Identification of Plasma Thrombopoietin Level and Its Significance in Patients with Aplastic Anemia and Myelodysplastic Syndrome.

Objective Our objective was to investigate the concentration of plasma thrombopoietin (TPO) in patients with aplastic anemia (AA) and myelodysplastic syndrome (MDS), as well as its relationship with patients' responses to recombined human TPO (rhTPO) therapy. Methods We detected the concentration of plasma TPO in 31 patients with AA, 27 patients with MDS, and 11 normal controls using enzyme-linked immunosorbent assay. Results The median concentration of plasma TPO in patients with AA, MDS, and controls was (841.08 ± 768.64), (212.41 ± 338.93), and (35.09 ± 18.21) pg/mL, respectively. The TPO concentration in patients with AA and MDS was significantly higher than that in controls ( p < 0.05). The median platelet (PLT) counts were (184 ± 34) ×10 9 /L in the control group and (24 ± 19) ×10 9 /L and (80 ± 71) ×10 9 /L in AA and MDS patients, respectively. Negative correlations were found between plasma TPO concentration and PLT counts as well as megakaryocytes in bone marrow ( p < 0.05). In AA patients treated with rhTPO, a negative correlation was observed between increased PLT counts and pretreatment TPO levels ( p < 0.05). Conclusion Plasma TPO concentration in AA and MDS was significantly higher than that in normal controls. Plasma TPO was negatively correlated with peripheral blood PLT counts and bone marrow megakaryocyte counts. The pretreatment TPO level may serve as a prognostic indicator for the therapeutic effect of rhTPO in AA patients.

Abnormal Macrophage Polarization in Patients with Myelodysplastic Syndrome.

BACKGROUND: This study is aimed at assessing the subsets of bone marrow macrophages in patients with myelodysplastic syndrome (MDS) and exploring the role of macrophages in the pathogenesis of MDS. METHODS: Thirty-eight newly diagnosed MDS patients were enrolled in the Department of Hematology of General Hospital of Tianjin Medical University from June 2015 to June 2016. Bone marrow monocytes and macrophage subsets (M1/M2) were detected in patients with MDS and normal controls by flow cytometry. M1 macrophages were cultured in vitro, and the expression of IL-1ß and TNF-α mRNA was measured using real-time polymerase chain reaction. RESULTS: Compared with the normal control group, the proportion of bone marrow monocytes was higher (2.11 ± 0.93% vs. 3.66 ± 3.38%), and the mean fluorescence intensity of surface molecule CD14 was lower in the higher-risk (HR) MDS group (639.05 ± 359.78 vs. 458.26 ± 306.72, p < 0.05). The ratio of M2 macrophages to monocytes was higher in patients with HR-MDS (1.82 ± 2.47% vs. 3.93 ± 3.81%, p < 0.05). The ratio of M1 to M2 macrophages was lower in the HR-MDS group (3.50 ± 3.22 vs. 1.80 ± 0.88, p < 0.05). The expression of IL-1ß and TNF-α mRNA in M1 macrophages was significantly lower in the MDS group (p < 0.05). CONCLUSIONS: Patients with MDS had abnormal macrophage polarization, which may be involved in the alteration of bone marrow microenvironments.

HCMV modulates c-Mpl/IEX-1 pathway-mediated megakaryo/thrombopoiesis via PDGFRα and αvß3 receptors after allo-HSCT.

Thrombocytopenia is a common complication of human cytomegalovirus (HCMV) infection in immunocompromised hosts, which contributes to poor prognosis even in patients receiving antiviral treatment. Here, we investigated the megakaryo/thrombopoiesis process, including the involvement of the c-Mpl/IEX-1 pathway, after HCMV infection, identified receptors mediating the interaction between megakaryocytes (MKs) and HCMV, and explored novel therapeutic targets. Our data shows that HCMV directly infects megakaryocytes in patients with HCMV DNAemia and influences megakaryopoiesis via the c-Mpl/IEX-1 pathway throughout megakaryocyte maturation, apoptosis, and platelet generation in vivo and in vitro. After treatment with inhibitors of PDGFRα and αvß3, the HCMV infection rate in MKs was significantly reduced, suggesting that IMC-3G3 and anti-αvß3 are potential therapeutic alternatives for viral infection. In summary, our study proposes a possible mechanism and potential treatments for thrombocytopenia caused by HCMV infection and other viral diseases associated with abnormal hemostasis.

Prediction of postpartum hemorrhage in pregnant women with immune thrombocytopenia: Development and validation of the MONITOR model in a nationwide multicenter study.

Globally, postpartum hemorrhage (PPH) is the leading cause of maternal death. Women with immune thrombocytopenia (ITP) are at increased risk of developing PPH. Early identification of PPH helps to prevent adverse outcomes, but is underused because clinicians do not have a tool to predict PPH for women with ITP. We therefore conducted a nationwide multicenter retrospective study to develop and validate a prediction model of PPH in patients with ITP. We included 432 pregnant women (677 pregnancies) with primary ITP from 18 academic tertiary centers in China from January 2008 to August 2018. A total of 157 (23.2%) pregnancies experienced PPH. The derivation cohort included 450 pregnancies. For the validation cohort, we included 117 pregnancies in the temporal validation cohort and 110 pregnancies in the geographical validation cohort. We assessed 25 clinical parameters as candidate predictors and used multivariable logistic regression to develop our prediction model. The final model included seven variables and was named MONITOR (maternal complication, WHO bleeding score, antepartum platelet transfusion, placental abnormalities, platelet count, previous uterine surgery, and primiparity). We established an easy-to-use risk heatmap and risk score of PPH based on the seven risk factors. We externally validated this model using both a temporal validation cohort and a geographical validation cohort. The MONITOR model had an AUC of 0.868 (95% CI 0.828-0.909) in internal validation, 0.869 (95% CI 0.802-0.937) in the temporal validation, and 0.811 (95% CI 0.713-0.908) in the geographical validation. Calibration plots demonstrated good agreement between MONITOR-predicted probability and actual observation in both internal validation and external validation. Therefore, we developed and validated a very accurate prediction model for PPH. We hope that the model will contribute to more precise clinical care, decreased adverse outcomes, and better health care resource allocation.

Overt gastrointestinal bleeding following haploidentical haematopoietic stem cell transplantation: incidence, outcomes and predictive models.

Gastrointestinal bleeding (GIB) accounts for a significant proportion of life-threatening bleeding cases occurring after allogeneic haematopoietic stem cell transplantation (allo-HSCT). However, data on GIB after haploidentical HSCT (haplo-HSCT) are not available. A total of 3180 patients received haplo-HSCT at Peking University People's Hospital from January 2015 to November 2019, and GIB occurred in 188 of these patients (incidence of 5.9%). Platelet counts <30 × 109/L, viral hepatitis, acute kidney injury (AKI), gastrointestinal disease or bleeding before HSCT and sinusoidal obstruction syndrome (SOS) were determined to be significant risk factors for the occurrence of GIB after haplo-HSCT. Grade III-IV acute graft-versus-host disease (aGVHD), AKI, thrombotic microangiopathy (TMA), disseminated intravascular coagulation (DIC) and gastrointestinal disease or bleeding before HSCT were significantly related to mortality in patients with GIB after haplo-HSCT. The predictive models developed for the occurrence and mortality of GIB performed well in terms of discrimination, and they might assist clinicians with personalised strategies for GIB prevention and treatment in patients after haplo-HSCT.

Outcomes of symptomatic venous thromboembolism after haploidentical donor hematopoietic stem cell transplantation and comparison with human leukocyte antigen-identical sibling transplantation.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is regarded as a curative therapy for majority of hematologic malignancies and some non-malignant hematologic diseases. Venous thromboembolism (VTE) has become increasingly recognized as a severe complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). OBJECTIVES: To show the characteristics of VTE after haploidentical donor hematopoietic stem cell transplantation (HID-HSCT) and make comparisons with matched related donor HSCT (MRD-HSCT). PATIENTS/METHODS: A retrospective nested case-control study design was used, cases with VTE and matched controls were selected, with 3534 patients underwent HID-HSCT and 1289 underwent MRD-HSCT. RESULTS: During follow-up, 114 patients with VTE were identified. The incidence of VTE in HID-HSCT group was similar to that of MRD-HSCT group (2.4% versus 2.3%, P = 0.92). In HID-HSCT group, VTE occurred at a median time of 92.5 days, which was earlier than MRD-HSCT group (243.5 days). For HID-HSCT, advanced disease status, cardiovascular risk factors, acute graft-versus-host disease (aGVHD), and relapse were the independent risk factors for VTE. For MRD-HSCT, cardiovascular risk factors, aGVHD, and relapse were associated with VTE. Overall survival (OS) of patients following HID-HSCT and MRD-HSCT were similar, but the OS in patients with VTE was significantly lower than patients without VTE. CONCLUSIONS: There was no statistical difference in the incidence of VTE after HID-HSCT compared with MRD-HSCT. The development of VTE adversely impacted the OS after allo-HSCT.

ADAM28 promotes tumor growth and dissemination of acute myeloid leukemia through IGFBP-3 degradation and IGF-I-induced cell proliferation.

ADAM28 has been shown to relate with tumor proliferation and prognosis. The expression of ADAM28 is up-regulated in acute myeloid leukemia (AML). However, the mechanism by which ADAM28 regulates the leukemic cell and the prognostic relevance with AML remain unknown. Here, we found that the expression level of ADAM28 was significantly elevated in AML patients suffering a relapse compared with those remaining in complete remission (CR). ADAM28 promoted the proliferation, migration and invasion in leukemic cells in vitro. Additionally, the increased expression of ADAM28 led to more IGFBP-3 degradation and IGF-I-induced cell proliferation. In a xenotransplantation mouse model, knockout of ADAM28 alleviated HL-60 cells growth and dissemination. The cumulative incidence of relapse (CIR) was significantly higher in patients with high ADAM28 expression. When separately considering the impact of ADAM28 on prognosis within the risk stratifications, patients with high ADAM28 expression levels had a significantly higher CIR in the favorable and intermediate-risk group but not in poor-risk group. Taken together, these data suggest a pivotal role for ADAM28 in regulating the proliferation and invasion of leukemic cells and in the prediction of relapse in AML patients.

Impaired Mitophagy of Nucleated Erythroid Cells Leads to Anemia in Patients with Myelodysplastic Syndromes.

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders characterized by cytopenia and dysplasia. Anemia is the most common symptom in patients with MDS. Mitophagy and mitochondrial dysfunction might be involved in the development of MDS. In this study, we investigated the change of mitophagy in erythroid precursors in MDS patients. We found that NIX-mediated mitophagy was impaired in bone marrow nucleated red blood cells (NRBC) of MDS patients, associated with an increased amount of damaged mitochondria and increased ROS level which might lead to apoptosis and ineffective erythropoiesis. The results showed that the amount of mitochondria in GlycoA+ NRBC positively correlated with the count of ring sideroblasts in bone marrow samples. Meanwhile, the level of autophagy-associated marker LC3B in GlycoA+ NRBC had a positive correlation with hemoglobin (Hb) levels, and the amount of mitochondria in GlycoA+ NRBC had a negative correlation with Hb levels in high-risk MDS patients. Our results indicated that mitophagy might involve the pathogenesis of anemia associated with MDS. Autophagy might be a novel target in treatments of MDS patients.

[Bone Marrow Microenvironment and Myelodysplastic Syndromes--Review].

Myelodysplastic syndromes (MDS) are a group of bone marrow failure diseases. The bone marrow microenvironment consists of bone marrow stromal cells (BMSC), growth factors and cytokines. The BMSC supporting haemopoiesis include mesenchymal stem cells (MSC), osteoblasts, endothelial cells and macrophages, but the adipocytes play a role in the suppression of hematopoiesis. Recently more and more researches indicate that the abnormality of bone marrow microenvironment involves in the pathogenesis and progression of MDS. In this review the abnormality of MDS bone marrow microenvironment is summarized briefly.