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Blood, Vol. 96 No. 1 (July 1), 2000:
pp. 50-57
CHEMOKINES
From the Department of Pediatrics, Children's Hospital of
Philadelphia; the Departments of Medicine and Pediatrics, University of
Pennsylvania School of Medicine; and the Department of Physiology,
Temple University School of Medicine, Philadelphia, PA.
Platelets play roles in both thrombosis and inflammation,
and chemokines that are released at sites of inflammation could potentially activate platelets. Among the chemokine receptors expressed
on platelets, the CXCR4 is the receptor for chemokine stromal
cell-derived factor-1 (SDF-1), and the CCR4 is the receptor for
macrophage-derived chemokine (MDC). Of the chemokines tested, SDF-1 and
MDC were the only 2 that activated platelets. Both are weak agonists,
but they enhanced response to low-dose adenosine 5'-diphosphate
(ADP), epinephrine, or serotonin. When SDF-1 and MDC were added
together, full and brisk platelet aggregation occurred. Platelet
activation by these 2 chemokines appears to involve distinct pathways:
SDF-1 inhibited an increase in cyclic adenosine monophosphate (cAMP)
following prostaglandin (PG) I2, while MDC had no effect. In contrast, MDC, but not SDF-1, lead to Ca++
mobilization by platelets. Further, second-wave aggregation induced by
MDC in platelet-rich plasma was inhibited by aspirin, ADP scavenger creatine phosphate/creative phosphokinase (CP/CPK), and
ARL-66096, an antagonist of the ADP P2TAC receptor involved
in adenylyl cyclase inhibition. But the aggregation was not affected by
A3P5PS, an inhibitor of the ADP P2Y receptor. SDF-1-induced
aggregation was inhibited by aspirin, but it was only slightly affected
by CP/CPK, ARL-66096, or A3P5PS. Finally, the presence of chemokines in
platelets was determined. Reverse transcriptase-polymerase chain
reaction studies with platelet RNA did not detect the presence of SDF-1 or MDC. In summary, SDF-1 and MDC are platelet agonists that activate distinct intracellular pathways. Their importance in the development of
thrombosis at sites of inflammation needs to be further evaluated.
(Blood. 2000;96:50-57)
Chemokines are small cytokines that are important as
intermediates in the inflammatory response.1,2
The chemokines fall into 2 major families: the CXC (or In addition to their importance in inflammation, chemokines have other
biological roles. In 1989 it was shown that platelet factor 4 (PF4)
inhibits megakaryocyte formation.6 Since then it has been
shown that in addition to PF4, other chemokines, specifically interleukin-8 (IL-8), macrophage inflammatory protein-1 The role of SDF-1 on mature megakaryocytes and platelets is unclear. In
our hands, mature megakaryocytes did not show a similar chemotactic
response as megakaryocyte progenitors.10 SDF-1 did not
inhibit or stimulate megakaryopoiesis, and we could not demonstrate a
Ca++ flux in cells stimulated with SDF-1. Others have found
similar results.11 However, Wang et al9 have
reported a modest but consistent stimulation of megakaryocyte colony
formation by SDF-1 and suggested that SDF-1, along with
thrombopoietin, is involved in the normal regulation of
megakaryopoiesis. Also data showing that SDF-1 increases the growth of
murine megakaryocytic colonies in the presence of thrombopoietin
have been published recently.15 In addition, the
ability of SDF-1 to attract maturing megakaryocytes may be
important for platelet formation.16
The presence of CXCR4 on platelets and the ability of SDF-1 to activate
platelets were also studied.10 There were approximately 2000 copies of CXCR4 per platelet, with an SDF-1 KD of 24 nmol/L. Similar values have been reported on other cells
lines. Using washed platelets, platelet activation was not detected,
possibly because the CXCR4 receptor was residually present on the
surface of the platelet, and the lack of platelet activation was due to an intracellular signaling block in circulating platelets. However, with platelets in platelet-rich plasma (PRP), SDF-1 acted as a weak
platelet agonist.
Other chemokines were tested to see if they could activate washed
platelets or platelets in PRP. These include: the CXC chemokines IL-8,
PF4, neutrophil-activating peptide-2 (NAP-2), and epithelial cell-derived neutrophil attractant-78 (ENA-78); the CC chemokines human MDC, RANTES (regulated on activation normal T expressed and
secreted), MIP-1 Materials
Isolation of human blood platelets
Measurements of platelet activation Platelet activation was measured using 3-4 × 108 platelets per mL of either freshly washed platelets or platelets in PRP. Four different measurements were completed: (1) extent of platelet aggregation, (2) activation of IIb/ 3 platelet surface expression, (3) P-selectin expression on
the platelet surface, and (4) amount of PF4 released from the platelet
-granules.
Measurement of thromboxane B2 formation in intact platelets Aliquots of washed platelets or platelets in PRP were stimulated for 5 minutes in an aggregometer cuvette with various agonists. This was then followed by freezing and thawing. The amount of thromboxane B2 (TxB2) formed in platelets was measured using the BIOTRAK Thromboxane B2 Enzymeimmunoassay System (Amersham International, Little Chalfont, England).Measurement of cyclic AMP formation in intact platelets Washed platelets were stimulated with 10 nmol/L carbacycline, the stable analogue of PGI2, in the presence of 7 mmol/L theophylline. We added 1 µmol/L ADP, 100 nmol/L SDF-1, or 100 nmol/L MDC for 5 minutes. The reaction was stopped by the addition of
an equal amount of ice-cold 10% trichloroacetic acid. The samples were centrifuged at 15 000 rpm for 5 minutes. The supernatants were extracted with 5 volumes of water-saturated ether and then lyophilized. Platelet cAMP concentrations were measured in the supernatants using
the 125I-cAMP radioimmunoassay kit (NEN; Life Science
Products, Inc, Boston, MA). These assays were completed in the presence
of 1 mmol/L aspirin to inhibit the cyclooxygenase pathway and to
abolish generation of TxA2.
Measurement of cytoplasmic Ca++ in platelets Cytosolic-free Ca++ was determined after the platelets were loaded with Fura-2/AM (Molecular Probes, Eugene, OR) for 30 minutes at room temperature.17 Excess Fura-2/AM was removed by washing cells in wash buffer, and the platelets were resuspended in resuspension buffer as described above. Fluorescence was recorded with an Aminco-Bowman Series-2 Luminescence Spectrometer (SLM Instruments, Inc, Urbana, IL). We stirred 1 mL aliquots of cells continuously in a warmed holder during the period of changes in fluorescence recording. Fluorescence was monitored at 340 and 380 nm for excitation and 510 nm for emission. The data were recorded as the relative ratio of fluorescence excited at 340 and 380 nm, and concentration of mobilized Ca++ was calculated using 224 nmol/L, the known dissociation constant of the Fura-2:Ca++ complex.Binding of 125I-MDC to platelets We resuspended 8 × 107 platelets in 75 µL of binding buffer (50 mmol/L HEPES (pH 7.4), 150 mmol/L sodium chloride (NaCl), 5 mmol/L magnesium dichloride (MgCl2), 1 mmol/L calcium dichloride (CaCl2), and 5% BSA. MDC was radiolabeled (IODO-Bead method; Pierce, Rockford, IL) according to the manufacturer's instructions. Next, 5 nmol/L 125I-MDC (specific activity, 429.2 × 1010 Bq/mmol [116 Ci/mmol]) was added to the cells with more cold MDC in an additional 25 µL binding buffer. The platelets were incubated at room temperature for 1 hour, and then unbound radioactivity was removed by filtering cells through a Whatman GF/C filter (Whatman International, Maidstone, England) presoaked in polyethylenimine. The filters were washed 3 times with 4 mL wash buffer comprising 50 mmol/L HEPES (pH 7.4), 150 mmol/L NaCl, 5 mmol/L MgCl2, and 1 mmol/L CaCl2. The filters were counted in a Beckman Gamma 5500 Counter (Beckman Instruments, Palo Alto, CA); the KD and the number of binding sites per platelet were calculated as described earlier.10Reverse transcriptase-polymerase chain reaction Reverse transcriptase-polymerase chain reaction (RT-PCR) was carried out as previously reported using messenger RNA (mRNA) that was isolated from cells and platelets (Quick-Pre mRNA purification Kit; Pharmacia, Piscataway, NJ).20 The total RNA was prepared using platelets obtained from 100 mL human blood, and the entire preparation was used for a single set of experiments. For these studies, the platelet-to-white-cell ratio was greater than 104:1. In addition, RNA was extracted from whole buffy coat cells so that total RNA was rich in white cells. CD34+ cells were expanded in a serum-free liquid system as described.20 Briefly, CD34+ A T mononuclear cells were
resuspended in 104 cells per mL Iscove's Modified
Dulbecco's medium (IMDM) supplemented with 25% artificial serum
containing 1% delipidated, deionized, and charcoal-treated BSA; 270 mg/mL iron-saturated transferrin; 20 mg/mL insulin; and 2 mmol/L
L-glutamine. The megakaryocyte colony-forming unit (CFU-Meg) growth was
stimulated with 50 ng/mL rHTPO and 10 ng/mL rHIL-3. Cultures were
incubated at 37°C in humidified atmosphere supplemented with 5%
carbon dioxide (CO2). Under these conditions, after 14 days, approximately 85% of the expanded cells were positive for
IIb/3.20 For RT-PCR analysis, cells were further
enriched for a population of positive IIb/3 cells (purity,
greater than 97%) by additional selection with immunomagnetic
beads (Miltenyl Biotec, Auburn, CA). Stromal cells were obtained as
described earlier.20
Activation of human washed platelets by chemokines We had previously found that washed platelets could not be activated by SDF-1,10 and repeat studies confirmed this finding (Figure 1A). Using human washed platelets, platelet aggregation studies were also done with other chemokines. The CC chemokine MDC stimulated washed platelets with a small but reproducible response (Figure 1A). A number of other CXC chemokines (IL-8, NAP-2, PF4, and ENA-78) and CC chemokines (MIP-1 and MCP-3) did not activate platelets, even at concentrations greater than that needed to activate other cell lines (data not shown).
Platelet-binding studies with MDC We had previously shown that SDF-1 binds to the CXCR4 receptor on the surface of platelets, with approximately 2000 sites per platelet and a KD of 24 nmol/L.10 We now examined whether CCR4, the chemokine receptor which was shown to bind MDC,24 is present on platelets. The CCR4-specific antibody (a gift from R&D Systems) does not bind to CCR4 on primary cells. Therefore, 125I-radiolabeled MDC was used to detect MDC binding to platelet membrane,25 and the binding characteristics of 125I-MDC were determined using displacement studies with increasing concentrations of unlabeled MDC (Figure 2A). It appears that there are approximately 4000 MDC binding sites per platelet, with a KD of 30 nmol/L. This number of sites and affinity is similar to that reported for SDF-1 and its receptor on platelets.10 While the 125I-MDC binding was completely inhibited by 1.25 µmol/L unlabeled MDC, the addition of cold SDF-1 at the same concentration did not affect MDC binding (data not shown).
Expression of CCR4 and chemokines in platelets Using oligonucleotides specific for CCR4 receptor, we were able to show the presence of the CCR4 message in platelets and megakaryocytes. RT-PCR of platelet and megakaryocyte total RNA demonstrated the presence of a 500-base pair (500-bp) band corresponding to the predicted product of CCR4 cDNA amplification (Figure 2B). There were no observed bands in the same condition when the reverse transcription step was omitted. Contamination with white cell RNA was ruled out by the absence of an LFA-12 chain message, which was negative for the same platelet RNA preparation (Figure 3).
Characterization of platelets in PRP activated by chemokines To examine the effect of these chemokines on platelet activation in a more physiological environment, platelet activation in PRP was studied. Full aggregation was achieved with 100 nmol/L MDC (Figure 4A). At concentrations of at least 10 nmol/L, MDC induced a dose-dependent biphasic activation of platelets with full aggregation, although the minimal concentration of MDC required for full activation was donor-dependent. The related chemokine TARC, which binds to the same receptor as MDC,24 induced only a primary wave of platelet aggregation, even at concentrations of 100 nmol/L (data not shown).
Additional measures of platelet activation We also measured other parameters of platelet activation in both washed platelets and platelets in PRP. Neither SDF-1 nor MDC could stimulate TxB2 formation in washed platelets, further supporting the fact that these chemokines are weak agonists (data not shown). When PRP was stimulated under aggregating conditions by various agonists, including 100 nmol/L SDF-1 and MDC, there was formation of TxB2, and PF4 was released from-granules (Figure 5A). However, platelet
stimulation by the 2 chemokines in nonaggregating conditions (unstirred
platelets in PRP) did not lead to activation, as indicated by
measurements of either surface expression of P-selectin or activation
of the IIb/3 receptor by the active-complex dependent mAb
PAC-117 (Figure 5B). This contrasts with the results from the stronger agonist, the TRAP peptide, which activates the PAR-1 thrombin receptor on human platelets.30 These findings
further demonstrate that these chemokines are weak platelet agonists. In addition, the secondary aggregation and release reaction observed in
PRP require close platelet-to-platelet contact, which takes place as
aggregates form in a rapidly stirred system and may be due in part to
the synergistic effects of TxA2 and released
ADP.31
Effect of chemokines on the inhibition of adenylyl cyclase in platelets Elevated concentrations of cAMP can inhibit platelet response to stimulation with various agonists. Agents, such as PGI2, stimulate adenylyl cyclase and increase platelet cAMP levels.32 A major intracellular effect of ADP on platelets is the inhibition of the cAMP levels, which leads to platelet aggregation.33 This is achieved by activation of the G i protein, which leads to the
inhibition of adenylyl cyclase.34 We investigated the ability of SDF-1 and MDC to inhibit the PG-stimulated adenylyl cyclase
activity in washed platelets (Figure 6).
Platelet cAMP concentrations measured in the presence of theophylline
rose after stimulation with 10 nmol/L carbacycline, the stable analog
of PGI2, and this increase was inhibited by 1 µmol/L ADP.
Like ADP, 100 nmol/L SDF-1 inhibited cAMP levels, but 100 nmol/L MDC
had little effect on this assay. Other chemokines tested, including RANTES, MCP-3, ENA-78, PF4, and Fractalkine2 (all at a
concentration of 100 nmol/L), had no significant effect on the cAMP
inhibition in platelets (data not shown). Thus, comparing chemokines
tested, SDF-1 appears to be unique in strongly inhibiting adenylyl
cyclase activity in platelets. Most of the chemokine receptors are
coupled through pertussis toxin-sensitive Gi proteins,
although coupling can also occur through the Gq
proteins.1 Our results suggest that, in
platelets, the SDF-1 receptor CXCR4 is coupled through a
Gi protein. On the other hand, the MDC receptor CCR4 may
be coupled to a different G protein, which does not signal by
inhibiting adenylyl cyclase.
Chemokine enhancement of agonist-stimulated platelet activation Because SDF-1 and MDC appear to activate different signal transduction pathways, we examined whether MDC can synergize with other weak platelet agonists. Aggregation of washed platelets induced by MDC was potentiated by epinephrine, a weak platelet agonist coupled to the2A receptor, which mediates inhibition of adenylyl
cyclase35 (Figure 7A). MDC
could also synergize with low concentrations of ADP, although using
washed platelets, neither 100 nmol/L MDC nor 1 µmol/L ADP alone
resulted in full aggregation. However, the addition of a chemokine with
the same amount of ADP resulted in vigorous platelet aggregation (data not shown). The synergism between MDC and ADP contrasts with our previously published observation that low concentrations of ADP do not
potentiate SDF-1 aggregation.10 However, as shown in Figure
7B, SDF-1 can synergize with serotonin (5HT), a weak platelet agonist.
Serotonin activates a platelet receptor that is coupled to activation
of phospholipase C (PLC).36 Our results using SDF-1 and 5HT
are similar to the findings of Jin and Kunapuli37 (Figure
7B). They showed that weak agonists, such as low
concentrations of ADP and 5HT, can synergize in
platelet activation. This suggests that SDF-1 and 5HT activate
platelets, in part, by nonoverlapping pathways.38 In fact,
our studies suggest that SDF-1 and MDC may be such a pair of
nonoverlapping weak agonists. While 100 nmol/L of each chemokine alone
cannot activate washed platelets, the 2 together resulted in platelet
activation (Figure 7C).
Effect of ADP receptor antagonists on chemokine-induced aggregation in platelets in PRP CP/CPK, a scavenger of ADP, inhibited the secondary wave of plasma platelet aggregation stimulated by MDC. We therefore tested MDC-stimulated platelet aggregation in the presence of inhibitors of the other pathways of ADP-induced signal transduction. The second wave of MDC-induced plasma platelet aggregation was inhibited by 1 µmol/L ARL-66096, an inhibitor of the proposed ADP P2TAC receptor involved in adenylyl cyclase inhibition (Figure 8A).37 However, aggregation was not affected by 100 µmol/L A3P5PS, an inhibitor of the P2Y1 ADP receptor involved in PLC activation (Figure 8B). In contrast, SDF-1-induced aggregation was only slightly affected by either ADP antagonists ARL-66096 or A3P5PS (Figure 8C and D). These data are consistent with the ability of SDF-1 to primarily activate platelets through decreasing cAMP levels, which requires granular release to lead to PLC activation and full platelet aggregation. MDC primarily activates aggregation through PLC and Ca++ mobilization and requires other agonists to inhibit adenylyl cyclase and fully aggregate platelets. Thus, it appears that initial platelet activation by SDF-1 and MDC involves distinct pathways. We hypothesize that part of this complementary activation of platelets (Figure 7C) is due to the fact that SDF-1 predominantly activates platelets by inhibiting adenylyl cyclase activity, and MDC predominantly activates platelets by stimulating PLC activity.
It has become clear that chemokine receptors are present on multiple hematopoietic lineages including the megakaryocytic lineage. We and others have demonstrated that a number of chemokine receptors, including the HIV coreceptor CXCR4, are present on developing megakaryocytes.9-11 The roles these receptors play during megakaryopoiesis and platelet formation and function are presently being explored by a number of laboratories. Such roles can include stimulation or inhibition of megakaryocyte formation, platelet formation, or platelet biology. In our previous studies, we were surprised to find that although the SDF-1 receptor CXCR4 is present on platelets, SDF-1 did not activate washed platelets in the presence of apyrase.10 We concluded that the CXCR4 receptor was important at a much earlier stage of megakaryopoiesis and that CXCR4 was only residually present on platelets. The loss or change of a cellular response to the binding of a chemokine by a particular chemokine receptor is well documented. For example, D'Apuzzo et al5 have shown that during B-cell differentiation, intracellular signaling through CXCR4 by SDF-1 changes. Ca++ mobilization by SDF-1 was observed in pro-B and pre-B cell lines, but cell lines representing higher stages of maturation were unresponsive.
We thank Dr Benjamin Doranz of the Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, for the 125I-labeled MDC and R&D Systems, Minneapolis, MN, for the CCR4-specific antibody.
Submitted October 21, 1999; accepted February 23, 2000.
Supported in part by grants HL61796 (M.A.K., M.R., and M.P.) and HL40387 (L.B. and M.P.) from the National Institutes of Health, Bethesda, MD.
Reprints: M. Anna Kowalska, Children's Hospital of Philadelphia, 34th Street & Civic Center Blvd, ARC, Room 314I, Philadelphia, PA 19104; e-mail: kowalska{at}emailchop.edu.
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.
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  M. A. Kowalska, S. A. Mahmud, M. P. Lambert, M. Poncz, and A. Slungaard Endogenous platelet factor 4 stimulates activated protein C generation in vivo and improves survival after thrombin or lipopolysaccharide challenge Blood, September 15, 2007; 110(6): 1903 - 1905. [Abstract] [Full Text] [PDF]
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M. P. Lambert, L. Rauova, M. Bailey, M. C. Sola-Visner, M. A. Kowalska, and M. Poncz Platelet factor 4 is a negative autocrine in vivo regulator of megakaryopoiesis: clinical and therapeutic implications Blood, August 15, 2007; 110(4): 1153 - 1160. [Abstract] [Full Text] [PDF]
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L. Lasagni, R. Grepin, B. Mazzinghi, E. Lazzeri, C. Meini, C. Sagrinati, F. Liotta, F. Frosali, E. Ronconi, N. Alain-Courtois, et al. PF-4/CXCL4 and CXCL4L1 exhibit distinct subcellular localization and a differentially regulated mechanism of secretion Blood, May 15, 2007; 109(10): 4127 - 4134. [Abstract] [Full Text] [PDF]
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D. E. Eslin, C. Zhang, K. J. Samuels, L. Rauova, L. Zhai, S. Niewiarowski, D. B. Cines, M. Poncz, and M. A. Kowalska Transgenic mice studies demonstrate a role for platelet factor 4 in thrombosis: dissociation between anticoagulant and antithrombotic effect of heparin Blood, November 15, 2004; 104(10): 3173 - 3180. [Abstract] [Full Text] [PDF]
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H. Shankar, S. Murugappan, S. Kim, J. Jin, Z. Ding, K. Wickman, and S. P. Kunapuli Role of G protein-gated inwardly rectifying potassium channels in P2Y12 receptor-mediated platelet functional responses Blood, September 1, 2004; 104(5): 1335 - 1343. [Abstract] [Full Text] [PDF]
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L. G. Coleman Jr, R. K. Polanowska-Grabowska, M. Marcinkiewicz, and A. R. L. Gear LDL oxidized by hypochlorous acid causes irreversible platelet aggregation when combined with low levels of ADP, thrombin, epinephrine, or macrophage-derived chemokine (CCL22) Blood, July 15, 2004; 104(2): 380 - 389. [Abstract] [Full Text] [PDF]
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A. Schafer, C. Schulz, M. Eigenthaler, D. Fraccarollo, A. Kobsar, M. Gawaz, G. Ertl, U. Walter, and J. Bauersachs Novel role of the membrane-bound chemokine fractalkine in platelet activation and adhesion Blood, January 15, 2004; 103(2): 407 - 412. [Abstract] [Full Text] [PDF]
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H. V. Yarovoi, D. Kufrin, D. E. Eslin, M. A. Thornton, S. L. Haberichter, Q. Shi, H. Zhu, R. Camire, S. S. Fakharzadeh, M. A. Kowalska, et al. Factor VIII ectopically expressed in platelets: efficacy in hemophilia A treatment Blood, December 1, 2003; 102(12): 4006 - 4013. [Abstract] [Full Text] [PDF]
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D. Kufrin, D. E. Eslin, K. Bdeir, J.-C. Murciano, A. Kuo, M. A. Kowalska, J. L. Degen, B. S. Sachais, D. B. Cines, and M. Poncz Antithrombotic thrombocytes: ectopic expression of urokinase-type plasminogen activator in platelets Blood, August 1, 2003; 102(3): 926 - 933. [Abstract] [Full Text] [PDF]
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 L. Agrawal, Z. Vanhorn-Ali, and G. Alkhatib Multiple determinants are involved in HIV coreceptor use as demonstrated by CCR4/CCL22 interaction in peripheral blood mononuclear cells (PBMCs) J. Leukoc. Biol., November 1, 2002; 72(5): 1063 - 1074. [Abstract] [Full Text] [PDF]
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S. Kim, C. Foster, A. Lecchi, T. M. Quinton, D. M. Prosser, J. Jin, M. Cattaneo, and S. P. Kunapuli Protease-activated receptors 1 and 4 do not stimulate Gi signaling pathways in the absence of secreted ADP and cause human platelet aggregation independently of Gi signaling Blood, May 15, 2002; 99(10): 3629 - 3636. [Abstract] [Full Text] [PDF]
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K. Balabanian, A. Foussat, L. Bouchet-Delbos, J. Couderc, R. Krzysiek, A. Amara, F. Baleux, A. Portier, P. Galanaud, and D. Emilie Interleukin-10 modulates the sensitivity of peritoneal B lymphocytes to chemokines with opposite effects on stromal cell-derived factor-1 and B-lymphocyte chemoattractant Blood, January 15, 2002; 99(2): 427 - 436. [Abstract] [Full Text] [PDF]
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A. Janowska-Wieczorek, M. Majka, J. Kijowski, M. Baj-Krzyworzeka, R. Reca, A. R. Turner, J. Ratajczak, S. G. Emerson, M. A. Kowalska, and M. Z. Ratajczak Platelet-derived microparticles bind to hematopoietic stem/progenitor cells and enhance their engraftment Blood, November 15, 2001; 98(10): 3143 - 3149. [Abstract] [Full Text] [PDF]
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C. Zhang, M. A. Thornton, M. A. Kowalska, B. S. Sachis, M. Feldman, M. Poncz, S. E. McKenzie, and M. P. Reilly Localization of distal regulatory domains in the megakaryocyte-specific platelet basic protein/platelet factor 4 gene locus Blood, August 1, 2001; 98(3): 610 - 617. [Abstract] [Full Text] [PDF]
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R. Guerriero, G. Mattia, U. Testa, C. Chelucci, G. Macioce, I. Casella, P. Samoggia, C. Peschle, and H. J. Hassan Stromal cell-derived factor 1{alpha} increases polyploidization of megakaryocytes generated by human hematopoietic progenitor cells Blood, May 1, 2001; 97(9): 2587 - 2595. [Abstract] [Full Text] [PDF]
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A. R. L. Gear, S. Suttitanamongkol, D. Viisoreanu, R. K. Polanowska-Grabowska, S. Raha, and D. Camerini Adenosine diphosphate strongly potentiates the ability of the chemokines MDC, TARC, and SDF-1 to stimulate platelet function Blood, February 15, 2001; 97(4): 937 - 945. [Abstract] [Full Text] [PDF]
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M. Majka, A. Janowska-Wieczorek, J. Ratajczak, M. A. Kowalska, G. Vilaire, Z. K. Pan, M. Honczarenko, L. A. Marquez, M. Poncz, and M. Z. Ratajczak Stromal-derived factor 1 and thrombopoietin regulate distinct aspects of human megakaryopoiesis Blood, December 15, 2000; 96(13): 4142 - 4151. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
comparison to other cytokines and growth factors.
Leukemia.
1998;12:371-381