Antiplatelet antibody predicts platelet desialylation and apoptosis in immune thrombocytopenia.

Immune thrombocytopenia (ITP) is a bleeding disorder caused by dysregulated B- and T- cell functions, which lead to platelet destruction. A well-recognized mechanism of ITP pathogenesis involves anti-platelet and anti-megakaryocyte antibodies recognizing membrane glycoprotein (GP) complexes, mainly GPIb/IX and GPIIb/IIIa. In addition to the current view of phagocytosis of the opsonised platelets by splenic and hepatic macrophages via their Fc γ receptors, antibodyinduced platelet desialylation and apoptosis have also been reported to contribute to ITP pathogenesis. Nevertheless, the relationship between the specific thrombocytopenic mechanisms and various types of anti-platelet antibodies has not been established. In order to ascertain such association, we used sera from 61 ITP patients and assessed the capacity of anti-platelet antibodies to induce neuraminidase 1 (NEU1) surface expression, RCA-1 lectin binding and loss of mitochondrial inner membrane potential on donors' platelets. Sera from ITP patients with detectable antibodies caused significant platelet desialylation and apoptosis. Anti-GPIIb/IIIa antibodies appeared more capable of causing NEU1 surface translocation while anti-GPIb/IX complex antibodies resulted in a higher degree of platelet apoptosis. In ITP patients with anti-GPIIb/IIIa antibodies, both desialylation and apoptosis were dependent on FcγRIIa signaling rather than platelet activation. Finally, we confirmed in a murine model of ITP that destruction of human platelets induced by anti-GPIIb/IIIa antibodies can be prevented with the NEU1 inhibitor oseltamivir. A collaborative clinical trial is warranted to investigate the utility of oseltamivir in the treatment of ITP.

Effect of Aspirin vs Enoxaparin on Symptomatic Venous Thromboembolism in Patients Undergoing Hip or Knee Arthroplasty: The CRISTAL Randomized Trial.

Importance: There remains a lack of randomized trials investigating aspirin monotherapy for symptomatic venous thromboembolism (VTE) prophylaxis following total hip arthroplasty (THA) or total knee arthroplasty (TKA). Objective: To determine whether aspirin was noninferior to enoxaparin in preventing symptomatic VTE after THA or TKA. Design, Setting, and Participants: Cluster-randomized, crossover, registry-nested trial across 31 hospitals in Australia. Clusters were hospitals performing greater than 250 THA or TKA procedures annually. Patients (aged ≥18 years) undergoing hip or knee arthroplasty procedures were enrolled at each hospital. Patients receiving preoperative anticoagulation or who had a medical contraindication to either study drug were excluded. A total of 9711 eligible patients were enrolled (5675 in the aspirin group and 4036 in the enoxaparin group) between April 20, 2019, and December 18, 2020. Final follow-up occurred on August 14, 2021. Interventions: Hospitals were randomized to administer aspirin (100 mg/d) or enoxaparin (40 mg/d) for 35 days after THA and for 14 days after TKA. Crossover occurred after the patient enrollment target had been met for the first group. All 31 hospitals were initially randomized and 16 crossed over prior to trial cessation. Main Outcomes and Measures: The primary outcome was symptomatic VTE within 90 days, including pulmonary embolism and deep venous thrombosis (DVT) (above or below the knee). The noninferiority margin was 1%. Six secondary outcomes are reported, including death and major bleeding within 90 days. Analyses were performed by randomization group. Results: Enrollment was stopped after an interim analysis determined the stopping rule was met, with 9711 patients (median age, 68 years; 56.8% female) of the prespecified 15 562 enrolled (62%). Of these, 9203 (95%) completed the trial. Within 90 days of surgery, symptomatic VTE occurred in 256 patients, including pulmonary embolism (79 cases), above-knee DVT (18 cases), and below-knee DVT (174 cases). The symptomatic VTE rate in the aspirin group was 3.45% and in the enoxaparin group was 1.82% (estimated difference, 1.97%; 95% CI, 0.54%-3.41%). This failed to meet the criterion for noninferiority for aspirin and was significantly superior for enoxaparin (P = .007). Of 6 secondary outcomes, none were significantly better in the enoxaparin group compared with the aspirin group. Conclusions and Relevance: Among patients undergoing hip or knee arthroplasty for osteoarthritis, aspirin compared with enoxaparin resulted in a significantly higher rate of symptomatic VTE within 90 days, defined as below- or above-knee DVT or pulmonary embolism. These findings may be informed by a cost-effectiveness analysis. Trial Registration: ANZCTR Identifier: ACTRN12618001879257.

Effect of Aspirin vs Enoxaparin on 90-Day Mortality in Patients Undergoing Hip or Knee Arthroplasty: A Secondary Analysis of the CRISTAL Cluster Randomized Trial.

Importance: Ischemic heart disease remains the leading cause of mortality following hip and knee arthroplasty. Due to its antiplatelet and cardioprotective properties, aspirin has been proposed as an agent that could reduce mortality when used as venous thromboembolism (VTE) prophylaxis following these procedures. Objective: To compare aspirin with enoxaparin in reducing 90-day mortality for patients undergoing hip or knee arthroplasty procedures. Design, Setting, and Participants: This study was a planned secondary analysis of the CRISTAL cluster randomized, crossover, registry-nested trial performed across 31 participating hospitals in Australia between April 20, 2019, and December 18, 2020. The aim of the CRISTAL trial was to determine whether aspirin was noninferior to enoxaparin in preventing symptomatic VTE following hip or knee arthroplasty. The primary study restricted the analysis to patients undergoing total hip or knee arthroplasty for a diagnosis of osteoarthritis only. This study includes all adult patients (aged ≥18 years) undergoing any hip or knee arthroplasty procedure at participating sites during the course of the trial. Data were analyzed from June 1 to September 6, 2021. Interventions: Hospitals were randomized to administer all patients oral aspirin (100 mg daily) or subcutaneous enoxaparin (40 mg daily) for 35 days after hip arthroplasty and 14 days after knee arthroplasty procedures. Main Outcomes and Measures: The primary outcome was mortality within 90 days. The between-group difference in mortality was estimated using cluster summary methods. Results: A total of 23 458 patients from 31 hospitals were included, with 14 156 patients allocated to aspirin (median [IQR] age, 69 [62-77] years; 7984 [56.4%] female) and 9302 patients allocated to enoxaparin (median [IQR] age, 70 [62-77] years; 5277 [56.7%] female). The mortality rate within 90 days of surgery was 1.67% in the aspirin group and 1.53% in the enoxaparin group (estimated difference, 0.04%; 95% CI, -0.05%-0.42%). For the subgroup of 21 148 patients with a nonfracture diagnosis, the mortality rate was 0.49% in the aspirin group and 0.41% in the enoxaparin group (estimated difference, 0.05%; 95% CI, -0.67% to 0.76%). Conclusions and Relevance: In this secondary analysis of a cluster randomized trial comparing aspirin with enoxaparin following hip or knee arthroplasty, there was no significant between-group difference in mortality within 90 days when either drug was used for VTE prophylaxis. Trial Registration: http://anzctr.org.au Identifier: ACTRN12618001879257.

Indirect detection of anti-platelet antibodies in immune thrombocytopenia.

Despite recent advances in the understanding and treatment of immune thrombocytopenia (ITP), its diagnosis remains clinical due to the lack of sensitive laboratory tests. The detection of anti-platelet antibodies (APA) in plasma, although highly specific, is notoriously insensitive. Specialised clinical platelet laboratories routinely perform a screening test of only one dilution for indirect APA testing by flow cytometry. We evaluated the presence of APA using several dilutions of plasma from 61 ITP patients. Herein, we report that serial dilutions can improve the diagnostic value of indirect APA assay for ITP. We show that performing just two dilutions (1:2 and 1:25) would capture over 90% of patients with detectable plasma APA. This method enables indirect testing to become a valuable tool to be incorporated into the management algorithm for ITP.

Serum thromboxane B2 compared to five other platelet function tests for the evaluation of aspirin effect in stable cardiovascular disease.

BACKGROUND: To assess the role of serum thromboxane B(2) (TXB(2)) measurements and the correlation between platelet function studies, in patients with stable cardiovascular disease on aspirin or clopidogrel. METHODS: 76 patients (47 on aspirin, 16 clopidogrel, 13 both) underwent assessment of TXB(2), whole blood aggregometry (WBA) after stimulation with (i) arachidonic acid (0.5mM), (ii) ADP (5 microM), (iii) collagen (1 and 5 microg/ml), PFA-100, and Cone and Plate Analyzer. Clopidogrel patients were additionally assessed by the VerifyNow System. RESULTS: TXB(2) values ranged between 0.2 and 56.2 ng/ml, with significant separation between those taking aspirin, clopidogrel and controls (0.45 ng/ml vs 6.85 ng/ml vs 12.97 ng/ml, p<0.001). There was moderate correlation between WBA-AA and TXB(2) (r=0.487, p<0.001), PFA-100((R)) (r=0.599, p<0.001), WBA-Col1 (r=0.424, p<0.001), WBA-Col1:5 (r=0.417, p<0.001), and between TXB(2) and PFA-100((R)) (r=0.509, p<0.001). The prevalence of aspirin non-responders for WBA-AA, TXB(2), PFA-100((R)), CPA and Coll1:5 was 13.1%, 8.2%, 14.8%, 9.7% and 16.4% respectively. Individual patients were not consistently classified as aspirin non-responders in all tests. Those with inadequate aspirin response on > or =3 tests had higher TXB(2) levels (mean 1.57+/-1.66, range 0.553-4.45 vs mean 0.45+/-0.18, range 0.23-1.50) (p=0.001). Clopidogrel suppressed TXB(2) (p=0.02), WBA-AA (p<0.001), WBA-Col1 (p=0.012) and WBA-ADP (p<0.001) compared to controls. TXB(2) in patients ingesting fish oil tablets was lower compared to those without (0.4 ng/ml vs 0.52 ng/ml, p=0.004). Obesity was associated with higher TXB(2) values (0.61 vs 0.41, p=0.01). CONCLUSION: Serum TXB(2) measurements are a direct measure of the pharmacological effect of aspirin, are easily performed and correlate with other measures of platelet function. Serum TXB(2) measurements could be a useful sole measure of aspirin non-response, and may be even more predictive when performed in tandem with a global measure of platelet function. Aspirin and clopidogrel both suppressed several platelet pathways.

Acquired Glanzmann thrombasthenia associated with platelet desialylation.

BACKGROUND: The notable discrepancy between platelet count and bleeding manifestations in immune thrombocytopenia (ITP) patients with acquired Glanzmann thrombasthenia (GT) has been described. OBJECTIVES: We aimed to examine the mechanisms responsible for thrombocytopenia and the bleeding phenotype in a patient with acquired GT. PATIENT, METHODS, AND RESULTS: A patient with primary ITP underwent splenectomy due to steroid intolerance. Despite platelet count normalization, bleeding continued. Platelet aggregometry was abnormal with all agonists except for ristocetin. Flow cytometry demonstrated the presence of antiplatelet antibody, which caused dose-dependent inhibition of fibrinogen and PAC-1 binding, induction of neuraminidase-1 expression as well as platelet desialylation in donor platelets. Indirect monoclonal antibody immobilization of platelet specific antigen assay (MAIPA) confirmed specificity to αIIb ß3 only, corroborated by binding on Chinese hamster ovary (CHO) cells expressing human glycoprotein αIIb ß3 but not GP Ib/IX. Both desialylation and neuraminidase expression were observed with plasma adsorbed on Ib/IX CHO cells and with the immunoglobulin G (IgG) fraction. Desialylation was inhibited in the presence of anti-Fc-gamma receptor IIa (FcγRIIa) antibody. A nonobese diabetic/severe combined immunodeficient ITP murine model was established, which showed rapid hepatic donor platelet clearance in the presence of patient IgG. Treatment of mice with the neuraminidase inhibitor oseltamivir significantly reduced antibody-induced platelet destruction. CONCLUSIONS: We report the first case of a patient with acquired GT due to ITP with FcγRIIa mediated platelet desialylation, independent of platelet activation. Treatment with neuraminidase inhibitor may prevent platelet clearance by anti-αIIb ß3 antibodies.

Panaxdiol Saponins Component Promotes Hematopoiesis and Modulates T Lymphocyte Dysregulation in Aplastic Anemia Model Mice.

OBJECTIVE: To investigate the potential efficacy of panaxadiol saponins component (PDS-C) in the treatment of aplastic anemia (AA) model mice. METHODS: Totally 70 mice were divided into 7 groups as follows: normal, model, low-, medium-, high-dose PDS-C (20, 40, 80 mg/kg, namely L-, M-, H-PDS-C), cyclosporine (40 mg/kg), and andriol (25 mg/kg) groups, respectively. An immune-mediated AA mouse model was established in BALB/c mice by exposing to 5.0 Gy total body irradiation at 1.0 Gy/min, and injecting with lymphocytes from DBA mice. On day 4 after establishment of AA model, all drugs were intragastrically administered daily for 15 days, respectively, while the mice in the normal and model groups were administered with saline solution. After treatment, the peripheral blood counts, bone marrow pathological examination, colony forming assay of bone marrow culture, T lymphocyte subpopulation analysis, as well as T-bet, GATA-3 and FoxP3 proteins were detected by flow cytometry and Western blot. RESULTS: The peripheral blood of white blood cell (WBC), platelet, neutrophil counts and hemoglobin (Hb) concentration were significantly decreased in the model group compared with the normal group (all P<0.01). In response to 3 dose PDS-C treatment, the WBC, platelet, neutrophil counts were significantly increased at a dose-dependent manner compared with the model group (all P<0.01). The myelosuppression status of AA was significantly reduced in M-, H-PDS-C groups, and hematopoietic cell quantity of bone marrow was more abundant than the model group. The colony numbers of myeloid, erythroid and megakaryocytic progenitor cells in the model group were less than those of the normal mice in bone marrow culture, while, PDS-C therapy enhanced proliferation of hematopoietic progenitor cells by significantly increasing colony numbers (all P<0.01). Furthermore, PDS-C therapy increased peripheral blood CD3+ and CD3+CD4+ cells and reduced CD3+CD8+ cells (P<0.05 or P<0.01). Meanwhile, PDS-C treatment at medium- and high doses groups also increased CD4+CD25+FoxP3+ cells, downregulated T-bet protein expression, and upregulated GATA-3 and FoxP3 protein expressions in spleen cells (P<0.05). CONCLUSION: PDS-C possesses dual activities, promoting proliferation hematopoietic progenitor cells and modulating T lymphocyte immune functions in the treatment of AA model mice.

Ginseng-Derived Panaxadiol Saponins Promote Hematopoiesis Recovery in Cyclophosphamide-Induced Myelosuppressive Mice: Potential Novel Treatment of Chemotherapy-Induced Cytopenias.

OBJECTIVE: To investigate the potential efficacy of panaxadiol saponins component (PDS-C), a biologically active fraction isolated from total ginsenosides, to reverse chemotherapy-induced myelosuppression and pancytopenia caused by cyclophamide (CTX). METHODS: Mice with myelosuppression induced by CTX were treated with PDS-C at a low- (20 mg/kg), moderate- (40 mg/kg), or high-dose (80 mg/kg) for 7 consecutive days. The level of peripheral white blood cell (WBC), neutrophil (NEU) and platelet (PLT) were measured, the histopathology and colony formation were observed, the protein kinase and transcription factors in hematopoietic cells were determined by immunohistochemical staining and Western blot. RESULTS: In response to PDS-C therapy, the peripheral WBC, NEU and PLT counts of CTX-induced myelosuppressed mice were significantly increased in a dose-dependent manner. Similarly, bone marrow histopathology examination showed reversal of CTX-induced myelosuppression with increase in overall bone marrow cellularity and the number of hematopoietic cells (P<0.01). PDS-C also promoted proliferation of granulocytic and megakaryocyte progenitor cells in CTX-treated mice, as evidenced by significantly increase in colony formation units-granulocytes/monocytes and -megakaryocytes (P<0.01). The enhancement of hematopoiesis by PDS-C appears to be mediated by an intracellular signaling pathway, this was evidenced by the up-regulation of phosphorylated mitogen-activated protein kinase (p-MEK) and extracellular signal-regulated kinases (p-ERK), and receptor tyrosine kinase (C-kit) and globin transcription factor 1 (GATA-1) in hematopoietic cells of CTX-treated mice (P<0.05). CONCLUSIONS: PDS-C possesses hematopoietic growth factor-like activities that promote proliferation and also possibly differentiation of hematopoietic progenitor cells in myelosuppressed mice, probably mediated by a mechanism involving MEK and ERK protein kinases, and C-kit and GATA-1 transcription factors. PDS-C may potentially be a novel treatment of myelosuppression and pancytopenia caused by chemotherapy.

Pharmacodynamics, pharmacokinetics and clinical efficacy of apixaban in the treatment of thrombosis.

INTRODUCTION: Venous thromboembolism (VTE) is a common disorder. Heparin and vitamin K antagonists have been the standard treatment for VTE for over 50 years. The development of apixaban and other direct oral anticoagulants has greatly increased the range of anticoagulants available for the treatment of VTE. AREA COVERED: Studies on the chemistry, pharmacodynamics and pharmacokinetics of apixaban are reviewed. Its clinical efficacy and safety are discussed, with an emphasis on randomized controlled Phase III clinical trials on treatment of thrombosis. EXPERT OPINION: Apixaban is a safe and effective anticoagulant for VTE treatment. It has several attractive features: its oral activity, rapid action, limited drug- interaction profile and limited need for laboratory monitoring. An antidote may become available in the near future. Further studies of certain patient populations such as patients with cancers, elderly (aged 75 years and older) and those with severe renal and liver disease, are required as these patients have not yet been studied in sufficient numbers. As clinical trials included only selected patients, data from these studies may not reflect the 'real-life' patients in clinical practice. There is therefore an unmet need for large post-registration studies of unselected 'real-life' patients, such as registry studies, to validate the clinical trial findings.

The effects of panaxadiol saponins on megakaryocytic maturation and immune function in a mouse model of immune thrombocytopenia.

We have identified a biologically active component, panaxadiol saponins component (PDS-C), from Chinese ginseng herb extract. Panaxadiol saponins component contains five ginsenoside monomers with total purity of 92.44%. In this study, the BALB/c mouse model with immune thrombocytopenia (ITP) was established by injection of antiplatelet antibody every other day for 5 total times; the peripheral blood platelet counts steadily decreased to 20%-30% of normal levels and remained decreased for about 10 days. The antiplatelet antibody was derived from the sera of guinea pigs immunized with the platelets of BALB/c mice. Mice with ITP were treated with PDS-C at a low, a moderate, or a high dose for 10 consecutive days. We observed that the peripheral blood platelet counts of ITP mice were significantly higher than that of ITP controls (untreated) after treatment of PDS-C in a dose-dependent manner. Treatment with PDS-C also increased the mature megakaryocytes in the bone marrow of treated ITP animals with a concomitant decease of immature megakaryocyte precursors. Furthermore, macrophage phagocytosis of exogenous erythrocytes in the intra-abdominal cavity of ITP mice was inhibited by PDS-C treatment, indicating that PDS-C also could modulate immune function and may possibly prevent phagocytosis of antibody-coated platelets. Altogether, our findings suggest that PDS-C may have a dual role, promoting proliferation and differentiation of megakaryocytes, as well as modulating immune function, and it may therefore be very helpful in the treatment of ITP.

Low prevalence of heparin-induced thrombocytopenia after cardiac surgery in Thai patients.

INTRODUCTION: Heparin induced-thrombocytopenia (HIT) has been well recognized in Western countries. However, there are no data in the Thai population. We therefore investigated the prevalence of anti-platelet factor 4 (PF4)/heparin antibodies, HIT, and its thrombotic complications in Thai patients undergoing cardiac surgery using unfractionated heparin. MATERIALS AND METHODS: Seventy-three consecutive patients were prospectively enrolled in this study. Blood samples before operation and week 1, week 2, and week 3 after operation were collected from each patient for HIT antibody screening by enzyme-linked immunosorbent assay using IgG antibody specific to the PF4/heparin complex. Positive samples were further analyzed by (14)C-serotonin release assay. Complete blood count was performed daily during the first week, then weekly for 3 weeks. RESULTS: No patient had detectable anti-PF4/heparin antibodies at baseline. Five patients sero-converted during the course of the study for anti-PF4/heparin IgG: 3 (4.1%) at week 1, 4 (5.5%) at week 2, and 5 (6.8%) at week 3 after surgery. However, none of these patients had anti-PF4/heparin antibodies that resulted in (14)C-serotonin release to be considered clinically significant antibodies. Post-operative thrombocytopenia after the operation was found in 35 patients (47.9%), but was not considered to be caused by HIT. Thromboembolic events occurred in 3 patients (4.1%) during follow up; however, none of these patients had positive PF4/heparin antibody tests. CONCLUSIONS: Our study represents the first study to examine Thai patients exposed to heparin in the context of cardiac surgery. We found a lower prevalence of positive anti-PF4/heparin antibodies and clinical HIT than previously published studies.

Research and development of the effective components of panaxdiol saponin as new Chinese patent medicine for treating hemocytopenia.

Pancytopenia (hemocytopenia) such as pr imary immune primary thrombocytopenia (ITP), aplastic anemia and chronic neutropenia (agnogenic leukocytopenia) were of ten t reated by glucocor t icoids, androgen and often treated glucocorticoids, immunosuppressive agents at present, but the response to these treatments has not been always satisfactory, and may cause serious adverse events. Our research has identified a biological active component in ginseng extract and the active component, panaxadiol saponins component (PDS-C), was isolated from total saponins of ginsenosides, and formulated into capsules named as Painengda. We successfully obtained approval from State Food and Drug Administration (SFDA) of China in 2010 to conduct clinical trials of PDS-C as class-five new Chinese patent medicine. Phase I and phase II clinical trials of PDS-C and Painengda Capsule were carried out in the treatment of ITP and agnogenic leukocytopenia. The composition and content of PDS-C have been analyzed and defined by high-performance liquid chromatography-chromatographymass spectrometry (HPLC-MS) and HPLC using specific monomers of ginsenosides as the reference standards. mass PDS-C is very efficacious for treating mice and rats with ITP and aplastic anemia, and myelosuppression caused by chemotherapy or radiation. Our animal model studies and cell biology and molecular biology experiments demonstrated that PDS-C possessed dual activities, namely that of promoting proliferation and differentiation of hematopoietic progenitor cells, and that of regulating the immune function. PDS-C and Painengda Capsule as a new Chinese patent medicine have been successfully transferred to industry. We believe that PDS-C is effective and safe in the treatment of refractory hemocytopenia. The advantages are that it is effective in small doses, it is convenient to use because of its oral administration, its lack of adverse events, it could be used alone or in combination with pharmacological agents, which improve the efficacy and decrease adverse events.

Effects of notoginosides on proliferation and upregulation of GR nuclear transcription factor in hematopoietic cells.

AIM: To investigate the effects of panax notoginosides (PNS) on the proliferation of human hematopoietic stem/progenitor cells, and to explore the signaling pathway of the nuclear transcription factor of the glucocorticoid receptor (GR-NTF) initiated by PNS related with the proliferation. METHODS: The human CD34+ cells and bone marrow nuclear cells were exposed to PNS at a concentration of 0, 10, 25, 50, and 100 mg/L, respectively, in semi-solid culture system to observe colony forming unite of all lineages, granulocyte, erythrocyte, and megakaryocyte (CFUGEMM, CFU-GM, CFU-E, and CFU-MK). Three lineages of human hematopoietic cell lines, including granulocytic HL-60, erythrocytic K562, megakaryocytic CHRF- 288, and Meg-01 cells were incubated with PNS at 20 mg/L for 14 d. Meanwhile, dexamethasone (Dex) was used as a positive control. The nuclear protein of the cells was analyzed by Western blotting with monoclonal antibodies against the amino or carboxyl terminus of GR-NTF. Electrophoretic mobility shift assay performed by using the 32P-radiolabeled GR-NTF consensus oligonucleotide. RESULTS: PNS promoted the proliferation of CD34+ cells and significantly raised the colony numbers of CFU-GEMM by 34.7%+/-16.0% over the non-PNS control (P<0.01). PNS also enhanced the proliferation of CFU-GM, CFU-E, and CFU-MK by 39.3%+/- 5.7%, 33.3%+/-7.3%, and 26.2%+/-3.2%, respectively. GR-NTF protein levels of either the amino or carboxyl terminus in K562, CHRF-288, and Meg-01 treated by PNS increased by 2.4-2.8 fold and 1.3- 3.9 fold over the untreated cells. GR-NTF binding activity, initiated by either PNS or Dex, was apparently elevated to form the complex of GR-NTF with DNA as higher density bands in K562 and CHRF-288 cells, and some activity appeared as a band in HL-60 cells induced by PNS. CONCLUSION: PNS displayed the action of hematopoietic growth factor-like or synergistic efficacy to promote proliferation of human progenitor cells, may play a role in the upregulation of gene expression related to proliferation of hematopoietic cells through increasing the GR-NTF synthesis and its DNA binding activity.