Pathogenesis And Treatment Progress Of Thrombocytopenia Following Hematopoietic Stem Cell Transplantation

Background and ObjectiveHematopoietic stem cell transplantation(HSCT) has been developed as an effective treatment for patients with hematological malignancy. Thrombocytopenia is a common complication of HSCT, and it occurs in 8-37% of HSCT recipients. Previous studies showed thrombocytopenia is among the most consistent and strongest negative survival predictors following HSCT, while its underlying mechanism is remained uncertain. This study describes the clinical features, risk factors, and outcome of thrombocytopenia patients undergoing HSCT. Furthermore, in order to investigated the possible pathogenesis of thrombocytopenia following HSCT, megakaryocyte(MK) ploidy distributions in allo-HSCT recipients with or without prolonged thrombocytopenia and healthy volunteers were measured, thrombopoietin(TPO) level and anti c-Mpl antibody were detected,platelet associated antibody and MK associated antibody were determined. Currently, the treatment of thrombocytopenia post-HSCT is limited. We performed an open-label study of a new therapy of thrombocytopenia patients following HSCT.Methods1. Two hundred and thirty-nine patients who received allo-HSCT in our hospital from April to December, 2013 were enrolled in the study. Among them, there were 141 males and 98 females with a median age of 32(3-58). According to platelet levels post-HSCT,patients were divided into 4 groups: mild, moderate, severe and normal level. According to different types of platelet recovery, patients were divided into 3 groups: delay plateletrecovery(DPR), secondary failure of platelet recovery(SFPR) and good graft function(GGF). Transplant type, mononuclear cell(MNC), CD34+ cells infused, disease status at transplantation, relapse, ABO compatibility, Ⅱ- Ⅳ o acute graft-versus-host disease(a GVHD), extensive chronic graft-versus-host disease(c GVHD), active infections,cytomegalovirus(CMV), Epstein-Barr virus(EBV) and T cell subsets were determined, to investigate the predisposing factors associated with the disease.2. In order to investigated the possible pathogenesis of thrombocytopenia following HSCT, patients with thrombocytopenia following HSCT at our institute were selected.Thirty-one patients with thrombocytopenia(PLT<60×109/L) for at least one week, with recovery of all other peripheral blood cell lines were enrolled. Among them, there were 17 males and 14 females with a median age of 38(14-52). Additionally, 27 patients with good graft function and 19 healthy volunteers were selected as control. MK ploidy distributions, TPO level, anti c-Mpl antibody, platelet associated antibody and MK associated antibody were detected.3. In order to explore an effective therapy for thrombocytopenia post-HSCT, 13 patients with severe thrombocytopenia after HSCT were enrolled. Patients received decitabine in combination with TPO therapy. A platelet count <100×109/L pre-treatment,an absolute increase of 30×109/L or more was defined as a “major response”. In the case of platelet transfusion-dependent patients, stabilization of the platelet count and platelet transfusion independence constituted a major response. A platelet count <100 × 109/L pre-treatment, an increase in platelet count with a net increase >10 ×109/L but <30 ×109/L were designated “minor response”; Patients transfusion-dependent, or with a net platelet increase <10×109/L were defined as “no response”.Results:1. The study of risk factors, and outcome of thrombocytopenia patients undergoing HSCT showed Ⅱ-Ⅳo a GVHD and active infections were independently associated with increased risk of severe thrombocytopenia post-HSCT, the incidence of extensive c GVHDin patients with thrombocytopenia was significantly higher than patients with normal platelet level. The dose of CD34+ cells infused were significantly lower in patients with mild and moderate thrombocytopenia. Patients with advanced-stage disease before HSCT and relapse-stage post HSCT were associated with low platelet counts. Additionally,transplant type, MNC, ABO compatibility, EBV infections did not differ significantly among patient with and without thrombocytopenia. Patients with thrombocytopenia had a lower overall survival.Ⅱ-Ⅳo a GVHD and active infections were independently associated with increased risk of SFPR, Ⅱ-Ⅳo a GVHD were independently associated with increased risk of DPR.The dose of CD34+ cells infused were significantly lower in patients with DPR and SFPR than GGF. Patients with advanced-stage disease before HSCT and relapse-stage post HSCT were associated with a high rate of SFPR. Additionally, transplant type, MNC, ABO compatibility, EBV infections did not differ significantly among patient with and without thrombocytopenia. Patients with DPR and SFPR had a lower overall survival than GGF.2. In the study of pathogenesis of thrombocytopenia following HSCT, the allo-HSCT patients who had thrombocytopenia exhibited significant shifts toward low ploidy cells(left shift), which were accompanied by a marked increase in 2N cells and significant decreases in 8N and 16 N cells, in a comparison of non-thrombocytopenic allo-HSCT recipients. TPO levels in thrombocytopenia patients were significantly higher than non-thrombocytopenic patients and healthy volunteers, while the anti c-Mpl antibody were comparable. MK associated antibody increased significantly in patients with thrombocytopenia, while platelet associated antibody did not.3. In the study of the treatment of thrombocytopenia following HSCT, a major response was observed in 12 of 13 patients, 1 patient received minor response, with a median time of platelet transfusion independence of 22 days. No considerable myelosuppression, febrile neutropenia, or nonhematologic toxicities were observed during the study period.Conclusions:1. Various factors were associated with platelet recovery following HSCT, Ⅱ-Ⅳo a GVHD and active infections were independently associated with increased risk of thrombocytopenia post-HSCT. Furthermore, advanced-stage disease, relapse of the disease and low CD34+ cells infused were the significant risk factors. Thrombocytopenia was a poor prognostic factor after HSCT.2. Disorder of MK proliferation and maturity, increased MK destruction induced by antibody may contribute to the thrombocytopenia following HSCT.3. Low-dose decitabine can enhance platelet count in severe thrombocytopenia patient post-HSCT, without any adverse effects.