Selectin Blockade Decreases Adventitial Inflammation and Attenuates Intimal Hyperplasia in Rat Carotid Arteries After Balloon Injury Arterioscler Thromb Vasc Biol, November 1, 2004; 24(11): 2063 - 2068. [Abstract] [Full Text] [PDF]
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K. C. Wood, R. P. Hebbel, and D. N. Granger Endothelial cell P-selectin mediates a proinflammatory and prothrombogenic phenotype in cerebral venules of sickle cell transgenic mice Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1608 - H1614. [Abstract] [Full Text] [PDF]
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 W. C. Aird The Hematologic System as a Marker of Organ Dysfunction in Sepsis Mayo Clin. Proc., July 1, 2003; 78(7): 869 - 881. [Abstract] [PDF]
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 T. Katayama, Y. Kusanagi, M. Kiyomura, H. Ochi, and M. Ito Leukocyte behaviour and permeability in the rat mesenteric microcirculation following induction of ovulation Hum. Reprod., June 1, 2003; 18(6): 1179 - 1184. [Abstract] [Full Text] [PDF]
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W. C. Aird The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome Blood, May 15, 2003; 101(10): 3765 - 3777. [Abstract] [Full Text] [PDF]
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M. C. Berndt Induction of Platelet-Endothelial Interactions in Postcapillary Venules in Hypercholesterolemia: Critical Role of P-Selectin Arterioscler Thromb Vasc Biol, April 1, 2003; 23(4): 525 - 527. [Full Text] [PDF]
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W. H. Cerwinka, D. Cooper, C. F. Krieglstein, C. R. Ross, J. M. McCord, and D. N. Granger Superoxide mediates endotoxin-induced platelet-endothelial cell adhesion in intestinal venules Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H535 - H541. [Abstract] [Full Text] [PDF]
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 J. Russell, D. Cooper, A. Tailor, K. Y. Stokes, and D. N. Granger Low venular shear rates promote leukocyte-dependent recruitment of adherent platelets Am J Physiol Gastrointest Liver Physiol, January 1, 2003; 284(1): G123 - G129. [Abstract] [Full Text] [PDF]
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 T. E. Warkentin, W. C. Aird, and J. H. Rand Platelet-Endothelial Interactions: Sepsis, HIT, and Antiphospholipid Syndrome Hematology, January 1, 2003; 2003(1): 497 - 519. [Abstract] [Full Text] [PDF]
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 S. Kashiwagi, M. Kajimura, Y. Yoshimura, and M. Suematsu Nonendothelial Source of Nitric Oxide in Arterioles But Not in Venules: Alternative Source Revealed In Vivo by Diaminofluorescein Microfluorography Circ. Res., December 13, 2002; 91 (12): e55 - e64. [Abstract] [Full Text] [PDF]
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W. H. Cerwinka, D. Cooper, C. F. Krieglstein, M. Feelisch, and D. N. Granger Nitric oxide modulates endotoxin-induced platelet-endothelial cell adhesion in intestinal venules Am J Physiol Heart Circ Physiol, March 1, 2002; 282(3): H1111 - H1117. [Abstract] [Full Text] [PDF]
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Y. Shen, J.-f. Dong, G. M. Romo, W. Arceneaux, A. Aprico, E. E. Gardiner, J. A. Lopez, M. C. Berndt, and R. K. Andrews Functional analysis of the C-terminal flanking sequence of platelet glycoprotein Ibalpha using canine-human chimeras Blood, January 1, 2002; 99(1): 145 - 150. [Abstract] [Full Text] [PDF]
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 K. Nishijima, J. Kiryu, A. Tsujikawa, M. Honjo, A. Nonaka, K. Yamashiro, H. Tanihara, S. J. Tojo, Y. Ogura, and Y. Honda In Vivo Evaluation of Platelet-Endothelial Interactions after Transient Retinal Ischemia Invest. Ophthalmol. Vis. Sci., August 1, 2001; 42(9): 2102 - 2109. [Abstract] [Full Text] [PDF]
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