Different doses of prophylactic platelet transfusion for preventing bleeding in people with haematological disorders after myelosuppressive chemotherapy or stem cell transplantation

Summary of findings for the main comparison. Prophylactic platelet transfusions with low‐dose schedule compared to prophylactic platelet transfusions with standard‐dose schedule for people with a haematological disorder

Prophylactic platelet transfusions with a low‐dose schedule compared to prophylactic platelet transfusions with a standard‐dose schedule for prevention of haemorrhage after chemotherapy and stem cell transplantation
Patient or population: People with a haematological disorder Settings: After chemotherapy or a stem cell transplant Intervention: Prophylactic platelet transfusions with low‐dose schedule versus standard‐dose schedule
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Prophylactic platelet transfusions with standard‐dose schedule	Prophylactic platelet transfusions with low‐dose schedule
Number of participants with at least 1 clinically significant bleeding event up to 30 days from study entry	605 per 1000	629 per 1000 (575 to 684)	RR 1.04 (0.95 to 1.13)	1170 (4 studies)	⊕⊕⊕⊝ moderate¹
Number of days on which bleeding occurred per participant up to 30 days from study entry	The mean number of days with clinically significant bleeding per participant was 0.17 days lower (0.51 lower to 0.17 higher) (fixed effect)			230 (2 studies)	⊕⊕⊝⊝ low^1,2	We could not incorporate the largest study (840 participants) into the meta‐analysis (Slichter 2010); this also showed no difference in the number of days of bleeding between study arms (Table 3)
Number of participants with WHO grade 3 or 4 bleeding up to 30 days from study entry	91 per 1000	122 per 1000 (83 to 176)	RR 1.33 (0.91 to 1.92)	1059 (3 studies)	⊕⊕⊝⊝ low^1,2
Time to first bleeding episode (days)	Not estimable	Not estimable	Not estimable	959 (2 studies)	See comment	The 2 studies reported the outcome in different formats, and the results could not be integrated into a meta‐analysis (Table 4). The largest study (840 participants) showed no difference between study arms (Slichter 2010)
Number of platelet transfusions per participant up to 30 days from study entry	Not estimable	Not estimable	Not estimable	1070 (3 studies)	See comment	The 3 studies reported the outcome in different formats, and results could not be integrated into a meta‐analysis (Table 5). 2 of the 3 studies (959 participants) showed that a low‐dose transfusion strategy led to significantly more transfusion episodes (Heddle 2009; Slichter 2010)
Mortality from all causes up to 30 days from study entry	9 per 1000	19 per 1000 (6 to 55)	RR 2.04 (0.70 to 5.93)	1070 (3 studies)	⊕⊕⊝⊝ low^1,2
Quality of life ‐ not reported	Not estimable	Not estimable	Not estimable	‐	See comment	None of the studies reported quality of life
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ The studies were at risk of bias. Sources of bias were due to lack of blinding, protocol deviation, and attrition bias. The quality of the evidence was downgraded by 1 due to risk of bias. ² The number of cases was very low, the quality of the evidence was downgraded by 1 due to imprecision.

Summary of findings 2. Prophylactic platelet transfusions with low‐dose schedule versus high‐dose schedule for preventing bleeding in people with haematological disorders after chemotherapy or stem cell transplantation

Prophylactic platelet transfusion with low‐dose schedule versus high‐dose schedule for preventing bleeding in people with haematological disorders after chemotherapy or stem cell transplantation
Patient or population: People with a haematological disorder Settings: After chemotherapy or a stem cell transplant Intervention: Prophylactic platelet transfusions with a low‐dose schedule versus high‐dose schedule
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Prophylactic platelet transfusions with a high‐dose schedule	Prophylactic platelet transfusions with a low‐dose schedule
Number of participants with at least 1 clinically significant bleeding event up to 30 days from study entry	699 per 1000	713 per 1000 (650 to 776)	RR 1.02 (0.93 to 1.11)	849 (1 study)	⊕⊕⊕⊝ moderate¹
Number of days on which bleeding occurred per participant up to 30 days from study entry	Not estimable	Not estimable	Not estimable	849 (1 study)	See comment	There was no significant difference between the study arms, according to the study authors (Table 3)
Number of participants with WHO grade 3 or 4 bleeding up to 30 days from study entry	100 per 1000	119 per 1000 (82 to 170)	RR 1.20 (0.82 to 1.77)	849 (1 study)	⊕⊕⊝⊝ low^1,2
Time to first bleeding episode	Not estimable	Not estimable	Not estimable	849 (1 study)	See comment	There was no significant difference between the study arms, according to the study authors (Table 4)
Mortality from all causes up to 30 days from study entry	16 per 1000	22 per 1000 (8 to 57)	RR 1.33 (0.50 to 3.54)	849 (1 study)	⊕⊕⊝⊝ low^1,2
Number of platelet transfusions per participant	Not estimable	Not estimable	Not estimable	849 (1 study)	See comment	There was a significant increase in the number of platelet transfusions between the study arms, according to the study authors (Table 5)
Quality of life ‐ not reported	Not estimable	Not estimable	Not estimable	‐	See comment	None of the studies reported quality of life
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ The study was at risk of bias. Sources of bias were due to lack of blinding, protocol deviation, and attrition bias. The quality of the evidence was downgraded by 1 due to risk of bias. ² The number of cases was very low, the quality of the evidence was downgraded by 1 due to imprecision.

Summary of findings 3. Prophylactic platelet transfusions with high‐dose schedule versus standard‐dose schedule for preventing bleeding in people with haematological disorders after chemotherapy or stem cell transplantation

Prophylactic platelet transfusion with high‐dose schedule versus standard‐dose schedule for preventing bleeding in participants with haematological disorders after chemotherapy or stem cell transplantation
Patient or population: People with a haematological disorder Settings: After chemotherapy or a stem cell transplant Intervention: Prophylactic platelet transfusions with a high‐dose schedule versus standard‐dose schedule
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Prophylactic platelet transfusions with standard‐dose schedule	Prophylactic platelet transfusions with a high‐dose schedule
Number of participants with at least 1 clinically significant bleeding event up to 30 days from study entry	624 per 1000	637 per 1000 (581 to 693)	RR 1.02 (0.93 to 1.11)	951 (2 studies)	⊕⊕⊕⊝ moderate¹
Number of days on which bleeding occurred per participant up to 30 days from study entry	Not estimable	Not estimable	Not estimable	855 (1 study)	See comment	There was no significant difference between the study arms, according to the study authors (Table 3)
Number of participants with WHO grade 3 or 4 bleeding up to 30 days from study entry	90 per 1000	100 per 1000 (66 to 151)	RR 1.11 (0.73 to 1.68)	855 (1 study)	⊕⊕⊝⊝ low^1,2
Time to first bleeding episode (days)	Not estimable	Not estimable	Not estimable	855 (1 study)	See comment	There was no significant difference between the study arms, according to the study authors (Table 4)
Number of platelet transfusions per participant up to 30 days from study entry	Not estimable	Not estimable	Not estimable	1005 (3 studies)	See comment	The studies reported the results in different formats, therefore the results could not be integrated (Table 5). The largest study (855 participants) showed no difference in the number of platelet transfusions between a standard‐ and high‐dose transfusion regimen (Slichter 2010)
Mortality from all causes up to 30 days from study entry	9 per 1000	16 per 1000 (5 to 55)	RR 1.71 (0.51 to 5.81)	855 (1 study)	⊕⊕⊝⊝ low^1,2	The number of deaths was very low in both study arms
Quality of life ‐ not reported	Not estimable	Not estimable	Not estimable	‐	See comment	None of the studies reported quality of life
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ The studies were at risk of bias. Sources of bias were due to lack of blinding, protocol deviation, and attrition bias. The quality of the evidence was downgraded by 1 due to risk of bias. ² The number of cases was very low, the quality of the evidence was downgraded by 1 due to imprecision.

Background

Description of the condition

Haematological malignancies account for between 8% and 9% of all new cancers reported in the United Kingdom and United States (CDC 2012; ONS 2012), and their incidence is increasing (11% to 14% increase in new cases of lymphoma and myeloma between 1991 to 2001 and 2008 to 2010) (Cancer Research UK 2013). The prevalence of these disorders is also increasing due to increased survival rates (Coleman 2004; Rachet 2009). These improved survival rates are due to the introduction of myelosuppressive chemotherapy treatments and the use of stem cell transplantation (Burnett 2011; Fielding 2007; Patel 2009). Over 50,000 haematopoietic stem cell transplants (HSCTs) are carried out annually worldwide (Gratwohl 2010), and are used to treat both malignant and non‐malignant haematological disorders. Autologous HSCT is the most common type of HSCT (57% to 59%) (Gratwohl 2010; Passweg 2012). However, chemotherapy and stem cell transplantation can lead to prolonged periods of severe thrombocytopenia (De la Serna 2008; Heddle 2009a; Rysler 2010; Stanworth 2013; Wandt 2012).

Platelet transfusions are used in modern clinical practice to prevent and treat bleeding in thrombocytopenic patients with bone marrow failure secondary to chemotherapy or stem cell transplantation. The ready availability of platelet concentrates has undoubtedly made a major contribution in allowing the development of intensive treatment regimens for haematological disorders (malignant and non‐malignant) and other malignancies. The first demonstration of the effectiveness of platelet transfusions was performed in 1910 (Duke 1910). However, it was not until the 1970s and 1980s that the use of platelet transfusions became standard treatment for thrombocytopenic patients with bone marrow failure (Blajchman 2008). Alongside changes in supportive care, the routine use of platelet transfusions in people with haematological disorders since that time has led to a marked decrease in the number of haemorrhagic deaths associated with thrombocytopenia (Slichter 1980). This has resulted in a considerable increase in the demand for platelet concentrates. Currently, platelet concentrates are the second most frequently used blood component. Administration of platelet transfusions to people with haematological disorders now constitutes a significant proportion (up to 67%) of all platelets issued (Cameron 2007; Greeno 2007; Pendry 2011), and the majority of these (69%) are given to prevent bleeding (Estcourt 2012b).

Patients can become refractory to platelet transfusions. In an analysis of the TRAP 1997 study data, there was a progressive decrease in the post‐transfusion platelet count increments and time interval between transfusions as the number of preceding transfusions increased (Slichter 2005). This effect was seen irrespective of whether or not patients had developed detectable human leukocyte antigen (HLA) antibodies (Slichter 2005).

Platelet transfusions are also associated with adverse events. Mild to moderate reactions to platelet transfusions include rigors, fever, and urticaria (Heddle 2009b). Although these reactions are not life‐threatening, they can be extremely distressing for the patient. Rarer but more serious sequelae include: anaphylaxis; transfusion‐transmitted infections; transfusion‐related acute lung injury; and immunomodulatory effects (Benson 2009; Blumberg 2009; Bolton‐Maggs 2012; Heddle 2009b; Knowles 2010; Knowles 2011; Pearce 2011; Popovsky 1985; Silliman 2003).

Any strategy that can safely decrease the need for prophylactic platelet transfusions in haematology patients will have significant logistical and financial implications as well as decreasing patients’ exposure to the risks of transfusion.

Description of the intervention

Platelet transfusions have an obvious beneficial effect in the management of active bleeding in people with haematological malignancy and severe thrombocytopenia. However, questions still remain about how this limited resource should be used to prevent severe and life‐threatening bleeding (Estcourt 2011). Prophylactic platelet transfusions for people with chemotherapy‐induced thrombocytopenia became standard practice following the publication of several small randomised controlled trials (RCTs) in the late 1970s and early 1980s (Higby 1974; Murphy 1982; Solomon 1978). There are two main methods for producing platelet components. Apheresis platelet components (one donor per transfusion) requires platelet donors to be connected to a cell separator for at least 90 minutes. Pooled platelet components are derived from platelets within several whole‐blood donations.

Dose of prophylactic platelet transfusions

The platelet dose is the number of platelets contained within a standard platelet transfusion. For adults, the usual dose given is a single apheresis unit or a pool of four to six whole blood‐derived platelets, with the absolute number of platelets in the range of 300 x 10⁹ to 600 x 10⁹ (Stanworth 2005). The experimental interventions will be low‐dose or high‐dose platelet transfusion strategies. Low‐dose platelet transfusions will be platelet transfusions containing a similar dose to that given in the low‐dose arm of Slichter 2010 (1.1 x 10¹¹/m² ± 25%). High‐dose platelet transfusions will be platelet transfusions containing a similar dose to that given in the high‐dose arm of Slichter 2010 (4.4 x 10¹¹/m² ± 25%). If the exact dose is unknown, we will use the study's own definition of high dose or low dose.

How the intervention might work

Optimal dose of prophylactic platelets

The dose of the platelet product transfused was based upon the perceived need to raise the patient's platelet count above a certain safe threshold. Over the years, our understanding of bleeding in people with thrombocytopenia has advanced, and there is now evidence to suggest that patients require only approximately 7100 platelets/µL per day to maintain haemostasis (Hanson 1985). Platelets have been shown to provide an endothelial supportive function by plugging gaps in the endothelium of otherwise intact blood vessels. Animal studies have shown that thrombocytopenia is associated with the gradual thinning of the vessel wall endothelium over time and, that if thrombocytopenia persists, gaps gradually occur between adjacent endothelial cells (Blajchman 1981; Kitchens 1975; Nachman 2008). This thinning and fenestration of the endothelium is accompanied by the ongoing and increased use of circulating platelets to prevent the loss of red blood cells through these gaps.

A mathematical model predicted that smaller, more frequent doses of platelets would be as effective as higher doses of platelets in maintaining patients' platelet counts above an agreed threshold (Hersh 1998). This raised the question of whether thrombocytopenic bleeding could be prevented with a lower platelet dose (Tinmouth 2003). Such a strategy has potential economic and resource advantages, as fewer platelet transfusions might be required and donor exposures might be reduced.

Several studies have attempted to address this question. The two largest studies came to different conclusions (Heddle 2009a; Slichter 2010). One trial was stopped early because of an excess of World Health Organization (WHO) grade 4 bleeding (Heddle 2009a), and the other study found no difference in bleeding between treatment arms (Slichter 2010).

Assessment of bleeding

A bleeding assessment has been seen as a more clinically relevant measure of the effect of platelet transfusions than surrogate markers such as the platelet increment.

Any review that uses bleeding as a primary outcome measure needs to assess the way that the trials have recorded bleeding. Unfortunately, the way bleeding has been recorded and assessed has varied markedly between trials (Cook 2004; Estcourt 2013a; Heddle 2003).

Retrospective analysis of bleeding leads to a risk of bias because bleeding events may be missed, and only more severe bleeding is likely to have been documented. Prospective bleeding assessment forms provide more information and are less likely to miss bleeding events. However, different assessors may grade the same bleed differently, and it is very difficult to blind the assessor to the intervention.

The majority of trials have used the WHO system, or a modification of it, for grading bleeding (Estcourt 2013a; Koreth 2004; WHO 1979). One limitation of all the scoring systems based on the WHO system is that the categories are relatively broad and subjective, meaning that a small change in a participant's bleeding risk may not be detected. Another limitation is that the modified WHO categories are partially defined by whether a bleeding participant requires a blood transfusion. The threshold for intervention may vary between clinicians and institutions, and so the same level of bleeding may be graded differently in different institutions.

The definition of what constitutes clinically significant bleeding has varied between studies. Although the majority of more recent platelet transfusion studies have classified it as WHO grade 2 or above (Heddle 2009a; Slichter 2010; Stanworth 2010; Wandt 2012), in the past there has been greater heterogeneity (Cook 2004; Estcourt 2013a; Koreth 2004). The difficulties of assessing and grading bleeding may limit the ability to compare results between studies, and this needs to be kept in mind when reviewing the evidence for the effectiveness of prophylactic platelet transfusions at different doses.

Why it is important to do this review

Although considerable advances have been made in platelet transfusion therapy in the last 40 years, three major areas continue to provoke debate.

Firstly, what is the optimal prophylactic platelet dose to prevent thrombocytopenic bleeding?
Secondly, which threshold should be used to trigger the transfusion of prophylactic platelets?
Thirdly, are prophylactic platelet transfusions superior to therapeutic platelet transfusions for the prevention or control, or both, of life‐threatening thrombocytopenic bleeding?

The initial formulation of this Cochrane review attempted to answer these questions, but the evidence at the time was insufficient for us to draw any definitive conclusions (Stanworth 2004). This review was updated (Estcourt 2012a). For clarity and simplicity, we have now split the review to answer each question separately.

This review focuses solely on the first question: What is the optimal prophylactic platelet dose to prevent thrombocytopenic bleeding?

Avoiding the need for unnecessary prophylactic platelet transfusions in haematology patients will have significant logistical and financial implications for national health services as well as decreasing patients' exposure to the risks of transfusion. These factors are perhaps even more important in the development of platelet transfusion strategies in low‐income countries, where access to blood components is much more limited than in high‐income countries (Verma 2009).

The previous version of this review showed that there was no difference in the number of participants who developed WHO grade 2 or above bleeding between a low‐dose, standard‐dose, or high‐dose platelet transfusion strategy (Estcourt 2012a). However, the review was unable to establish whether there was any difference in the number of days on which bleeding occurred or in the number of participants with severe or life‐threatening haemorrhage (WHO grade 3 to 4) between the various platelet dose strategies.

This review did not assess the evidence for the answers to the second and third questions, as these are the focus of separate Cochrane reviews, nor did it assess the use of alternative agents instead of prophylactic platelet transfusions because this is the focus of another review.

This review did not assess whether there are any differences in the efficacy of apheresis versus whole‐blood derived platelet products, the efficacy of pathogen‐reduced platelet components, the efficacy of HLA‐matched versus random‐donor platelets, or differences between ABO identical and ABO non‐identical platelet transfusions, as recent systematic reviews have covered these topics (Butler 2013; Heddle 2008; Pavenski 2013; Shehata 2009).

Objectives

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs). There were no restrictions on language or publication status.

Types of participants

People with haematological disorders receiving treatment with myelosuppressive chemotherapy or stem cell transplantation, or both. We included people of all ages, in both inpatient and outpatient clinical settings. If trials consisted of mixed populations of patients, for example patients with diagnoses of solid tumours, we only used data from the haematological subgroups. If subgroup data for haematological patients were not provided (after contacting the authors of the trial), we excluded the trial if fewer than 80% of participants had a haematological disorder. We excluded any participants who were not being treated with myelosuppressive chemotherapy or a stem cell transplant. We included participants with non‐malignant haematological disorders (for example aplastic anaemia, congenital bone marrow failure syndromes) if they were being treated with an allogeneic stem cell transplant.

Types of interventions

Participants in both treatment arms received transfusions of platelet concentrates, prepared either from individual units of whole blood or by apheresis, and given prophylactically to prevent bleeding. Prophylactic platelet transfusions are typically given when blood platelet counts fall below a given trigger level. There was no restriction on the frequency of platelet transfusions, type of platelet component, or platelet count transfusion threshold, although we took this information into account in the analysis where available.

We included the following comparisons:

Low‐dose versus standard‐dose platelet transfusions
Low‐dose versus high‐dose platelet transfusions
High‐dose versus standard‐dose platelet transfusions

Low‐dose platelet transfusions were platelet transfusions containing a similar dose to that given in the low‐dose arm of Slichter 2010 (1.1 x 10¹¹/m² ± 25%). Standard‐dose platelet transfusions were platelet transfusions containing a similar dose to that given in the intermediate‐dose arm of Slichter 2010 (2.2 x 10¹¹/m² ± 25%). High‐dose platelet transfusions were platelet transfusions containing a similar dose to that given in the high‐dose arm of Slichter 2010 (4.4 x 10¹¹/m² ± 25%). If the exact dose was unknown, we used the study's own definition of high dose, standard dose, or low dose.

Types of outcome measures

Primary outcomes

Number and severity of bleeding episodes within 30 days from the start of the study:

The number of participants with at least one bleeding episode.
The total number of days on which bleeding occurred per participant.
The number of participants with at least one episode of severe or life‐threatening haemorrhage.
Time to first bleeding episode from the start of the study.

Secondary outcomes

Mortality (all causes, secondary to bleeding, and secondary to infection) within 30 days and 90 days from the start of the study.
Number of platelet transfusions per participant and number of platelet components per participant within 30 days from the start of the study.
Number of red cell transfusions per participant and number of red cell units per participant within 30 days from the start of the study.
Platelet transfusion interval within 30 days from the start of the study.
Proportion of participants requiring additional interventions to stop bleeding (surgical; medical, e.g. tranexamic acid; other blood products, e.g. fresh frozen plasma, cryoprecipitate) within 30 days from the start of the study.
Overall survival within 30, 90, and 180 days from the start of the study.
Proportion of participants achieving complete remission within 30 days and 90 days from the start of the study.
The total time in hospital within 30 days from the start of the study.
Adverse effects of treatments (transfusion reactions, thromboembolism, transfusion‐transmitted infection, development of platelet antibodies, development of platelet refractoriness) within 30 days from the start of the study.
Quality of life, as defined by the individual studies.

We expressed all primary and secondary outcomes in the formats defined in the Measures of treatment effect section of this review if data were available, except for two of our outcomes, which we planned to be only narrative reports. These were:

Platelet transfusion interval, as this can be calculated in many different ways and it was unlikely that the exact methodology would be reported sufficiently to allow us to combine the data, the data was therefore reported in a table.
Assessment of quality of life. We planned to use the study's own measure as there is no definitive patient‐reported outcome measure for this patient group (Estcourt 2014e). However, no study reported quality of life.

Search methods for identification of studies

The Systematic Review Initiative Information Specialist (CD) formulated updated search strategies in collaboration with the Cochrane Haematological Malignancies Review Group based on those used in previous versions of this review (Estcourt 2012a; Stanworth 2004).

Electronic searches

Bibliographic databases

We searched for RCTs in the following databases:

CENTRAL (Cochrane Library 2015, Issue 6, 23 July 2015) (Appendix 1)
MEDLINE (OvidSP, 1946 to 23 July 2015) (Appendix 2)
PubMed (epublications only, on 23 July 2015) (Appendix 3)
Embase (OvidSP, 1974 to 23 July 2015) (Appendix 4)
CINAHL (EBSCOhost, 1937 to 23 July 2015) (Appendix 5)
UKBTS/SRI Transfusion Evidence Library (www.transfusionevidencelibrary.com) (1950 to 23 July 2015) (Appendix 6)
Web of Science: Conference Proceedings Citation Index‐Science (CPCI‐S) (Thomson Reuters, 1990 to 23 July 2015) (Appendix 7)
LILACS (BIREME/PAHO/WHO, 1982 to 23 July 2015) (Appendix 8)
IndMed (ICMR‐NIC, 1985 to 23 July 2015) (Appendix 9)
KoreaMed (KAMJE, 1997 to 23 July 2015) (Appendix 10)
PakMediNet (2001 to 23 July 2015) (Appendix 10)

We updated searches from the original search in January 2002, Stanworth 2004, and the updated search on 10 November 2011, Estcourt 2012a. We combined searches in MEDLINE, Embase, and CINAHL with adaptations of the Cochrane RCT search filters, as detailed in the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2011).

Databases of ongoing trials

We also searched ClinicalTrials.gov (http://clinicaltrials.gov/ct2/search) (Appendix 11), the WHO International Clinical Trials Registry (ICTRP) (http://apps.who.int/trialsearch/) (Appendix 11), the ISRCTN Register (http://www.controlled‐trials.com/isrctn/) (Appendix 12), the EU Clinical Trials Register (https://www.clinicaltrialsregister.eu/ctr‐search) (Appendix 12), and the Hong Kong Clinical Trials Register (http://www.hkclinicaltrials.com/) (Appendix 13) in order to identify ongoing trials to 23 July 2015.

All new search strategies are presented as indicated in Appendices 1‐13. Search strategies for both the original (2002) and update (2011) searches are presented in Appendix 14.

Searching other resources

We augmented database searching with the following:

Handsearching of reference lists

We checked references lists of all included trials, relevant review articles, and current treatment guidelines for further literature. We limited these searches to the 'first generation' reference lists.

Personal contacts

We contacted authors of relevant studies, study groups, and experts worldwide known to be active in the field for unpublished material or further information on ongoing studies.

Data collection and analysis

Selection of studies

Two independent review authors (LE, PB) initially screened all electronically derived citations and abstracts of papers identified by the review search strategy for relevance. We excluded studies clearly irrelevant at this stage.

Two independent review authors (LE, PB) then formally assessed the full texts of all potentially relevant trials for eligibility against the criteria outlined above. We resolved all disagreements by discussion without the need to consult a third review author (SS). We sought further information from study authors if the article contained insufficient data to make a decision about eligibility. We designed a study eligibility form for trials of platelet transfusion to help in the assessment of relevance, which included ascertaining whether the participants had haematological disorders, and whether the two groups could be defined in the trial on the basis of differences in use of prophylactic platelet transfusion doses. We recorded the reasons why potentially relevant studies failed to meet the eligibility criteria.

Data extraction and management

We updated the data extraction performed for the previous version of this review (Estcourt 2012a). This included data extraction for all new studies that we have included since the previous review and also for all new review outcomes that were not part of the previous review (for example platelet transfusion interval, quality of life).

Two review authors (LE, PB) conducted the data extraction according to the guidelines proposed by The Cochrane Collaboration (Higgins 2011a). Any disagreements between the review authors were resolved by consensus. The review authors were not blinded to names of authors, institutions, journals, or the outcomes of the trials. The data extraction forms had been piloted in the previous version of this review (Estcourt 2012a). Due to minor changes in the format, the forms were piloted on a further study; thereafter the two review authors (LE, PB) independently extracted data for all the studies. We extracted the following data.

General information

Review author's name, date of data extraction, study ID, first author of study, author's contact address (if available), citation of paper, objectives of the trial.

Trial details

Trial design, location, setting, sample size, power calculation, treatment allocation, randomisation, blinding, inclusion and exclusion criteria, reasons for exclusion, comparability of groups, length of follow‐up, stratification, stopping rules described, statistical analysis, results, conclusion, and funding.

Characteristics of participants

Age, gender, ethnicity, total number recruited, total number randomised, total number analysed, types of haematological disease, lost to follow‐up numbers, dropouts (percentage in each arm) with reasons, protocol violations, previous treatments, current treatment, prognostic factors.

Interventions

Experimental and control interventions, type of platelet given, timing of intervention, dosage of platelet given, compliance to interventions, additional interventions given especially in relation to red cell transfusions, any differences between interventions.

Assessment of bias

Sequence generation, allocation concealment, blinding (participants, personnel, and outcome assessors), incomplete outcome data, selective outcome reporting, other sources of bias.

Outcomes measured

Number and severity of bleeding episodes.
Mortality (all causes), and mortality due to bleeding.
Overall survival.
Proportion of participants achieving complete remission.
Time in hospital.
Number of platelet transfusions and platelet components.
Number of red cell transfusions and red cell components.
Adverse effects of treatments (e.g. transfusion reactions, thromboembolism, transfusion‐transmitted infection, development of platelet antibodies or platelet refractoriness).
Quality of life.

We used both full‐text versions and abstracts to retrieve the data. We extracted publications reporting on more than one trial using one data extraction form for each trial. We extracted trials reported in more than one publication on one form only. When these sources provided insufficient information, we contacted the authors and study groups for additional details.

One review author performed data entry into software, which a second review author checked for accuracy.

Assessment of risk of bias in included studies

We updated the 'Risk of bias' assessment to include study funding from the 'Risk of bias' assessment performed for the previous version of this review (Estcourt 2012a).

The assessment included information about the design, conduct, and analysis of the trial. We evaluated each criterion on a three‐point scale: low risk of bias, high risk of bias, or unclear (Higgins 2011c). To assess risk of bias, we addressed the following questions in the 'Risk of bias' table for each included study:

Was the allocation sequence adequately generated?
Was allocation adequately concealed?
Was knowledge of the allocated intervention adequately prevented during the study (including an assessment of blinding of participants, personnel, and outcome assessors)?
Were incomplete outcome data adequately addressed (for every outcome separately)?
Are reports of the study free of selective outcome reporting?
Was the study apparently free of other problems that could put it at risk of bias? This included assessing whether the protocol deviation was balanced between treatment arms.

Measures of treatment effect

For dichotomous outcomes, we recorded the number of outcomes in the treatment and control groups and estimated the treatment effect measures across individual studies as the relative effect measures (risk ratio with 95% confidence intervals (CIs)).

For continuous outcomes, we recorded the mean and standard deviations. For continuous outcomes measured using the same scale, the effect measure was the mean difference with 95% CIs, or the standardised mean difference for outcomes measured using different scales. For time‐to‐event outcomes, we extracted the hazard ratio from published data according to Parmar 1998 and Tierney 2007.

We did not report the number needed to treat to benefit with CIs and the number needed to treat to harm with CIs because there we saw no differences between any of the bleeding outcomes.

If we could not report the available data in any of the formats described above, we performed a narrative report.

Unit of analysis issues

We did not pre‐specify in the protocol how we would deal with any unit of analysis issues. There were no unit of analysis issues within the included studies.

Dealing with missing data

We dealt with missing data according to the recommendations in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). We contacted nine authors in order to obtain information that was missing or unclear in the published report.

Three authors supplied missing data (Heddle 2009; Slichter 2010; Tinmouth 2004). One author searched for missing data, but it was no longer available (Steffens 2002).

In trials that included people with haematological disorders as well as those with solid tumours or non‐malignant haematological disorders, we extracted data for the malignant haematology subgroup from the general trial data. We could not do this in two studies (Klumpp 1999; Lu 2011); we contacted the authors but they did not respond. We therefore excluded these studies from the review.

Within an outcome, the preferred analysis was an intention‐to‐treat analysis. Where data were missing, we recorded the number of participants lost to follow‐up for each trial.

Assessment of heterogeneity

If we considered studies to be sufficiently homogenous in their design, we conducted a meta‐analysis and assessed the statistical heterogeneity (Deeks 2011). We assessed statistical heterogeneity of treatment effects between trials using a Chi² test with a significance level at P < 0.1. We used the I² statistic to quantify possible heterogeneity (I² > 50% moderate heterogeneity, I² > 80% considerable heterogeneity). We explored potential causes of heterogeneity by sensitivity and subgroup analyses where possible.

Assessment of reporting biases

We did not perform a formal assessment of potential publication bias (small trial bias) (Sterne 2011), because the review included fewer than 10 trials.

Data synthesis

We performed analyses according to the recommendations of The Cochrane Collaboration (Deeks 2011). We used aggregated data for analysis. For statistical analysis, we entered data into Review Manager 2014.

Where meta‐analysis was feasible, we used the fixed‐effect model for pooling the data. We used the Mantel‐Haenszel method for dichotomous outcomes, and the inverse‐variance method for continuous outcomes. We used the generic inverse‐variance method for time‐to‐event outcomes.

We used the random‐effects model for sensitivity analyses as part of the exploration of heterogeneity. If we found heterogeneity, as expressed by the I², to be above 50%, we reported both the fixed‐effect and random‐effects models. If we found heterogeneity to be above 80%, we did not perform a meta‐analysis and commented on results as a narrative.

Summary of findings tables

We used GRADE 2014 to create 'Summary of findings' tables as suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2011). This included the number and severity of bleeding episodes within 30 days from the start of the study (number of participants with at least one bleeding episode; number of days on which bleeding occurred; number of participants with severe or life‐threatening bleeding; time to first bleeding episode), number of platelet transfusions within 30 days from the start of the study, 30‐day mortality, and quality of life.

Subgroup analysis and investigation of heterogeneity

We considered performing subgroup analysis on the following characteristics, if appropriate:

Presence of fever (> 38^oC)
Underlying disease
Type of treatment (autologous HSCT, allogeneic HSCT, or chemotherapy alone)
Age of the participant (paediatric, adults, older adults (> 60 years))

Due to lack of data, we performed only three of these four subgroup analyses: underlying disease, type of treatment, and age of the participant.

We did not perform meta‐regression because no subgroup contained more than 10 studies (Deeks 2011). We commented on differences between subgroups as a narrative.

Investigation of heterogeneity between studies also included, if appropriate:

Age of the study (as the type of platelet component has changed over the last 40 years)
Different prophylactic platelet transfusion thresholds

Only one study was performed more than 20 years ago (Roy 1973). We could not incorporate any of the data from this study into any of the meta‐analyses, and therefore we did not perform this investigation of heterogeneity.

Sensitivity analysis

We had intended to assess the robustness of our findings by the following two sensitivity analyses:

Including only those trials at low risk of bias
Including only those trials in which 20% of participants or less were lost to follow‐up.

None of the seven included trials had more that 20% of participants lost to follow‐up, and all of the trials had some threats to validity, therefore we performed neither pre‐planned sensitivity analysis.

Results

Description of studies

See Characteristics of included studies and Characteristics of excluded studies.

Results of the search

See PRISMA flow diagram Figure 1.

Figure 1

Study flow diagram.

The original search (conducted January 2002) identified a total of 3196 potentially relevant records (Stanworth 2004). After duplicates were removed, there were 2380 records; we excluded 2343 records on the basis of the abstract. Using the original inclusion/exclusion criteria, the original systematic review identified 37 studies that appeared relevant on the basis of their full text or abstract (Stanworth 2004). This was performed by one review author.

The updated search (conducted November 2011) identified a total of 2622 potentially relevant records. After duplicates were removed, there were 2054 records; two review authors excluded 1865 records on the basis of the abstract. We retrieved 152 full‐text articles for relevance. Two review authors reviewed these full‐text articles and those from the original review (a total of 189 records) (Estcourt 2012a).

The latest update of the search (conducted 23 July 2015) identified a total of 4923 potentially relevant records. After duplicates were removed, there were 3927 records; two of three review authors (LE, PB, CD) excluded 3921 records on the basis of the abstract. Two review authors (LE, PB) retrieved and reviewed for relevance 26 full‐text articles.

The previous systematic review, Estcourt 2012a, identified seven trials that compared different platelet transfusion doses (six completed trials (Heddle 2009; Roy 1973; Sensebe 2004; Slichter 2010; Steffens 2002; Tinmouth 2004) and one ongoing trial (Lu 2011)). This updated search identified one additional study (Akay 2015). In total, we assessed and deemed eligible for inclusion seven studies (Akay 2015; Heddle 2009; Roy 1973; Sensebe 2004; Slichter 2010; Steffens 2002; Tinmouth 2004).

Included studies

See Characteristics of included studies for full details of each study.

Ongoing studies

This updated review identified no ongoing studies that were eligible for inclusion. The previous systematic review, Estcourt 2012a, identified one potentially relevant trial that compared different doses of platelets; this has now been excluded from our review because more than 20% of study participants had a solid tumour, and no subgroup data were available (Lu 2011).

Studies contributing to the main outcomes

The seven RCTs (20 publications) were published between 1973 and 2015. There were 13 secondary citations of included studies (cited as secondary references for the relevant included studies).

See Table 1 for study characteristics, including number and type of participants, type of intervention (actual doses used), prophylactic platelet transfusion thresholds used, duration of study, type of platelet product, and primary outcome.

Table 1. Characteristics of studies

Study	Participants	Number	Intervention	Intervention adjusted to BSA ranges of Slichter 2010^a	Platelet count threshold for prophylactic transfusions	Duration of study	Type of platelet product	Primary outcome
Akay 2015	Adults with haematological malignancies	100	"Low dose" 3‐unit pooled product, or 1/2‐unit apheresis product "Standard dose" 6‐unit pooled product or single‐unit apheresis product	Actual dose not reported	Plt count ≤ 10 x 10⁹/L	Not reported	Apheresis and pooled platelet products	Not reported
Heddle 2009	Adults with hypoproliferative thrombocytopenia	129	(1.5 to 3.0 x 10¹¹ platelets/product) versus (3.0 to 6.0 x 10¹¹ platelets/product)	Low dose 0.8 to 1.7 x 10¹¹/m² BSA versus Standard dose 1.7 to 3.4 x 10¹¹/m² BSA	Depended on local transfusion trigger. Usually 10 x 10⁹/L	Mean of 14 to 15.8 days	Apheresis and pooled platelet products	Occurrence of a WHO grade 2 bleed or above
Roy 1973	Children with acute leukaemia	62	(0.5 x 10¹¹/10 kg) versus (0.9 to 1.1 x 10¹¹/10 kg)^b	0 to 4 years Low dose 1.1 x 10¹¹/m² BSA versus Standard dose 2.0 to 2.4 x 10¹¹/m² BSA 5 to 9 years Low dose 1.3 x 10¹¹/m² BSA versus Standard dose 2.4 to 2.9 x 10¹¹/m² BSA 10 to 18 years Standard dose 1.7 x 10¹¹/m² BSA versus High dose 3.1 to 3.7 x 10¹¹/m² BSA	Plt count ≤ 25 x 10⁹/L	Follow‐up for 24 hours post platelet transfusion	ABO‐identical pooled products	Not reported
Sensebe 2004	People with acute leukaemia or undergoing autologous SCT	101	(0.5 x 10¹¹/10 kg) versus (1.0 x 10¹¹/10 kg)^c	Standard dose 1.9 x 10¹¹/m² BSA versus High dose 3.9 x 10¹¹/m² BSA	Plt count < 20 x 10⁹/L	Not stated	Leucodepleted ABO‐compatible apheresis	Time between first transfusion and daily platelet count reaching 20 x 10⁹/L
Slichter 2010	People of any age receiving SCT or myelosuppressive chemotherapy	1351	(1.1 x 10¹¹/m² BSA ± 25%) versus (2.2 x 10¹¹/m² BSA ± 25%) versus (4.4 x 10¹¹/m² BSA ± 25%)	Low dose (1.1 x 10¹¹/m² BSA) (range 0.8 to 1.4 x 10¹¹/m² BSA) versus Intermediate dose (2.2 x 10¹¹/m² BSA) (range 1.7 to 2.8 x 10¹¹/m² BSA) versus High dose (4.4 x 10¹¹/m² BSA) (range 3.3 to 5.5 x 10¹¹/m² BSA)	Plt count ≤ 10 x 10⁹/L	Mean number of days 19.1	Apheresis and pooled platelet products	Grade 2 or higher bleeding
Steffens 2002	People age > 16 yrs with AML or undergoing an allogeneic SCT	54	(single apheresis unit) versus (triple apheresis unit)	Actual dose not reported. Study definition was standard versus high dose	Plt count ≤ 10 x 10⁹/L	Median time for people with AML 25.1 to 25.8 days. Median time for SCT 14.1 to 15.9 days	Apheresis	Not reported
Tinmouth 2004	People age > 16 yrs with acute leukaemia or receiving an autologous SCT	111	(1.9 to 2.5 x 10¹¹ platelets/transfusion) versus (3.4 to 4.4 x 10¹¹ platelets/transfusion)	Low dose 1.1 to 1.4 x 10¹¹/m² BSA versus Standard dose 1.9 to 2.5 x 10¹¹/m² BSA	Plt count < 10 x 10⁹/L	Median time 15 days	Leucodepleted random‐donor pooled platelets (PRP method)	Bayesian design. Lower dose of platelets would be safe and effective in preventing major bleeding events and would decrease total utilisation of platelets

AML: acute myeloid leukaemia
BSA: body surface area
Plt: platelet
PRP: platelet‐rich plasma
SCT: stem cell transplant

^a For adult participants, the average body surface area (BSA) was assumed to be 1.79 using data from Sacco 2010. In all studies containing adult participants we used this number to compare study doses to the Slichter 2010 study. For Roy 1973, the BSA was calculated for each age group: 0 to 4 years, 5 to 9 years, and 10 to 18 years. Approximate body weights were estimated for each age group and the BSA estimated using Sharkey 2001. The approximate weights were 0 to 4 years (13.5 kg), 5 to 9 years (23.3 kg), and 10 to 18 years (50.9 kg). These equate to approximate BSA of 0.62 (0 to 4 years), 0.87 (5 to 9 years), and 1.5 (10 to 15 years).

^b The original study stated that "higher dose" platelet transfusions = 0.06 to 0.07 units/lb and "lower dose" platelet transfusions = 0.03 units/lb (Roy 1973). The average platelet yield reported in the study was 7 x 10¹⁰ platelets per unit. Therefore "higher dose" platelets = 0.9 to 1.1 x 10¹¹platelets/10 kg and "lower dose" platelets = 0.46 x 10¹¹ platelets/10 kg.

^c Mean weight in both arms of the study was 69 kg.

Of the seven RCTs, four were single‐centre parallel RCTs (Akay 2015; Roy 1973; Steffens 2002; Tinmouth 2004), and three were multicentre parallel RCTs (Heddle 2009; Sensebe 2004; Slichter 2010). The number of participants randomised ranged from 54 in Steffens 2002 to 1351 in Slichter 2010.

One study was conducted in the 1970s (Roy 1973), five studies were conducted in the early to late 2000s (Heddle 2009; Sensebe 2004; Slichter 2010; Steffens 2002; Tinmouth 2004), and one study was conducted in the 2010s (Akay 2015). Two studies were conducted in the United States (Roy 1973; Slichter 2010), one in Canada (Tinmouth 2004), one in France (Sensebe 2004), one in Turkey (Akay 2015), and one in the United Kingdom (Steffens 2002), and one study was a multinational trial with centres in Canada, Norway, and the United States (Heddle 2009).

This updated review included one new study (Akay 2015). The original review identified two platelet dose studies (Klumpp 1999; Roy 1973). The previous update of this review identified five platelet dose studies (Heddle 2009; Sensebe 2004; Slichter 2010; Steffens 2002; Tinmouth 2004).

Participants

In total 1908 participants were randomised; of these, we included 1814 in the analyses. 91 participants (seven in Heddle 2009, five in Sensebe 2004, and 79 in Slichter 2010) were excluded from these studies because they did not receive a platelet transfusion. Three further patients were excluded from the Heddle 2009 study because there was no bleeding assessment data available.

Four of the studies included only adults (Akay 2015; Heddle 2009; Steffens 2002; Tinmouth 2004). Two of the studies included both adults and children (Sensebe 2004; Slichter 2010), and one study included only children (Roy 1973). All of the participants had hypoproliferative thrombocytopenia, but the cause of this varied between studies. All of the studies included participants with acute leukaemia, however only four of the studies specifically stated that acute promyelocytic leukaemia was an exclusion criteria (Heddle 2009; Sensebe 2004; Slichter 2010; Tinmouth 2004). Four of the studies included participants receiving an autologous stem cell transplant (Heddle 2009; Sensebe 2004; Slichter 2010; Tinmouth 2004). Three of the studies included participants receiving an allogeneic stem cell transplant (Heddle 2009; Slichter 2010; Steffens 2002).

Intervention

Five studies specified the dose of platelets used in each arm of the study (Heddle 2009; Roy 1973; Sensebe 2004; Slichter 2010; Tinmouth 2004), and we approximated the doses to the doses specified in Slichter 2010; and in two studies we used the study's own definition of whether it was a low‐dose, standard‐dose, or high‐dose transfusion (Akay 2015; Steffens 2002) (see Table 1).

Three studies compared low‐dose versus standard‐dose platelet transfusions (Akay 2015; Heddle 2009; Tinmouth 2004) (Table 1). One study compared low‐dose versus high‐dose platelet transfusions (Slichter 2010). Two studies compared standard‐dose versus high‐dose platelet transfusions (Sensebe 2004; Steffens 2002). Slichter 2010 performed a comparison between low‐dose, standard‐dose, and high‐dose platelet transfusions. Roy 1973 compared low‐dose versus standard‐dose platelet transfusions in the two younger age groups (0 to 4 and 5 to 9 years) and standard‐dose versus high‐dose platelet transfusions in the oldest age group (10 to 18 years).

The type of platelet product varied between studies: Roy 1973 and Tinmouth 2004 used pooled random‐donor platelets; Akay 2015, Heddle 2009, and Slichter 2010 used both apheresis and pooled platelet components; and Sensebe 2004 and Steffens 2002 used apheresis platelet components.

Six of the seven studies defined the platelet count threshold for prophylactic platelet transfusions: Akay 2015, Slichter 2010, Steffens 2002, and Tinmouth 2004 used a platelet count threshold of 10 x 10⁹/L; Sensebe 2004 used a platelet count threshold of 20 x 10⁹/L; and Roy 1973 used a platelet count threshold of 25 x 10⁹/L. In Heddle 2009, the prophylactic platelet transfusion threshold depended on local guidelines, but this was usually a platelet count threshold of 10 x 10⁹/L. In Akay 2015, the threshold was raised to 20 x 10⁹/L if the participants had WHO grade 1 bleeding or a fever.

Co‐interventions

None of the studies reported any co‐interventions. Five of the seven studies did not report a red cell transfusion policy, and two studies (unpublished data of Heddle 2009; Slichter 2010) reported that local practice at each centre determined the red cell transfusion policy.

Outcomes

Four of the seven studies defined a primary outcome (Heddle 2009; Sensebe 2004; Slichter 2010; Tinmouth 2004). In three of these studies, bleeding was the primary outcome measure (Heddle 2009; Slichter 2010; Tinmouth 2004), whereas in the fourth study the primary outcome was the time between the first platelet transfusion and the daily platelet count reaching 20 x 10⁹/L (Sensebe 2004), with bleeding reported as an adverse event. Only one of the seven studies reported on adverse events associated with platelet transfusions (Slichter 2010).

Excluded studies

See Characteristics of excluded studies for further details.

Twelve excluded studies compared different participant groups (Andrew 1993; Arnold 2006; Bai 2004; Fanning 1995; Gajic 2006; Gerday 2009; Hillbom 2008; Johansson 2007; Julmy 2009; Reed 1986; Spiess 2004; Vadhan‐Raj 2002).
Sixty‐four excluded studies compared different types of platelet formulations with outcome measures not relevant to the eligibility criteria (Agliastro 2006; Akkök 2007; Anderson 1997; Arnold 2004; Bentley 2000; Blumberg 2002; Blumberg 2004; Blundell 1996; Carr 1990; Couban 2002; De Wildt‐Eggen 2000; Diedrich 2005; Diedrich 2009; Dumont 2011; Gmur 1983; Goodrich 2008; Grossman 1980; Gurkan 2007; Harrup 1999; Heal 1993; Heckman 1997; Heddle 1994; Heddle 1999; Heddle 2002; Higby 1974; ISRCTN49080246; Kakaiya 1981; Kerkhoffs 2010; Lapierre 2003; Leach 1991; Lee 1989; Lozano 2010; Lozano 2011; McCullough 2004; Messerschmidt 1988; Mirasol 2010; Murphy 1982; Murphy 1986; NCT00180986; Oksanen 1991; Oksanen 1994; OPTIMAL Pilot Study; Pamphilon 1996; Rebulla 1997; Schiffer 1983; Shanwell 1992; Singer 1988; Sintnicolaas 1981; Sintnicolaas 1982; Sintnicolaas 1995; Slichter 1998; Slichter 2006; Solomon 1978; Stanworth 2013; Strindberg 1996; Sweeney 2000; TRAP 1997; van Marwijk 1991; van Rhenen 2003; Wandt 2012; Wang 2002; Williamson 1994; Zhao 2002; Zumberg 2002).
Three citations were guidelines (Follea 2004; Samama 2005; Tosetto 2009).
One citation was an audit (Qureshi 2007).
Thirty‐nine citations were reviews (including four systematic reviews) (Andreu 2009; Avvisati 2003; Benjamin 2002; Blajchman 2008; Buhrkuhl 2010; Casbard 2004; Cid 2007; Dzik 2004; Goodnough 2002; Goodnough 2005; Heal 2004; Heddle 2003; Heddle 2007; Jelic 2006; Levi 2002; Lordkipanidze 2009; Lozano 2003; Martel 2004; McNicol 2003; Paramo 2004; Poon 2003; Rabinowitz 2010; Rayment 2005; Razzaghi 2012; Roberts 2003; Sakakura 2003; Shehata 2009; Shen 2007; Slichter 2004; Slichter 2007; Slichter 2012; Sosa 2003; Strauss 2004; Strauss 2005; Tinmouth 2003; Wandt 2010; Wang 2005; Woodard 2002; Zeller 2014).
Twenty‐six studies were not RCTs (Aderka 1986; Callow 2002; Cameron 2007; Chaoui 2005; Chaurasia 2012; Decaudin 2004; Eder 2007; Elting 2002; Elting 2003; Friedmann 2002; Gil‐Fernandez 1996; Gmur 1991; Greeno 2007; Hardan 1994; Lawrence 2001; Navarro 1998; Nevo 2007; Norol 1998; Paananen 2009; Sagmeister 1999; Verma 2008; Wandt 1998; Wandt 2005; Wandt 2006; Weigand 2009; Zahur 2002).
Forty‐four citations were secondary citations of excluded studies (cited as secondary references for the relevant excluded studies).
In three studies fewer than 80% of the participants were haematological patients, and no data were available on the haematological subgroup (Goodnough 2001; Klumpp 1999; Lu 2011). We had included Klumpp 1999 in the original review, Stanworth 2004, but have now excluded it from the review because fewer than 80% of the participants were haematological patients, and no data were available on the haematological subgroup.

Risk of bias in included studies

See Figure 2 and Figure 3 for visual representations of the assessments of risk of bias across all studies and for each item in the individual studies. See the Characteristics of included studies section 'Risk of bias' table for further information about the bias identified within individual trials.

Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

All seven studies had some threats to validity (Akay 2015; Heddle 2009; Roy 1973; Sensebe 2004; Slichter 2010; Steffens 2002; Tinmouth 2004). The one study published in the 1970s had significant threats to validity; the majority of these were due to a lack of detail provided on the specific criteria and were thus judged as 'unclear' using the Cochrane 'Risk of bias' tool.

Allocation

Sequence generation

Three of the studies described adequate methods of sequence generation with computer‐generated block design (Heddle 2009; Slichter 2010; Tinmouth 2004). The other four studies were insufficiently reported for an adequate assessment to be made (Akay 2015; Roy 1973; Sensebe 2004; Steffens 2002).

Allocation concealment

Two of the studies described adequate allocation concealment (Heddle 2009; Tinmouth 2004). Heddle 2009 used a secure web‐based randomisation system, and Tinmouth 2004 used a sealed envelope system administered by blood bank staff. The other five studies were insufficiently reported for an adequate assessment to be made (Akay 2015; Roy 1973; Sensebe 2004; Slichter 2010; Steffens 2002).

Blinding

In two of the seven studies (Sensebe 2004; Tinmouth 2004), the medical staff were not blinded to the intervention. A further three studies could not be assessed for blinding of medical staff due to lack of information (Akay 2015; Roy 1973; Steffens 2002). The final two studies were designed as blinded studies, but the authors of both studies led us to believe that blinding was inadequate (Heddle 2009; Slichter 2010). In Heddle 2009, this was due to unbalanced early withdrawal of participants from the study by physicians (seven participants were withdrawn early from the study: one in the standard‐dose arm and six in the low‐dose arm). In Slichter 2010, it was noted that differences in the volume of platelets transfused led to loss of blinding.

Three studies were designed so that the bleeding assessors were blinded to the intervention (Heddle 2009; Roy 1973; Slichter 2010). Three studies provided insufficient information to determine whether bleeding assessors were blinded to the intervention (Akay 2015; Sensebe 2004; Steffens 2002). In one study (Tinmouth 2004), the bleeding assessor was unblinded to the outcome measure.

In four of the seven studies (Heddle 2009; Roy 1973; Slichter 2010; Tinmouth 2004), the final allocation of bleeding grade was performed by individuals blinded to the intervention (Heddle 2009; Roy 1973; Tinmouth 2004), or by the use of a computer algorithm (Slichter 2010). Akay 2015, Sensebe 2004 and Steffens 2002 provided insufficient information to determine whether individuals who graded bleeding were blinded to the intervention.

Incomplete outcome data

Two of the studies were at high risk of bias due to an imbalance in the amount of missing data between the arms of the study (Heddle 2009; Slichter 2010). In Slichter 2010, complete data were available on 71%, 82%, and 83% of platelet transfusions in the low‐dose, standard‐dose, and high‐dose arms of the study, respectively (this was a statistically significant difference). In Heddle 2009, more participants were withdrawn early from the study in the low‐dose arm.

Three of the studies were deemed as at low risk of bias due to incomplete outcome data (Roy 1973; Sensebe 2004; Tinmouth 2004), and two studies were not reported in enough detail for this to be assessed (Akay 2015; Steffens 2002).

Selective reporting

Only one of the seven studies was free of selective reporting (Slichter 2010). In three studies (Akay 2015; Sensebe 2004; Tinmouth 2004), we could not make an assessment due to a lack of information. Three studies were at risk of significant bias due to selective reporting (Heddle 2009; Roy 1973; Steffens 2002). In Heddle 2009, not all of the prespecified outcomes were reported (including platelet response; pre‐ and post‐transfusion bleeding grade in response to dose of therapeutic platelets transfused; cost analysis). In Roy 1973, a large amount of data had been collected, as demonstrated by the following sentence: "No correlation of the incidence of bleeding with sex, pre‐transfusion haematocrit, concomitant corticosteroid therapy or the use of anti‐neoplastic drugs was found". However, none of these results were reported. Steffens 2002 has only ever been reported as an abstract, although the abstract mentions that further outcomes (such as clinical efficacy and bleeding episodes) would be reported in more detail in the future this never occurred.

Other potential sources of bias

Protocol deviation

We considered three of the seven studies to be at a high risk of bias due to an imbalance in protocol deviations between the different arms of the studies (Heddle 2009; Slichter 2010; Tinmouth 2004). The other four studies were not reported in enough detail for an assessment to be made (Akay 2015; Roy 1973; Sensebe 2004; Steffens 2002).

In Heddle 2009, the platelet count that triggered a transfusion was higher in the low‐dose treatment group (35.9% of transfusions (158/440) given at a trigger of 16 x 10⁹/L or more) than in the standard‐dose group (24.7% of transfusions (66/267) given at a trigger of 16 x 10⁹/L or more). In Slichter 2010, a significantly smaller proportion of transfusions were within the assigned dose range when platelet counts were compared between low‐dose and standard‐dose groups (71% versus 80%) and between high‐dose and standard‐dose groups (70% versus 80%). In Tinmouth 2004, a total of 15 out of 164 transfusions contravened the protocol in the low‐dose arm, but only three out of 147 transfusions contravened the protocol in the standard‐dose arm.

Assessment and grading of bleeding

Six studies reported bleeding outcomes (Table 2). It was the primary outcome in three of these studies (Heddle 2009; Slichter 2010; Tinmouth 2004). These three studies all reported the method of assessing bleeding and the bleeding severity scale used. However, although in two of these three studies red blood cell usage was used to partially grade bleeding severity, neither study reported a definitive red cell transfusion policy, and both studies left the decision to transfuse up to local policies (Heddle 2009; Slichter 2010). Variations in red cell transfusion policies across centres within a trial could affect the assessment of bleeding grade and therefore lead to bias. Also, variations in the use of transfusions between studies could affect the results of any meta‐analysis.

See: Summary of findings for the main comparison Prophylactic platelet transfusions with low‐dose schedule compared to prophylactic platelet transfusions with standard‐dose schedule for people with a haematological disorder; Summary of findings 2 Prophylactic platelet transfusions with low‐dose schedule versus high‐dose schedule for preventing bleeding in people with haematological disorders after chemotherapy or stem cell transplantation; Summary of findings 3 Prophylactic platelet transfusions with high‐dose schedule versus standard‐dose schedule for preventing bleeding in people with haematological disorders after chemotherapy or stem cell transplantation

Table 2. Assessment and grading of bleeding within the included studies

Study	Bleeding primary outcome of study	Method of bleeding assessment reported	Frequency of assessment of bleeding	Bleeding severity scale used	RBC usage part of bleeding severity assessment	RBC transfusion policy
Akay 2015	No	No	For 48 hours after first platelet transfusion	WHO 1979	No	Not reported
Heddle 2009	Yes	Yes	Daily	Adapted WHO	Yes	Local practice at each centre (unpublished)
Slichter 2010	Yes	Yes	Daily	Adapted WHO	Yes	Local practice at each centre
Tinmouth 2004	Yes	Yes	Daily	Adapted Rebulla	No	Not reported
Roy 1973	Not reported	Yes	For 24 hours after each platelet transfusion	Study specific	No	Not reported
Sensebe 2004	No	No	Daily	WHO 1979	No	Not reported

RBC: red blood cell
WHO: World Health Organization

Other potential sources

Only two of the seven studies had further potential sources of bias (Roy 1973; Heddle 2009). Three of the studies were free of any other obvious sources of bias (Sensebe 2004; Slichter 2010; Tinmouth 2004), and two studies were reported in insufficient detail for an assessment to be made (Akay 2015; Steffens 2002).

In Roy 1973, there was a marked difference in population age groups between the two arms of the study; other baseline characteristics were not reported in sufficient detail for an assessment to be made. In Heddle 2009, discrepancies in the adjudication of bleeding grade occurred in 39% (433 out of 1150) of the bleeding days analysed, with most of these discrepancies occurring between the grade 1 and 2 classifications. However, agreement was eventually reached in most cases through consensus. Heddle 2009 was also stopped early due to a prespecified stopping guideline.

Effects of interventions

In all the included studies, the study's own definition of clinically significant bleeding was used, unless otherwise stated. If the study did not explicitly define clinically significant bleeding, we assumed that WHO grade 2 or above bleeding was clinically significant bleeding, because this definition has been used by the majority of newer studies (Heddle 2009; Slichter 2010; Stanworth 2013).

Primary outcomes

Six of the seven studies reported bleeding as an outcome (Akay 2015; Heddle 2009; Roy 1973; Sensebe 2004; Slichter 2010; Tinmouth 2004). Four of these six studies assessed bleeding on a daily basis (Heddle 2009; Sensebe 2004; Slichter 2010; Tinmouth 2004); one study assessed bleeding for 48 hours after the first platelet transfusion (Akay 2015); and one study only assessed bleeding for 24 hours after each platelet transfusion (Roy 1973) (see Table 2).

Five studies compared a low‐dose versus standard‐dose platelet transfusion strategy (Akay 2015; Heddle 2009; Roy 1973; Slichter 2010; Tinmouth 2004); one study compared a low‐dose versus high‐dose platelet transfusion strategy (Slichter 2010); and three studies compared a standard‐dose versus high‐dose platelet transfusion strategy (Roy 1973; Sensebe 2004; Slichter 2010).

Bleeding outcomes were reported within 30 days from the start of the study for five of the six studies (Akay 2015; Heddle 2009; Sensebe 2004; Slichter 2010; Tinmouth 2004); in the fifth study it was unclear how long the study lasted (Roy 1973).

Number of participants with at least one bleeding episode (within 30 days from the start of the study)

This was reported for five of the seven studies (Akay 2015; Heddle 2009; Sensebe 2004; Slichter 2010; Tinmouth 2004).

Four studies compared a low‐dose versus standard‐dose platelet transfusion strategy (Akay 2015; Heddle 2009; Slichter 2010; Tinmouth 2004). A meta‐analysis of this data showed no difference in the number of participants who had clinically significant bleeding (risk ratio (RR) 1.04, 95% confidence interval (CI) 0.95 to 1.13) with relatively narrow 95% confidence interval (Analysis 1.1).

One study compared a low‐dose versus high‐dose platelet transfusion strategy (Slichter 2010), hence we carried out no meta‐analysis. The study showed no difference in the number of participants who had clinically significant bleeding (RR 1.02, 95% CI 0.93 to 1.11) ((study data shown in Analysis 1.2).

Two studies compared a high‐dose versus standard‐dose platelet transfusion strategy (Sensebe 2004; Slichter 2010). A meta‐analysis of this data showed no difference in the number of participants who had clinically significant bleeding (RR 1.02, 95% CI 0.93 to 1.11) with relatively narrow 95% confidence interval (Analysis 1.3).

Total number of days on which bleeding occurred per participant (within 30 days from the start of the study)

Three of the studies reported on the number of days with a clinically significant bleeding event (Roy 1973; Heddle 2009; Slichter 2010, and a fourth study provided unpublished data (Tinmouth 2004). Only three of these four studies reported on the number of days on which bleeding occurred per patient (Heddle 2009; Slichter 2010; Tinmouth 2004) (Table 3).

Table 3. Number of days with a clinically significant bleeding event/participant

Study	Low dose		P value Low dose vs standard dose	Standard dose		P value Standard dose vs high dose	High dose
Study	Number of participants	Days	P value Low dose vs standard dose	Number of participants	Days	P value Standard dose vs high dose	Number of participants	Days
Heddle 2009	58	Mean 1.8 ± SD 3.23^a	Not reported	61	Mean 1.2 ± SD 2.02^a	NA	NA	NA
Slichter 2010	417	Median 1 IQR 0 to 4	0.9^b	423	Median 1 IQR 0 to 4	0.91^b	432	Median 1 IQR 0 to 4
Tinmouth 2004^c	56	Mean 0.375 ± SD 0.93^a	Not reported	55	Mean 0.65 ± SD 1.0^a	NA	NA	NA

IQR: interquartile range
NA: not applicable
SD: standard deviation

^aunpublished data
^bP value is not statistically significant.
^cTo improve comparison with the other studies, significant bleeding in this analysis was the number of days with bleeding that required a therapeutic platelet transfusion or local intervention. This differs from the study's definition of significant bleeding.

Slichter 2010 reported this as the median number of days with WHO grade 2 or above bleeding per participant (Table 3); no significant difference was seen between the three arms of the study.

Authors of two studies provided unpublished data on the mean number of days with bleeding per participant (Heddle 2009;Tinmouth 2004) (Analysis 1.4). In Tinmouth 2004 we re‐classified clinically significant bleeding as the number of days with bleeding that required an intervention or a therapeutic platelet transfusion (rather than the study definition, so as to decrease the differences in how bleeding events were defined between studies). Despite this, there was still moderate heterogeneity (I² = 63%) when we attempted to combine the data (Analysis 1.4). The results of the fixed‐effect (mean difference (MD) ‐0.17, 95% CI ‐0.51 to 0.17) and random‐effects (MD 0.04, 95% CI ‐0.78 to 0.86) meta‐analyses were similar (Analysis 1.4; Analysis 1.5).

There were several possible reasons for the quantitative differences observed in this analysis between the studies and hence the heterogeneity observed. Firstly, Tinmouth 2004 included 24 participants who never received a platelet transfusion; these participants were specifically excluded from analysis of Heddle 2009. Secondly, Tinmouth 2004 randomised participants at initiation of chemotherapy, and the study was stopped when they had a clinically significant bleed, whereas in Heddle 2009 participants were randomised when they received their first prophylactic platelet transfusion, and they remained within the study until platelet count recovery or discharge from hospital. Thirdly, the majority of participants in Tinmouth 2004 were receiving an autologous stem cell transplant (77/111), whereas in Heddle 2009 the majority of participants had acute leukaemia (103/119).

Number of participants with at least one episode of severe or life‐threatening haemorrhage (within 30 days from the start of the study)

Three of the studies reported the number of participants with WHO grade 3 or 4 bleeding (Heddle 2009; Slichter 2010). We performed a meta‐analysis that compared low‐dose versus standard‐dose platelet transfusion strategies and saw no difference (RR 1.33, 95% CI 0.91 to 1.92) (Analysis 1.6).

In Slichter 2010 (a three‐arm trial), no significant difference was seen between low‐dose and high‐dose platelet transfusion strategies in the incidence of grade 3 and 4 bleeding (RR 1.20, 95% CI 0.82 to 1.77) ((study data shown in Analysis 1.7), or between high‐dose and standard‐dose platelet transfusion strategies in the incidence of grade 3 and 4 bleeding (RR 1.11, 95% CI 0.73 to 1.68) (study data shown in Analysis 1.8).

Three of the studies reported the number of participants who could be classified as having grade 4 bleeding (Heddle 2009; Slichter 2010; Tinmouth 2004) (Analysis 1.9). We performed a meta‐analysis that compared low‐dose versus standard‐dose platelet transfusions and saw no significant difference (RR 1.87, 95% CI 0.86 to 4.08) (Analysis 1.9). In Slichter 2010, no significant difference was seen between low‐dose and high‐dose platelet transfusions in the incidence of grade 4 bleeding (RR 1.50, 95% CI 0.65 to 3.46) (study data shown in Analysis 1.10), or between high‐dose and standard‐dose platelet transfusions in the incidence of grade 4 bleeding (RR 1.10, 95% CI 0.43 to 2.83) (Analysis 1.11).

One of the studies reported the number of participants with bleeding that required a red cell transfusion (Heddle 2009). There was no statistically significant difference between the two arms of the study (RR 0.86, 95% CI 0.25 to 3.0) (Analysis 1.12).

One of the studies reported the number of participants with bleeding that caused cardiovascular compromise (Tinmouth 2004). There was no statistically significant difference between the two arms of the study (RR 2.95, 95% CI 0.12 to 70.82) ((study data shown in Analysis 1.13).

Time to first bleeding episode from the start of the study

Two of the seven studies reported this outcome (Heddle 2009; Slichter 2010). We could not perform a meta‐analysis because the studies reported the data in different formats. In Heddle 2009, no significant difference was seen in the time it took for participants receiving low‐dose or standard‐dose platelets to develop bleeding of WHO grade 2 or above. In Slichter 2010, there was no significant difference in the time to first significant bleeding event (Table 4).

Table 4. Time to first clinically significant bleeding event

Study	Low dose		P value Low dose vs standard dose	Standard dose		P value Standard dose vs high dose	High dose
Study	Number of participants	Days	P value Low dose vs standard dose	Number of participants	Days	P value Standard dose vs high dose	Number of participants	Days
Heddle 2009	58	Mean 11.2 ± SD 9.18^a	Not reported	61	Mean 9.7 ± SD 8.39^a	NA	NA	NA
Slichter 2010	417	Median 7 IQR 3 to 18	0.85^b	423	Median 7 IQR 3 to 19	0.66^b	432	Median 8 IQR 3 to 19

IQR: interquartile range
NA: not applicable
SD: standard deviation

^aunpublished data
^bP value is not statistically significant.

Secondary outcomes

Mortality

All‐cause mortality within 30 and 90 days from the start of the study

No studies reported hazard ratios for all‐cause mortality. Data on all‐cause mortality within 30 days were available for four of the studies. In two of these studies, this was published data (Sensebe 2004; Slichter 2010); in the other two studies, this was unpublished data (Heddle 2009; Tinmouth 2004). In Sensebe 2004, three deaths occurred over both arms of the study, all in participants with acute leukaemia, but no further details were given. In the other three studies, there was no significant difference in the mortality rates between the low‐dose versus standard‐dose arms (RR 2.04, 95% CI 0.70 to 5.93) (Analysis 1.14). In Slichter 2010, there was no difference between the low‐dose and high‐dose arms of the study (RR 1.33, 95% CI 0.50 to 3.54) (Analysis 1.15), or between the high‐dose versus standard‐dose arms of the study (RR 1.71, 95% CI 0.51 to 5.81) (Analysis 1.16).

No studies reported all‐cause mortality within 90 days.

Mortality secondary to bleeding within 30 and 90 days from the start of the study

No studies reported hazard ratios for mortality secondary to bleeding. Four of the six studies reported data on mortality secondary to bleeding within 30 days (Heddle 2009; Sensebe 2004; Slichter 2010; Tinmouth 2004). The mortality rate secondary to bleeding was very low. In all four studies, there was only one death attributable to bleeding (Slichter 2010); this was a participant in the high‐dose platelet transfusion arm who died secondary to a pulmonary haemorrhage (Analysis 1.17).

No studies reported mortality secondary to bleeding within 90 days.

Mortality secondary to infection within 30 and 90 days from the start of the study

No studies reported hazard ratios for mortality secondary to infection. Only one study reported data on mortality secondary to infection within 30 days (Tinmouth 2004). No deaths occurred in either study arm.

No studies reported mortality secondary to infection within 90 days.

Number of platelet transfusions per participant and number of platelet components per participant within 30 days from the start of the study

Six of the seven studies reported on the number of platelet transfusions per participant (Table 5). The duration of the study was unclear for Roy 1973, and was more than 30 days.

Table 5. Number of platelet transfusions and red cell transfusions

Study	Intervention	Number of participants	Number of platelet transfusion episodes/participant	P value	Total platelet utilisation	P value	Number of red cell transfusions/participant	P value
Low‐dose versus standard‐dose platelets (within 30 days)
Heddle 2009	Low dose 0.8 to 1.7 x 10¹¹/m²	58	Mean 9.5 ± SD 7.8	< 0.001	Number of donor exposures MD 4.1; 95% CI ‐4.3 to 12.4	0.335^a	Mean 6.1 ± SD 4.19^b	Not reported
	Standard dose 1.7 to 3.4 x 10¹¹/m²	61	Mean 5.3 ± SD 3.2				Mean 5.23 ± SD 3.58^b
Slichter 2010	Low dose 1.1 x 10¹¹ platelets/m² ± 25%	417	Median 5 IQR 3 to 9	< 0.001	Median 9.3 x 10¹¹ IQR 4.9 to 17.9	0.002	Median 4 IQR 2 to 8	0.62^a
	Standard dose 2.2 x 10¹¹ platelets/m² ± 25%	423	Median 3 IQR 2 to 6		Median 11.3 x 10¹¹ IQR 7.0 to 22.8		Median 4 IQR 2 to 8
Tinmouth 2004	Low dose 1.1 to 1.4 x 10¹¹/m²	56	Median 1 IQR 0.75 to 5	Not reported	Median 3 WBD units Range 0 to 49	Bayesian analysis 89% probability low‐dose platelets reduce total number of units transfused per participant	Median 4.5 Range 0 to 16	Not reported
	Standard dose 1.9 to 2.5 x 10¹¹/m²	55	Median 1 IQR 1 to 4		Median 5 WBD units Range 0 to 110		Median 4 Range 0 to 12
Low‐dose versus standard‐dose platelets (duration of study unclear)
Roy 1973 (Aged 0 to 9)	Low dose 1.1 to 1.3 x 10¹¹/m²	17	Mean 4.8	Not reported	Not reported	Not reported	Not reported	Not reported
	Standard dose 2.0 to 2.9 x 10¹¹/m²	28	Mean 5.5
Low‐dose versus high‐dose platelets (within 30 days)
Slichter 2010	Low dose 1.1 x 10¹¹ platelets/m² ± 25%	417	Median 5 IQR 3 to 9	< 0.001	Median 9.3 x 10¹¹ IQR 4.9 to 17.9	< 0.001	Median 4 IQR 2 to 8	0.90^a
	High dose 4.4 x 10¹¹ platelets/m² ± 25%	432	Median 3 IQR 2 to 6		Median 19.6 x 10¹¹ IQR 10.6 to 37.4		Median 4 IQR 2 to 8
Standard‐dose versus high‐dose platelets (within 30 days)
Sensebe 2004	Standard dose 1.9 x 10¹¹/m²	48	Median 3 Range 1 to 12	0.037	Mean 14.9 x 10¹¹	0.156^a	Not reported	Not reported
	High dose 3.9 x 10¹¹/m²	48	Median 2 Range 1 to 13		Mean 18.5 x 10¹¹
Slichter 2010	Standard dose 2.2 x 10¹¹ platelets/m² ± 25%	423	Median 3 IQR 2 to 6	0.09^a	Median 11.3 x 10¹¹ IQR 7.0 to 22.8	< 0.001	Median 4 IQR 2 to 8	0.70^a
	High dose 4.4 x 10¹¹ platelets/m² ± 25%	432	Median 3 IQR 2 to 6		Median 19.6 x 10¹¹ IQR 10.6 to 37.4		Median 4 IQR 2 to 8
Steffens 2002	Standard dose (Single apheresis unit)	28	Median 6 Range 1 to 14	Not reported	Mean 6.0 units Range 1 to 14	Not reported	Not reported	Not reported
	High dose (Triple apheresis unit)	26	Median 3.23 Range 1 to 8		Mean 9.7 units Range 3 to 23
Standard‐dose versus high‐dose platelets (duration of study unclear)
Roy 1973 (Aged 10 to 18)	Standard dose 1.7 x 10¹¹/m²	15	Mean 4	Not reported	Not reported	Not reported	Not reported	Not reported
	High dose 3.1 to 3.7 x 10¹¹/m²	2	Mean 7

CI: confidence interval
IQR: interquartile range
MD: mean difference
SD: standard deviation
WBD: whole blood derived

^aP value is not statistically significant.
^bunpublished data

We could not perform a meta‐analysis because the studies reported data in different ways (Table 5). Two of the three studies comparing a low‐dose versus standard‐dose platelet transfusion showed a significantly smaller number of platelet transfusion episodes in the standard‐dose arm (Heddle 2009; Slichter 2010). Only two of the four studies comparing a high‐dose versus standard‐dose platelet transfusion reported P values (Sensebe 2004; Slichter 2010). Sensebe 2004 showed a significant difference in the number of platelet transfusion episodes, whereas Slichter 2010 did not. Overall, it appears that higher platelet doses led to fewer platelet transfusion episodes.

Four of the seven studies reported on the number of platelet components per participant within 30 days; again, we could not perform a meta‐analysis because the studies reported the data in different ways (Table 5).

Two of the three studies comparing a low‐dose versus standard‐dose platelet transfusion strategy showed a significant reduction in the total amount of platelets used (Slichter 2010; Tinmouth 2004). Only two of the four studies comparing a high‐dose versus standard‐dose platelet transfusion reported P values (Sensebe 2004; Slichter 2010). Slichter 2010 showed a significant difference in the total platelet utilisation, whereas Sensebe 2004 did not. Overall, it appears that higher platelet doses led to a higher total platelet utilisation.

Number of red cell transfusions per participant and number of red cell units per participant within 30 days from the start of the study

Three of the seven studies reported on the number of red cell transfusions per participant (Heddle 2009; Slichter 2010; Tinmouth 2004) (Table 5). We could not perform a meta‐analysis because the studies reported the data in different ways. In Heddle 2009, the mean difference in red cell transfusions per thrombocytopenic day was reported and showed no significant difference between low‐dose versus standard‐dose platelet transfusions (Table 5). In Slichter 2010, no significant difference was seen between the various arms of the study in the number of red cell transfusions participants received (Table 5). In Tinmouth 2004, no formal statistical analysis was reported.

Platelet transfusion interval within 30 days from the start of the study

Five of the seven studies reported the platelet transfusion interval (Heddle 2009; Sensebe 2004; Slichter 2010; Steffens 2002; Tinmouth 2004) (Table 6). All of the studies that reported on statistical significance showed that there was a significantly shorter transfusion interval in the low‐dose arm compared to the standard‐dose arm (Table 6), and a significantly shorter transfusion interval in the standard‐dose arm compared to the high‐dose arm (Table 6).

Table 6. Platelet transfusion interval

Study	Intervention	Number of participants	Platelet transfusion interval/participant (days)	P value
Low‐dose versus standard‐dose platelets (within 30 days)
Heddle 2009	Low dose 0.8 to 1.7 x 10¹¹/m²	58	Mean 1.8 SD 1.1	< 0.001
Heddle 2009	Standard dose 1.7 to 3.4 x 10¹¹/m²	61	Mean 2.8 SD 1.8	< 0.001
Slichter 2010	Low dose 1.1 x 10¹¹ platelets/m² ± 25%	417	Median 1.1 IQR 0.7 to 2.1	< 0.001
Slichter 2010	Standard dose 2.2 x 10¹¹ platelets/m² ± 25%	423	Median 1.9 IQR 0.9 to 3.1	< 0.001
Tinmouth 2004	Low dose 1.1 to 1.4 x 10¹¹/m²	56	Median 2 Range 1 to 4.5	Not reported
Tinmouth 2004	Standard dose 1.9 to 2.5 x 10¹¹/m²	55	Median 3 Range 1 to 5	Not reported
Low‐dose versus high‐dose platelets (within 30 days)
Slichter 2010	Low dose 1.1 x 10¹¹ platelets/m² ± 25%	417	Median 1.1 IQR 0.7 to 2.1	< 0.001
Slichter 2010	High dose 4.4 x 10¹¹ platelets/m² ± 25%	432	Median 2.9 IQR 1.2 to 4.7	< 0.001
High‐dose versus standard‐dose platelets (within 30 days)
Sensebe 2004	Standard dose 1.9 x 10¹¹/m²	48	Median time 2.6 95% CI 1.9 to 2.7	0.001
Sensebe 2004	High dose 3.9 x 10¹¹/m²	48	Median time 4.0 95% CI 3.5 to 4.7	0.001
Slichter 2010	Standard dose 2.2 x 10¹¹ platelets/m² ± 25%	423	Median 1.9 IQR 0.9 to 3.1	< 0.001
Slichter 2010	High dose 4.4 x 10¹¹ platelets/m² ± 25%	432	Median 2.9 IQR 1.2 to 4.7	< 0.001
Steffens 2002	Standard dose (Single apheresis unit)	28	3.1 days	Not reported
Steffens 2002	High dose (Triple apheresis unit)	26	4.9 days	Not reported

CI: confidence interval
IQR: interquartile range

SD: standard deviation

Proportion of patients requiring additional interventions to stop bleeding (surgical; medical, e.g. tranexamic acid; other blood products, e.g. fresh frozen plasma, cryoprecipitate) within 30 days from the start of the study

None of the seven studies reported additional interventions to stop bleeding.

Overall survival within 30, 90, and 180 days from the start of the study

None of the seven studies reported overall survival rates.

Proportion of participants achieving complete remission within 30 and 90 days from the start of the study

None of the seven studies reported complete remission rates.

Total time in hospital within 30 days from the start of the study

None of the seven studies reported the length of time that the participants were in hospital.

Adverse effects of treatments within 30 days from the start of the study

Transfusion reactions

Only Slichter 2010 reported on transfusion reactions secondary to platelet transfusions (study data shown in Analysis 1.18), and documented a large number of events that occurred during or within four hours of a platelet transfusion. Wheezing was the only adverse event that occurred more frequently in the high‐dose arm compared to the standard‐dose arm (RR 6.85, 95% CI 1.57 to 29.98). However, there was no significant difference in the frequency of wheezing when the low‐dose arm was compared with the high‐dose arm (RR 0.52, 95% CI 0.21 to 1.27), therefore it is possible that this is a type I error (i.e. a false positive). The study authors have now published an analysis based on a proportion of transfusions in which there was no missing data (5034 platelet transfusions to 1102 participants from a total of 8158 platelet transfusions to 1231 participants) (Slichter 2010). In a multivariate analysis taking into account platelet source, platelet storage duration, ABO matching, sex of recipient, number of previous transfusions, type of treatment, and age of participants, participants assigned to high‐dose platelet components were more likely to experience any transfusion‐related adverse event than participants assigned to standard‐dose or low‐dose component groups (odds ratio for high‐dose versus standard‐dose, 1.50, 95% CI 1.10 to 2.05; three‐group comparison P = 0.02).

Thromboembolic disease

Only one study reported on thromboembolic disease (Slichter 2010), documenting three episodes of venous thromboembolism in the low‐dose platelet transfusion arm and none in the standard‐dose or high‐dose platelet transfusion arms. There was no significant difference between the arms of the study in the frequency of thromboembolic disease (study data shown in Analysis 1.19). Slichter 2010 also reported veno‐occlusive disease of the liver, with six cases in the low‐dose arm, five cases in the standard‐dose arm, and two cases in the high‐dose arm. There was no significant difference in the frequency of veno‐occlusive disease between the low‐dose and standard‐dose arms of the study, or between the standard‐dose and high‐dose arms of the study.

Human leukocyte antigen (HLA) antibodies/platelet refractoriness

None of the seven studies reported on the development of HLA antibodies or platelet refractoriness.

Quality of life (as defined by the individual studies)

None of the seven studies reported quality of life.

Prespecified subgroup analyses

Presence of fever

None of the studies commented on an association between fever and bleeding risk.

Underlying disease

One study commented on disease subgroup and bleeding risk (Tinmouth 2004).

Number of participants with at least one clinically significant bleeding episode (within 30 days from the start of the study)

In Tinmouth 2004, eight out of 34 participants with acute leukaemia had significant bleeding, whereas only two out of 77 participants receiving an autologous transplant (myeloma, non‐Hodgkin's lymphoma, and Hodgkin's lymphoma) had significant bleeding (both of these participants bled when the platelet counts were greater than 100 x 10⁹/L).

Type of treatment

Two of the studies commented on treatment subgroup and bleeding risk (Slichter 2010; Tinmouth 2004).

Number of participants with at least one clinically significant bleeding episode (within 30 days from the start of the study)

In Tinmouth 2004, eight out of 34 participants receiving chemotherapy had significant bleeding, whereas only two out of 77 participants receiving an autologous transplant had significant bleeding (both of these participants bled when the platelet counts were greater than 100 x 10⁹/L). In Slichter 2010, bleeding of WHO grade 2 or greater occurred in 79% of recipients of allogeneic stem cell transplants (413 participants), 73% of participants with haematological cancers receiving chemotherapy (228 participants), and 57% of participants undergoing autologous or syngeneic stem cell transplantation (245 participants).

Only Tinmouth 2004 reported the number of participants who bled for each treatment category for each treatment arm (Analysis 1.20).

Total number of days on which bleeding occurred per participant (within 30 days from the start of the study)

In Tinmouth 2004, the total number of days on which bleeding occurred per participant was mean 1.5 days in the low‐dose arm versus 2.4 days in the standard‐dose arm for participants receiving chemotherapy. In participants receiving an autologous stem cell transplant, the total number of days on which bleeding occurred per participant was mean 0.2 days in the low‐dose arm versus 0.6 days in the standard‐dose arm. This included minor bleeding (unpublished data provided by the author).

Age of participant

One study included both children and adults and commented on bleeding risk and the age of the participant (Slichter 2010). This study analysed 1272 participants, including 200 paediatric participants, who had at least one study platelet transfusion. Similar numbers of patients were enrolled in each of the paediatric groups: 0 to 5 years (N = 66), 6 to 12 years (N = 69), and 13 to 18 years (N = 65), while the majority of participants were adults aged 19 years or older (N = 1072). The minimum age was 9 months, and the maximum age was 83 years.

Number of participants with at least one clinically significant bleeding episode (within 30 days from the start of the study)

In Slichter 2010, younger children were significantly more likely than adults to have at least one day of grade 2 or higher bleeding while on study (86%, 88%, 77%, and 67%, for ages 0 to 5, 6 to 12, 13 to 18, and 19+ years, respectively) (P < 0.001). The effect of age on the bleeding outcome was not affected by the assigned platelet dose, according to the study authors.

Total number of days on which bleeding occurred per participant (within 30 days from the start of the study)

In Slichter 2010, the median number of days with WHO grade 2 or higher bleeding was 3 (interquartile range (IQR) 1 to 6.5) in children aged 0 to 5; 3 (IQR 1 to 6) in children aged 6 to 12; and 3 (IQR 0 to 9.5) in children aged 13 to 18 versus 1 (IQR 0 to 4) in adults (P < 0.001). The effect of age on the bleeding outcome was not affected by the assigned platelet dose, according to the study authors.

Number of participants with at least one episode of severe or life‐threatening bleeding (within 30 days from the start of the study)

In Slichter 2010, the percentage of participants with WHO grade 3 or higher bleeding was 6%, 18%, 20%, and 10% for ages 0 to 5, 6 to 12, 13 to 18, and 19+ years, respectively (data derived from figure).

Time to first bleeding episode from the start of the study (within 30 days from the start of the study)

In Slichter 2010, the time to first episode of WHO grade 2 or higher bleeding (days) was median 3.0, 5.5, 6.0, and 11.0 for the four age groups, respectively; P < 0.001 in participants receiving a haematopoietic stem cell transplant. The effect of age on the bleeding outcome was not affected by the assigned platelet dose, according to the study authors.

Platelet transfusion threshold

Three of the six included studies used a threshold of 10 x 10⁹/L (Slichter 2010; Steffens 2002; Tinmouth 2004), and one of the studies used a threshold of 10 x 10⁹/L at the majority of study sites (Heddle 2009). One of the studies used a platelet transfusion threshold of 20 x 10⁹/L (Sensebe 2004), and one of the studies used a platelet count transfusion threshold of 25 x 10⁹/L (Roy 1973). Of the two studies that used a different platelet count threshold (Roy 1973; Sensebe 2004), only data from one of these studies, Sensebe 2004, were incorporated into any of the meta‐analyses. Exclusion of data from this study had no effect on the results of the meta‐analyses (Analysis 1.1; Analysis 1.17).

Discussion

The main objective of this review of prophylactic platelet transfusions was to answer the question what is the optimal prophylactic platelet dose to prevent thrombocytopenic bleeding in people with haematological disorders undergoing myelosuppressive chemotherapy or stem cell transplantation.

Summary of main results

Seven RCTs met our inclusion criteria for this review; all had data available. Five compared a low‐dose versus standard‐dose platelet transfusion, one compared a low‐dose versus high‐dose platelet transfusion, and four compared a standard‐dose versus a high‐dose platelet transfusion strategy.

These trials were carried out over a 42‐year time period and enrolled 1908 participants from fairly comparable patient populations. All of these studies contained separate data for each arm and could be critically appraised. One of these studies was conducted over an uncertain time period that included more than one course of chemotherapy; because of this none of the study data could be included into any of the analyses (Roy 1973).

The findings of the review led to the following main conclusions:

Overall, a low‐dose prophylactic platelet transfusion policy appears to be as effective as a standard‐dose or high‐dose prophylactic platelet transfusion policy with regard to rates of clinically significant bleeding. This included:

Number of participants with a clinically significant bleeding event (WHO grade 2 or above)
Number of days with clinically significant bleeding per participant
Number of participants with severe or life‐threatening bleeding
Time to first clinically significant bleeding episode

We saw this effect irrespective of the participant's age, underlying treatment, or diagnosis.

There was a clear increase in the number of platelet transfusion episodes in the low‐dose group; however there was a significant reduction in the total number of platelets used per participant in the low‐dose group. A high‐dose transfusion strategy led to a longer transfusion interval than the standard dose strategy; however, in the largest study (Slichter 2010), this did not lead to an increase in the number of transfusion episodes.

There is some evidence that a high‐dose transfusion strategy may lead to an increase in transfusion‐related adverse events compared to a standard‐ or low‐dose strategy.

There was no evidence of any difference in overall mortality between treatment arms.

Quality of life was not reported for any of the studies.

Overall completeness and applicability of evidence

The large number of participants within these studies provided strong evidence of no difference in the proportion of participants with bleeding between low‐dose, standard‐dose, and high‐dose platelet transfusions. This is reflected in the narrow confidence intervals around the point estimates.

Although Heddle 2009 and Slichter 2010 both used a WHO grading system for bleeding, the categorisation of bleeding varied between the studies. In Slichter 2010, less severe bleeding was categorised as grade 2. For example, in Heddle 2009 epistaxis that lasted for more than an hour or required packing was classed as grade 2 bleeding, whereas in Slichter 2010 if a participant had epistaxis that lasted for more than 30 minutes in any given 24‐hour period, it was classified as grade 2 bleeding. Also, in Heddle 2009, ecchymoses larger than 10 cm in size were classified as grade 2 bleeding, whereas in Slichter 2010 purpura greater than 2.54 cm (1 inch) in diameter were classified as grade 2 bleeding.

We only included data from Akay 2015 in the number of participants with bleeding; however, no participants in either of the study arms had bleeding that was greater than WHO grade 1 within 48 hours of the first platelet transfusion.

We did not include data from Roy 1973 within any of the analyses because the time frame over which data were reported was very unclear; the study was not conducted over one course of chemotherapy and appeared to be longer than the prespecified time frame of 30 days from the start of the study for all bleeding and platelet transfusion outcomes (the only outcomes that Roy 1973 reported). Also, assessment of bleeding was not performed on a daily basis during the study, but only for the 24 hours following each platelet transfusion.

Data from Steffens 2002 was limited because the study has only been published as an abstract, and the authors were unable to provide any additional information.

Five of the seven studies reported the number of platelets in the platelet component (Heddle 2009; Roy 1973; Sensebe 2004; Slichter 2010; Tinmouth 2004), and therefore we could approximate the doses used in these studies to the doses in Slichter 2010 using an average body surface area for adults (Sacco 2010) and children (Sharkey 2001). The only study that changed the dose categorisation using these estimates from the study's original definition of low dose, standard dose, or high dose was Roy 1973. However, we did not include Roy 1973 in any of this review's analyses.

Quality of the evidence

GRADE assessment

The GRADE quality of evidence was moderate due to a serious risk of bias for:

Number of participants with at least one clinically significant bleeding event up to 30 days from study entry (low dose versus standard dose; low dose versus high dose; and high dose versus standard dose)

The GRADE quality of evidence was low due to a serious risk of imprecision and a serious risk of bias for:

Number of days on which bleeding occurred per participant up to 30 days from study entry (low dose versus standard dose and high dose versus standard dose)
Number of participants with WHO grade 3 or 4 bleeding up to 30 days from study entry (low dose versus standard dose; low dose versus high dose; and high dose versus standard dose)
Mortality from all causes up to 30 days from study entry (low dose versus standard dose; low dose versus high dose; and high dose versus standard dose)

We did not downgrade the quality of evidence due to a serious risk of heterogeneity because:

Participants within the studies were from similar patient groups.
This review assessed all platelet doses within the review against the low dose, standard dose, and high dose defined in this review and based on the doses within the Slichter 2010 study; we have reported these adjusted doses in Table 1.
Two studies used a different platelet count threshold to the other studies (Roy 1973; Sensebe 2004). However, we only incorporated data from Sensebe 2004 into any of the meta‐analyses. Exclusion of data from this study had no effect on the results of the meta‐analyses (Analysis 1.1; Analysis 1.17).

Risk of bias assessment

The ability to assess the quality of the evidence due to risk of bias was limited due to most of the studies not reporting study methodology in adequate detail. For example, only two of the seven studies reported allocation concealment as adequate (Heddle 2009; Tinmouth 2004), and and only three of the seven studies reported sequence generation as adequate (Heddle 2009; Slichter 2010; Tinmouth 2004).

Two studies that reported adequate blinding of the bleeding assessor documented compromise to the blinding process of participants and clinicians due to the different volumes of platelets to be transfused (Heddle 2009; Slichter 2010). Therefore, none of the studies reported adequate blinding of participants or clinicians.

Two studies were at high risk of bias due to an imbalance in the amount of missing data between the arms of the study (Heddle 2009; Slichter 2010).

We considered three of the seven studies as at high risk of bias due to an imbalance in protocol deviations between the different arms of the studies (Heddle 2009; Slichter 2010; Tinmouth 2004).

Potential biases in the review process

There were no obvious biases within the review process. We conducted a wide search, carefully assessed the relevance of each paper identified, and placed no restrictions on the language in which the paper was originally published. We included studies that had not been published or had only been published as an abstract and were not expected to be published in full. In this review, one study fulfilled this criterion (Steffens 2002).

We did not perform a formal assessment of potential publication bias (small‐trial bias), because we included only seven trials within this review.

Agreements and disagreements with other studies or reviews

One platelet transfusion review has recently been published in this area (Kumar 2014).

Kumar 2014 performed a systematic review of the use of platelet transfusions in common clinical settings, including the comparison of different platelet transfusion doses. Their review identified five studies with "analysable data" (Heddle 2009; Roy 1973; Sensebe 2004; Slichter 2010; Tinmouth 2004).

Our review agreed with the Kumar 2014 review, both reviews found that there was no difference in the risk of a significant bleeding event between a low‐dose and standard‐dose and high‐dose and standard‐dose platelet transfusion policy. Nor was any difference found in all‐cause mortality or mortality due to bleeding. Our review agreed with the Kumar review in finding that participants in the low‐dose platelet transfusion group underwent a greater number of platelet transfusion episodes than participants in the standard‐dose group, however overall platelet usage was lower.

Our review is more comprehensive than the Kumar 2014 review. We identified a study not previously reviewed (Akay 2015), as well as including study data from a study only published as an abstract (Steffens 2002). We included outcomes not assessed within the Kumar 2014 review. These included: time to first bleeding episode; total number of days on which bleeding occurred per participant; number of participants with severe or life‐threatening bleeding; number of days with clinically significant bleeding; overall survival; proportion of participants achieving complete remission; time in hospital; number of platelet transfusions and platelet components; number of red cell transfusions and red cell components; adverse effects of treatments (for example transfusion reactions, thromboembolism, transfusion‐transmitted infection, development of platelet antibodies or platelet refractoriness); and quality of life. The Kumar 2014 review authors performed meta‐analyses when the included studies had different durations of observation (for example one course of chemotherapy, in Heddle 2009, Sensebe 2004, Slichter 2010, and Tinmouth 2004, versus several courses of chemotherapy, in Roy 1973. Their review did not perform a detailed assessment of the risk of bias of the included studies, nor did it consider reasons for heterogeneity between the included studies. We performed a detailed quality assessment of all identified studies and highlighted their weaknesses and shortcomings.

Figure 1

Study flow diagram.

Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Analysis 1.1

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 1 Number of participants with at least one clinically significant bleeding event ‐ low dose versus standard dose.

Analysis 1.2

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 2 Number of participants with at least one clinically significant bleeding event ‐ low dose versus high dose.

Analysis 1.3

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 3 Number of participants with at least one clinically significant bleeding event ‐ high dose versus standard dose.

Analysis 1.4

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 4 Number of days with clinically significant bleeding per participant low dose versus standard dose (fixed effect).

Analysis 1.5

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 5 Number of days with clinically significant bleeding per participant low dose versus standard dose (random effects).

Analysis 1.6

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 6 Number of participants with WHO Grade 3 or 4 bleeding ‐ low dose versus standard dose.

Analysis 1.7

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 7 Number of participants with WHO Grade 3 or 4 bleeding ‐ low dose versus high dose.

Analysis 1.8

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 8 Number of participants with WHO Grade 3 or 4 bleeding ‐ high dose versus standard dose.

Analysis 1.9

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 9 Number of participants with WHO Grade 4 bleeding ‐ low dose versus standard dose.

Analysis 1.10

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 10 Number of participants with WHO Grade 4 bleeding ‐ low dose versus high dose.

Analysis 1.11

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 11 Number of participants with WHO Grade 4 bleeding ‐ high dose versus standard dose.

Analysis 1.12

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 12 Number of participants with bleeding requiring a red cell transfusion.

Analysis 1.13

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 13 Number of participants with bleeding causing cardiovascular compromise.

Analysis 1.14

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 14 Mortality from all causes ‐ low dose vs. standard dose.

Analysis 1.15

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 15 Mortality from all causes ‐ low dose vs. high dose.

Analysis 1.16

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 16 Mortality from all causes ‐ high dose vs. standard dose.

Analysis 1.17

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 17 Mortality from bleeding.

Analysis 1.18

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 18 Number of participants with platelet transfusion reactions.

Analysis 1.19

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 19 Thromboembolic disease.

Analysis 1.20

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 20 Number of participants with a significant bleeding episode ‐ autologous stem cell transplant versus intensive chemotherapy.

Analysis 1.21

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 21 Number of participants with a significant bleeding episode ‐ autologous stem cell transplant versus allogeneic stem cell transplant.

Analysis 1.22

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 22 Time to first significant bleeding event.

Prophylactic platelet transfusions with a low‐dose schedule compared to prophylactic platelet transfusions with a standard‐dose schedule for prevention of haemorrhage after chemotherapy and stem cell transplantation
Patient or population: People with a haematological disorder Settings: After chemotherapy or a stem cell transplant Intervention: Prophylactic platelet transfusions with low‐dose schedule versus standard‐dose schedule
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Prophylactic platelet transfusions with standard‐dose schedule	Prophylactic platelet transfusions with low‐dose schedule
Number of participants with at least 1 clinically significant bleeding event up to 30 days from study entry	605 per 1000	629 per 1000 (575 to 684)	RR 1.04 (0.95 to 1.13)	1170 (4 studies)	⊕⊕⊕⊝ moderate¹
Number of days on which bleeding occurred per participant up to 30 days from study entry	The mean number of days with clinically significant bleeding per participant was 0.17 days lower (0.51 lower to 0.17 higher) (fixed effect)			230 (2 studies)	⊕⊕⊝⊝ low^1,2	We could not incorporate the largest study (840 participants) into the meta‐analysis (Slichter 2010); this also showed no difference in the number of days of bleeding between study arms (Table 3)
Number of participants with WHO grade 3 or 4 bleeding up to 30 days from study entry	91 per 1000	122 per 1000 (83 to 176)	RR 1.33 (0.91 to 1.92)	1059 (3 studies)	⊕⊕⊝⊝ low^1,2
Time to first bleeding episode (days)	Not estimable	Not estimable	Not estimable	959 (2 studies)	See comment	The 2 studies reported the outcome in different formats, and the results could not be integrated into a meta‐analysis (Table 4). The largest study (840 participants) showed no difference between study arms (Slichter 2010)
Number of platelet transfusions per participant up to 30 days from study entry	Not estimable	Not estimable	Not estimable	1070 (3 studies)	See comment	The 3 studies reported the outcome in different formats, and results could not be integrated into a meta‐analysis (Table 5). 2 of the 3 studies (959 participants) showed that a low‐dose transfusion strategy led to significantly more transfusion episodes (Heddle 2009; Slichter 2010)
Mortality from all causes up to 30 days from study entry	9 per 1000	19 per 1000 (6 to 55)	RR 2.04 (0.70 to 5.93)	1070 (3 studies)	⊕⊕⊝⊝ low^1,2
Quality of life ‐ not reported	Not estimable	Not estimable	Not estimable	‐	See comment	None of the studies reported quality of life
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ The studies were at risk of bias. Sources of bias were due to lack of blinding, protocol deviation, and attrition bias. The quality of the evidence was downgraded by 1 due to risk of bias. ² The number of cases was very low, the quality of the evidence was downgraded by 1 due to imprecision.

Prophylactic platelet transfusion with low‐dose schedule versus high‐dose schedule for preventing bleeding in people with haematological disorders after chemotherapy or stem cell transplantation
Patient or population: People with a haematological disorder Settings: After chemotherapy or a stem cell transplant Intervention: Prophylactic platelet transfusions with a low‐dose schedule versus high‐dose schedule
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Prophylactic platelet transfusions with a high‐dose schedule	Prophylactic platelet transfusions with a low‐dose schedule
Number of participants with at least 1 clinically significant bleeding event up to 30 days from study entry	699 per 1000	713 per 1000 (650 to 776)	RR 1.02 (0.93 to 1.11)	849 (1 study)	⊕⊕⊕⊝ moderate¹
Number of days on which bleeding occurred per participant up to 30 days from study entry	Not estimable	Not estimable	Not estimable	849 (1 study)	See comment	There was no significant difference between the study arms, according to the study authors (Table 3)
Number of participants with WHO grade 3 or 4 bleeding up to 30 days from study entry	100 per 1000	119 per 1000 (82 to 170)	RR 1.20 (0.82 to 1.77)	849 (1 study)	⊕⊕⊝⊝ low^1,2
Time to first bleeding episode	Not estimable	Not estimable	Not estimable	849 (1 study)	See comment	There was no significant difference between the study arms, according to the study authors (Table 4)
Mortality from all causes up to 30 days from study entry	16 per 1000	22 per 1000 (8 to 57)	RR 1.33 (0.50 to 3.54)	849 (1 study)	⊕⊕⊝⊝ low^1,2
Number of platelet transfusions per participant	Not estimable	Not estimable	Not estimable	849 (1 study)	See comment	There was a significant increase in the number of platelet transfusions between the study arms, according to the study authors (Table 5)
Quality of life ‐ not reported	Not estimable	Not estimable	Not estimable	‐	See comment	None of the studies reported quality of life
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ The study was at risk of bias. Sources of bias were due to lack of blinding, protocol deviation, and attrition bias. The quality of the evidence was downgraded by 1 due to risk of bias. ² The number of cases was very low, the quality of the evidence was downgraded by 1 due to imprecision.

Prophylactic platelet transfusion with high‐dose schedule versus standard‐dose schedule for preventing bleeding in participants with haematological disorders after chemotherapy or stem cell transplantation
Patient or population: People with a haematological disorder Settings: After chemotherapy or a stem cell transplant Intervention: Prophylactic platelet transfusions with a high‐dose schedule versus standard‐dose schedule
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Prophylactic platelet transfusions with standard‐dose schedule	Prophylactic platelet transfusions with a high‐dose schedule
Number of participants with at least 1 clinically significant bleeding event up to 30 days from study entry	624 per 1000	637 per 1000 (581 to 693)	RR 1.02 (0.93 to 1.11)	951 (2 studies)	⊕⊕⊕⊝ moderate¹
Number of days on which bleeding occurred per participant up to 30 days from study entry	Not estimable	Not estimable	Not estimable	855 (1 study)	See comment	There was no significant difference between the study arms, according to the study authors (Table 3)
Number of participants with WHO grade 3 or 4 bleeding up to 30 days from study entry	90 per 1000	100 per 1000 (66 to 151)	RR 1.11 (0.73 to 1.68)	855 (1 study)	⊕⊕⊝⊝ low^1,2
Time to first bleeding episode (days)	Not estimable	Not estimable	Not estimable	855 (1 study)	See comment	There was no significant difference between the study arms, according to the study authors (Table 4)
Number of platelet transfusions per participant up to 30 days from study entry	Not estimable	Not estimable	Not estimable	1005 (3 studies)	See comment	The studies reported the results in different formats, therefore the results could not be integrated (Table 5). The largest study (855 participants) showed no difference in the number of platelet transfusions between a standard‐ and high‐dose transfusion regimen (Slichter 2010)
Mortality from all causes up to 30 days from study entry	9 per 1000	16 per 1000 (5 to 55)	RR 1.71 (0.51 to 5.81)	855 (1 study)	⊕⊕⊝⊝ low^1,2	The number of deaths was very low in both study arms
Quality of life ‐ not reported	Not estimable	Not estimable	Not estimable	‐	See comment	None of the studies reported quality of life
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ The studies were at risk of bias. Sources of bias were due to lack of blinding, protocol deviation, and attrition bias. The quality of the evidence was downgraded by 1 due to risk of bias. ² The number of cases was very low, the quality of the evidence was downgraded by 1 due to imprecision.

Table 1. Characteristics of studies

Study	Participants	Number	Intervention	Intervention adjusted to BSA ranges of Slichter 2010^a	Platelet count threshold for prophylactic transfusions	Duration of study	Type of platelet product	Primary outcome
Akay 2015	Adults with haematological malignancies	100	"Low dose" 3‐unit pooled product, or 1/2‐unit apheresis product "Standard dose" 6‐unit pooled product or single‐unit apheresis product	Actual dose not reported	Plt count ≤ 10 x 10⁹/L	Not reported	Apheresis and pooled platelet products	Not reported
Heddle 2009	Adults with hypoproliferative thrombocytopenia	129	(1.5 to 3.0 x 10¹¹ platelets/product) versus (3.0 to 6.0 x 10¹¹ platelets/product)	Low dose 0.8 to 1.7 x 10¹¹/m² BSA versus Standard dose 1.7 to 3.4 x 10¹¹/m² BSA	Depended on local transfusion trigger. Usually 10 x 10⁹/L	Mean of 14 to 15.8 days	Apheresis and pooled platelet products	Occurrence of a WHO grade 2 bleed or above
Roy 1973	Children with acute leukaemia	62	(0.5 x 10¹¹/10 kg) versus (0.9 to 1.1 x 10¹¹/10 kg)^b	0 to 4 years Low dose 1.1 x 10¹¹/m² BSA versus Standard dose 2.0 to 2.4 x 10¹¹/m² BSA 5 to 9 years Low dose 1.3 x 10¹¹/m² BSA versus Standard dose 2.4 to 2.9 x 10¹¹/m² BSA 10 to 18 years Standard dose 1.7 x 10¹¹/m² BSA versus High dose 3.1 to 3.7 x 10¹¹/m² BSA	Plt count ≤ 25 x 10⁹/L	Follow‐up for 24 hours post platelet transfusion	ABO‐identical pooled products	Not reported
Sensebe 2004	People with acute leukaemia or undergoing autologous SCT	101	(0.5 x 10¹¹/10 kg) versus (1.0 x 10¹¹/10 kg)^c	Standard dose 1.9 x 10¹¹/m² BSA versus High dose 3.9 x 10¹¹/m² BSA	Plt count < 20 x 10⁹/L	Not stated	Leucodepleted ABO‐compatible apheresis	Time between first transfusion and daily platelet count reaching 20 x 10⁹/L
Slichter 2010	People of any age receiving SCT or myelosuppressive chemotherapy	1351	(1.1 x 10¹¹/m² BSA ± 25%) versus (2.2 x 10¹¹/m² BSA ± 25%) versus (4.4 x 10¹¹/m² BSA ± 25%)	Low dose (1.1 x 10¹¹/m² BSA) (range 0.8 to 1.4 x 10¹¹/m² BSA) versus Intermediate dose (2.2 x 10¹¹/m² BSA) (range 1.7 to 2.8 x 10¹¹/m² BSA) versus High dose (4.4 x 10¹¹/m² BSA) (range 3.3 to 5.5 x 10¹¹/m² BSA)	Plt count ≤ 10 x 10⁹/L	Mean number of days 19.1	Apheresis and pooled platelet products	Grade 2 or higher bleeding
Steffens 2002	People age > 16 yrs with AML or undergoing an allogeneic SCT	54	(single apheresis unit) versus (triple apheresis unit)	Actual dose not reported. Study definition was standard versus high dose	Plt count ≤ 10 x 10⁹/L	Median time for people with AML 25.1 to 25.8 days. Median time for SCT 14.1 to 15.9 days	Apheresis	Not reported
Tinmouth 2004	People age > 16 yrs with acute leukaemia or receiving an autologous SCT	111	(1.9 to 2.5 x 10¹¹ platelets/transfusion) versus (3.4 to 4.4 x 10¹¹ platelets/transfusion)	Low dose 1.1 to 1.4 x 10¹¹/m² BSA versus Standard dose 1.9 to 2.5 x 10¹¹/m² BSA	Plt count < 10 x 10⁹/L	Median time 15 days	Leucodepleted random‐donor pooled platelets (PRP method)	Bayesian design. Lower dose of platelets would be safe and effective in preventing major bleeding events and would decrease total utilisation of platelets
AML: acute myeloid leukaemia BSA: body surface area Plt: platelet PRP: platelet‐rich plasma SCT: stem cell transplant ^a For adult participants, the average body surface area (BSA) was assumed to be 1.79 using data from Sacco 2010. In all studies containing adult participants we used this number to compare study doses to the Slichter 2010 study. For Roy 1973, the BSA was calculated for each age group: 0 to 4 years, 5 to 9 years, and 10 to 18 years. Approximate body weights were estimated for each age group and the BSA estimated using Sharkey 2001. The approximate weights were 0 to 4 years (13.5 kg), 5 to 9 years (23.3 kg), and 10 to 18 years (50.9 kg). These equate to approximate BSA of 0.62 (0 to 4 years), 0.87 (5 to 9 years), and 1.5 (10 to 15 years). ^b The original study stated that "higher dose" platelet transfusions = 0.06 to 0.07 units/lb and "lower dose" platelet transfusions = 0.03 units/lb (Roy 1973). The average platelet yield reported in the study was 7 x 10¹⁰ platelets per unit. Therefore "higher dose" platelets = 0.9 to 1.1 x 10¹¹platelets/10 kg and "lower dose" platelets = 0.46 x 10¹¹ platelets/10 kg. ^c Mean weight in both arms of the study was 69 kg.

Table 1. Characteristics of studies

Table 2. Assessment and grading of bleeding within the included studies

Study	Bleeding primary outcome of study	Method of bleeding assessment reported	Frequency of assessment of bleeding	Bleeding severity scale used	RBC usage part of bleeding severity assessment	RBC transfusion policy
Akay 2015	No	No	For 48 hours after first platelet transfusion	WHO 1979	No	Not reported
Heddle 2009	Yes	Yes	Daily	Adapted WHO	Yes	Local practice at each centre (unpublished)
Slichter 2010	Yes	Yes	Daily	Adapted WHO	Yes	Local practice at each centre
Tinmouth 2004	Yes	Yes	Daily	Adapted Rebulla	No	Not reported
Roy 1973	Not reported	Yes	For 24 hours after each platelet transfusion	Study specific	No	Not reported
Sensebe 2004	No	No	Daily	WHO 1979	No	Not reported
RBC: red blood cell WHO: World Health Organization

Table 2. Assessment and grading of bleeding within the included studies

Table 3. Number of days with a clinically significant bleeding event/participant

Study	Low dose		P value Low dose vs standard dose	Standard dose		P value Standard dose vs high dose	High dose
Study	Number of participants	Days	P value Low dose vs standard dose	Number of participants	Days	P value Standard dose vs high dose	Number of participants	Days
Heddle 2009	58	Mean 1.8 ± SD 3.23^a	Not reported	61	Mean 1.2 ± SD 2.02^a	NA	NA	NA
Slichter 2010	417	Median 1 IQR 0 to 4	0.9^b	423	Median 1 IQR 0 to 4	0.91^b	432	Median 1 IQR 0 to 4
Tinmouth 2004^c	56	Mean 0.375 ± SD 0.93^a	Not reported	55	Mean 0.65 ± SD 1.0^a	NA	NA	NA
IQR: interquartile range NA: not applicable SD: standard deviation ^aunpublished data ^bP value is not statistically significant. ^cTo improve comparison with the other studies, significant bleeding in this analysis was the number of days with bleeding that required a therapeutic platelet transfusion or local intervention. This differs from the study's definition of significant bleeding.

Table 3. Number of days with a clinically significant bleeding event/participant

Table 4. Time to first clinically significant bleeding event

Study	Low dose		P value Low dose vs standard dose	Standard dose		P value Standard dose vs high dose	High dose
Study	Number of participants	Days	P value Low dose vs standard dose	Number of participants	Days	P value Standard dose vs high dose	Number of participants	Days
Heddle 2009	58	Mean 11.2 ± SD 9.18^a	Not reported	61	Mean 9.7 ± SD 8.39^a	NA	NA	NA
Slichter 2010	417	Median 7 IQR 3 to 18	0.85^b	423	Median 7 IQR 3 to 19	0.66^b	432	Median 8 IQR 3 to 19
IQR: interquartile range NA: not applicable SD: standard deviation ^aunpublished data ^bP value is not statistically significant.

Table 4. Time to first clinically significant bleeding event

Table 5. Number of platelet transfusions and red cell transfusions

Study	Intervention	Number of participants	Number of platelet transfusion episodes/participant	P value	Total platelet utilisation	P value	Number of red cell transfusions/participant	P value
Low‐dose versus standard‐dose platelets (within 30 days)
Heddle 2009	Low dose 0.8 to 1.7 x 10¹¹/m²	58	Mean 9.5 ± SD 7.8	< 0.001	Number of donor exposures MD 4.1; 95% CI ‐4.3 to 12.4	0.335^a	Mean 6.1 ± SD 4.19^b	Not reported
	Standard dose 1.7 to 3.4 x 10¹¹/m²	61	Mean 5.3 ± SD 3.2				Mean 5.23 ± SD 3.58^b
Slichter 2010	Low dose 1.1 x 10¹¹ platelets/m² ± 25%	417	Median 5 IQR 3 to 9	< 0.001	Median 9.3 x 10¹¹ IQR 4.9 to 17.9	0.002	Median 4 IQR 2 to 8	0.62^a
	Standard dose 2.2 x 10¹¹ platelets/m² ± 25%	423	Median 3 IQR 2 to 6		Median 11.3 x 10¹¹ IQR 7.0 to 22.8		Median 4 IQR 2 to 8
Tinmouth 2004	Low dose 1.1 to 1.4 x 10¹¹/m²	56	Median 1 IQR 0.75 to 5	Not reported	Median 3 WBD units Range 0 to 49	Bayesian analysis 89% probability low‐dose platelets reduce total number of units transfused per participant	Median 4.5 Range 0 to 16	Not reported
	Standard dose 1.9 to 2.5 x 10¹¹/m²	55	Median 1 IQR 1 to 4		Median 5 WBD units Range 0 to 110		Median 4 Range 0 to 12
Low‐dose versus standard‐dose platelets (duration of study unclear)
Roy 1973 (Aged 0 to 9)	Low dose 1.1 to 1.3 x 10¹¹/m²	17	Mean 4.8	Not reported	Not reported	Not reported	Not reported	Not reported
	Standard dose 2.0 to 2.9 x 10¹¹/m²	28	Mean 5.5
Low‐dose versus high‐dose platelets (within 30 days)
Slichter 2010	Low dose 1.1 x 10¹¹ platelets/m² ± 25%	417	Median 5 IQR 3 to 9	< 0.001	Median 9.3 x 10¹¹ IQR 4.9 to 17.9	< 0.001	Median 4 IQR 2 to 8	0.90^a
	High dose 4.4 x 10¹¹ platelets/m² ± 25%	432	Median 3 IQR 2 to 6		Median 19.6 x 10¹¹ IQR 10.6 to 37.4		Median 4 IQR 2 to 8
Standard‐dose versus high‐dose platelets (within 30 days)
Sensebe 2004	Standard dose 1.9 x 10¹¹/m²	48	Median 3 Range 1 to 12	0.037	Mean 14.9 x 10¹¹	0.156^a	Not reported	Not reported
	High dose 3.9 x 10¹¹/m²	48	Median 2 Range 1 to 13		Mean 18.5 x 10¹¹
Slichter 2010	Standard dose 2.2 x 10¹¹ platelets/m² ± 25%	423	Median 3 IQR 2 to 6	0.09^a	Median 11.3 x 10¹¹ IQR 7.0 to 22.8	< 0.001	Median 4 IQR 2 to 8	0.70^a
	High dose 4.4 x 10¹¹ platelets/m² ± 25%	432	Median 3 IQR 2 to 6		Median 19.6 x 10¹¹ IQR 10.6 to 37.4		Median 4 IQR 2 to 8
Steffens 2002	Standard dose (Single apheresis unit)	28	Median 6 Range 1 to 14	Not reported	Mean 6.0 units Range 1 to 14	Not reported	Not reported	Not reported
	High dose (Triple apheresis unit)	26	Median 3.23 Range 1 to 8		Mean 9.7 units Range 3 to 23
Standard‐dose versus high‐dose platelets (duration of study unclear)
Roy 1973 (Aged 10 to 18)	Standard dose 1.7 x 10¹¹/m²	15	Mean 4	Not reported	Not reported	Not reported	Not reported	Not reported
	High dose 3.1 to 3.7 x 10¹¹/m²	2	Mean 7
CI: confidence interval IQR: interquartile range MD: mean difference SD: standard deviation WBD: whole blood derived ^aP value is not statistically significant. ^bunpublished data

Table 5. Number of platelet transfusions and red cell transfusions

Table 6. Platelet transfusion interval

Study	Intervention	Number of participants	Platelet transfusion interval/participant (days)	P value
Low‐dose versus standard‐dose platelets (within 30 days)
Heddle 2009	Low dose 0.8 to 1.7 x 10¹¹/m²	58	Mean 1.8 SD 1.1	< 0.001
Heddle 2009	Standard dose 1.7 to 3.4 x 10¹¹/m²	61	Mean 2.8 SD 1.8	< 0.001
Slichter 2010	Low dose 1.1 x 10¹¹ platelets/m² ± 25%	417	Median 1.1 IQR 0.7 to 2.1	< 0.001
Slichter 2010	Standard dose 2.2 x 10¹¹ platelets/m² ± 25%	423	Median 1.9 IQR 0.9 to 3.1	< 0.001
Tinmouth 2004	Low dose 1.1 to 1.4 x 10¹¹/m²	56	Median 2 Range 1 to 4.5	Not reported
Tinmouth 2004	Standard dose 1.9 to 2.5 x 10¹¹/m²	55	Median 3 Range 1 to 5	Not reported
Low‐dose versus high‐dose platelets (within 30 days)
Slichter 2010	Low dose 1.1 x 10¹¹ platelets/m² ± 25%	417	Median 1.1 IQR 0.7 to 2.1	< 0.001
Slichter 2010	High dose 4.4 x 10¹¹ platelets/m² ± 25%	432	Median 2.9 IQR 1.2 to 4.7	< 0.001
High‐dose versus standard‐dose platelets (within 30 days)
Sensebe 2004	Standard dose 1.9 x 10¹¹/m²	48	Median time 2.6 95% CI 1.9 to 2.7	0.001
Sensebe 2004	High dose 3.9 x 10¹¹/m²	48	Median time 4.0 95% CI 3.5 to 4.7	0.001
Slichter 2010	Standard dose 2.2 x 10¹¹ platelets/m² ± 25%	423	Median 1.9 IQR 0.9 to 3.1	< 0.001
Slichter 2010	High dose 4.4 x 10¹¹ platelets/m² ± 25%	432	Median 2.9 IQR 1.2 to 4.7	< 0.001
Steffens 2002	Standard dose (Single apheresis unit)	28	3.1 days	Not reported
Steffens 2002	High dose (Triple apheresis unit)	26	4.9 days	Not reported
CI: confidence interval IQR: interquartile range SD: standard deviation

Table 6. Platelet transfusion interval

Comparison 1. Prophylactic platelet transfusion with one dose schedule versus another dose schedule

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number of participants with at least one clinically significant bleeding event ‐ low dose versus standard dose Show forest plot	4	1170	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.95, 1.13]

2 Number of participants with at least one clinically significant bleeding event ‐ low dose versus high dose Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3 Number of participants with at least one clinically significant bleeding event ‐ high dose versus standard dose Show forest plot	2	951	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.93, 1.11]

4 Number of days with clinically significant bleeding per participant low dose versus standard dose (fixed effect) Show forest plot	2	230	Mean Difference (IV, Fixed, 95% CI)	‐0.17 [‐0.51, 0.17]

5 Number of days with clinically significant bleeding per participant low dose versus standard dose (random effects) Show forest plot	2	230	Mean Difference (IV, Random, 95% CI)	0.04 [‐0.78, 0.86]

6 Number of participants with WHO Grade 3 or 4 bleeding ‐ low dose versus standard dose Show forest plot	3	1059	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [0.91, 1.92]

7 Number of participants with WHO Grade 3 or 4 bleeding ‐ low dose versus high dose Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

8 Number of participants with WHO Grade 3 or 4 bleeding ‐ high dose versus standard dose Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

9 Number of participants with WHO Grade 4 bleeding ‐ low dose versus standard dose Show forest plot	3	1070	Risk Ratio (M‐H, Fixed, 95% CI)	1.87 [0.86, 4.08]

10 Number of participants with WHO Grade 4 bleeding ‐ low dose versus high dose Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

11 Number of participants with WHO Grade 4 bleeding ‐ high dose versus standard dose Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

12 Number of participants with bleeding requiring a red cell transfusion Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

13 Number of participants with bleeding causing cardiovascular compromise Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

14 Mortality from all causes ‐ low dose vs. standard dose Show forest plot	3	1070	Risk Ratio (M‐H, Fixed, 95% CI)	2.04 [0.70, 5.93]

15 Mortality from all causes ‐ low dose vs. high dose Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

16 Mortality from all causes ‐ high dose vs. standard dose Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

17 Mortality from bleeding Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

17.1 Low dosage platelet transfusions versus standard dose platelet transfusions	3	859	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
17.2 High dosage platelet transfusions versus standard dosage platelet transfusions	2	739	Risk Ratio (M‐H, Fixed, 95% CI)	1.47 [0.06, 35.90]
18 Number of participants with platelet transfusion reactions Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

18.1 Allergic reaction or hypersensitivity: Low dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.2 Allergic reaction or hypersensitivity: High dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.3 Hypotension: Low dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.4 Hypotension: High dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.5 Dyspnoea: Low dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.6 Dyspnoea: High dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.7 Hypoxia: Low dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.8 Hypoxia: High dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.9 Wheezing: Low dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.10 Wheezing: High dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.11 Wheezing: Low dosage platelet transfusions versus high dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.12 Haemolysis: Low dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.13 Haemolysis: High dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.14 Rigors or chills: Low dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.15 Rigors or chills: High dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.16 Fever: Low dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.17 Fever: High dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.18 Infection: Low dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.19 Infection: High dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
19 Thromboembolic disease Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

19.1 Low dose platelet transfusions versus standard dose platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
19.2 Low dose platelet transfusions versus high dose platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
19.3 High dose platelet transfusions versus standard dose platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
20 Number of participants with a significant bleeding episode ‐ autologous stem cell transplant versus intensive chemotherapy Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

20.1 Autologous HSCT	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
20.2 Intensive chemotherapy	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
21 Number of participants with a significant bleeding episode ‐ autologous stem cell transplant versus allogeneic stem cell transplant Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

22 Time to first significant bleeding event Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 1. Prophylactic platelet transfusion with one dose schedule versus another dose schedule