Published online before print September 2, 2004, doi: 10.1161/01.RES.0000143899.73453.11
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© 2004 American Heart Association, Inc.
Molecular Medicine |
Tumor Necrosis Factor-
–Converting Enzyme (ADAM17) Mediates GPIb Shedding From Platelets In Vitro and In Vivo
From the CBR Institute for Biomedical Research (W.B., C.L.P., G.C., V.S.D., U.H.v.A., D.D.W.) and the Department of Pathology (W.B., V.S.D., U.H.v.A., D.D.W.), Harvard Medical School, Boston, Mass; and Wyeth Research (Y.Z.), Cambridge, Mass.
Correspondence to Dr Denisa D. Wagner, Harvard Medical School, CBR Institute for Biomedical Research, 800 Huntington Ave, Boston, MA 02115-6399. E-mail wagner{at}cbr.med.harvard.edu
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Abstract |
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Interaction of the platelet receptor glycoprotein (GP) Ib-V-IX with von Willebrand factor exposed at a site of vascular injury is an essential step in the initiation of a hemostatic plug. Proteolytic cleavage (shedding) of the GPIb
subunit was first described >25 years ago, the protease mediating this event as well as its physiological function, however, have not been elucidated. We reported recently that shedding of GPIb induced by platelet storage or mitochondrial injury involves a platelet-derived metalloproteinase(s). Here we show that GPIb shedding in response to mitochondrial injury or physiological activation is inhibited in platelets obtained from chimeric mice, which express inactive tumor necrosis factor- converting enzyme (TACE
Zn/Zn) in blood cells only. Shedding was also inhibited in mouse and human platelets in the presence of 2 potent TACE inhibitors: TAP1 and TMI-1. Our data further suggest that TACE is important in the regulation of GPIb expression in vivo because we observed an 
90% reduction in soluble GPIb (glycocalicin) in plasma of TACEZn/Zn chimeras as well as significantly increased levels of GPIb on circulating platelets. In contrast, shedding of P-selectin from activated platelets was not affected by the mutation in TACE. Damaged TACEZn/Zn platelets were further characterized by a markedly improved post-transfusion recovery and hemostatic function in mice. In conclusion, our data demonstrate that TACE is expressed in platelets and that it is the key enzyme mediating shedding of GPIb.
Key Words: platelets • TACE • GPIb, shedding
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Introduction |
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Cellular activation often results in the rapid proteolysis of a wide range of transmembrane proteins such as growth factors/cytokines, growth factor/cytokine receptors, and adhesion molecules. This process, known as ectodomain shedding, regulates many cellular functions and has been implicated in pathologies such as Alzheimer’s disease and cancer.1 The majority of these shedding events are mediated by zinc-dependent proteinases, most importantly members of the matrix metalloproteinase (MMP)2 and a disintegrin and metalloproteinase (ADAM)3 family of proteinases. Initially identified as a sheddase for tumor necrosis factor-
(TNF-), TNF-–converting enzyme (TACE; ADAM17) was also shown to mediate the release of many other cell surface transmembrane proteins, including adhesion molecules such as L-selectin and vascular cell adhesion molecule 1 (VCAM-1).4–6 Inactivation of the metalloproteinase activity of TACE by targeted deletion of the Zn2+-binding domain in mice (TACEZn/Zn) results in perinatal lethality, demonstrating the importance of ectodomain shedding in vivo.4
In platelets, proteolytic cleavage has been identified as a key mechanism to regulate the surface expression of a variety of adhesion receptors, including P-selectin, CD40 ligand, and the glycoprotein (GP) V and GPIb subunits of the von Willebrand factor receptor complex, GPIb-V-IX.7–9 GPIb-V-IX plays an important role in the adhesion of circulating platelets to sites of vascular injury.10,11 Cellular activation leads to internalization of GPIb-V-IX as well as ectodomain shedding of the GPIb subunit from the cell surface.9,12 Soluble GPIb (glycocalicin [GC]) is normally found in plasma at concentrations of 2 µg/mL and 20 µg/mL in humans13 and mice,12 respectively. Its physiological function is not known. We demonstrated recently that GPIb shedding in damaged platelets correlates with the clearance of such cells and that release of GPIb and platelet clearance require the activation of endogenous metalloproteinase(s).14 Although it is well documented that platelets can mobilize several MMPs15 as well as ADAM1016 on cellular activation, the proteinase mediating GPIb shedding has not yet been identified.
To investigate whether TACE plays a role in the shedding of GPIb, we generated TACEZn/Zn chimeric mice that lack the enzyme in blood cells only. Our results demonstrate that TACE mediates shedding of GPIb from platelets and that it is the major sheddase responsible for generation of GC in mice.
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Materials and Methods |
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Animals
C57BL/6 wild-type mice were purchased from The Jackson Laboratory. TACE+/
Zn mutant mice (C57BL/6J/129Sv background)4 were kindly provided by Dr Jaques Peschon at Amgen (Seattle, Wash). Experimental procedures were approved by the Animal Care and Use Committee of the CBR Institute For Biomedical Research.
Materials
ADP, phorbol 12-myristate 13-acetate (PMA), thrombin, carbonyl cyanide m-chlorophenylhydrazone (CCCP), ferric chloride, human fibrinogen (Sigma), calcein acetoxymethyl ester (AM), calcein red-orange AM (Molecular Probes), P-selectin ELISA (R&D Systems), and N(R)-[2-(hydroxyaminocarbonyl)methyl]-4-methylpentanoyl-L-naphthylalanyl-L-alanine amide TNF- protease inhibitor (TAPI) (Calbiochem) were purchased. Inhibitor 4-[[4-(2-butynyloxy)phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-(3S)-thiomorpholinecarboxamide (TMI-1)17 was provided by Wyeth (Cambridge, Mass). Collagen-related peptides (CRPs) were a kind gift from Dr J. Hartwig (Boston, Mass). Antibodies against mouse P-selectin, mouse L-selectin, human GPIb, and human GPIX (BD PharMingen), human fibrinogen (DAKO), mouse neutrophil marker Ly-6 G (also known as myeloid differentiation antigen Gr-1) (eBiosciences), and mouse GPIb, GPIX, and integrin IIbß3 (emfret ANALYTICS) were purchased.
Generation of TACEZn/Zn Chimeras
Fetal liver cells were isolated from TACE+/+ and TACEZn/Zn sibling embryos at day 16.5 of development and injected into irradiated C57BL/6J recipient mice (1250 rad; 1x107 cells per mouse). The genotype of the embryos was initially identified phenotypically (open eye at birth)4 and subsequently verified by polymerase chain reaction (PCR).
Surface Expression of L-Selectin
Whole blood was diluted 10-fold in red blood cell lysis buffer (155 mmol/L NH4Cl, 10 mmol/L KHCO3, and 0.1 mmol/L Na2EDTA, pH 7.4) and incubated for 5 minutes at room temperature (RT). After washing, leukocytes were resuspended in modified Tyrode’s-HEPES buffer, activated with PMA (200 ng/mL) for 10 minutes, and stained with monoclonal antibodies against L-selectin and Ly-6G (10 minutes at RT). Samples were analyzed by flow cytometry.
Expression of Glycoproteins on Resting and Activated Platelets
Platelets (1x106) were either kept resting or treated with thrombin or ADP (in the presence of 5 µmol/L thromboxane A2 analog U46619) for 5 minutes at RT, stained with saturating amounts of fluorophore-coupled antibodies, and immediately analyzed.
GPIb Shedding From Mouse and Human Platelets
Mouse and human platelets were isolated and analyzed for GPIb expression.14 Mouse platelets were treated with 100 µmol/L CCCP (60 minutes), 200 ng/mL PMA (10 minutes), 0.5 U/mL thrombin (10 minutes), or 5 µg/mL CRP (10 minutes). Human platelets were treated for 5 hours with 100 µmol/L CCCP. We obtained informed consent from all donors and approval from the institutional review board of the CBR Institute for Biomedical Research. TAPI and TMI-1 were added at the indicated concentrations 5 minutes before addition of CCCP. CCCP, PMA, TAPI, and TMI-1 were dissolved in dimethyl sulfoxide (DMSO); the final concentration of DMSO in any sample did not exceed 1% v/v. For flow cytometry, samples were stained with saturating amounts of anti-GPIb mAb pop4-PE (15 minutes at RT) and immediately analyzed on a FACScalibur. For immunoblotting, samples were diluted in 2x sodium dodecyl sulfate sample buffer, separated by SDS-PAGE (7.5%) under reducing conditions, and transferred to a polyvinylidene fluoride membrane. The membrane was first incubated with 2.5 µg/mL anti-GPIb mAb p0p5,12 followed by rabbit anti-rat–horseradish peroxidase (1 µg/mL).Proteins were visualized by enhanced chemiluminescence. The Western blot was quantified by densitometry using NIH Image software on digitized photographs.
P-Selectin Shedding In Vivo
Platelets were labeled with 25 µg/mL biotin for 10 minutes at RT, washed once, resuspended in modified Tyrode’s-HEPES buffer containing 5 mmol/L EDTA, and activated with 0.1 U/mL thrombin for 10 minutes. After incubation with hirudin (0.5 U/mL for 10 minutes), platelets were intravenously infused into the retro-orbital plexus of mice (1.5x108 platelets per 15 g body weight). Blood was taken 3 hours after platelet transfusion. Diluted blood samples were stained with streptavidin-PE and anti-P-selectin–fluorescein isothiocyanate (10 minutes at RT) and analyzed on a FACScalibur.
Aggregometry
To determine platelet aggregation, light transmission was measured using washed platelets adjusted to a platelet concentration of 3x108 platelets/mL with modified Tyrode’s buffer containing 1 mmol/L CaCl2 (thrombin) or plasma (ADP). Agonists were added as 100-fold concentrates, and transmission was recorded over 14 minutes on a Chrono-Log 4-channel optical aggregation system (Chrono-Log).
Platelet Counts
Platelet counts in whole blood were determined by flow cytometry according to a method described previously by Alugupalli et al.18 Briefly, 30 µL diluted whole blood samples (1/20 in PBS containing 10 U/mL heparin) were labeled with anti-IIbß3 mAb JON1-PE (10 minutes at RT), and samples were diluted by the addition of 950 µL PBS. SPHERO rainbow fluorescence polystyrene beads (Sperotech Inc.) were added as an internal standard at a final concentration of 105 beads/mL. Platelets and beads were resolved on the basis of the scatter characteristics and their fluorescence signals.
Bleeding Time Measurement
A 3-mm segment of the tail was amputated from age-matched TACE+/+ and TACEZn/Zn chimeric mice. The tail was immersed in PBS at 37°C, and the time required for the stream of blood to stop was defined as the bleeding time.
In Vivo Thrombosis Model
Platelets were labeled for 10 minutes with calcein-green (5 µg/mL) or calcein-red/orange (2.5 µg/mL) and infused into 3- to 5-week-old anesthetized male mice. The mesentery was exposed through a midline abdominal incision, and injury was induced by application of FeCl3.19 Vessels were monitored until cessation of blood flow lasted longer than 10 seconds.
Platelet Recovery and Survival in Mice
Platelets were labeled with 1 µg/mL calcein-green for 15 minutes at RT, washed once, resuspended in modified Tyrode’s-HEPES buffer, and intravenously infused into the retro-orbital plexus of mice (0.75x108 platelets per 15 g body weight). For determination of the in vivo recovery and survival of transfused platelets, blood samples were collected at various time points after transfusion using heparin-coated microcapillaries. Diluted whole blood samples (1/20 in PBS containing 10 U/mL heparin) were stained with anti-IIbß3 mAb JON1-PE and analyzed by flow cytometry to determine the percentage of calcein-positive platelets. Platelets were identified by forward scatter characteristics and fluorescence 2.
Statistics
Unless stated otherwise, results are reported as mean value±SD. The statistical significance was assessed by Student t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Platelet adhesion and thrombus formation at sites of vascular injury is a highly regulated process that involves various adhesion/activating receptors on the platelet surface, including GPIb
.11 We and others demonstrated recently that ectodomain shedding is a key mechanism for the regulation of GPIb on the platelet surface and that shedding is dependent on endogenous metalloproteinase activity.9,14
Generation of TACE Chimeric Mice
To study a potential role of TACE in the cleavage of GPIb, we generated chimeric mice that express inactive TACE in blood cells only. For that purpose, we transplanted irradiated wild-type recipient mice with fetal liver cells isolated from TACE+/+ or TACEZn/Zn embryos. To determine the percentage of chimerism, we took advantage of the fact that TACE mediates shedding of the adhesion receptor L-selectin from activated leukocytes.20 In contrast to controls, >98% of the neutrophils from all TACEZn/Zn chimeras tested did not downregulate surface-expressed L-selectin when activated by PMA (Figure 1), demonstrating that these cells were of donor origin. The absence of native TACE in blood cells obtained from TACEZn/Zn chimeras was confirmed by PCR on leukocytes isolated from several chimeric mice (data not shown).
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Characterization of Platelets Obtained From TACEZn/Zn Chimeras
Examination of mice 6 weeks after fetal liver cell transplantation demonstrated similar platelet counts (Figure 2A) and platelet size (data not shown) in TACE+/+ and TACEZn/Zn chimeras. To investigate whether the absence of functional TACE in blood cells affects primary hemostasis, we compared the tail bleeding times in TACE+/+ and TACEZn/Zn mice. No significant difference in the bleeding times was observed between TACE+/+ and TACEZn/Zn mice (182.3±20.0 and 168.5±21.5, respectively; P=0.65; Figure 2B). When compared with controls, TACEZn/Zn platelets showed normal aggregation in response to 0.1 U/mL thrombin or 1 µmol/L ADP (Figure 3A). To evaluate whether TACE activity plays a role in platelet degranulation, we next measured surface expression of P-selectin by flow cytometry. No significant differences in P-selectin expression were observed between TACE+/+ and TACEZn/Zn platelets stimulated with various concentrations of thrombin or ADP (in the presence of the thromboxane A2 analog U46619; Figure 3B).
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Shedding of GPIb Is Inhibited in TACEZn/Zn Platelets
We next studied the surface expression of GPIb in response to mitochondrial injury (induced by CCCP, a lipid-soluble amphipathic molecule that uncouples oxidative phosphorylation21), or activation with various agonists in platelets obtained from TACE+/+ and TACEZn/Zn chimeras. As shown in Figure 4A, treatment with CCCP or PMA led to a >90% decrease in GPIb staining on the surface of TACE+/+ platelets, whereas almost no decrease was observed on TACEZn/Zn platelets. In contrast, no difference in the surface expression of GPIX was observed between TACE+/+ and TACEZn/Zn platelets treated with PMA (89.2±1.1% versus 90.3±0.7%, respectively, with 100% referring to GPIX staining on untreated platelets) or CCCP (95.6±0.7% and 95.2±0.8%, respectively), indicating that the surface expression of GPIb predominantly decreased because of shedding and not internalization of the GPIb-V-IX receptor complex. Consistently, elevated levels of GC were found in the supernatant of TACE+/+ but not TACEZn/Zn platelets during treatment with CCCP or PMA (Figure 4B). In addition, TACE-mediated release of GC into the supernatant was observed during activation of platelets by the physiological agonist thrombin or CRPs. These data demonstrate that TACE is expressed in platelets and that it is the key enzyme mediating shedding of GPIb from the surface of injured or activated mouse platelets.
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P-Selectin is also shed from activated platelets in mice, resulting in an increase in soluble P-selectin in plasma.7 To study a potential role of TACE in P-selectin shedding, we transfused thrombin-activated TACEZn/Zn platelets into TACEZn/Zn chimeras. As in wild-type controls, P-selectin staining was rapidly lost from transfused TACEZn/Zn platelets, indicating that the receptor was shed from the cell surface (Figure 4C). Shedding was further confirmed by a concomitant increase of soluble P-selectin in the plasma of transfused mice (data not shown).
TACE Inhibitors Prevent GPIb Shedding From Human Platelets
To our knowledge, humans with TACE deficiency have not been reported, which most likely is to be explained by the embryonic lethality of such a genetic defect.4 To confirm that TACE is also responsible for the cleavage of human GPIb, we studied the effect of 2 potent TACE inhibitors, TAPI22 and TMI-1,17 on CCCP-induced shedding of human and mouse GPIb. Both compounds are hydroxamate-based inhibitors, which have been shown to block TACE-mediated cleavage of TNF- peptide with an IC50 of 100 nmol/L and 10 nmol/L, respectively. As shown in Figure 5, both compounds effectively blocked shedding of GPIb from human and mouse platelets (IC50(TAPI): 110 nmol/L and 700 nmol/L, respectively, and IC50(TMI-1): 9 nmol/L and 50 nmol/L, respectively). And although both inhibitors are not specific for TACE, their inhibitory effects suggest that TACE may also mediate GPIb shedding from human platelets.
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TACE Mediates Shedding of GPIb In Vivo
To demonstrate the physiological importance of TACE for the shedding of GPIb in blood, we next determined the levels of GC in plasma of chimeric mice. When compared with TACE+/+ mice, the GC levels in TACEZn/Zn chimeras were reduced by 90% (Figure 6A), demonstrating that TACE is the major protease mediating shedding of GPIb from platelets in vivo.
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In addition to the marked reduction in plasma GC, we observed slightly elevated levels of GPIb on freshly isolated TACEZn/Zn platelets when compared with TACE+/+ platelets (P<0.0001). It is important to note that there was no difference in the expression of either GPIX, another subunit of the GPIb-V-IX receptor complex that is not susceptible to proteolytic cleavage, or the major platelet integrin IIbß3 (Figure 6B).
Improved Recovery and Function of Damaged TACEZn/Zn Platelets on Transfusion Into Mice
We described recently that mitochondrial platelet injury after treatment with CCCP not only induces shedding of GPIb but leads to a markedly reduced post-transfusion recovery of these platelets in mice.14 We further showed that the cellular changes leading to both GPIb shedding and platelet clearance involve metalloproteinase activity. To test whether TACE activity plays a role in the clearance of damaged platelets in vivo, we studied the recovery of CCCP-treated TACE+/+ and TACEZn/Zn platelets transfused into wild-type recipient mice (Figure 7A). Although CCCP treatment markedly reduced the immediate recovery of wild-type platelets (57% reduction), it had little effect on TACEZn/Zn platelets (24% reduction). Interestingly, 24 hours after platelet transfusion, no difference in the numbers of untreated and CCCP-treated TACEZn/Zn platelets were detectable. In contrast, the numbers of circulating CCCP-treated wild-type platelets were still 65% lower than those of untreated wild-type cells.
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To test whether damaged (CCCP-treated) TACE+/+ and TACEZn/Zn platelets are functional in vivo, we performed intravital microscopy studies in a model of arterial thrombosis.19 To compare the adhesion of both platelet preparations in the same animal, mice were infused with 2x108 CCCP-treated TACE+/+ platelets labeled with calcein-red/orange and 1x108 CCCP-treated TACEZn/Zn platelets labeled with calcein-green. As shown in Figure 7B, CCCP-treated TACEZn/Zn platelets showed a markedly improved adhesion to the damaged vascular wall as well as a better incorporation into the growing thrombus.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Binding of von Willebrand factor to the GPIb
subunit of the platelet membrane glycoprotein GPIb-V-IX is essential in the cascade of events leading to thrombus formation.10,11 Shedding of GPIb, as determined by the presence of GC in the supernatant of activated platelets, was first described in 1978.23 However, so far, neither the protease mediating GPIb shedding nor the physiological importance of this event has been elucidated. We now provide evidence that shedding of GPIb in vitro and in vivo is mainly mediated by TACE (ADAM17). TACE is a well-known sheddase for a variety of surface-expressed proteins, including adhesion molecules such as L-selectin and VCAM-1.24 However, genetic inactivation of TACE in mice results in embryonic lethality,4 making it difficult to study its role as a sheddase in vivo. To study the role of TACE in GPIb shedding, we generated chimeric mice expressing inactive TACE (TACEZn/Zn) in blood cells only. Platelets obtained from TACEZn/Zn chimeras did not shed significant amounts of GPIb in response to mitochondrial injury or cellular activation as induced by thrombin, CRPs, or PMA (Figure 4), indicating that TACE may play a major role in GPIb shedding in vivo. The latter hypothesis was confirmed by 2 complementary observations: (1) an 90% reduction in GC levels in plasma from TACEZn/Zn chimeras when compared with controls, and (2) significantly more GPIb expressed on the surface of circulating TACEZn/Zn platelets (Figure 6). The fact that we detected residual amounts of GC in all plasma samples obtained from TACEZn/Zn chimeras indicates that GPIb shedding from platelets can be mediated in part by a less efficient proteinase, probably another member of the metalloproteinase family. Such a second minor mechanism for shedding has also been reported for other TACE substrates such as L-selectin5 and VCAM-1.6 Furthermore, GPIb shedding from mouse and human platelets was inhibited by nanomolar concentrations of 2 highly effective TACE inhibitors: TAPI22 and TMI-117 (Figure 5). Although both compounds inhibit other metalloproteinases, we think that in combination with the mouse data, these results make a strong case for TACE as the enzyme that mediates shedding of human GPIb.
The question of what determines the substrate specificity of TACE has not been resolved.24 The sequences cleaved in various proteins are highly variable, suggesting that sequences distal to the cleavage site are also involved. In platelets, several surface receptors, including P-selectin, CD40 ligand, and the GPV and GPIb subunits of the GPIb-V-IX complex,7–9 have been identified as substrates for proteolytic degradation; the responsible proteases have not been identified so far. Our data demonstrate that TACE is not responsible for the shedding of P-selectin from activated mouse platelets (Figure 4C), indicating that TACE is not the universal protease mediating cleavage of platelet surface receptors. We also recently identified the platelet collagen receptor GPVI as a substrate for metalloproteinase-mediated shedding.25 Preliminary studies indicate that TACE is involved in the shedding of GPVI from damaged mouse platelets (W.B., 2004, unpublished data). However, the physiological importance of this event is unclear because GPVI shedding in vivo has only been described in 1 patient experiencing idiopathic thrombocytopenia purpura.26
Inactivation of TACE in circulating blood cells did not affect platelet counts (Figure 2A) or platelet size in mice, suggesting that TACE function is not required during platelet generation. Our data on platelet degranulation and aggregation (Figure 3) suggest that TACEZn/Zn platelets have normal in vitro responses toward platelet agonists such as ADP or thrombin. Furthermore, tail bleeding time studies did not show any major defect in primary hemostasis in TACEZn/Zn chimeras (Figure 2B), indicating that the shedding of GPIb does not play a major role in primary hemostasis. These results are in line with our previous observations showing that thrombus formation in whole blood perfused over a collagen surface is not affected by the presence of a broad-range metalloproteinase inhibitor, GM6001.14 Further in vivo and ex vivo studies will be required to investigate whether TACE-mediated shedding of GPIb or other surface receptors affects thrombus formation under high shear rate conditions.
We showed recently that inhibition of metalloproteinase activity during in vitro aging or mitochondrial injury markedly improves the post-transfusion recovery and the hemostatic function of such platelets in mice.14 We have now identified TACE as the metalloproteinase responsible for the development of the cellular changes leading to platelet clearance and reduced hemostatic function (Figure 7). The data presented here further confirm our recent finding that shedding of GPIb may serve as an indicator for the quality of stored platelets because we found a close relationship between TACE-mediated cleavage of GPIb and the recovery of transfused platelets in mice.
In summary, we suggest that TACE is the major sheddase for platelet GPIb and that TACE inhibitors could modulate GPIb shedding in vivo and in vitro during platelet storage.
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Acknowledgments |
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This work was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health grants P01 HL56949 and R37 HL41002 (D.D.W.) and the Deutsche Forschungsgemeinschaft (W.B.). We thank Drs Robert Schaub and Janos Polgar for helpful discussions, Heather Mitchell for technical assistance, and Lesley Cowan for help with preparing this manuscript.
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Footnotes |
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Original received February 25, 2004; resubmission received July 12, 2004; revised resubmission received August 16, 2004; accepted August 19, 2004.
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D. Varga-Szabo, I. Pleines, and B. Nieswandt Cell Adhesion Mechanisms in Platelets Arterioscler. Thromb. Vasc. Biol., March 1, 2008; 28(3): 403 - 412. [Abstract] [Full Text] [PDF]
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L. F. Brass, L. Zhu, and T. J. Stalker Novel Therapeutic Targets at the Platelet Vascular Interface Arterioscler. Thromb. Vasc. Biol., March 1, 2008; 28(3): s43 - s50. [Abstract] [Full Text] [PDF]
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R. K. Andrews, D. Karunakaran, E. E. Gardiner, and M. C. Berndt Platelet Receptor Proteolysis: A Mechanism for Downregulating Platelet Reactivity Arterioscler. Thromb. Vasc. Biol., July 1, 2007; 27(7): 1511 - 1520. [Abstract] [Full Text] [PDF]
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S. P. Jackson The growing complexity of platelet aggregation Blood, June 15, 2007; 109(12): 5087 - 5095. [Abstract] [Full Text] [PDF]
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B. Aktas, M. Pozgajova, W. Bergmeier, S. Sunnarborg, S. Offermanns, D. Lee, D. D. Wagner, and B. Nieswandt Aspirin Induces Platelet Receptor Shedding via ADAM17 (TACE) J. Biol. Chem., December 2, 2005; 280(48): 39716 - 39722. [Abstract] [Full Text] [PDF]
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T. Rabie, A. Strehl, A. Ludwig, and B. Nieswandt Evidence for a Role of ADAM17 (TACE) in the Regulation of Platelet Glycoprotein V J. Biol. Chem., April 15, 2005; 280(15): 14462 - 14468. [Abstract] [Full Text] [PDF]
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