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Therapeutic efficacy and safety of pathogen-reduced platelet components: Results of a meta-analysis of randomized controlled trials
Cid, J., Charry, P., Lozano, M.
Vox sanguinis. 2024
Abstract
BACKGROUND AND OBJECTIVES Clinical efficacy and safety of pathogen-reduced platelet concentrates (PR-PCs) concerning bleeding prevention are still debated despite conclusive real-world data from multiple countries where PR-PCs are transfused routinely. We performed a meta-analysis of randomized controlled trials (RCTs) comparing the clinical efficacy and safety of conventional platelet components (PCs) and PR-PCs prepared with the amotosalen/ultraviolet A light (INTERCEPT platelet concentrate [I-PC]) or riboflavin/ultraviolet light (Mirasol platelet concentrate [M-PC]) technologies, transfused in thrombocytopenic adult patients. MATERIALS AND METHODS A literature search was conducted, and 10 RCTs met the criteria for inclusion in this meta-analysis. Summary odds ratios (ORs) of clinically significant bleeding (World Health Organization [WHO] bleeding grade ≥2), severe bleeding (WHO bleeding score ≥3) and all-cause mortality were calculated. RESULTS The use of I-PC was not associated with an increase in the OR of clinically significant bleeding when compared to non-treated PCs (OR, 1.12; 95% CI: 0.89-1.41; p = 0.33), whereas transfusions with M-PC showed an increase in clinically significant bleeding (OR, 1.34; 95% CI: 1.03-1.75; p = 0.03). The OR of severe bleeding did not increase with either I-PC or M-PC (OR 0.88; 95% CI: 0.59-1.31; p = 0.52 for I-PC; OR 1.25; 95% CI: 0.66-2.37; p = 0.49 for M-PC). In the case of all-cause mortality, compared to non-treated PC, I-PC showed an OR of 0.61 (95% CI: 0.36-1.04; p = 0.07), and M-PC showed an OR of 3.04 (95% CI: 0.81-11.47; p = 0.1). CONCLUSION No differences were observed concerning the clinical efficacy and safety of overall PR-PCs when compared to non-treated PCs. However, differences are evident when analysing platelets prepared with the two PR technologies independently.
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2.
Platelet Transfusion before CVC Placement in Patients with Thrombocytopenia
van Baarle FLF, van de Weerdt EK, van der Velden Wjfm, Ruiterkamp RA, Tuinman PR, Ypma PF, van den Bergh WM, Demandt AMP, Kerver ED, Jansen AJG, et al
The New England journal of medicine. 2023;388(21):1956-1965
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Editor's Choice
Abstract
BACKGROUND Transfusion guidelines regarding platelet-count thresholds before the placement of a central venous catheter (CVC) offer conflicting recommendations because of a lack of good-quality evidence. The routine use of ultrasound guidance has decreased CVC-related bleeding complications. METHODS In a multicenter, randomized, controlled, noninferiority trial, we randomly assigned patients with severe thrombocytopenia (platelet count, 10,000 to 50,000 per cubic millimeter) who were being treated on the hematology ward or in the intensive care unit to receive either one unit of prophylactic platelet transfusion or no platelet transfusion before ultrasound-guided CVC placement. The primary outcome was catheter-related bleeding of grade 2 to 4; a key secondary outcome was grade 3 or 4 bleeding. The noninferiority margin was an upper boundary of the 90% confidence interval of 3.5 for the relative risk. RESULTS We included 373 episodes of CVC placement involving 338 patients in the per-protocol primary analysis. Catheter-related bleeding of grade 2 to 4 occurred in 9 of 188 patients (4.8%) in the transfusion group and in 22 of 185 patients (11.9%) in the no-transfusion group (relative risk, 2.45; 90% confidence interval [CI], 1.27 to 4.70). Catheter-related bleeding of grade 3 or 4 occurred in 4 of 188 patients (2.1%) in the transfusion group and in 9 of 185 patients (4.9%) in the no-transfusion group (relative risk, 2.43; 95% CI, 0.75 to 7.93). A total of 15 adverse events were observed; of these events, 13 (all grade 3 catheter-related bleeding [4 in the transfusion group and 9 in the no-transfusion group]) were categorized as serious. The net savings of withholding prophylactic platelet transfusion before CVC placement was $410 per catheter placement. CONCLUSIONS The withholding of prophylactic platelet transfusion before CVC placement in patients with a platelet count of 10,000 to 50,000 per cubic millimeter did not meet the predefined margin for noninferiority and resulted in more CVC-related bleeding events than prophylactic platelet transfusion. (Funded by ZonMw; PACER Dutch Trial Register number, NL5534.).
PICO Summary
Population
Patients with severe thrombocytopenia enrolled in the PACER randomised controlled trial (n= 338).
Intervention
Placement of a central venous catheter (CVC) with one unit of prophylactic platelet transfusion (188 placements).
Comparison
Placement of an CVC without a platelet transfusion (185 placements).
Outcome
A total of 373 episodes of CVC placement involving 338 patients were included in the per-protocol primary analysis. Catheter-related bleeding of grade 2 to 4 occurred in 9 of 188 patients (4.8%) in the transfusion group and in 22 of 185 patients (11.9%) in the no-transfusion group (relative risk, 2.45; 90% confidence interval (CI), [1.27, 4.70]). Catheter-related bleeding of grade 3 or 4 occurred in 4 of 188 patients (2.1%) in the transfusion group and in 9 of 185 patients (4.9%) in the no-transfusion group (relative risk, 2.43; 95% CI [0.75, 7.93]). There were 15 adverse events, of these events 13 (all grade 3 catheter-related bleeding [4 in the transfusion group and 9 in the no-transfusion group]) were categorized as serious. The net savings of withholding prophylactic platelet transfusion before CVC placement was $410 per catheter placement.
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3.
Risk of HLA antibody generation after receipt of Mirasol versus standard platelets in the MIPLATE randomized trial
Kaidarova Z, Di Germanio C, Custer B, Norris PJ
Transfusion. 2023
Abstract
BACKGROUND Human leukocyte antigen (HLA) alloimmunization can occur after platelet transfusion. These antibodies can complicate future platelet transfusions or organ transplantation. Animal data suggest that Mirasol pathogen reduction treatment (PRT) can prevent alloimmunization after transfusion. STUDY DESIGN AND METHODS The MIPLATE trial enrolled 330 of a planned 660 participants with hematological malignancies at risk for grade 2 or greater bleeding. The study was halted early for futility after a planned interim analysis. Participants were randomized to receive PRT versus standard control platelets. Serum samples were collected from participants at baseline (pretransfusion), weekly for the first 4 weeks, then at days 42 and 56. HLA antibody levels were determined using a commercial multianalyte bead-based assay. HLA antibody levels were analyzed using low, medium, and high cutoffs based on prior studies. RESULTS The rate of alloimmunization was low in both arms of the study, particularly at the high HLA antibody cutoff (total of 6 of 277 subjects at risk, or 2.2%). The risk of alloimmunization did not differ between study arms, nor did the risk of immune refractoriness to platelet transfusion. CONCLUSIONS The data do not support the conclusion that Mirasol exerted a protective effect against alloimmunization after platelet transfusion in the MIPLATE trial.
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A randomized cross-over study of cryopreserved platelets in prophylactic transfusions of thrombocytopenic patients
Ang, A. L., Gan, L. S. H., Tuy, T. T., Ang, C. H., Tan, C. W., Tan, H. H., Shu, P. H., Zhang, Q., Cao, Y., Moorakonda, R. B., et al
Transfusion. 2023
Abstract
BACKGROUND The short shelf-life of liquid-stored platelets (LP) at 20-24°C poses shortage and wastage challenges. Cryopreserved platelets have significantly extended shelf-life, and were safe and efficacious for therapeutic transfusions of bleeding patients in the Afghanistan conflict and phase 2 randomized studies. Although hematology patients account for half of platelets demand, there is no randomized study on prophylactic cryopreserved platelet transfusions in them. METHODS We performed a phase 1b/2a randomized cross-over study comparing the safety and efficacy of cryopreserved buffy coat-derived pooled platelets (CP) to LP in the prophylactic transfusions of thrombocytopenic hematology patients. RESULTS A total of 18 adults were randomly assigned 1:1 to CP and LP for their first thrombocytopenic period (TP) of up to 28-days. A total of 14 crossed over to the other platelet-arm for the second TP. Overall, 17 subjects received 51 CP and 15 received 52 LP. CP-arm had more treatment emergent adverse event (29.4% vs. 13.3% of subjects, 9.8% vs. 3.8% of transfusions) than LP-arm but all were mild. No thromboembolism was observed. Both arms had similar bleeding rates (23.5% vs. 26.7% of subjects) which were all mild. Subjects in CP-arm had lower average corrected count increments than LP-arm (mean [SD] 5.6 [4.20] vs. 22.6 [9.68] ×10(9) /L at 1-4 h, p < .001; 5.3 [4.84] vs. 18.2 [9.52] ×10(9) /L at 18-30 h, p < .001). All TEG parameters at 1-4 h and maximum amplitude (MA) at 18-30 h improved from baseline post-CP transfusion (p < .05) though improvements in K-time and MA were lower than LP (p < .05). DISCUSSION During shortages, CP may supplement LP in prophylactic transfusions of thrombocytopenic patients.
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The impact of pathogen-reduced platelets in acute leukaemia treatment on the total blood product requirement: a subgroup analysis of an EFFIPAP randomised trial
Garban F, Vilotitch A, Tiberghien P, Bosson JL
Transfusion medicine (Oxford, England). 2022
Abstract
OBJECTIVE To evaluate the impact of pathogen-reduced (PR) platelet transfusions on blood products requirement for clinical practice. BACKGROUND PR platelets are increasing in use as standard blood products. However, few randomised trials have evaluated their impact on bleeding control or prevention. Furthermore, PR platelets recirculate less than untreated platelets. METHODS A subgroup study of the randomised clinical trial EFFIPAP compared three arms of platelet preparations (PR: P-PRP/PAS, additive solution: P-PAS and plasma P-P arms respectively). The subgroup of acute leukaemia patients, in their chemotherapy induction phase, included 392 patients (133 P-PRP/PAS arm, 132 P-PAS arm and 130 P-P arm). Blood requirements were analysed across over periods of 7 days. RESULTS The number of platelet transfusions per week was significantly higher in the P-PRP/PAS group 2.3 [1.6-3.3] compared to the control groups 1.9 [1.3-2.8] and 2.0 [1.3-3.0] for P-P and P-PAS groups respectively (p < 0.0001). However, the total number of platelets transfused per week was not different. The number of red blood cell concentrates (RBC) transfusion per week did not differ either. CONCLUSION In a homogeneous group of patients, platelet pathogen reduction resulted in an increased number of platelet units transfused per week while having no impact on the total number of platelets transfused or the number of RBC transfusion; resulting to an average requirement of 2 RBC and 2-3 platelets transfusions per week of marrow aplasia.
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6.
Procedure-related bleeding risk in patients with cirrhosis and severe thrombocytopenia
Alvaro D, Caporaso N, Giovanni Giannini E, Iacobellis A, Morelli M, Toniutto P, Violi F
European journal of clinical investigation. 2021;:e13508
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Abstract
BACKGROUND Gaps of knowledge still exist about the potential association between severe thrombocytopenia and increased risk of procedure-associated bleeding in patients with liver disease. METHODS In this narrative review we aimed at examining the association between procedure-related bleeding risk and platelet count in patients with cirrhosis and severe thrombocytopenia in various settings. We updated to 2020 a previously conducted literature search using MEDLINE/PubMed and EMBASE. The search string included clinical studies, adult patients with chronic liver disease and thrombocytopenia undergoing invasive procedures, any interventions and comparators, and haemorrhagic events of any severity as outcome. RESULTS The literature search identified 1,276 unique publications, 15 studies met the inclusion criteria and were analysed together with those identified by the previously search. Most of the new studies included in our analysis did not assess the association between post-procedural bleeding risk and platelet count alone in patients with chronic liver disease. Furthermore, some results could have been biased by prophylactic platelet transfusions. A few studies found that severe thrombocytopenia may be predictive of bleeding following percutaneous liver biopsy, dental extractions, percutaneous ablation of liver tumours, and endoscopic polypectomy. CONCLUSIONS Currently available literature cannot support definitive conclusions about the appropriate target platelet counts to improve the risk of bleeding in cirrhotic patients who underwent invasive procedures; moreover, it showed enormous variability in the use of prophylactic platelet transfusions.
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Expected individual benefit of prophylactic platelet transfusions in hemato-oncology patients based on bleeding risks
Cornelissen LL, Caram-Deelder C, Fustolo-Gunnink SF, Groenwold RHH, Stanworth SJ, Zwaginga JJ, van der Bom JG
Transfusion. 2021
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Editor's Choice
Abstract
BACKGROUND Prophylactic platelet transfusions prevent bleeding in hemato-oncology patients, but it is unclear how any benefit varies between patients. Our aim was to assess if patients with different baseline risks for bleeding benefit differently from a prophylactic platelet transfusion strategy. STUDY DESIGN AND METHODS Using the data from the randomized controlled TOPPS trial (Trial of Platelet Prophylaxis), we developed a prediction model for World Health Organization grades 2, 3, and 4 bleeding risk (defined as at least one bleeding episode in a 30 days period) and grouped patients in four risk-quartiles based on this predicted baseline risk. Predictors in the model were baseline platelet count, age, diagnosis, disease modifying treatment, disease status, previous stem cell transplantation, and the randomization arm. RESULTS The model had a c-statistic of 0.58 (95% confidence interval [CI] 0.54-0.64). There was little variation in predicted risks (quartiles 46%, 47%, and 51%), but prophylactic platelet transfusions gave a risk reduction in all risk quartiles. The absolute risk difference (ARD) was 3.4% (CI -12.2 to 18.9) in the lowest risk quartile (quartile 1), 7.4% (95% CI -8.4 to 23.3) in quartile 2, 6.8% (95% CI -9.1 to 22.9) in quartile 3, and 12.8% (CI -3.1 to 28.7) in the highest risk quartile (quartile 4). CONCLUSION In our study, generally accepted bleeding risk predictors had limited predictive power (expressed by the low c-statistic), and, given the wide confidence intervals of predicted ARD, could not aid in identifying subgroups of patients who might benefit more (or less) from prophylactic platelet transfusion.
PICO Summary
Population
Haemato-oncology patients enrolled in the TOPPS trial (n= 600).
Intervention
Platelet transfusions based on a threshold of 10 × 10 9/L (Prophylactic arm, n= 299).
Comparison
Platelet transfusions in case of active bleeding (Therapeutic arm, n= 301).
Outcome
47% of patients (279) developed at least one WHO grade 2, 3, or 4 bleeding during 30-day follow-up. The model had a c-statistic of 0.58. There was little variation in predicted risks (quartiles 46%, 47%, and 51%), but prophylactic platelet transfusions gave a risk reduction in all risk quartiles. The absolute risk difference was 3.4% in the lowest risk quartile (quartile 1), 7.4% in quartile 2, 6.8% in quartile 3, and 12.8% in the highest risk quartile (quartile 4).
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An epitope-based approach of HLA-matched platelets for transfusion: a noninferiority crossover randomized trial
Marsh JC, Stanworth SJ, Pankhurst LA, Kallon D, Gilbertson AZ, Pigden C, Deary AJ, Mora AS, Brown J, Laing ES, et al
Blood. 2021;137(3):310-322
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Editor's Choice
Abstract
Platelet transfusion refractoriness results in adverse outcomes and increased health care costs. Managing refractoriness resulting from HLA alloimmunization necessitates the use of HLA antigen-matched platelets but requires a large platelet donor pool and does not guarantee full matching. We report the first randomized, double-blind, noninferiority, crossover trial comparing HLA epitope-matched (HEM) platelets with HLA standard antigen-matched (HSM) platelet transfusions. Alloimmunized, platelet-refractory, thrombocytopenic patients with aplastic anemia, myelodysplastic syndrome, or acute myeloid leukemia were eligible. HEM platelets were selected using HLAMatchMaker epitope (specifically eplet) matching. Patients received up to 8 prophylactic HEM and HSM transfusions provided in random order. The primary outcome was 1-hour posttransfusion platelet count increment (PCI). Forty-nine patients were randomized at 14 UK hospitals. For intention to treat, numbers of evaluable transfusions were 107 and 112 for HEM and HSM methods, respectively. Unadjusted mean PCIs for HEM and HSM methods were 23.9 (standard deviation [SD], 15) and 23.5 (SD, 14.1), respectively (adjusted mean difference, -0.1; 95% confidence interval [CI], -2.9 to 2.8). Because the lower limit of the 95% CI was not greater than the predefined noninferiority limit, the HEM approach was declared noninferior to the HSM approach. There were no differences in secondary outcomes of platelet counts, transfusion requirements, and bleeding events. Adequate 1-hour PCI was more frequently observed, with a mean number of 3.2 epitope mismatches, compared with 5.5 epitope mismatches for inadequate 1-hour increments. For every additional epitope mismatch, the likelihood of an adequate PCI decreased by 15%. Epitope-matched platelets should be considered to support HLA alloimmunized patients. This trial was registered at www.isrctn.com as #ISRCTN23996532.
PICO Summary
Population
Alloimmunized, platelet-refractory, thrombocytopenic patients with aplastic anemia, myelodysplastic syndrome, or acute myeloid leukemia (n= 49).
Intervention
HLA epitope-matched (HEM) platelet transfusions.
Comparison
HLA standard antigen-matched (HSM) platelet transfusions.
Outcome
For intention to treat, numbers of evaluable transfusions were 107 and 112 for HEM and HSM methods, respectively. Unadjusted mean platelet count increments (PCI) for HEM and HSM methods were 23.9 (standard deviation [SD], 15) and 23.5 (SD, 14.1), respectively. There were no differences in secondary outcomes of platelet counts, transfusion requirements, and bleeding events. Adequate 1-hour PCI was more frequently observed, with a mean number of 3.2 epitope mismatches, compared with 5.5 epitope mismatches for inadequate 1-hour increments.
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Postnatal intervention for the treatment of FNAIT: a systematic review
Baker JM, Shehata N, Bussel J, Murphy MF, Greinacher A, Bakchoul T, Massey E, Lieberman L, Landry D, Tanael S, et al
Journal of perinatology : official journal of the California Perinatal Association. 2019
Abstract
OBJECTIVE Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is associated with life-threatening bleeding. This systematic review of postnatal management of FNAIT examined transfusion of human platelet antigen (HPA) selected or unselected platelets, and/or IVIg on platelet increments, hemorrhage and mortality. STUDY DESIGN MEDLINE, EMBASE and Cochrane searches were conducted until 11 May 2018. RESULT Of 754 neonates, 382 received platelet transfusions (51%). HPA-selected platelets resulted in higher platelet increments and longer response times than HPA-unselected platelets. However, unselected platelets generally led to sufficient platelet increments to 30 x 10(9)/L, a level above which intracranial hemorrhage or other life-threatening bleeding rarely occurred. Platelet increments were not improved with the addition of IVIg to platelet transfusion. CONCLUSION Overall, HPA-selected platelet transfusions were more effective than HPA-unselected platelets but unselected platelets were often effective enough to achieve clinical goals. Available studies do not clearly demonstrate a benefit for addition of IVIg to platelet transfusion.
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A systematic literature review on the use of platelet transfusions in patients with thrombocytopenia
Newland A, Bentley R, Jakubowska A, Liebman H, Lorens J, Peck-Radosavljevic M, Taieb V, Takami A, Tateishi R, Younossi ZM
Hematology (Amsterdam, Netherlands). 2019;24(1):679-719
Abstract
Objective: Investigate globally, current treatment patterns, benefit-risk assessments, humanistic, societal and economic burden of platelet transfusion (PT). Methods: Publications from 1998 to June 27, 2018 were identified, based on databases searches including MEDLINE(R); Embase and Cochrane Database of Systematic Reviews. Data from studies meeting pre-specified criteria were extracted and validated by independent reviewers. Data were obtained for efficacy and safety from randomized controlled trials (RCTs); data for epidemiology, treatment patterns, effectiveness, safety, humanistic and societal burden from real-world evidence (RWE) studies; and economic data from both. Results: A total of 3425 abstracts, 194 publications (190 studies) were included. PT use varied widely, from 0%-100% of TCP patients; 1.7%-24.5% in large studies (>1000 patients). Most were used prophylactically rather than therapeutically. 5 of 43 RCTs compared prophylactic PT with no intervention, with mixed results. In RWE studies PT generally increased platelet count (PC). This increase varied by patient characteristics and hence did not always translate into a clinically significant reduction in bleeding risk. Safety concerns included infection risk, alloimmunization and refractoriness with associated cost burden. Discussion: In RCTs and RWE studies there was significant heterogeneity in study design and outcome measures. In RWE studies, patients receiving PT may have been at higher risk than those not receiving PT creating potential bias. There were limited data on humanistic and societal burden. Conclusion: Although PTs are used widely for increasing PC in TCP, it is important to understand the limitations of PTs, and to explore the use of alternative treatment options where available.