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Exploration of risk factors of platelet transfusion refractoriness and its impact on the prognosis of hematopoietic stem cell transplantation: a retrospective study of patients with hematological diseases
Song, X., Qi, J., Li, X., Zhou, M., He, J., Chu, T., Han, Y.
Platelets. 2023;34(1):2229905
Abstract
Platelet transfusion refractoriness (PTR) is an intractable issue in hematological patients, which increases bleeding risks and hospitalization costs to a great extent. We reviewed 108 patients with hematological diseases including acute leukemia, myelodysplastic syndrome, aplastic anemia, and others who received allogeneic hematopoietic stem cell transplantation (HSCT) from January 2019 through December 2020. After multivariable logistic regression, we found that splenomegaly (odds ratio [OR] = 26.98, p < .001) and JAK mutation (OR = 17.32, p = .024) were independent risk factors for PTR. During the period of transplantation, patients in the PTR group had a significantly higher platelet transfusion demand, which was reflected in the increased number of platelet transfusions (10.23 ± 6.696 vs. 5.06 ± 1.904, p < .001). After multivariate adjustment, PTR turned out to be independently associated with worse overall survival (hazard ratio = 2.794, 95% confidence interval = 1.083-7.207, p = .034). In conclusion, we found that splenomegaly and JAK gene mutation were independent risk factors for PTR in patients with hematological diseases. A history of PTR prior to allo-HSCT indicates a poor prognosis. What is the context?Platelet transfusion refractoriness is a critical issue, and it greatly increases bleeding risks and hospitalization costs.Patients with hematological diseases tend to develop PTR.PTR results from immune and nonimmune factors and the latter account for 80–90%.At present, there are few studies focused on the inducing factors of PTR, and the specific mechanism is not clear.What is new?In this study, we investigated 108 patients with hematological disorders who received allogeneic HSCT from January 2019 to December 2020.We found that splenomegaly and JAK gene mutation were independent risk factors for PTR in patients with hematological diseases.PTR had a passive effect on the prognosis of patients after HSCT, as indicated by worse OS and a trend toward lower platelets after transplantation.PTR might affect megakaryocyte reconstitution after transplantation.What is the impact?This study provides evidence that hematological patients with splenomegaly should be alert to the occurrence of PTR, which often indicates a worse prognosis of transplantation.Spleen reduction and JAK inhibitors in the treatment of PTR are worth exploring.AbbreviationsPLT: platelets; PTR: platelet transfusion refractoriness; HSCT hematopoietic stem cell transplantation; OR: odds ratio; HR: hazard ratio; CI: confidence interval; IQR: interquartile range; SD: standard deviation; HLA: human leukocyte antigen; HPA: human platelet antigen; OS: overall survival; RFS: relapse free survival; PI: post-transfusion increment; PPR: percentage platelet recovery; CCI: corrected count increment; ICU: intensive care unit; AA: aplastic anemia; MDS: myelodysplastic syndrome; AML: acute myeloid leukemia; ALL: acute lymphocytic leukemia; CML: chronic myeloid leukemia; CMML chronic myelomonocytic leukemia; MPN: myeloproliferative neoplasm; SI: splenic irradiation; Abs: antibodies; CR: complete remission; DAC: decitabine; GVHD graft-versus-host disease; BM: bone marrow; PB: peripheral blood. eng
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Intensity of endogenous thrombocytopenia after autologous stem cell transplantation in patients prophylactically transfused with platelets
Voß, A., Doescher, A., Kapels, H. H., Seltsam, A., Greinacher, A., Metzner, B., Müller, T. H.
Vox sanguinis. 2023
Abstract
BACKGROUND AND OBJECTIVES Large clinical trials have demonstrated that some patient groups with hypoproliferative thrombocytopenia benefit from prophylactic platelet transfusions, while in others, a therapeutic transfusion regimen might be sufficient. The remaining capacity to generate endogenous platelets might be helpful to select the platelet transfusion regimen. We assessed whether the recently described method of digital droplet polymerase chain reaction (PCR) can be used to assess the endogenous platelet levels in two groups of patients undergoing high-dose chemotherapy with autologous stem cell transplantation (ASCT). MATERIALS AND METHODS Multiple myeloma (n = 22) patients received high-dose melphalan alone (HDMA); lymphoma patients (n = 15) received BEAM or TEAM (B/TEAM) conditioning. Patients with a total platelet count <10 G/L received prophylactic apheresis platelet concentrates. Daily endogenous platelet counts were measured by digital droplet PCR for at least 10 days post-ASCT. RESULTS Post-transplantation B/TEAM patients received their first platelet transfusion on average 3 days earlier than HDMA patients (p < 0.001) and required about twofold more platelet concentrates (p < 0.001). The endogenous platelet count fell ≤5 G/L for a median of 115 h (91-159; 95% confidence interval) in B/TEAM-treated patients compared to 12.6 h (0-24) (p < 0.0001) in HDMA-treated patients. Multivariate analysis confirmed this profound effect of the high-dose regimen (p < 0.001). The CD-34(+) -cell dose in the graft was inversely correlated with the intensity of endogenous thrombocytopenia in B/TEAM-treated patients. CONCLUSION Monitoring endogenous platelet counts detects the direct effects of myelosuppressive chemotherapies on platelet regeneration. This approach may help to develop a platelet transfusion regimen tailored to specific patient groups.
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[Incidence and clinical significance of platelet transfusion refractoriness after allogeneic hematopoietic stem cell transplantation in patients with chronic myelomonocytic leukemia]
Zhao, C., Zhao, X. S., Wang, Y., Yan, C. H., Xu, L. P., Zhang, X. H., Liu, K. Y., Huang, X. J., Sun, Y. Q.
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi. 2022;43(9):738-744
Abstract
Objective: To retrospectively analyze the incidence and clinical significance of platelet transfusion refractoriness (PTR) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with chronic myelomonocytic leukemia (CMML) . Methods: A cohort of 55 CMML patients received allo-HSCT at Peking University Institute of Hematology during 2004-2021 were retrospectively assessed. The incidence of PTR within 30 days after allo-HSCT was retrospectively analyzed, and the impact on clinical outcomes and bleeding event were compared between patients with platelet transfusion refractoriness (PTR) or effective platelet transfusion (EPT) . Results: The incidence of PTR after allo-HSCT in CMML patients was 25.5% (14/55) . PTR patients had a lower rate of platelet engraftment than EPT patients (28.6% vs 100%) , and the median time of engraftment was 67 (33-144) days and 21 (9-157) days respectively (P<0.010) . There was no significant difference between two groups in acute graft-versus-host disease (aGVHD) and chronic graft-versus-host disease (cGVHD) (P=0.183, P=0.455) . After following-up a median of 684 (24-3978) days, the 1-year overall survival (OS) and 1-year leukemia free survival (LFS) in PTR and EPT patients were (35.4±13.9) % vs (75.1±7.8) % (P=0.037) and (28.1±13.3) % vs (65.3±8.2) % (P=0.072) , respectively. The transplant-related mortality (TRM) were (48.2±2.4) % and (9.0±0.25) %, respectively (P=0.009) . Bleeding events occurred in five patients (35.7%) of PTR and 2 patients (4.9%) of EPT (P=0.009) . Conclusion: In CMML patients with allo-HSCT, the incidence of PTR is 25.5%, which was associated with delayed platelet engraftment, increased bleeding events, inferior OS and increased TRM.
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[The Effect of Immunized Platelet Transfusion Refractoriness on Allo-HSCT Patients with Malignant Hematological Diseases]
Zuo, Y. L., Zhai, J. P., Li, Y., Jiang, M., Cui, Q. Y., Tang, X. W., Zhao, Y. M., Zhang, J. M.
Zhongguo shi yan xue ye xue za zhi. 2021;29(6):1923-1928
Abstract
OBJECTIVE To investigate the characteristics of platelet antibody in patients with hematological diseases, so as to research the effect of immunized platelet transfusion refractoriness (PTR) on the prognosis of allogeneic hematopoietic stem cell transplantation (allo-HSCT) recepients with malignant hematological diseases patients. METHODS The clinical data of platelet antibody positive patients tested by Capture-P in the First Affiliated Hospital of Soochow University from July 1, 2014 to July 1, 2019 were retrospectively analyzed, including sex, age, disease, platelet transfusion assessments, CD34(+) cells, transplant prognosis, and so on. RESULTS In 5 years, 913 (7.28%) hematologic patients with platelet antibody positive were identified, the detection rate of females (513 cases) were higher than males (400 cases). Among the 913 patients, the antibody positive rates of 520 patients with malignant hematological diseases (acute myeloid leukemia, acute lymphoblastic leukemia and myelodysplastic syndrome) showed significantly statistical different (10.27%, 8.01%, and 7.20%) (P<0.01), and the positive rate of the acute myeloid leukemia of those patients was higher than myelodysplastic syndrome patients(α<0.0125). There were 35 cases diagnosed as immunized PTR before allo-HSCT, the platelet increments, 14 h correct count increment, progression-free survival rate and overall survival rate of those patients were significantly lower than those in negative transfusion effective patients (P<0.01), while the percentage of ABO matching was significantly higher (α<0.0125). CONCLUSION The positive rate of platelet antibody identification is high in females and acute myeloid leukemia patients, and immunized PTR caused by antibody is a risk factor for poor prognosis of allo-HSCT in malignant hematological disease patients.
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The assessment of platelet function by thromboelastometry as a point-of-care test to guide Intercept-treated platelet support in hemato-oncological patients and hematopoietic stem cell transplantation recipients
Leitner, G. C., Ho, M., Tolios, A., Hopfinger, G., Rabitsch, W., Wohlfarth, P.
Transfusion. 2020
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Abstract
BACKGROUND Pathogen inactivation (PI) techniques for platelet concentrates (PCs) are one of the latest innovations to improve blood safety and reduce the risk of transfusion-transmitted infections (TTIs). An impaired function and in vivo recovery of platelets as well as an increased PC demand are concerns regarding these techniques. The intent of this study was to evaluate the hemostatic effect of PCs treated with the Intercept System by thromboelastometry (TEM) and to assess the clinical validity of its results in comparison to post-transfusion increase (PTI) and corrected count increment (CCI). STUDY-DESIGN AND METHODS This prospective-observational study included 47 patients (m:f = 25:22; median age: 54 years [21-70]) of our Bone Marrow Transplantation unit with hemato-oncological malignancies transfused with Intercept-treated PCs. Serial TEM measurements were performed just before and 1 hour after PC transfusion and were analyzed for their correlation with PTI and CCI as well as for clinical variables. RESULTS The majority of our patients had received a hematopoietic stem cell transplantation (HSCT) (n = 41; 87%). In median 9 (1-50) PCs were transfused. Serial TEM, PTI, and CCI measurements were available for 150 transfusion episodes. The median platelet dose transfused was 2.65 x 10(11) /unit (1.8-6). The median CCI was 9.250 (0-28.000). We observed a significant improvement in TEM parameters (p < 0.05) after transfusion of PI PCs, which did not mandatory correlate with the 1-hour PTI and CCI. CONCLUSION Serial TEM measurements indicate the hemostatic effect of Intercept-treated PCs. The 1-hour PTI and CCI may not appropriately reflect the in vivo function of platelets after PI PC transfusion.
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Alternatives, and adjuncts, to prophylactic platelet transfusion for people with haematological malignancies undergoing intensive chemotherapy or stem cell transplantation.
Desborough, M., Estcourt, L. J., Doree, C., Trivella, M., Hopewell, S., Stanworth, S. J., Murphy, M. F.
Cochrane Database of Systematic Reviews. 2016;(8):CD010982
Abstract
BACKGROUND Platelet transfusions are used in modern clinical practice to prevent and treat bleeding in people with thrombocytopenia. Although considerable advances have been made in platelet transfusion therapy since the mid-1970s, some areas continue to provoke debate especially concerning the use of prophylactic platelet transfusions for the prevention of thrombocytopenic bleeding. OBJECTIVES To determine whether agents that can be used as alternatives, or adjuncts, to platelet transfusions for people with haematological malignancies undergoing intensive chemotherapy or stem cell transplantation are safe and effective at preventing bleeding. SEARCH METHODS We searched 11 bibliographic databases and four ongoing trials databases including the Cochrane Central Register of Controlled Trials (CENTRAL, 2016, Issue 4), MEDLINE (OvidSP, 1946 to 19 May 2016), Embase (OvidSP, 1974 to 19 May 2016), PubMed (e-publications only: searched 19 May 2016), ClinicalTrials.gov, World Health Organization (WHO) ICTRP and the ISRCTN Register (searched 19 May 2016). SELECTION CRITERIA We included randomised controlled trials in people with haematological malignancies undergoing intensive chemotherapy or stem cell transplantation who were allocated to either an alternative to platelet transfusion (artificial platelet substitutes, platelet-poor plasma, fibrinogen concentrate, recombinant activated factor VII, desmopressin (DDAVP), or thrombopoietin (TPO) mimetics) or a comparator (placebo, standard care or platelet transfusion). We excluded studies of antifibrinolytic drugs, as they were the focus of another review. DATA COLLECTION AND ANALYSIS Two review authors screened all electronically derived citations and abstracts of papers identified by the review search strategy. Two review authors assessed risk of bias in the included studies and extracted data independently. MAIN RESULTS We identified 16 eligible trials. Four trials are ongoing and two have been completed but the results have not yet been published (trial completion dates: April 2012 to February 2017). Therefore, the review included 10 trials in eight references with 554 participants. Six trials (336 participants) only included participants with acute myeloid leukaemia undergoing intensive chemotherapy, two trials (38 participants) included participants with lymphoma undergoing intensive chemotherapy and two trials (180 participants) reported participants undergoing allogeneic stem cell transplantation. Men and women were equally well represented in the trials. The age range of participants included in the trials was from 16 years to 81 years. All trials took place in high-income countries. The manufacturers of the agent sponsored eight trials that were under investigation, and two trials did not report their source of funding.No trials assessed artificial platelet substitutes, fibrinogen concentrate, recombinant activated factor VII or desmopressin.Nine trials compared a TPO mimetic to placebo or standard care; seven of these used pegylated recombinant human megakaryocyte growth and differentiation factor (PEG-rHuMGDF) and two used recombinant human thrombopoietin (rhTPO).One trial compared platelet-poor plasma to platelet transfusion.We considered that all the trials included in this review were at high risk of bias and meta-analysis was not possible in seven trials due to problems with the way data were reported.We are very uncertain whether TPO mimetics reduce the number of participants with any bleeding episode (odds ratio (OR) 0.40, 95% confidence interval (CI) 0.10 to 1.62, one trial, 120 participants, very low quality evidence). We are very uncertain whether TPO mimetics reduce the risk of a life-threatening bleed after 30 days (OR 1.46, 95% CI 0.06 to 33.14, three trials, 209 participants, very low quality evidence); or after 90 days (OR 1.00, 95% CI 0.06 to 16.37, one trial, 120 participants, very low quality evidence). We are very uncertain whether TPO mimetics reduce platelet transfusion requirements after 30 days (mean difference -3.00 units, 95% CI -5.39 to -0.61, one trial, 120 participants, very low quality evidence). No deaths occurred in either group after 30 days (one trial, 120 participants, very low quality evidence). We are very uncertain whether TPO mimetics reduce all-cause mortality at 90 days (OR 1.00, 95% CI 0.24 to 4.20, one trial, 120 participants, very low quality evidence). No thromboembolic events occurred for participants treated with TPO mimetics or control at 30 days (two trials, 209 participants, very low quality evidence). We found no trials that looked at: number of days on which bleeding occurred, time from randomisation to first bleed or quality of life.One trial with 18 participants compared platelet-poor plasma transfusion with platelet transfusion. We are very uncertain whether platelet-poor plasma reduces the number of participants with any bleeding episode (OR 16.00, 95% CI 1.32 to 194.62, one trial, 18 participants, very low quality evidence). We are very uncertain whether platelet-poor plasma reduces the number of participants with severe or life-threatening bleeding (OR 4.00, 95% CI 0.56 to 28.40, one trial, 18 participants, very low quality evidence). We found no trials that looked at: number of days on which bleeding occurred, time from randomisation to first bleed, number of platelet transfusions, all-cause mortality, thromboembolic events or quality of life. AUTHORS' CONCLUSIONS There is insufficient evidence to determine if platelet-poor plasma or TPO mimetics reduce bleeding for participants with haematological malignancies undergoing intensive chemotherapy or stem cell transplantation. To detect a decrease in the proportion of participants with clinically significant bleeding from 12 in 100 to 6 in 100 would require a trial containing at least 708 participants (80% power, 5% significance). The six ongoing trials will provide additional information about the TPO mimetic comparison (424 participants) but this will still be underpowered to demonstrate this level of reduction in bleeding. None of the included or ongoing trials include children. There are no completed or ongoing trials assessing artificial platelet substitutes, fibrinogen concentrate, recombinant activated factor VII or desmopressin in people undergoing intensive chemotherapy or stem cell transplantation for haematological malignancies.
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Therapeutic platelet transfusion versus routine prophylactic transfusion in patients with haematological malignancies: an open-label, multicentre, randomised study
Wandt, Hannes, Schaefer-Eckart, Kerstin, Wendelin, Knut, Pilz, Bettina, Wilhelm, Martin, Thalheimer, Markus, Mahlknecht, Ulrich, Ho, Anthony, Schaich, Markus, Kramer, Michael, et al
Lancet. 2012;380(9850):1309-16
Abstract
BACKGROUND Routine prophylactic platelet transfusion is the standard of care for patients with severe thrombocytopenia. We assessed the effect of a new strategy of therapeutic platelet transfusion on the number of transfusions and safety in patients with hypoproliferative thrombocytopenia. METHODS We did a multicentre, open-label, randomised parallel-group trial at eight haematology centres in Germany. Patients aged 16-80 years, who were undergoing intensive chemotherapy for acute myeloid leukaemia or autologous haemopoietic stem-cell transplantation for haematological cancers, were randomly assigned via a computer-generated randomisation sequence to receive either platelet transfusion when bleeding occurred (therapeutic strategy) or when morning platelet counts were 10x10(9) per L or lower (prophylactic strategy). Investigators undertaking interventions were not masked to group assignment. The primary endpoint was the number of platelet transfusions. Analysis was by intention to treat. This trial is registered, NCT00521664. FINDINGS 197 patients were assigned the prophylactic strategy and 199 the therapeutic strategy. Of 391 patients analysed, the therapeutic strategy reduced the mean number of platelet transfusions by 33.5% (95% CI 22.2-43.1; p<0.0001) in all patients (2.44 [2.22-2.67] in prophylactic group vs 1.63 [1.42-1.83] in therapeutic group), 31.6% (18.6-42.6; p<0.0001) in those with acute myeloid leukaemia (2.68 [2.35-3.01] vs 1.83 [1.58-2.10]), and 34.2% (6.6-53.7; p=0.0193) in those who had had autologous transplantation (1.80 [1.45-2.15] vs 1.18 [0.82-1.55]. We noted no increased risk of major haemorrhage in patients who had undergone autologous transplantation. In those with acute myeloid leukaemia, risk of non-fatal grade 4 (mostly CNS) bleeding was increased. We recorded 15 cases of non-fatal haemorrhage: four retinal in each transfusion group, and one vaginal and six cerebral in the therapeutic group. 12 patients died in the study: two from fatal cerebral haemorrhages in the therapeutic group, and ten (five in each treatment group) unrelated to major bleeding. INTERPRETATION The therapeutic strategy could become a new standard of care after autologous stem-cell transplantation; however, prophylactic platelet transfusion should remain the standard for patients with acute myeloid leukaemia. The new strategy should be used by some haematology centres only if the staff are well educated and experienced in the new approach and can react in a timely way to first signs of CNS bleeding. FUNDING Deutsche Krebshilfe eV (German Cancer Aid).Copyright © 2012 Elsevier Ltd. All rights reserved.