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Prophylactic platelet transfusions versus no prophylaxis in hospitalized patients with thrombocytopenia: A systematic review with meta‐analysis

2022; Wiley; Volume: 62; Issue: 10 Linguagem: Inglês

10.1111/trf.17064

1537-2995

Carl Thomas Anthon, Anders Granholm, Praleene Sivapalan, Núria Zellweger, Frédéric Pène, Kathryn Puxty, Anders Perner, Morten Hylander Møller, Lene Russell,

Blood disorders and treatments

Thrombocytopenia is a common condition in several populations of hospitalized patients, including those with hematological and solid tumor cancer,1, 2 those with chronic liver disease,3 and critically ill neonates4 and adults,5 and it has been associated with increased rates of bleeding, transfusion requirements, and mortality.6-9 Prophylactic platelet transfusions are often recommended in patients with severe thrombocytopenia, but the supporting evidence is primarily derived from trials in hematological patients10-12 and clinical practice varies considerably.13-15 Prior to prophylactic platelet transfusion, the risk of bleeding and the beneficial effects of transfusion must be viewed in light of the potentially harmful effects, which, although rare, include serious and potentially life-threatening reactions, such as anaphylaxis, transfusion-transmitted infections, and transfusion-related acute lung injury.16 Harm from platelet transfusions has been observed in randomized clinical trials (RCTs) among preterm infants17 and patients with intracerebral hemorrhage.18 Therefore, we aimed to assess the benefits and harms of prophylactic platelet transfusions versus no prophylaxis on patient-important outcomes in hospitalized patients with thrombocytopenia. We hypothesized that the evidence base for non-hematological patients would be sparse and uncertain. This systematic review with meta-analyses and trial sequential analyses (TSA) was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42021236014) and conducted in accordance with a published protocol.19 We followed the recommendations by the Cochrane Collaboration,20 the Grading of Recommendations Assessment, Development and Evaluation (GRADE)21 approach and the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement (checklist available in Supplement S1).22 All RCTs and cluster RCTs comparing prophylactic platelet transfusion in any dose versus no prophylaxis or placebo in non-bleeding hospitalized patients with thrombocytopenia (as defined in the trials) were eligible for inclusion without restriction regarding age, diagnoses, or settings. Cohort studies, case–control studies, reviews, quasi-randomized trials, and cross-over trials were excluded. We did not allow concomitant use of other interventions unless they were used in both allocation groups. Clinically important bleeding, nosocomial infection, venous or arterial thrombo-embolic, and transfusion-related adverse events were defined in the included trials. The unit of analysis was randomized patients, and all outcomes were assessed at the longest follow-up.19 Additional details are available in the protocol19 and Supplement S3. We collected data on the number of units of platelets, red blood cells (RBC) and fresh frozen plasma (FFP) transfused per participant. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, and Epistemonikos and searched for ongoing trials in the U.S. National Library of Medicine (ClinicalTrials.gov), EU Clinical Trials Register, and the World Health Organization (WHO) International Clinical Trials Registry. The searches were conducted without restrictions on language or publication status on March 29, 2021 and updated in PubMed on February 3, 2022 (Supplement S4). All records were independently screened for eligibility by two authors (CTA, AG, PS, and NZ). Potential eligible articles were assessed in full text by two authors (CTA, AG, PS, and NZ). We resolved disagreements by discussion and consulted a third author (MHM and LR) if needed. We used Covidence (https://www.covidence.org; Veritas Health Innovation, Melbourne, Australia) to facilitate the study selection. Two authors independently (CA and AG) extracted data from the included studies. We extracted data on trial characteristics, population characteristics, interventions, co-interventions, outcomes, and process variables as specified above (Supplement S5). We contacted the corresponding authors at least twice for clarifications and unpublished or missing outcome data, if applicable. We resolved disagreements by discussion and involved a third author (MHM and LR) if needed. Two authors independently (CA and PS) assessed the risk of bias using the Risk of Bias 2.0 tool.23 We assessed the risk of bias on the outcome level within all five domains: "bias arising from the randomization process," "bias due to deviations from intended interventions," "bias due to missing outcome data," "bias in measurement of the outcome," and "bias in selection of the reported result." For each outcome in each RCT, the overall risk of bias judgment was judged as low risk of bias if all domains were judged to be low risk of bias, as some concerns if at least one domain was judged to be of some concerns, and as high risk of bias if at least one domain were judged to be high risk of bias.20, 23 Disagreements were resolved by consulting a third author (AG or MHM). We planned to base our primary conclusions on results from RCTs with an overall low risk of bias,19 but this was only feasible for the primary outcome as no trials were judged to be low risk of bias for the secondary outcomes. We calculated relative risks (RRs) with confidence intervals (CIs) for dichotomous outcomes and mean differences (MDs) with CIs for continuous outcomes. We contacted the corresponding authors for additional data if alternative statistical measures for continuous outcomes were reported.19 We did not convert medians and interquartile range (IQR) to means and SDs, as correct conversion requires normally distributed data. Instead, we reported the results descriptively. Results are based on the analysis of intention-to-treat populations, and data was analyzed for superiority regardless of the original trial designs. We adjusted thresholds for statistical significance using a compromise between no adjustment and a complete Bonferroni adjustment.24, 25 We divided the pre-specified p-value (.05) with the value half-way between 1 (no adjustment) and the number of primary or secondary outcomes meta-analyzed (Bonferroni adjustment).24, 25 As we were able to meta-analyze the primary outcome and three secondary outcomes, the thresholds considered statistically significant were a p-value of <.05 and <.025, respectively. For outcomes that were not meta-analyzed, a p-value of <.05 were considered statistically significant. The reported CIs and TSA-adjusted CIs matched these significance thresholds. We assessed statistical heterogeneity by the calculation of inconsistency (I2), diversity (D2) statistics, and the χ2 test for subgroup differences and considered a p-value of <.05 as statistically significant.19 We report results from fixed effect models (FEM) if the I2 = 0%. If I2 > 0% we used both FEM and random effects models (REM) and based conclusions on the most conservative estimate (highest p-value).19 Results from both FEM and REM for the primary analyses are presented in Supplement S9. Additional details and the a priori hypothesized directions of subgroup effects are available in the protocol19 and in Supplement S6. Clinical heterogeneity was assessed using the Clinical Diversity in Meta-analysis tool26 and the credibility of the subgroup analyses were assessed using the Instrument for assessing the Credibility of Effect Modification Analyses (ICEMAN) tool.27 We planned to assess small trial bias but as all analyses included fewer than 10 RCTs, this was not feasible.19 We conducted TSA to assess the risk of random errors due to repetitive testing in cumulative meta-analyses.28 In short, TSA estimates the required information size (RIS) needed for a conclusive meta-analysis to detect or reject a predefined effect size. When data are sparse and/or statistical diversity is present, the TSA will adjust (expand) the CIs to account for the uncertainty around the overall effect estimate.28 We report TSA-adjusted CIs when feasible. We applied trial sequential monitoring boundaries according to 15% RR reduction for dichotomous outcomes and a MD of 1 day for continuous outcomes, an alpha of 5% and 2.5% for the primary and secondary outcomes, respectively, a beta of 10%, and a control event rate or variance suggested by the control groups in trials reporting on the outcome.19 TSA is not feasible if the accrued information size was less than 5% of the RIS and in these circumstances, full TSAs were not presented. Analyses were conducted using R version 4.1.0 (R Core Team, R Foundation for Statistical Computing, Vienna, Austria) with the "meta" package (version 5.1.0), and TSA was performed using the Copenhagen Trial Unit's TSA Software version 0.9.5.10b (available from http://www.ctu.dk/tsa). We conducted a sensitivity analysis on the primary and secondary outcomes.19 We performed analyses that included all bleeding episodes (i.e., not restricted to clinically important bleedings) and analyses restricted to long-term all-cause mortality, defined as mortality beyond 90 days. The impact of missing outcome data was assessed by performing best-worst and worst-best (BW/WB) case analyses,24 and the information from zero-event trials was accounted for by performing empirical continuity corrections.29 The overall certainty of evidence was rated independently by two authors (CA and AG) using the GRADE methodology21 and disagreements were settled by discussion. We rated the certainty for each outcome as high, moderate, low, or very low based on assessments of risk of bias, inconsistency, indirectness, imprecision, and small trial bias. We screened 15,696 records, assessed 66 records in full text and included nine trials in the qualitative synthesis30-38; one trial did not report any relevant outcome data34 and one trial was ongoing.37 Hence, seven RCTs30-33, 35, 36, 38 enrolling a total of 1642 participants were included in the quantitative analysis (Figure 1).39 The trials were published from 1980 until 2017.30-36, 38 Five trials were published as full reports,30, 32, 33, 36, 38 one as a letter to the editor,35 one as an abstract,34 and one remained unpublished.31 The smallest trial randomized 12 patients34 whereas the largest randomized 600 patients.36 Two trials were conducted at multiple centres36, 38 and all trials were conducted in hospitalized patients with hematological malignancies31, 33-36, 38 or dengue fever.30, 32 One trial included pediatric (hematological) patients only,33 and one was a non-inferiority trial.36 Trial characteristics are presented in Table 1 and further detailed in the Supplement S7. Pakistan 1 Dengue HDU Primary: Secondary: Canada 1 Hospital ward Primary: Not specified Secondary: Singapore, Malaysia 5 Hospital wardb Primary: Secondary: USA 1 Hospital wardb Primary: Not specified Secondary: Netherlands 1b Hospital wardb Primary: Not specified Secondary: USA 1b Hospital wardb Primary: Not specified Secondary: United Kingdom, Australia 14 Hospital ward Primary: Secondary: Germany 8 Hospital ward Primary: Secondary: China 1 Unclear Other causes of chronic live disease than chronic hepatitis B infection, previous decompensation, intracranial hemorrhage, use of anti-platelet or anticoagulants therapy within 4 weeks, esophageal variceal bleeding within 1 week, platelet transfusion within 1 week, malignant disease, pregnancy or breastfeeding, severe chronic extra-hepatic disease. Considered not suitable for inclusion by researchers. Primary: Secondary: Netherlands 11 Hospital ward/ICU Primary: Secondary: All trials assessed prophylactic platelet transfusion compared with no prophylaxis; however, in two trials, prophylactic platelet transfusions were also administered in the no prophylaxis group under specific circumstances with a perceived high risk of bleeding.35, 38 Two trials administered prophylactic platelets in both groups prior to invasive procedures or surgery31, 36 and most trials administered platelets in both treatment groups when bleeding occurred.31, 32, 35, 36, 38 One trial used a platelet count ≤30 × 109/L as a threshold for prophylactic transfusion,30 five trials used ≤20 × 109/L31-35 and two trials used ≤10 × 109/L.36, 38 Duration of the intervention, type of platelets, number of units administered per transfusion and platelets per unit varied between trials (Table 2). Clinically important bleeding: "Severe bleeding" defined as WHO grade 3 and 4 Any bleeding: "New onset bleeding" defined as WHO grade 1–4 Assessor: Not reported Assessment: Patients were assessed for WHO bleeding ever 12 h Clinically important bleeding: "Severe bleeding" Any bleeding: "Mild bleeds" defined as bleeds not requiring active intervention Assessor: The clinical team performed the assessment Assessment: Daily clinical assessment for signs of bleeding. Fundoscopic examination twice daily when the platelet count was ≤20 × 109/L. Supportive care plus 4 units RD (platelets/unit not reported) platelets each day the platelet count was ≤20 × 109/L up until day 7 or discharge If bleeding occurred, platelet transfusions were given at the clinician's discretion in both groups Clinically important bleeding: Defined according to the WHO 2009 dengue guidelines: gum, nose, hemoptysis, hematuria, hematemesis, melaena, melaena or hematemesis-not controlled by procedure, menorrhagia, menorrhagia or intermenstrual bleeding-not controlled by progesterone, intermenstrual, hematoma, menses, others Definition of any bleeding: Not reported Assessor: Not reported Assessment: Daily clinical assessment from day 1 until day 7 or discharge and at day 21 (+/−3) Definition of clinically important bleeding: Serious bleeding episodes (bleeds) was defined as nasal or oral bleeding requiring packing, gross gastrointestinal bleeding, gross genitourinary bleeding, any central nervous system bleeding, or bleeding requiring red blood cell transfusion. Uncomplicated dermal bleeding was not included. Definition of any bleeding: Not reported Assessor: Not reported Assessment: Not reported Clinically important bleeding: Not reported Any bleeding: Not reported Assessor: Not reported Assessment: Not reported Clinically important bleeding: NA Any bleeding: NA Assessor: NA Assessment: NA Platelet transfusion with 1 unit of primarily RD (>240 × 109/L platelets/unit) platelets when platelet count was 200 × 109/unit) platelets was given when platelet count was ≤10 × 109/L If bleeding continued despite one platelet transfusion, further transfusions was given at the discretion of the treating clinician in both groups Clinically important bleeding: "Clinically relevant bleeding" was defined as a modified WHO grade 2 or higher Any bleeding: Not reported Assessor: A physician or experienced nurse (unblinded). Two investigators masked to treatment strategy later transformed the bedside bleeding report into modified WHO categories. Assessment: Clinical bleeding assessments was performed twice daily Clinically important bleeding: NA Any bleeding: NA Assessor: NA Assessment: NA Platelet transfusion with 1 unit of RD (platelets/unit not reported) platelets prior to placement of central catheters The proceduralist can administer rescue platelets at clinical indication in both arms in case of procedure related bleeding Clinically important bleeding: Modified WHO grade 2–4 Any bleeding: Not reported Assessor: Not reported Assessment: Clinical bleeding will be assessed at 1 h and 24 h post-procedural. Clinical photos taken at 1 h and 24 h will be used to evaluate size of hematoma in a blinded fashion. Two trials reported bleeding as the primary outcome.32, 36 Three trials explicitly described who performed the assessment of bleeding outcomes31, 36, 38 and the method of bleeding assessment was described in five trials.30-32, 36, 38 Newer trials typically used the WHO scale in the original30 or a modified version36, 38 to grade bleeding severity whereas older studies either used a study specific bleeding scale31 or none at all.33, 34 We used the trials' definitions of clinically important bleeding, which varied substantially (Table 2). An overview of risk of bias for all outcomes are provided in Table 3, with supportive comments available in Supplement S8. For the primary outcome, one trial was judged as overall low risk of bias. The domains "bias due to deviations from intended interventions" and "bias in selection of the reported results" were generally of concern in the remaining trials. For the remaining outcomes, all trials were judged to be of "some concerns" or "high risk of bias" with the domain "bias in measurement of the outcome" representing concerns for subjective outcomes. One low risk of bias trial reported data on all-cause mortality at the longest follow-up (n = 598) and showed uncertain results (RR 0.81; 95% CI 0.22 to 2.97, p = .75).36 TSA could not be performed as only 0.6% of the RIS of 102,293 patients had been accrued. The certainty of evidence was low (Table 4). The sensitivity analysis was consistent with the primary analysis (Supplement S13). ⊕⊕◯◯ Low ⊕◯◯◯ Very low ⊕◯◯◯ Very low ⊕⊕◯◯ Low ⊕◯◯◯ Very low ⊕◯◯◯ Very low ⊕⊕◯◯ Low Five trials reported data on all-cause mortality at longest follow-up (n = 1398).32, 33, 35, 36, 38 Conventional meta-analysis showed uncertain results (FEM, RR of 0.99; 95% CI 0.58 to 1.68, p = .97) (Figure 2). TSA could not be performed as only 2.0% of the RIS of 52,950 patients had been accrued. We observed no statistical heterogeneity (I2 = 0%; p = .91, D2 = 0%) and low clinical diversity (Supplement S10). The certainty of evidence was very low (Table 4). Subgroup analyses did not indicate heterogeneity of the treatment effect (Supplement S11), but the credibility was rated as very low as the analysis of effect modification was based solely on a between-trial comparison and the number of trials was very low (Supplement S12). Sensitivity analyses for long-term all-cause mortality (>90 days) and empirical continuity correction were consistent with the primary analysis, but BW/WB case scenarios showed conflicting results (Supplement S13). Five trials reported data on clinically important bleeding (n = 1276).31-33, 36, 38 The conventional meta-analysis indicated that prophylactic platelet transfusion may reduce the proportion of patients with at least one episode of clinically important bleeding (REM, RR 0.70, 97.5% CI 0.53 to 0.92, p < .01) (Figure 3), but the TSA showed that only 13.4% of the RIS of 9546 patients had been accrued (TSA adjusted CI 0.26 to 1.87) (Figure 4). We detected significant statistical heterogeneity (I2 = 59%; p = .04, D2 = 72%), partly explained by the moderate clinical diversity (Supplement S10). Despite this, all individual trial point estimates favored the prophylaxis group. The certainty of evidence was very low (Table 4). Data from a subgroup of patients with acute myeloid leukemia (n = 190) from one of the larger trials were not included, as they were reported per treatment cycle received, but showed fewer clinically important bleeding episodes in the prophylactic group (n = 96, 245 cycles) as compared to the therapeutic group (n = 94, 198 cycles); 24% (95% CI 18% to 30%) versus 51% (95% CI 43% to 59%).38 Sensitivity analyses were consistent with the primary analysis, but the results were no longer statistically significant for all bleeding episodes (i.e., not restricted to clinically important bleedings) and in BW/WB case scenarios (Supplement S13). Two trials reported data on this outcome (n = 654) but the available summary data did not allow meta-analysis.33, 36 A smaller trial reported the mean number of days with clinically important bleeding to be 1.9 days in the prophylactic group versus 2.2 days in the no prophylaxis group33 (n = 56) and a larger trial (n = 598) indicated that prophylactic platelet transfusions slightly reduced the number of days with clinically important bleeding (MD 0.5, 95% CI 0.1 to 0.9, p = .01). The TSA was redundant as more than 100% of the RIS of 261 had been accrued. We detected moderate clinical diversity (Supplement 10). The certainty of evidence was low (Table 4). Sensitivity analysis provided similar results (Supplement S13). A third trial38 (n = 396) reported on the percentage of days with clinically important bleeding out of the total number of days on which a morning platelet count was available and found that the prophylactic strategy generally reduced the percentage of days with bleeding, with a larger effect on days with platelet counts <10 × 109/L. As data was not reported with individual patients as the unit of analysis, the trial was not included in the meta-analysis, CDIM-evaluation, nor the GRADE evidence profile for this outcome. One trial reported data on infections (n = 598) as part of serious adverse events, and we assumed that these infections were nosocomial.36 The author did not have further details readily available. We found inconclusive results (RR of 0.94, 95% CI 0.46 to 1.91, p = .86) and TSA could not be performed as only 1.2% of the RIS of 48,730 patients had been accrued. The certainty of evidence was low (Table 4). Sensitivity analysis provided similar results (Supplement S13). Three trials reported data on this outcome (n = 1310).32, 36, 38 The conventional meta-analysis showed inconclusive results (REM, RR 2.54, 97.5% CI 0.27 to 23.61, p = .35) (Supplement S9). TSA could not be performed as only 0.2% of the RIS of 73,050 patients had been accrued. There were considerable differences in the reported event rates between studies, and we detected statistical heterogeneity (I2 = 60%; p = .08, D2 = 94%) and moderate clinical diversity (Supplement S10). The certainty of evidence was very low (Table 4). The empirical continuity correction agreed with the primary analysis, but the BW/WB case scenarios showed conflicting results (Supplement S13). Three trials reported data on this outcome (n = 1310)32, 36, 38 but the statistical summary measures differed and only data from two trials were pooled.32, 38 These pooled results in the conventional meta-analysis suggested that the effect of the intervention may be of little to no clinical importance (FEM, MD −0.23, 97.5% CI −0.60 to 0.13, p = .16) (Supplement S9). The third study reported a median (IQR) length of stay of 12 (9–18) in both groups with no impact from prophylactic platelet transfusion.36 We did not detect statistical heterogeneity (I2 = 0%; p = .33, D2 = 0%,) but found moderate clinical diversity (Supplement S10). The certainty of evidence was low (Table 4). BW/WB case scenarios showed conflicting results (Supplement S13). No trials reported data on venous or arterial thromboembolic events, days alive without life support, or health-related quality of life. Two studies reported the number of platelet units and red blood cell units transfused per participant (n = 989).36, 38 Conventional meta-analysis indicated that patients in the prophylaxis group received more platelet units as compared with the no prophylaxis group (REM, MD 1.00, 95% CI 0.53 to 1.47, p < .01, I2 = 57%) and possibly fewer red blood cell units (FEM, MD −0.25, 95% CI −0.58 to 0.07, p = .13, I2 = 0%) (Supplement S14). This systematic review identified seven RCTs with relevant outcome data comparing prophylactic platelet transfusion to no prophylaxis in 1642 hospitalized patients with thrombocytopenia.30-33, 35, 36, 38 We found uncertain results for all-cause mortality at longest follow-up between patients allocated to prophylactic platelet transfusion versus no prophylaxis when analyzing low risk of bias trials only and when incorporating data from all trials. The uncertainty about the effect is substantial since the conventional CIs were wide and included both clinically relevant harm and benefit and less than 5% of the RIS had been accrued. The overall certainty of evidence was low or very low, respectively, indicating that the present evidence is insufficient to draw conclusions on the effect of prophylactic platelet transfusions on all-cause mortality. The primary argument for the use of prophylactic platelet transfusions in patients with severe thrombocytopenia is to prevent bleeding.10-12 We found that prophylactic platelet transfusion may reduce the proportion of patients with at least one episode of clinically important bleeding. However, less than 15% of the RIS has been accrued, the TSA-adjusted CI was wide and included clinically relevant benefit and harm, and the overall certainty of evidence was very low. We observed substantial statistical heterogeneity, partly due to clinical heterogeneity, as the included trials were conducted over a period of 37 years and had substantial differences in patient populations, interventions, timing of outcome measurement, and in definitions, assessments, and grading of clinically important bleeding. Despite the different pathophysiology and etiology of bleeding in patients with hematological malignancy and dengue fever,40, 41 all point estimates favored the prophylaxis group, indicating a similar effect of prophylactic platelet transfusion. Only two trials reported on the number of days with clinically important bleeding per participant, which was found to be slightly lower in the prophylaxis group. Taken together, the evidence suggests that prophylactic platelet transfusion may reduce the risk of clinically important bleeding, but uncertainty remains. For the remaining secondary outcomes, we found substantial uncertainty around effect estimates for the proportions of patients experiencing at least one nosocomial infection or transfusion-related adverse event, and the evidence was too sparse to draw any meaningful conclusions. For the length of hospital stay, we found the difference between the allocation groups to be of little or no clinical importance, but the certainty of evidence was low. No trials reported on venous or arterial thrombotic events, days alive without life support or health-related quality of life. Our findings concur with a previous systematic review in patients with hematological disorders treated with myelosuppressive chemotherapy or stem cell transplantation that also found high levels of heterogeneity in the timing of outcome measurements and in the definitions and assessment of bleeding and uncertainty around the effect on mortality and adverse events.42 As our review had a wider scope, but still ended up including many of the same trials, it adds to the uncertainty around the effect of prophylactic platelet transfusions in patients outside the hematological setting. This review has several strengths. We conducted the review in accordance with the protocol19 and followed the recommendations by the Cochrane Collaboration20 including independent selection of studies, data extraction, and assessment of risk bias using the ROB 2.0 tool.23 We used TSA to estimate the RIS and calculate TSA-adjusted CIs where feasible.28 We used the GRADE21 approach to grade the overall certainty of evidence and we evaluated clinical diversity and subgroup credibility using the CDIM tool26 and the ICEMAN tool,27 respectively. This review also has important limitations. First, due to the wide scope of the review, the included trials were heterogenous with respect to the populations, duration, and dose of the intervention, timing of outcome measurements and definitions, assessments, and grading of bleeding outcomes, which makes direct comparison uncertain. However, as we found only low to moderate clinical diversity for all outcomes and as the evidence base was sparse and event rates rare, conducting meta-analysis to answer the research questions seems justified. Further, we found no indications of very serious inconsistency in the results. Second, the number of patients and event rates were generally low, which led to imprecise results and increased risk of type two errors. In particular, omitting patients with acute myeloid leukemia from one of the larger trials due to the data format might have underestimated the effect of prophylactic platelet transfusions on clinically important bleeding as these patients in general are at increased risk of bleeding due to a longer duration of profound thrombocytopenia.38 Third, newer trials defined clinically important bleeding as WHO grade ≥2,30, 36, 38 which has been challenged as WHO grade 2 bleeding may not be considered clinically important.43 Fourth, most outcomes were at risk of bias, which may decrease the overall validity of our results. Fifth, there was insufficient evidence to assess harm from prophylactic platelet transfusions; and sixth, the included patient populations were restricted to hematology-oncology patients and dengue fever patients, limiting the generalizability to other hospitalized patient populations with different reasons for thrombocytopenia, such as neonates, surgical patients, and ICU patients. In conclusion, prophylactic platelet transfusion may reduce clinically important bleeding in hospitalized patients with hematological malignancy or dengue fever, but the evidence is very uncertain, and the generalizability to other patient populations is unclear. The effects on mortality and adverse events are uncertain and data from non-hematological settings are sparse. To move forward, RCTs are warranted to test the benefits and harms of platelet transfusion in diverse hospitalized populations with thrombocytopenia. We would like to sincerely thank Dr. David C. Lye, Dr. Gemma L. Crighton and Dr. Larry Grossman for providing additional information upon request. The primary and last author received funding from the Research Council of Rigshospitalet, Copenhagen, Denmark. The primary author also received funding from the Ehrenreich Foundation. The funding parties were not involved in the conduct of this review. The Department of Intensive Care at Rigshospitalet (CA, AG, PS, MHM, AP, and LR) has received funding for other projects from the Novo Nordisk Foundation, Pfizer, Sygeforsikringen "danmark" and Fresenius Kabi and conducts contract research for AM-Pharma. FP has received personal fees from Gilead and an institutional grant from Alexion for other projects. KP and NZ have no conflict of interests. Appendix S1. Supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.