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Blood, Vol. 93 No. 8 (April 15), 1999:
pp. 2506-2514
By
From the Hematology Division, Ospedali Riuniti, Bergamo, Italy; the
Istituto di Ricerche Farmacologiche Mario Negri Consorzio Mario Negri
Sud, S. Maria Imbaro, Italy; and NegriBergamo Laboratories, Bergamo,
Italy.
Granulocyte colony-stimulating factor (G-CSF) enhances neutrophil
functions in vitro and in vivo. It is known that neutrophil-derived products can alter the hemostatic balance. To understand whether polymorphonuclear leukocyte (PMN) activation, measured as PMN degranulation and phenotypical change, may be associated to hemostatic alterations in vivo, we have studied the effect of recombinant human
G-CSF (rHuG-CSF) administration on leukocyte parameters and hemostatic
variables in healthy donors of hematopoietic progenitor cells (HPCs).
Twenty-six consecutive healthy donors receiving 10 µg/kg/d rHuG-CSF
subcutaneously for 5 to 7 days to mobilize HPCs for allogeneic
transplants were included in the study. All of them responded to
rHuG-CSF with a significant white blood cell count increase. Blood
samples were drawn before therapy on days 2 and 5 and 1 week after
stopping rHuG-CSF treatment. The following parameters were evaluated:
(1) PMN activation parameters, ie, surface CD11b/CD18 antigen
expression, plasma elastase antigen levels and cellular elastase
activity; (2) plasma markers of endothelium activation, ie,
thrombomodulin (TM) and von Willebrand factor (vWF) antigens; (3)
plasma markers of blood coagulation activation, ie, F1+2, TAT
complex, D-dimer; and (4) mononuclear cell (MNC) procoagulant activity
(PCA) expression. The results show that, after starting rHuG-CSF, an in
vivo PMN activation occurred, as demonstrated by the significant
increment of surface CD11b/CD18 and plasma elastase antigen levels.
Moreover, PMN cellular elastase activity, which was significantly
increased at 1 day of treatment, returned to baseline at day 5 to 6, in
correspondence with the elastase antigen peak in the circulation. This
change was accompanied by a parallel significant increase in plasma
levels of the two endothelial and the three coagulation
markers. The PCA generated in vitro by unstimulated MNC
isolated from rHuG-CSF-treated subjects was not different from that of
control cells from untreated subjects. However, endotoxin-stimulated
MNC isolated from on-treatment individuals produced significantly more
PCA compared with both baseline and control samples. All of the
parameters were decreased or normal 1 week after stopping treatment.
These data show that rHuG-CSF induces PMN activation and transiently
affects some hemostatic variables in healthy HPC donor subjects. The
clinical significance of these findings remains to be established.
GRANULOCYTE colony-stimulating factor
(G-CSF) stimulates the proliferation and differentiation of
hematopoietic progenitor cells (HPCs) and the release of mature
granulocytes from bone marrow. It also induces mobilization of
CD34+ HPCs in circulating blood.1,2 These
properties justify the expanding use of recombinant human G-CSF
(rHuG-CSF) in clinical conditions, including chronic idiopathic
neutropenia, chemotherapy-induced myelosuppression, and mobilization of
HPCs in the circulation with or without prior
chemotherapy.3 Recently, it has been administered to normal
subjects to mobilize (and collect) HPCs for allogeneic
transplantation.3,4
Several studies in vitro5-7 and in vivo8,9 have
documented the neutrophil-activating effect of G-CSF, indicating that it should be considered a potent immediate activator of mature circulating cells capable of priming respiratory burst, inducing the
release of secretory vesicles and cytoplasmic granules, and modulating
expression of surface adhesion molecules.
Upon activation, polymorphonuclear leukocytes (PMN) release reactive
oxygen species and intracellular proteases that possess several
activities on endothelial cells and platelets and may modify the
hemostatic balance towards a prothrombotic state. In vitro experiments
have indeed shown that leukocyte elastase and cathepsin G can induce
detachment10,11 or even lysis12,13 of
endothelial cells. In addition, independently from a cell-damaging effect, these proteases may modify endothelial cell function involved in thromboregulation. In this respect, PMN-derived proteases have been
reported to prevent thrombin-induced prostacyclin production by
endothelial cells14; cathepsin G has also been shown to
induce the plasminogen activator inhibitor release by the
endothelium.15 Proteolysis of components of the endothelial
surface, namely heparan-sulphated proteoglycans16 or
thrombomodulin,17 by elastase and cathepsin G also may
contribute to impair the nonthrombogenicity of the endothelium.
Furthermore, the potential thrombogenic effects of PMN-derived
proteases include the direct potent platelet activation elicited by
cathepsin G18,19 and the enhancing effect of
elastase.20 Finally, besides the cellular effects, elastase
can directly proteolyze and inactivate natural inhibitors of blood
coagulation, including protein C,21 protein
S,22 tissue factor pathway inhibitor,23 antithrombin,24 and heparin cofactor II,25 thus
impairing potent antithrombotic mechanisms.
In addition to endogenous products release, G-CSF-activated
neutrophils present phenotype changes involving the expression of
surface adhesion molecules,7-9 including integrins (eg,
CD11b/CD18) and selectins (eg, L-selectin), which mediate PMN adhesion
to endothelial cells and platelets.26,27 It has been shown
that G-CSF can increase PMN adhesive function in vitro and in
vivo.7,28,29 Besides other implications, this property is
relevant for the in vivo biological activity of PMN-derived proteases.
In fact, this phenomenon allows the formation of a close
microenviroment in which these enzymes are released and protected
against inhibitors and their interaction with the substrate
facilitated.30-32
Taking into account all the observations reported above, we evaluated
in an established in vivo model in which G-CSF injection in healthy
humans results in neutrophil activation whether endothelial cell
perturbance and imbalance of the hemostatic system may also occur. We
report here on the evaluation of PMN activation status in vivo, as
measured by degranulation parameters and phenotypical change, and a
series of variables reflecting perturbance of the endothelium and
activation of blood coagulation and monocytes in a group of healthy
donors receiving rHuG-CSF to mobilize HPCs for allografting.
Donor Subjects
Samples
Routine Hematological Assays White blood cell (WBC) differential counts, hematocrit counts, hemoglobin counts, red blood cell (RBC) counts, and platelet counts were determined by automated methods by a NE800 Analyzer (Dasit, Milan, Italy).Assays of PMN Activation PMN membrane CD11b/CD18. The expression of PMN CD11b/CD18 antigen was measured in whole blood by direct immunofluorescence using flow cytometry analysis and monoclonal antibodies (MoAbs). Cells were incubated with phycoerythrin (PE)-conjugated mouse antihuman CD11b MoAb (Becton Dickinson, Mountain View, CA) or with isotype-identical negative control MoAb (IgG2a PE; Becton Dickinson) for 30 minutes at 4°C in the dark. After erythrocyte lysis, samples were analyzed by a FACScan flow cytometer (Becton Dickinson). PMN were selectively gated using their forward and side scatter properties. The results were expressed as mean fluorescence units (MIF). Plasma PMN elastase antigen.
This is the plasma marker to test the release of azurophil granule
content. Elastase coupled to its natural inhibitor PMN elastase proteolytic activity assay. Elastase activity was measured in PMN lysates by monitoring the rate of release of p-nitroanilide from the specific chromogenic substrate N-Succinil-Ala-Ala-Val-p-nitroanilide (Sigma, St Louis, MO). Five microliters of a 100 mmol/L solution of the specific synthetic substrate dissolved in N-methylpirrolidinone (final concentration, 0.5 mmol/L) was added to the cell lysate and its cleavage was monitored spectrophotometrically by following the release of p-nitroanilide at 410 nm. The activity of the samples was then compared with a standard curve prepared with different concentrations of purified elastase. Markers of Endothelial Cell Activation The parameters of endothelium damage studied were the plasma concentrations of thrombomodulin (TM) and von Willebrand factor (vWF).33 TM is the endothelial membrane receptor for thrombin.34 vWF is a multimeric protein synthesized and released from endothelial cells, which are important for the mechanism of platelet adhesion to the vessel wall.35 The multimeric structure of vWF determines its biological activity, ie, high molecular weight (HMW) vWF multimers are functionally more potent than other forms of vWF.Markers of Hypercoagulation As markers of in vivo clotting activation, the plasma levels of prothrombin fragment F1+2 (F1+2), thrombin-antithrombin (TAT) complex, and D-dimer were measured. These are enzyme-inhibitor complexes or byproducts of the coagulation reactions, liberated during clotting activation, which provide a biochemical tool for the definition of the hypercoagulable state and are modulated by therapy.38,39PCA of MNC The PCA expressed by circulating MNC, identified as tissue factor (TF), represented the parameter of white blood cell-mediated clotting activation. This activity plays an important role in physiological and pathological conditions.40
Statistical Analysis The Mann Whitney U-test was used to assess the significance of differences between the mean baseline values of the donors versus the untreated control group. To test the intragroup differences over time, the ANOVA one-way analysis of variance for repeated measures and Fisher's test for multiple comparisons were used. Differences were considered significant at a P value less than .05.
Table 1 shows the variations of the healthy
donors' hematological parameters at the different times of the study.
At baseline (T0), before the start of rHuG-CSF treatment, none of the
subjects had hematological abnormalities. Then, all of them responded
to rHuG-CSF administration, with a significant increase in WBC count (on T1 and T2: P < .01 v T0). Accordingly, the
circulating PMN fraction was significantly increased. Also, the
monocytic fraction resulted increased. WBC, PMN, and monocytes were
back to the basal values 1 week after HPC collection and rHuG-CSF
discontinuation (T3). No significant modifications occurred to the
other parameters during treatment, except for the median platelet
count, which tended to decrease on T2, at the peak of rHuG-CSF-induced
leukocytosis. After apheresis (T3), this reduction became statistically
significant. Also at this time, the hematocrit, hemoglobin, and RBC
counts were slightly, but significantly decreased compared with the
baseline.
PMN Activation Markers Cytofluorimetric analysis (Fig 1A).
The baseline expression of the surface
Plasma elastase antigen levels (Fig 1B). The concentration of this marker (at T0 = 59.9 ± 28.4 µg/L, P = NS v normal controls) increased after starting rHuG-CSF administration, peaking at T2 (635.5 ± 60.6 µg/L, P < .01). It decreased to 45.9 ± 27.7 µg/L after stopping the growth factor administration (T3 v T0: P = NS). PMN cellular elastase activity (Fig 1C). At T0, cellular elastase activity was in the normal control range values; rHuG-CSF administration resulted in a significant elevation of this activity from T0 to T1 (T1 v T0: 626 ± 116 v 352 ± 72 ng/106 cells; P < .05). Thereafter, the enzyme activity started to decrease on T2, before leukapheresis (441 ± 35 ng/106 cells; T2 v T0, P = NS), and even more on T3 (327 ± 48 ng/106 cells; T3 v T0, P = NS). Endothelial Cell Markers At T0, the levels of circulating endothelial cell markers of the donors were within the normal range values. A significant increment of TM and vWF was observed during rHuG-CSF treatment (Fig 2A and B). In both cases, the increments peaked at T2, before HPC apheresis (T2 v T0: TM = 65 ± 22 v 32 ± 12 ng/mL, P < .01; vWF:Ag = 241% ± 72% v 114% ± 26%, P < .01). At T3, both parameters were decreased back to the baseline values. In 6 subjects, the multimeric structure of vWF was analyzed at the different time intervals. vWF multimeric analysis showed a normal pattern of multimeric distribution as shown by autoradiography of a representative donor (Fig 3) and by densitometric analysis. The percentage of LMW multimer fraction was comparable in normal controls (21.6% ± 2.4%) and in donors on rHuG-CSF (T2: 21.7% ± 3.2%) as well as the area of HMW fraction (controls: 20.6% ± 2.1%; donors [T2]: 19.1% ± 1.8%). In the same plasma samples obtained during rHuG-CSF administration were found the 225-kD subunit as well as the normal 189-, 176-, and 140-kD fragments. No new fragments were detected. The proportion of the intact 225-kD subunit was comparable, at the different times, when calculated by densitometric analysis (T0: 71.4% ± 4.2%; T2: 67.2% ± 6.3%; T3: 71.5% ± 4.5%).
Plasma Markers of Hypercoagulation HPC donors showed pretreatment normal values of plasma F1+2, TAT complex, and D-dimer. During the days of rHuG-CSF administration, a gradual increment of these markers was observed (Fig 4A, B, and C). On T2, the levels of all three parameters were all significantly greater as compared with T0 (T2 v T0: F1+2 = 2.17 ± 0.39 v 0.95 ± 0.09 nmol/L, P < .01; TAT complex = 4.72 ± 0.39 v 3.55 ± 0.25 ng/mL, P < .05; D-dimer = 0.37 ± 0.04 v 0.29 ± 0.04 µg/mL; P < .05). However, the increment of the plasma D-dimer remained within the range of normal control values. On T3, the mean plasma levels of F1+2 and D-dimer were both decreased back to pretreatment values, whereas the TAT complex levels, although decreased, remained above the upper limit of normal control values.
Statistical Correlations As shown in Table 2, at any time of observation there was a significant positive correlation between the plasma level of elastase- 1AT complex and the number of circulating
PMN cells. Furthermore, the elastase-1AT complex concentration
positively correlated to the plasma levels of both endothelial markers,
vWF and TM, and to the levels of F1+2. Significant positive
correlations also were found between TM and vWF and F1+2 versus both
TAT complex and D-dimer.
MNC PCA MNC were freshly isolated from 6 donor subjects on T0, T2, and T3. The PCA was evaluated before and after 4 hours of incubation with and without 1 µg/mL LPS. The results indicate that freshly isolated donors' MNC as well as control MNC had virtually no PCA (not shown). After 4 hours of incubation at 37°C, in LPS-stimulated samples (+LPS; Fig 5, right panel) there was a significant increase in the PCA generated in vitro by donors' MNC obtained at T2 (during rHuG-CSF administration), compared with that of MNC at T0 (before starting) and T3 (after stopping treatment). Instead, in the absence of stimulus ( LPS; Fig 5, left panel), there were
no significant differences between the PCA of donor MNC from all of the
time points.
A variety of functions of activated PMN can interfere with the hemostatic system. To test the hypothesis as to whether PMN activation is associated with hemostatic changes in vivo, we have analyzed in a group of healthy HPC donors receiving rHuG-CSF the PMN activation status, as measured by parameters of PMN degranulation and phenotypical change, simultaneously to a series of plasma variables reflecting ongoing endothelial and clotting activation.
The authors are grateful to S. Bertoletti and A. Vignoli (Hematology Division, Ospedali Riuniti Bergamo, Bergamo, Italy) and to C. Rossi (Mario Negri Institute, Bergamo Laboratories, Bergamo, Italy) for technical assistance.
Submitted May 11, 1998; accepted December 10, 1998.
Supported in part by the Italian National Research Council (Convenzione CNR-Consorzio Mario Negri Sud). M.M. is a recipient of a fellowship of the Associazione Italiana Ricerca sul Cancro (AIRC).
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. section 1734 solely to indicate this fact.
Address reprint requests to A. Falanga, MD, Hematology Division, Ospedali Riuniti Bergamo, Largo Barozzi 1, 24100 Bergamo, Italy.
1.
Gabrilove J:
The development of granulocyte colony-stimulating factor in its various clinical applications.
Blood
80:1382, 1992 2. Lieschke GJ, Burgess AW: Granulocyte colony-stimulating factor and granulocyte-macrophage colony stimulating factor. N Engl J Med 327:28, 1992[Medline] [Order article via Infotrieve]
3.
Anderlini P, Przepiorka D, Champlin R, Korbling M:
Biologic and clinical effects of granulocyte colony-stimulating factor in normal individuals.
Blood
88:2819, 1996
4.
Goldman J:
Peripheral blood stem cells for allografting.
Blood
85:1413, 1995
5.
Nathan CF:
Respiratory burst in adherent human neutrophils: Triggering by colony-stimulating factors CSF-GM and CSF-G.
Blood
73:301, 1989 6. Sullivan R, Griffin JD, Simons ER, Schafer AI, Meshulam T, Fredette JP, Maas AK, Gadenne AS, Leavitt JL, Melnick DA: Effects of recombinant human granulocyte and macrophage-stimulating factors on signal transduction pathways in human granulocytes. J Immunol 139:3422, 1987[Abstract]
7.
Yuo A, Kitagawa S, Ohsaka A, Miyazono K, Okabe T, Urabe A, Takaku F:
Recombinant human granulocyte colony-stimulating factor as an activator of human granulocytes: Potentiation of responses triggered by receptor-mediated agonists and stimulation of C3bi receptor expression and adherence.
Blood
74:2144, 1989
8.
Chatta GS, Price TH, Allen RC, Dale DC:
Effects of in vivo recombinant methionyl human granulocyte colony-stimulating factor on the neutrophil response and peripheral blood colony-forming cells in healthy young and elderly adult volunteers.
Blood
84:2923, 1994
9.
de Haas M, Kerst JM, van der Schoot CE, Calafat J, Hack CE, Nuijens JH, Roos D, van Oers RHJ, von dem Borne AEGKr:
Granulocyte colony-stimulating factor administration to healthy volunteers: Analysis of the immediate activating effects on circulating neutrophils.
Blood
84:3885, 1994 10. Harlan JM, Killen PD, Harker LA, Striker GE, Wright DG: Neutrophil-mediated endothelial injury in vitro mechanism of cell detachment. J Clin Invest 68:1394, 1981 11. Kolpakov V, D'Adamo MC, Salvatore L, Amore C, Mironov A, Iacoviello L, Donati MB: Neutrophils derived cathepsin G induces potentially thrombogenic changes in human endothelial cells: A scanning electron microscopy study in static and dynamic conditions. Thromb Haemost 72:140, 1994[Medline] [Order article via Infotrieve] 12. Varani J, Ginsburg I, Schuger L, Gibbs DF, Bromberg J, Johnson KJ, Ryan US, Ward PA: Endothelial cell killing by neutrophils. Synergistic interaction of oxygen products and proteases. Am J Pathol 135:435, 1989[Abstract] 13. Chignard M, Balloy V, Renesto P: Leukocyte elastase-mediated release of von Willebrand factor from cultured endothelial cells. Eur Resp J 6:79, 1993
14.
Weksler BB, Jaffe EA, Brower MS, Cole OF:
Human leukocyte cathepsin G and elastase specifically suppress thrombin-induced prostacyclin production in human endothelial cells.
Blood
74:1627, 1989 15. Pintucci G, Iacoviello L, Castelli MP, Amore C, Evangelista V, Cerletti C, Donati MB: Cathepsin G-induced release of PAI-1 in the culture medium of endothelial cells: A new thrombogenic role for polymorphonuclear leukocytes? J Lab Clin Med 122:69, 1993[Medline] [Order article via Infotrieve]
16.
Key NS, Platt JL, Vercellotti GM:
Vascular endothelial cell proteoglycans are susceptible to cleavage by neutrophils.
Arterioscler Thromb
12:836, 1992 17. Abe H, Okajima K, Okabe H, Takatsuki K, Binder BR: Granulocyte proteases and hydrogen peroxide synergistically inactivate thrombomodulin of endothelial cells in vitro. J Lab Clin Med 123:874, 1994[Medline] [Order article via Infotrieve] 18. Selak MA, Chignard M, Smith JB: Cathepsin G is a strong platelet agonist released by neutrophils. Biochem J 251:293, 1988[Medline] [Order article via Infotrieve] 19. Cerletti C, Evangelista V, Molino M, de Gaetano G: Platelet activation by polymorphonuclear leukocyte: Role of Cathepsin G and P-selectin. Thromb Haemost 74:218, 1995[Medline] [Order article via Infotrieve]
20.
Renesto P, Chignard M:
Enhancement of catepsin G-induced platelet activation by leukocyte elastase: Consequence for the neutrophil-mediated platelet activation.
Blood
82:139, 1993 21. Eckle I, Seitz R, Egbring R, Kolb G, Havemann K: Protein C degradation in vitro by neutrophil elastase. Biol Chem Hoppe Seyler 372:1007, 1991[Medline] [Order article via Infotrieve] 22. Eckle I, Seitz R, Egbring R, Kolb G, Havemann K: Protein S degradation in vitro by neutrophil elastase. Scand J Clin Lab Invest 53:281, 1993[Medline] [Order article via Infotrieve]
23.
Higuchi DA, Wun TC, Likert KM, Broze GJ:
The effect of leukocyte elastase on tissue factor pathway inhibitor.
Blood
79:1712, 1992
24.
Jordan RE, Kilpatrick J, Nelson RM:
Heparin promotes the inactivation of antithrombin by neutrophyl elastase.
Science
237:777, 1987 25. Sie P, Dupouy D, Dol F, Boneu B: Inactivation of heparin cofactor II by polymorphonuclear leukocytes. Thromb Res 47:657, 1987[Medline] [Order article via Infotrieve]
26.
Carlos TM, Harlan JM:
Leukocyte-endothelial adhesion molecules.
Blood
84:2068, 1994
27.
Buttrum SM, Hatton R, Nash GB:
Selectin-mediated rolling of neutrophils on immobilized platelets.
Blood
82:1165, 1993 28. Yong KL, Linch DC: Differential effects of granulocyte- and granulocyte-macrophage colony-stimulating factors (G- and GM-CSF) on neutrophil adhesion in vitro and in vivo. Eur J Haematol 49:251, 1992[Medline] [Order article via Infotrieve] 29. Hakansson L, Hoglund M, Jonsson U-B, Torsteinsdotter I, Xu X, Venge P: Effects of in vivo administration of G-CSF on neutrophil and eosinophil adhesion. Br J Haematol 98:603, 1997[Medline] [Order article via Infotrieve] 30. Weiss SJ: Tissue distruction by neutrophils. N Engl J Med 320:365, 1989[Medline] [Order article via Infotrieve]
31.
Evangelista V, Piccardoni P, White JG, de Gaetano G, Cerletti C:
Catepsin G-dependent platelet stimulation by activated polymorphonuclear leukocytes and its inhibition by antiproteinases: Role of P-selectin mediated cell-cell adhesion.
Blood
81:2947, 1993 32. Evangelista V, Manarini S, Rotondo S, Martelli N, Polischuck R, McGregor JL, de Gaetano G, Cerletti C: Platelet/polymorphonuclear leukocyte interaction in dinamic conditions: Evidence of adhesion cascade and cross-talk between P-selectin and the b2 integrin CD11b/CD18. Blood 88:4185, 1996 33. Blann AD, Taberner DA: A reliable marker of endothelial cell dysfunction: Does it exist? Br J Haematol 90:244, 1995[Medline] [Order article via Infotrieve]
34.
Dittman WA, Majierus PW:
Structure and function of thrombomodulin: A natural anticoagulant.
Blood
75:329, 1990
35.
Ruggeri ZM, Zimmerman TS:
The complex multimeric composition of factor VIII/von Willebrand factor.
Blood
57:1140, 1981 36. Ruggenenti P, Galbusera M, Plata Cornejo R, Bellavita P, Remuzzi G: Thrombotic thrombocytopenic purpura: Evidence that infusion rather than removal of plasma induces remission of the disease. Am J Kidney Dis 21:314, 1993[Medline] [Order article via Infotrieve] 37. Dent JA, Galbusera M, Ruggeri ZM: Heterogeneity of plasma von Willebrand factor multimers resulting from proteolysis of the costituent subunit. J Clin Invest 88:774, 1991
38.
Falanga A, Iacoviello L, Evangelista V, Consonni R, Belotti D, D'Orazio A, Donati MB, Barbui T:
Loss of blast cell procoagulant activity and improvement of hemostatic variables in patients with acute promyelocytic leukemia given all-trans-retinoic acid.
Blood
86:1072, 1995 39. Falanga A, Levine MN, Consonni R, Gritti G, Delaini F, Oldani E, Julian JA, Barbui T: The effect of very-low-dose warfarin on markers of hypercoagulation in metastatic breast cancer: Results from a randomized trial. Thromb Haemost 79:23, 1998[Medline] [Order article via Infotrieve] 40. Semeraro N, Colucci M: Tissue factor in health and disease. Thromb Haemost 78:759, 1997[Medline] [Order article via Infotrieve] 41. Semeraro N, Montemurro P, Conese M, Giordano D, Stella M, Restaino A, Cagnazzo G, Colucci M: Procoagulant activity of mononuclear phagocytes from different anatomical sites in patients with gynecological malignancies. Int J Cancer 45:251, 1990[Medline] [Order article via Infotrieve]
42.
Conway EM, Nowakowski B, Steiner-Mosonyi M:
Human neutrophils synthetize thrombomodulin that does not promote thrombin-dependent protein C activation.
Blood
80:1254, 1992 43. Xu S, Hoglund M, Venge P: The effect of granulocyte colony-stimulating factor (G-CSF) on the degranulation of secondary granule proteins from human neutrophils in vivo may be indirect. Br J Haematol 93:558, 1996[Medline] [Order article via Infotrieve]
44.
Pajkrt D, Manten A, van der Poll T, Tiel-van Buul MMC, Jansen J, ten Cate JW, van Deventer JH:
Modulation of cytokine release and neutrophil function by granulocyte colony-stimulating factor during endotoxemia in humans.
Blood
90:1415, 1997
45.
Hartung T, Docke WD, Gantner F, Krieger G, Sauer A, Stevens P, Volk HD, Wendel A:
Effect of granulocyte colony-stimulating factor treatment on ex vivo blood cytokine response in human volunteers.
Blood
85:2482, 1995
46.
Pollmacher T, Korth C, Mullington J, Schreiber W, Sauer J, Vedder H, Galanos C, Holsboer F:
Effects of granulocyte colony-stimulating factor on plasma cytokine and cytokine receptor levels and on the in vivo host response to endotoxin in healthy men.
Blood
87:900, 1996 47. Bussolino F, Wang JM, Defilippi O, Turrini F, Sanavio F, Edgell CJS, Aglietta M, Arese P, Mantovani A: Granulocyte- and granulocyte-macrophage colony stimulating factors induce endothelial cells to migrate and proliferate. Nature 337:471, 1989[Medline] [Order article via Infotrieve] 48. Rivera J, Zuazu I, Sanchez MJ, Rosillo MC, Arribas F, Heras I, Moraleda JM, Vicente V: Effect of G-CSF on the hemostatic system. Thromb Haemost 71:804, 1994[Medline] [Order article via Infotrieve] 49. Shimoda K, Okamura S, Inaba S, Okamura T, Ohga S, Urda K, Niho Y: Granumlocyte colony-stimulating factor and platelet aggregation. Lancet 341:633, 1993[Medline] [Order article via Infotrieve] 50. Oshaka A, Saionji K, Kuwaki T, Takeshima T, Igari J: Granulocyte colony-stimulating factor administration modulates the surface expression of effector cell molecules on human monocytes. Br J Haematol 89:465, 1995[Medline] [Order article via Infotrieve] 51. Shimoda K, Okamura S, Harada N, Kondo S, Okamura T, Niho Y: Identification of a functional receptor for granulocyte colony stimulating factor on platelets. J Clin Invest 91:1310, 1993 52. Conti JA, Scher HI: Acute arterial thrombosis after escalated-dose Methotrexate, Vinblastine, Doxorubicin, and Cisplatin chemotherapy with recombinant granulocyte colony stimulating factor. Cancer 70:2699, 1992[Medline] [Order article via Infotrieve] 53. Kawachi Y, Watanabe A, Uchida T, Yoshizawa K, Kurooka N, Setsu K: Acute arterial thrombosis due to platelet aggregation in a patient receiving granulocyte colony-stimulating factor. Br J Haematol 94:413, 1996[Medline] [Order article via Infotrieve]
54.
Barbui T, Finazzi G, Grassi A, Marchioli R:
Thrombosis in cancer patients treated with hematopoietic growth factors 55. Rickles FR, Levine MN, Edwards RL: Haemostatic alterations in cancer patients. Cancer Metast Rev 11:237, 1992[Medline] [Order article via Infotrieve]
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  O. B. Ekmekci, G. Ozturk, H. Ekmekci, D. Atay, M. Yanasik, S. Anak, and O. Devecioglu Effects of rhG-CSF Plus Dexamethasone on Hemostatic Parameters in Healthy Granulocyte Donors: Role of u-PA and Nitric Oxide Clinical and Applied Thrombosis/Hemostasis, December 1, 2009; 15(6): 689 - 694. [Abstract] [PDF]
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|
|
 |
|
 E. N. Brown and J. D. Herrington Review of the Relationship Between Venous Thromboembolism, Malignancy and Its Treatment Journal of Pharmacy Practice, April 1, 2008; 21(2): 126 - 137. [Abstract] [PDF]
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|
|
 |
|
 P. Anderlini and R. E. Champlin Biologic and molecular effects of granulocyte colony-stimulating factor in healthy individuals: recent findings and current challenges Blood, February 15, 2008; 111(4): 1767 - 1772. [Abstract] [Full Text] [PDF]
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|
 M R Ray, S Mukherjee, S Roychoudhury, P Bhattacharya, M Banerjee, S Siddique, S Chakraborty, and T Lahiri Platelet activation, upregulation of CD11b/CD18 expression on leukocytes and increase in circulating leukocyte-platelet aggregates in Indian women chronically exposed to biomass smoke Human and Experimental Toxicology, November 1, 2006; 25(11): 627 - 635. [Abstract] [PDF]
|
|
|
|
 |
|
 I. Ben-Dor, S. Fuchs, and R. Kornowski Potential Hazards and Technical Considerations Associated With Myocardial Cell Transplantation Protocols for Ischemic Myocardial Syndrome J. Am. Coll. Cardiol., October 17, 2006; 48(8): 1519 - 1526. [Abstract] [Full Text] [PDF]
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|
|
F. Passamonti, E. Rumi, D. Pietra, M. G. D. Porta, E. Boveri, C. Pascutto, L. Vanelli, L. Arcaini, S. Burcheri, L. Malcovati, et al. Relation between JAK2 (V617F) mutation status, granulocyte activation, and constitutive mobilization of CD34+ cells into peripheral blood in myeloproliferative disorders Blood, May 1, 2006; 107(9): 3676 - 3682. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Sainz and M. Sata Targeting bone marrow to treat vascular diseases: Accelerated vascular healing by colony stimulating factor Cardiovasc Res, April 1, 2006; 70(1): 3 - 5. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Valgimigli, G. M. Rigolin, C. Cittanti, P. Malagutti, S. Curello, G. Percoco, A. M. Bugli, M. D. Porta, L. Z. Bragotti, L. Ansani, et al. Use of granulocyte-colony stimulating factor during acute myocardial infarction to enhance bone marrow stem cell mobilization in humans: clinical and angiographic safety profile Eur. Heart J., September 2, 2005; 26(18): 1838 - 1845. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Balabanian, B. Lagane, J. L. Pablos, L. Laurent, T. Planchenault, O. Verola, C. Lebbe, D. Kerob, A. Dupuy, O. Hermine, et al. WHIM syndromes with different genetic anomalies are accounted for by impaired CXCR4 desensitization to CXCL12 Blood, March 15, 2005; 105(6): 2449 - 2457. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. D. Garlichs, S. Eskafi, I. Cicha, A. Schmeisser, B. Walzog, D. Raaz, C. Stumpf, A. Yilmaz, J. Bremer, J. Ludwig, et al. Delay of neutrophil apoptosis in acute coronary syndromes J. Leukoc. Biol., May 1, 2004; 75(5): 828 - 835. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. El Ouriaghli, H. Fujiwara, J. J. Melenhorst, G. Sconocchia, N. Hensel, and A. J. Barrett Neutrophil elastase enzymatically antagonizes the in vitro action of G-CSF: implications for the regulation of granulopoiesis Blood, March 1, 2003; 101(5): 1752 - 1758. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Valenzuela-Fernandez, T. Planchenault, F. Baleux, I. Staropoli, K. Le-Barillec, D. Leduc, T. Delaunay, F. Lazarini, J.-L. Virelizier, M. Chignard, et al. Leukocyte Elastase Negatively Regulates Stromal Cell-derived Factor-1 (SDF-1)/CXCR4 Binding and Functions by Amino-terminal Processing of SDF-1 and CXCR4 J. Biol. Chem., May 3, 2002; 277(18): 15677 - 15689. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-P. Levesque, Y. Takamatsu, S. K. Nilsson, D. N. Haylock, and P. J. Simmons Vascular cell adhesion molecule-1 (CD106) is cleaved by neutrophil proteases in the bone marrow following hematopoietic progenitor cell mobilization by granulocyte colony-stimulating factor Blood, September 1, 2001; 98(5): 1289 - 1297. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Falanga, M. Marchetti, V. Evangelista, A. Vignoli, M. Licini, M. Balicco, S. Manarini, G. Finazzi, C. Cerletti, and T. Barbui Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera Blood, December 15, 2000; 96(13): 4261 - 4266. [Abstract] [Full Text] [PDF]
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TOP
ABSTRACT
INTRODUCTION
1 to 10
2 integrin CD11b/CD18 by
donor PMN was not different from that of control subject PMN (donor
v control, MIF values: 137.62 ± 21 v 125 ± 32;
P = not significant [NS]). In response to rHuG-CSF, the
expression of CD11b/CD18 by donor PMN significantly increased over the
pretreatment values (T1 = 376 ± 55 MIF; and T2 = 366 ± 92 MIF;
P < .05). However, 1 week after stopping rHuG-CSF (T3), the
membrane CD11b/CD18 was decreased and returned to baseline (186 ± 20 MIF, P =NS).
1AT complex during rHuG-CSF administration. (C) Elastase
activity of lysed PMN isolated from citrated whole blood. The results
are the mean ± SEM. Dashed lines represent the cut-off of normal
control values (mean + 2SD). Statistical analysis by ANOVA for
repeated measures and Fisher's test for multiple comparisons is shown.
*P < .05, **P < .01 v T0.
A meta-analysis.
Thromb Haemost
75:368, 1996