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Pathogen-reduced platelets for the prevention of bleeding

  1. Caroline Butler1,
  2. Carolyn Doree2,
  3. Lise J Estcourt3,
  4. Marialena Trivella4,
  5. Sally Hopewell5,
  6. Susan J Brunskill2,
  7. Simon Stanworth3,
  8. Michael F Murphy6,*

Editorial Group: Cochrane Haematological Malignancies Group

Published Online: 28 MAR 2013

Assessed as up-to-date: 25 FEB 2013

DOI: 10.1002/14651858.CD009072.pub2


How to Cite

Butler C, Doree C, Estcourt LJ, Trivella M, Hopewell S, Brunskill SJ, Stanworth S, Murphy MF. Pathogen-reduced platelets for the prevention of bleeding. Cochrane Database of Systematic Reviews 2013, Issue 3. Art. No.: CD009072. DOI: 10.1002/14651858.CD009072.pub2.

Author Information

  1. 1

    Oxford Radcliffe Hospital NHS Trust, Haematology Department, Maidenhead, UK

  2. 2

    NHS Blood and Transplant, Systematic Review Initiative, Oxford, UK

  3. 3

    NHS Blood and Transplant, Haematology/Transfusion Medicine, Oxford, UK

  4. 4

    The Cochrane Collaboration, Cochrane Operations Unit, Oxford, UK

  5. 5

    University of Oxford, Centre for Statistics in Medicine, Oxford, Oxfordshire, UK

  6. 6

    John Radcliffe Hospital, NHS Blood and Transplant, Oxford, UK

*Michael F Murphy, NHS Blood and Transplant, John Radcliffe Hospital, Headley Way, Headington, Oxford, OX3 9BQ, UK. mike.murphy@nhsbt.nhs.uk.

Publication History

  1. Publication Status: New
  2. Published Online: 28 MAR 2013

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Characteristics of included studies [ordered by study ID]
Agliastro 2006

MethodsType of study: parallel-group, randomised controlled trial

Type of publication: abstract

Setting and country: hospital, Palermo, Italy

Number of centres: unclear

Dates of trial (start and end): July 2005 - not reported

Treatment period + follow-up: not reported

Power calculation performed?: not reported


Participants30 thrombocytopenic paediatric patients with either solid or haematological malignancies were randomised to 1 of 2 intervention groups:

i) PCT: Intercept® PCT platelets (N = 19)

ii) Control: standard platelets (N = 11)

Number analysed for primary outcome: 30

Actively bleeding patients excluded?: not reported

Patients with platelet refractoriness or alloimmunisation excluded?: not reported


Interventionsi) PCT: Intercept® PCT platelets produced from 5 pooled buffy coats, storage solution not reported

ii) Control: apheresed standard platelets, storage solution not reported

Storage duration of platelets and timing of platelet dose measurement: not reported

Transfusion trigger: therapeutic ("bleeding symptomatology"), no further information reported

% off-protocol transfusions: not reported


OutcomesStudy outcomes (primary outcome unclear): pre- and post-transfusion platelet count; 24-hr corrected count increment (CCI); the continuing of bleeding (scale not reported); transfusion reactions; transfusion refractoriness


NotesSource(s) of funding: not reported

Intervention exposure: multiple dose


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo information provided

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnclear whether any randomised patients were lost to follow-up or withdrawn from treatment. All patients enrolled were randomly divided between the 2 interventions and received at least 1 platelet transfusion.

Selective reporting (reporting bias)Unclear riskStudy published as an abstract only, original study protocol not available for comparison. Minimal participant background characteristics reported. The average platelet dose of both interventions was reported but no timings of platelet dose measurement or storage duration of platelets were reported. Comparability of interventions and patients unclear. All outcomes listed in methods section were reported but no standard deviations were given for pre and post-transfusion platelet counts and 24 hour CCI.

Other biasLow riskNone identified

Cazenave 2010

MethodsType of study: parallel-group, non-inferiority, randomised controlled trial

Type of publication: full

Setting and country: blood transfusion centres and hospitals, France

Number of centres: 6

Dates of trial: December 2005 to September 2007 (recruitment period only)

Treatment period + follow-up: maximum 28-day treatment period with a 28-day follow-up period, starting the day after the last on-protocol transfusion

Power calculation performed?: yes


Participants118 adult (≥ 16 years) haemato-oncological patients with thrombocytopenia expected to receive at least 2 platelet transfusions were randomised to 1 of 2 intervention groups:

i) PCT: Mirasol® PCT platelets (N = 60)

ii) Control: standard platelets (N = 58)

Number analysed for primary outcome: 110 (56/54), 8 patients were excluded as they did not require platelet transfusion

Actively bleeding patients excluded?: yes - "Patients were excluded if any of the following criteria were present: ... active bleeding requiring one or more red cell transfusions; ... and any other medical condition that could compromise participation."

Patients with platelet refractoriness or alloimmunisation excluded?: yes - "history of refractoriness to PLT transfusion (two successive CCI1hour < 5000); presence of HLA antibodies, positive lymphocytotoxicity test or previously documented alloimmunization to PLTS".


Interventionsi) PCT: apheresed or 6 pooled buffy coat Mirasol® PCT platelets (riboflavin + ultraviolet light treatment), suspended in plasma

ii) Control: apheresed or 6 pooled buffy coat standard platelets suspended in plasma

TIming of measurement of platelet dose and gamma irradiation: not reported

Storage duration of platelets: up to 5 days

Transfusion trigger: prophylactic or therapeutic: platelet count 10 x 109/L when clinical risk factors absent; 20 x 109/L when fever, hypertension, evidence of Grade 2 mucositis, lesions with bleeding potential and/or a rapid decrease in platelet count occurring within 72 hrs; 50 x 109/L if antithrombotics were administered, if there was evidence of fibrinolysis or coagulopathy, or invasive surgery required

% off-protocol transfusions: PCT platelets group: 17.7%; standard platelets group: 23.2%


OutcomesPrimary: 1-hour CCI for each of a maximum of 8 on-protocol platelet transfusions per patient occurring within the 28-day treatment period

Secondary: 24-hour CCI; interval between transfusions; number of platelet and red blood cell transfusions per subject during the treatment period; number of platelets transfused; evidence of refractoriness, frequency of transfusion associated infections and bleeding

Safety outcomes: adverse events, serious adverse events, bleeding status on days of platelet transfusion, transfusion-associated infections and death


NotesSource(s) of funding: CaridianBCT (Mirasol®), of which the corresponding author, RP Goodrich, is an employee

Intervention exposure: multiple dose


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"The random treatment allocation scheme involved stratification by centre and blocking and was computer generated by the coordinating centre (MedPass International, Paris, France)."

Allocation concealment (selection bias)Low risk"Patient allocation was performed at each site using opaque envelopes containing the treatment assignment"

Blinding of participants and personnel (performance bias)
All outcomes
High riskBlinding of participants and personnel was not possible due to slight yellow colour of the PCT platelets product

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Those individuals assessing PLT (platelet) counts and performing patient assessments were blinded to the patient's treatment allocation."

Incomplete outcome data (attrition bias)
All outcomes
Low riskClear Schulz 2010 flow diagram identifying the number of patients withdrawn or lost to follow-up, all such patients included in follow-up

Selective reporting (reporting bias)Low riskAll outcomes specified in methods were reported

Other biasLow riskAt least 15% of patients were re-recruited to a second cycle with the same randomisation schedule. Data from the second cycle was, however, not reported.

De Francisci 2004

MethodsType of study: parallel-group, randomised controlled trial

Type of publication: abstract

Setting and country: hospital, Italy

Number of centres: not reported

Dates of trial (start and end): April 2003 - unclear

Treatment period + follow-up: platelet requirement observed for the first 2 weeks post-transfusion. Follow-up for adverse events or side effects at 1, 3 and 6 months post-transfusion

Power calculation performed?: not reported


Participants44 patients divided into 2 groups

1st group: 28 adult (≥ 16 years) cirrhotic thrombocytopenic patients on a waiting list for liver transplantation requiring platelet transfusions before invasive procedures who were divided into 2 random groups:

i) PCT: Intercept® PCT platelets (N = 14)

ii) Control: standard platelets (N = 14)

Number analysed for primary outcome: 28

Actively bleeding patients excluded?: not reported

Patients with platelet refractoriness or alloimmunisation excluded?: not reported

2nd group: 16 paediatric with congenital cyanogen cardiopathy subjected to cardiac surgery who, during extracorporeal circulation, required platelet transfusions per protocol due to platelet consumption, were divided into 2 random groups:

i) PCT: Intercept® PCT platelets (N = 8)

ii) Control: standard platelets (N = 8)

Number analysed for primary outcome: 16

Actively bleeding patients excluded?: not reported

Patients with platelet refractoriness or alloimmunisation excluded?: not reported


Interventionsi) PCT: Intercept® PCT platelets, prepared from an unreported number of buffy coats, storage solution and gamma irradiation not reported

ii) Control: standard platelets, method of platelet preparation, storage solution and gamma irradiation not reported

Timing of platelet dose measurement and duration of platelet storage: not reported

Transfusion trigger: prophylactic (prior to invasive procedure for cirrhotic group, perioperatively, according to protocol for paediatric cardiac patients), no further information reported

% off-protocol transfusions: not reported


OutcomesStudy outcomes (primary outcome unclear): pre and post-transfusion platelet count; 1 and 24-hour CCI; bleeding; transfusion reactions; requirement for additional platelet transfusions during the following 2 weeks


NotesSource(s) of funding: not reported

Intervention exposure: not reported but appears to be a single transfusion episode


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod of random sequence generation not reported

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo information provided

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll randomised patients received the intervention and no losses to follow-up or treatment withdrawals were reported following randomisation

Selective reporting (reporting bias)High riskStudy published as an abstract only, original study protocol not available for comparison. Minimal patient background characteristics reported. 1-hour CCI not reported for the cirrhotic group. No standard deviations reported for mean 1- and 24-hour CCIs. Pre and post-transfusion platelet counts not reported for either intervention.

Other biasLow riskNone identified

Janetzko 2005

MethodsType of study: parallel-group, randomised controlled trial

Type of publication: full

Setting and country: European Hospitals in Germany, France and Switzerland

Number of centres: 3

Dates of trial (start and end): not reported

Treatment period + follow-up: maximum 28-day treatment period (or until 7 days without platelet transfusion, 'PLT transfusion independence') + 7-day surveillance period

Power calculation performed?: yes


Participants44 adult (> 16 years) haemato-oncological patients with thrombocytopenia requiring platelet transfusions during medical treatment were randomised to 1 of 2 intervention groups:

i) PCT: Intercept® PCT platelets (N = 22)

ii) Control: standard platelets (N = 22)

Number analysed for primary outcome: 43 (22/21) (1 did not require platelet transfusion)

Actively bleeding patients excluded?: yes, "The following criteria results in exclusion from entry into the study, but did not constitute reasons for removing patients from the study once enrolled:...active haemorrhage"

Patients with platelet refractoriness or alloimmunisation excluded?: yes, "prior history of refractoriness to PLT transfusion"


Interventionsi) PCT: Intercept® PCT platelets collected via apheresis, suspended in 30% to 45% plasma and 55% to 70% InterSol® platelet additive solution (PAS). Gamma irradiated at discretion of investigators at 1 of 3 sites

ii) Control: apheresed standard platelets, stored in 100% plasma. Gamma irradiated at discretion of the investigators at individual sites.

Timing of platelet dose measurement: at time of issue

Storage duration of platelets: up to 5 days
Transfusion trigger: prophylaxis (platelet count 20 x 109/L or pre-procedure); treatment of clinical bleeding, to prepare for an invasive therapeutic or diagnostic intervention

% off-protocol transfusions: PCT platelets group: 16.5%; standard PLT group: 7%


OutcomesPrimary: 1-hour count increment and corrected counted increment (CCI) for the first 8 study platelet transfusions

Secondary: 1- and 24-hour count increment and CCI for all study platelet transfusions; 24-hour post-transfusion platelet counts by longitudinal regression analysis; frequency of and interval between study platelet transfusions; clinical haemostasis after platelet transfusion; number of red cell transfusions; frequency of acute platelet transfusion reactions; frequency of platelet transfusion–attributed bacteraemia; frequency of refractoriness (clinical and immunologic) to platelet transfusion; evidence of human leucocyte antigens (HLA) alloantibody formation; evidence for antibodies directed against potential amotosalen-related neoantigens; overall safety and tolerability


NotesSources of funding: Baxter Healthcare Corporation (InterSol®) and Cerus Corporation (Intercept®)

Intervention exposure: multiple dose


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskConfirmation received through direct author contact: use of an automated, inter-active voice activated randomisation system used by the Transfusion Co-ordinator with secured access to treatment assignment. Access to the system required knowledge of a 4 digit site-specific ID number.

Allocation concealment (selection bias)Low riskConfirmation received through direct author contact: only the Transfusion Co-ordinator knew the randomisation assignment as this person was charged with preparation of study PC.

Blinding of participants and personnel (performance bias)
All outcomes
High riskConfirmation received through direct author contact: patients, primary care physicians, investigators and the sponsors were blinded as to the randomisation assignment in order to avoid bias. PCT and standard platelet concentrates were labelled and handled so as to maintain blinding of the patients and study including the use of brown over-wrap. One site was unable to use the over-wrap due to enforced haemovigilance programmes and in all sites the over-wrap could be lifted to check the platelet labelling or appearance prior to transfusion.

Comment: unblinding of participants and personnel could affect self reporting of bleeding severity and ordering of further red cell or platelet transfusions

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Haemostatic assessments were performed ... by trained personnel blinded to the treatment assignment". "AEs were assessed (and) graded ... by the study staff, blinded to treatment assignment".

Incomplete outcome data (attrition bias)
All outcomes
Low riskConfirmation received through direct author contact of withdrawals, losses to follow-up and reasons for exclusion from randomisation

Selective reporting (reporting bias)Low riskAll outcomes specified in methods were reported, full details of the 24-hour platelet counts, CIs and CCIs for all transfusions received through direct author contact

Other biasLow riskNone identified

Kerkhoffs 2010

MethodsType of study: parallel-group, non-inferiority, randomised controlled trial

Type of publication: full

Setting and country: haematology wards, The Netherlands

Number of centres: 8

Dates of trial (start and end): March 2007 to May 2009

Treatment period + follow-up: 5 platelet transfusions received over a maximum study period of 42 days after the first on-protocol transfusion

Power calculation performed?: yes, 100 patients required in each study arm. However, the recruitment to the PCT platelets arm was halted early on advice from the DSMB due to significantly more bleeding episodes and lower CCIs in the PCT platelets group. This arm of the trial was therefore underpowered with only 84 patients receiving PCT platelets.


Participants278 adult (≥ 18 years) haemato-oncological patients with (or expected to have) thrombocytopenia and expected to require 2 or more platelet transfusions were randomised to 1 of 3 intervention groups:

i) Intercept® PCT platelets (PCT) (N = 85)

ii) Standard platelets stored in InterSol® PAS (PASIII) (N = 94)

iii) Standard platelets stored in plasma (Plasma) (N = 99)

Number analysed for primary outcome: 278 (17 of the recruited 295 were ineligible: 13 did not require transfusion; 4 had anti-HLA antibodies)

Actively bleeding patients excluded?: no

Patients with platelet refractoriness or alloimmunisation excluded?: yes, "immunological refractoriness to random platelet transfusions due to human leucocyte antigen (HLA) - and/or human platelet antigen (HPA) - antibodies or clinical relevant auto-antibodies"


InterventionsThree interventions, all produced from 5 whole blood buffy coats, gamma-irradiated at the request of the hospital

i) PCT: Intercept® PCT platelets, stored in PAS (35% plasma; 65% InterSol®)

ii) PASIII: platelets stored in PAS (35% plasma; 65% InterSol®)

iii) Plasma (control): standard platelets suspended in 100% plasma

Timing of platelet dose measurement: prior to storage

Storage duration of platelets: up to 7 days

Transfusion trigger: prophylactic and therapeutic (thresholds: platelet count 40 x 109/L in endoscopic evaluation of the GI or respiratory tract (without biopsies), diagnostic puncture with a thin needle, lumbar puncture, extraction of a central venous catheter and minor surgery; 60 x 109/L in cases of bleeding, endoscopic evaluation with biopsies, dental extraction, placement of central venous catheter and major surgery (with exception of neurosurgery and cardiac surgery); 100 x 109/L in cases of cerebral bleeding, diffuse alveolar haemorrhage, neurosurgery and cardiac surgery)

% off-protocol transfusions: PCT platelets group: 34%; standard PLT group: 18%


OutcomesPrimary: 1-hour CCI

Secondary: 24-hour CCI; bleeding; red cell transfusion requirement; platelet transfusion requirement; platelet transfusion interval; adverse transfusion reactions


NotesSource(s) of funding: Sanquin Blood Bank

Intervention exposure: multiple dose

Additional notes: interim analysis planned after 300 transfusions: "Two criteria for early stopping of an experimental arm were defined: (i) a negative 24 hr CCI (decrement) not caused by immunological factors in more than 20% of transfusions; (ii) statistically significant more bleeding complications (CTCAE > 2) compared with the Plasma arm."


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskConfirmation through direct author contact: randomisation was performed by computer (web-based), stratified by centre on a 1:1:1 ratio

Allocation concealment (selection bias)Low riskConfirmation through direct author contact: randomisation performed by web-based computer

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label study, blinding not performed. High risk, as bleeding assessments potentially performed (or reported) by both participants and physicians and are necessarily subjective in nature.

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen-label study, blinding not performed

Incomplete outcome data (attrition bias)
All outcomes
Low riskFlow diagram from randomisation to end of follow-up period provided

Selective reporting (reporting bias)Low riskProtocol consulted and confirmation received through direct author contact of clarification of bleeding grades, adverse events, laboratory response to platelet transfusions and red cell/platelet transfusion requirements.

Other biasLow riskNone identified

Lozano 2011

MethodsType of study: parallel-group, non-inferiority, randomised controlled trial

Type of publication: full

Setting and country: haematology-oncology departments: Spain, UK, France, Sweden

Number of centres: 4

Dates of trial (start and end): October 2005 to July 2009

Treatment period + follow-up: 24-hour study period with 15-day follow-up post-transfusion (any adverse event followed up for 4 days post-transfusion, serious adverse events for 15 days)

Power calculation performed?: yes


Participants242 adult (≥ 16 years) haemato-oncological patients with (or expected to have) thrombocytopenia requiring platelet transfusion were randomised to 1 of 2 intervention groups:

i) PCT: Intercept® PCT platelets (N = 123)

ii) Control: standard platelet transfusion (N = 119)

Number analysed for primary outcome: 211 (105/106) received study transfusion for intention-to-treat analysis, performed but not reported. 199 (101/98) included in reported per protocol analysis. 12 patients excluded from analysis: 2 control patients due to "invalid platelet counts [>100x109/L]"; 3 control patients due to death; 7 not reported (4 PCT platelets, 3 control group).

Actively bleeding patients excluded?: not excluded at randomisation but the study transfusion was postponed "if the subject had ... active haemorrhage associated with reduction in haemoglobin >1.0g/dL or 10% within 24 hours, in the previous 12 hours prior to study transfusion."

Patients with platelet refractoriness or alloimmunisation excluded?: yes, "prior history of clinical refractoriness to platelet transfusion"

Major protocol violations were reported for 7 patients (2 PCT, 5 standard platelets) who either did not fulfil the inclusion criteria or had reason for exclusion that was not detected prior to receiving the study transfusion.


Interventionsi) PCT: pooled buffy coat derived or apheresed Intercept® PCT platelets, suspended in PAS (65% InterSol®:35% Plasma). Gamma irradiated at the investigators request. Bacterial culture performed if requested by study investigator.

ii) Control: standard platelets, collected from buffy coats or apheresis, suspended in PAS (65% T-Sol®/SSP, 35% plasma). Gamma irradiated at the investigators request.

Timing of platelet dose measurement: day 5

Storage duration of platelets: 6 or 7 days

Transfusion trigger: prophylaxis (platelet count 10 to 20 x 109/L)

% off-protocol transfusions: not reported. 15.2% participants in the PCT platelets group received off protocol transfusions versus 11.3% in the standard PLT group.


OutcomesPrimary: 1-hour CCI

Secondary: 1 and 24-hour count increment; 24-hour CCI; 1- and 24-hour post-transfusion platelet count; platelet and red cell transfusion requirement during 24-hour post-transfusion period; time interval between the study transfusion and the next platelet transfusion; clinical haemostatic assessments; acute transfusion reactions; adverse events


NotesSource(s) of funding: Cerus Corporation (Intercept®) of which at least 4 authors are employees

Intervention exposure: single dose

Additional notes: in order to reach a target threshold platelet content per transfusion (3.0 x 1011/unit), PCT platelet products collected by apheresis were produced by increasing the collection by 10% whilst an additional buffy coat could be added to the pooled PCT products to compensate for processing losses


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskConfirmation through direct author contact: "Patients were randomly assigned to PRP [PCT platelets] or Reference in a 1:1 ratio (using a permuted block randomisation with fixed block sizes)". Randomisation was "computer generated using an IVRS (interactive voice recognition system)"

Allocation concealment (selection bias)Low riskConfirmation through direct author contact: randomisation was conducted by each study site Transfusion Co-ordinator who opened the next randomisation code envelope to determine the treatment assignment. "They were instructed and signed an agreement not to discuss randomisation assignment with other study personnel"

Blinding of participants and personnel (performance bias)
All outcomes
Low riskConfirmation through direct author contact: "All study personnel and medical care personnel, except for the Transfusion Coordinator, were blinded to treatment assignment. ... Study PCs were in identical containers with identical labels"

Study reported as double-blinded

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Haemostatic assessments were performed by trained personnel blinded to treatment assignment."

Incomplete outcome data (attrition bias)
All outcomes
Low risk7 patients 1-hour CCI and 22 patients 24-hour CCI was not reported after receipt of study transfusion without reason but were evenly distributed between PCT platelets and control arms. One PCT product platelet dose was not measured before transfusion.

Selective reporting (reporting bias)Low riskAll outcomes specified in methods were reported and supported by data received through direct author contact

Other biasLow riskNone identified

McCullough 2004

MethodsType of study: parallel-group, non-inferiority, randomised controlled trial
Type of publication: full
Setting and country: hospitals, USA
Number of centres: 12
Dates of trial (start and end): July 1999 to February 2001
Treatment period + follow-up: maximum 28-day treatment period + 7-day surveillance period
Power calculation performed?: yes


Participants671 paediatric and adult (> 6 years of age) haemato-oncological patients with thrombocytopenia were randomised to 1 of 2 intervention groups to receive platelet transfusions for up to 28 days or until transfusion independence (7 days without platelet transfusion) prior to day 28:

i) PCT: Intercept® PCT platelets (N = 335)

ii) Control: standard platelets (N = 336)

Number analysed (primary outcome): 645 (318/327) (26 participants did not require platelet transfusion and so were not included in the analysis)

Actively bleeding patients excluded?: no

Patients with platelet refractoriness or alloimmunisation excluded?: yes, "positive lymphocytotoxic antibody (> 20% panel reactive antibody at screening) or history of clinical refractoriness"


InterventionsPCT: apheresed Intercept® PCT platelets suspended in 30% to 45% plasma and 70% to 55% Intersol® PAS, gamma irradiated if required

Control: apheresed standard platelets, stored in 100% plasma, gamma irradiated if required

Timing of measurement of platelet dose: pre issue

Storage duration of platelets: up to 5 days

Transfusion trigger: prophylactic and therapeutic (overt bleeding or pre invasive procedure)

% off-protocol transfusions: PCT platelets group: 8.5%; standard platelets group: 4.8%


OutcomesPrimary: proportion of patients with WHO grade 2 bleeding on any day during period of platelet support

Secondary: number of patients with WHO grade 3 or 4 bleeding; number of days of WHO grade 2 bleeding; 1 and 24 hour CIs and CCIs; number of days to next platelet transfusion; number of platelet transfusions; incidence of platelet refractoriness; number of red blood cell transfusions

Safety endpoints: number of platelet transfusion reactions; development of antibody to potential amotosalen neoantigens; overall safety


NotesSource(s) of funding: Cerus and Baxter Healthcare Corporations. 12 authors were either employees of Baxter or Cerus Corporation or received indirect payment from Baxter or Cerus.

Intervention exposure: multiple dose


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskConfirmation through direct author contact: "Randomization was conducted by authorized site personnel who telephoned a computerized, central, randomisation system (Interactive Voice Response System). The randomisation was stratified by site and blocked using variable block sizes."

Allocation concealment (selection bias)Low riskAs above. Confirmation through direct author contact: "Platelet processing coordinators were the only personnel with a Personal Identification Number (PIN) that could be used to access the randomisation system"

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"All individuals involved in the clinical care and assessment of patients were blinded to study treatment assignment. These individuals included the principal investigator, clinical study coordinators and nurses making haemostatic assessments, clinicians and nurses caring for the patient, and the study sponsor." Study participants also blinded, confirmed through direct author contact.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskSee above

Incomplete outcome data (attrition bias)
All outcomes
Low risk18 patients (9 PCT platelets, 9 control patients) did not complete transfusion period for 'other' reasons, author reported that a variety of non-specific reasons were given but no details reported

Comment: low risk of bias as equal numbers of patients from both arms were involved

Selective reporting (reporting bias)Low riskAll outcomes specified in methods were reported; missing standard deviations and other data provided by direct contact with author

Other biasLow riskNone identified

Simonsen 2006

MethodsType of study: cross-over, non-inferiority, 2 treatment period, randomised controlled trial

Type of publication: full

Setting and country: hospital, Denmark

Number of centres: 1

Dates of trial (start and end): October 2003 to April 2004

Treatment period + follow-up: maximum 45 days; 15 days from randomisation to first transfusion, minimum 24-hour washout period between study transfusions, maximum 28 days until second study transfusion and 24-hour follow-up following both study transfusions

Power calculation performed?: yes


Participants28 adult (≥ 18 years) haemato-oncological patients with (or expected to have) thrombocytopenia requiring platelet transfusions were randomly assigned to 1 of 2 treatment sequences:

i) Sequence PCT-Control: patients received a single Intercept® PCT platelets transfusion followed by a single standard platelet transfusion when the patient's transfusion threshold was next reached with a minimum 24-hour washout period between interventions; or

ii) Sequence Control-PCT: patients received a single standard platelet transfusion followed by a single Intercept® PCT platelet transfusion when the patient's transfusion threshold was next reached with a minimum 24-hour washout period between interventions

Number analysed for primary outcome: 20 for per protocol analysis, intention-to-treat analysis also performed but not reported (N = 25). 3 patients did not receive either intervention; 3 received only one intervention; 2 had major protocol violations (details not reported).

Actively bleeding patients excluded?: yes, "the inclusion criteria did not accept patients with severe bleeding"

1 patient received each study transfusion twice as they were recruited to 2 separate cycles of the trial; this was not thought to pose a significant impact on the trial outcomes as only a single patient was included twice

1 patient received the study intervention despite postponement criteria being present. 2 patients (1 in each sequence) failed to receive both study transfusions.

Patients with platelet refractoriness or alloimmunisation excluded?: yes, "history of refractoriness to PLT transfusion (defined by at least two successive PLT transfusions with a 1-hr PLT corrected count increment [CCI] of <5000)"


Interventionsi) PCT: 4 pooled buffy coat collected Intercept® PCT platelets suspended in PAS (30% to 45% plasma, 55% to 70% Intersol®). Gamma irradiated at request of physician

ii) Control: 4 pooled buffy coat collected platelets suspended in TSol® PAS (55% to 70% Tsol®, 30% to 45% plasma). Gamma irradiated at request of physician

Timing of platelet dose measurement: measured at completion of processing and again at the time of issue on day 7 (confirmed through direct author contact)

Storage duration of platelets: 7 days

Transfusion trigger: prophylactic (platelet count 10 to 20 x 109/L)

% off-protocol transfusions: not reported. 66.7% of patients received off protocol transfusions after PCT platelets in the PCT-Control sequence versus 36.4% after standard PLTs in the Control-PCT arm


OutcomesPrimary: 1-hour CCI

Secondary: 1-hour count increment; time to next platelet transfusion; change in haemostatic score before and after study platelet transfusion; frequency of acute platelet transfusion reactions up to 24-hours post-transfusion


NotesSource(s) of funding: Cerus Corporation (Intercept®) and Baxter Healthcare Corporation (InterSol® and TSol®). 2 authors were employees of Cerus Corporation at the time of publication and a further senior employee (L. Corash) critically reviewed the manuscript.

Intervention exposure: single dose

Additional notes: a significant period-by-treatment effect was identified when both sequences were compared with a reduced 1-hour CCI in the group that received PCT after standard platelets compared with those that received PCT platelets first. The study published data for both sequences combined and separately for each arm however the baseline characteristics of the participants recruited to the 2 sequences were very different (e.g. post HSCT 33.3% PRP-control, 64% control-PRP; post chemotherapy 66.7% PRP-control, 36% control-PRP). This could in itself explain the differences in their mean 1-hour CCIs. The first period of this study was included in the meta-analyses of this review where possible.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskConfirmation through direct author contact: "Patients were randomized to receive, as first study transfusion, Intercept® or Reference treatment in a 1:1 ratio using a permuted block randomization with fixed block sizes". Randomisation was "computer generated using an IVRS (interactive voice recognition system)"

Allocation concealment (selection bias)Low riskConfirmation through direct author contact: "Upon enrolment of each new patient, the Transfusion Coordinator (or her back-up) opened the code envelope identified by the next lowest available patient number"

Blinding of participants and personnel (performance bias)
All outcomes
Low riskConfirmation through direct author contact: "Patients, primary care physicians, the Clinical Coordinator, and the clinical monitor were blinded as to the randomisation assignment in order to avoid bias. INTERCEOT and Reference platelet concentrates were labelled and handled identically so as to maintain blinding for the patients and study personnel"

Blinding of outcome assessment (detection bias)
All outcomes
Low riskSee above, in addition: "Haemostatic assessments were performed by clinical personnel blinded to treatment sequence."

Incomplete outcome data (attrition bias)
All outcomes
Low riskClear figures reported for patients who did not complete transfusion period including losses to follow-up or withdrawal from study. One platelet dose measurement was not performed in the PCT-Standard platelet sequence arm.

Selective reporting (reporting bias)Low riskAll outcomes specified in methods were reported

Other biasLow riskNone identified

Slichter 2006

MethodsType of study: cross-over, 2 treatment period, randomised controlled trial

Type of publication: full

Setting and country: blood centres, USA

Number of centres: 2

Dates of trial (start and end): not reported

Treatment period + follow-up: maximum 14-day treatment + 28-day observation period

Power calculation performed: not done. "The study was designed to enrol at least 10 patients with paired bleeding time assessments."


Participants60 adult (≥ 18 years) haemato-oncological, thrombocytopenic patients requiring prophylactic platelet transfusions, with a haematocrit level of at least 25%, were randomised to 1 of 2 treatment sequences:

i) PCT-Control: a single Intercept® PCT platelet transfusion followed by a single standard platelet transfusion when the transfusion threshold was next reached (N = 16)

ii) Control-PCT: a single standard platelet transfusion followed by a single Intercept® PCT platelet transfusion when the transfusion threshold was next reached (N = 16)

Number analysed for primary outcome: 32 (10 received no study transfusion; 18 patients excluded due to a mid-study protocol amendment to "incorporate changes in PLT processing and inventory management")

Actively bleeding patients excluded?: yes, "Patients were excluded from enrolment based on the presence of factors known to affect post-transfusion PLT response or haemostasis:....significant haemorrhage the day before enrolment"

Patients with platelet refractoriness or alloimmunisation excluded?: yes, "lymphocytotoxic antibody panel reactivity of at least 20 percent"


Interventionsi) PCT: apheresed Intercept® PCT platelets, suspended in PAS (35% plasma: 65% Intersol®). Gamma irradiated at the request of the physician.

ii) Control: apheresed standard platelets stored in 100% plasma. Gamma irradiated at request of the physician.

Double platelet doses were received by participants of both study arms to attain a target dose of 6 x 1011/unit. Direct author contact confirmed that higher doses were required due to bleeding time measurements. Timing of platelet dose measurement: not reported

Storage duration of platelets: up to 5 days

Transfusion trigger: prophylaxis (platelet count < 20 x 109/L)

% off-protocol transfusions: not reported


OutcomesPrimary: cutaneous template bleeding time assessments by 2 incisions made at 1 to 2 hours and 18 to 24 hours post-transfusion

Secondary: 1 to 2-hour count increment and CCI; 18 to 24-hour count increment and CCI; transfusion interval to next platelet transfusion; clinical haemostatic assessments; adverse events (combined unless acute transfusion reactions); pre and post-transfusion plasma amotosalen concentration


NotesSource(s) of funding: Cerus Corporation (Intercept®) and Baxter Healthcare Corporation (InterSol®). At least 1 author, L.Corash, is an employee of Cerus Corporation

Intervention exposure: single dose

Patients received red cell transfusions during the study to maintain a haematocrit of at least 25% "because low Hct levels may cause prolonged bleeding times"

Additional notes: a change of protocol for platelet preparation mid study required 18 of the 50 patients who received the study products to be removed from the efficacy outcomes. All 50 were, however, included in the safety outcomes therefore protocol violations were frequent.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskConfirmation through direct author contact: Randomisation was "computer generated using an IVRS (interactive voice recognition system)" using a randomised sequence crossover design.

Allocation concealment (selection bias)Low risk"Randomisation to PCT or reference platelet transfusions as the first or second transfusion was provided by an interactive voice recognition system that was called by the research staff after each patient's enrolment in the study."

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Hospital staff...and study patients were blinded to the type of PLT transfusion given."

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Principal Investigators, hospital staff, research staff performing the bleeding times, anyone evaluating clinical haemostasis, and study patients were blinded to the type of PLT transfusion given."

Incomplete outcome data (attrition bias)
All outcomes
Low riskClear figures reported for patients who did not complete transfusion period including losses to follow-up or withdrawal from study. 1 patient however was not assessed for post-transfusion bleeding in the PCT platelets group.

Selective reporting (reporting bias)Low riskAll outcomes specified in methods were reported

Other biasLow riskNone identified

van Rhenen 2003

MethodsType of study: parallel-group, randomised controlled trial

Type of publication: full

Setting and country: European Blood Centres, The Netherlands, Sweden, France and United Kingdom

Number of centres: 4

Dates of trial (start and end): June 1998 to June 2000

Treatment period + follow-up: 56-day transfusion period + 28-day surveillance period (Cycle 1). A second cycle was then commenced if patients continued to require platelet support for an additional 56-day transfusion period + 28-day surveillance period (Cycle 2). The same intervention was assigned for both cycles.

Power calculation performed?: yes


Participants106 paediatric and adult (≥ 12 years) haemato-oncological patients with thrombocytopenia (or receiving therapy expected to cause thrombocytopenia) requiring platelet transfusions were randomised to 1 of 2 interventions:

i) PCT: Intercept® PCT platelets (N = 54)

ii) Control: standard platelets (N = 52)

Number analysed (primary outcome): 103 (52/51) (3 did not require transfusion)

Actively bleeding patients excluded?: no

Patients with platelet refractoriness or alloimmunisation excluded?: yes, "history of alloimmunization or refractoriness to platelet transfusion".


Interventionsi) PCT: Intercept® PCT platelets prepared from 5 to 6 pooled buffy coats and stored in PAS (65% InterSol:35% plasma). Gamma irradiation not performed.

ii) Control: standard platelets prepared from 4 to 6 buffy coats, stored either in 100% plasma, or PAS (35% plasma: 65% TSol®) Gamma irradiated as requested by physician

Timing of platelet dose measurement: at issue

Storage duration of platelets: up to 5 days

Transfusion trigger: prophylactic (platelet count < 20 x 109/L) or therapeutic to treat active bleeding

% off-protocol transfusions: PCT platelets group: 20.3%; standard platelets group: 10.5%


OutcomesPrimary: 1-hour count increment and CCI

Secondary: 24-hour count increment and CCI; platelet transfusion requirement during platelet support period; interval between platelet transfusions; clinical haemostasis before and after transfusion; red cell transfusion requirement; incidence of refractoriness to platelet transfusion; incidence of alloimmunisation; transfusion-related adverse events; all other adverse events


NotesSource(s) of funding: Cerus Corporation (Intercept®) and Baxter Healthcare Corporation (InterSol®). 6 of the 20 authors were employed by one of these manufacturing companies at the time of publication.

Intervention exposure: multiple dose


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskConfirmation through direct author contact: "Upon enrolment, the Transfusion Coordinator for the site telephoned the central randomisation computer system (IVRS - Interactive Voice Response System) to receive a site-specific patient number and treatment assignment."

Allocation concealment (selection bias)Low riskConfirmation through direct author contact: "Access to the randomisation system required a site-specific Personal Identification Number restricted to the Transfusion Coordinator. Only the transfusion coordinator and one alternate had access to this PIN at each site"

Blinding of participants and personnel (performance bias)
All outcomes
Low riskConfirmation through direct author contact: "Patients, primary care physicians, investigators and the Sponsors were blinded as to the randomisation assignment in order to avoid bias. PRP (PCT) and reference platelet concentrates were labelled and handled in identical containers so as to maintain blinding for the patients and study personnel."

Blinding of outcome assessment (detection bias)
All outcomes
Low riskSee above

Incomplete outcome data (attrition bias)
All outcomes
Low riskThrough confirmation from direct author contact, clear figures reported for patients who did not complete transfusion period including losses to follow-up or withdrawal from study

Selective reporting (reporting bias)Low riskAll outcomes specified in methods were reported

Other biasLow risk12 patients were re-recruited to a second cycle of the study with the same randomisation (10 PCT, 2 standard platelets). All study outcome data were either reported or available through direct author contact for cycle 1 only.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Ambruso 2009Outcomes: measured neoantigen formation not clinical effectiveness

Andreu 1993Outcomes: measured HLA alloimmunisation not clinical effectiveness

AuBuchon 2005Participants: healthy subjects

Blundell 1996Intervention: platelets were treated with ultraviolet-B irradiation only. UVB irradiation is used to prevent the formation of antiplatelet alloantibodies and refractoriness to platelet transfusions, not to reduce or remove pathogens.

Corash 2000Participants: healthy subjects

Dumont 2010Participants: healthy subjects

TRAP 1997Intervention: platelets were treated with ultraviolet-B irradiation only. UVB irradiation is used to prevent the formation of antiplatelet alloantibodies and refractoriness to platelet transfusions, not to reduce or remove pathogens.

 
Characteristics of studies awaiting assessment [ordered by study ID]
Johansson 2012

MethodsSingle-centre, randomised, cross-over, prospective pilot study

Participants20 haematology-oncology patients with or expected to develop thrombocytopenia requiring at least three platelet transfusions

InterventionsEach patient to receive two prophylactic study transfusions of 2- to 4-day-old pooled buffy coat-derived platelets - one Mirasol® pathogen-reduced platelet transfusion (MIR) and one standard platelet transfusion (REF) - randomised on a 1:1 cross-over basis,delivered as MIR-REF or REF-MIR.

OutcomesPrimary Outcome Measure: Haemostatic function 1 hour pre- and post- study platelet transfusions using computerised thromboelastography (TEG).

Secondary Outcome Measures: Bleeding assessments 12 hours pre- and post-transfusions, platelet counts 1 hour pre- and post-transfusions, adverse transfusion reactions (within 24 hours), serious adverse events (within 24 hours).

NotesTrial targeted 20 patients, but this paper is an interim analysis of only 10 patients with complete data.

Trial is part of the Pathogen Reduction Extended Storage Study (PRESS) registered at ClinicalTrials.gov ID: NCT01368211.

 
Characteristics of ongoing studies [ordered by study ID]
Kerkhoffs 2013

Trial name or titlePREPAReS (Pathogen Reduction Evaluation & Predictive Analytical Rating Score) Study

MethodsNon-inferiority, parallel-group, single-blind, multi-centre RCT

Participants375 patients with acute myeloid leukaemia (including those undergoing stem cell therapy) requiring platelet transfusion

InterventionsPooled buffy coat-derived Mirasol® pathogen-reduced platelet concentrates versus standard plasma platelet concentrates

OutcomesPrimary Outcome Measure: CTCAE bleeding grade ≥ 2 bleeding complications of patients receiving platelet concentrates stored 1 to 5 days

Secondary Outcome Measures: 1 and 24-hour CI; 1 and 24-hour CCI; adverse transfusion reactions; total transfusion requirement of red cells and platelets; platelet transfusion interval; rate of HLA allo-immunisation; in vitro quality markers related with the 1-hour or 24-hour CCI; clinical factors interacting on primary endpoint, including in vivo variables of immunological responses and of haemostasis in the recipients after transfusion as compared prior to transfusion.

Starting dateMarch 2010

Contact informationJLH Kerkhoffs, HagaHospital, Leyweg 275, 2545 CH, Den Haag, The Netherlands. j.kerkhoffs@hagaziekenhuis.nl

NotesEstimated end date: January 2014

Netherlands Trial Register ID: NTR2106.

Supported by: Sanquin Blood Bank; Terumo BCT

International multi-centre study based in The Netherlands and Canada

Rebulla 2009

Trial name or titleIPTAS (Italian Pathogen Reduction Technology Assessment Study)

MethodsMulti-centre (involving 7 large blood transfusion services), non-inferiority, randomised, prospectively controlled study (confirmed through direct author contact)

Participants828 adult haematology-oncology patients expected to require 2 or more platelet transfusions

InterventionsGroup 1: Intercept® pathogen-reduced platelets versus standard platelets

Group 2: Mirasol® pathogen-reduced platelets versus standard platelets

All participants scheduled to receive on-protocol platelet transfusions until: 1) platelet transfusion independence; 2) detection of refractoriness; 3) discharge or death, for a maximum of 4 weeks

OutcomesPrimary Outcome Measure: Incidence of bleeding of grade 2 or greater in recipients of PRT platelets versus incidence in recipients of control (standard) platelets
Secondary Outcome Measures: Time to the first grade 2 or greater bleeding event after the first study transfusion; Proportion of transfusions given to treat breakthrough bleeding; Number of days with grade 2 or greater bleeding during the period of platelet transfusion support; Number of platelet units transfused per day of thrombocytopenic platelet support; Proportion of patients with acute transfusion reactions; Post-transfusion platelet count increments; Total dose of platelets transfused per day of thrombocytopenic platelet support.

Starting dateOctober 2010

Contact informationPrincipal Investigator: P Rebulla, The Italian Pathogen reduction Technology Assessment Study (IPTAS) Research Group; Italian National Blood Centre, National Institute of Health, Rome, Italy. Email: prebulla@policlinico.mi.it

NotesEstimated end date: December 2013

Supported by the Italian Ministry of Health in addition to grants from Cerus and CaridianBCT

Original protocol available at: http://www.bloodtransfusion.it/articoli/47/en/Doi%200013.pdf; ClinicalTrials.gov ID: NCT01642563.

Tiberghien 2013

Trial name or titleEFFIPAP (Evaluation of the Efficacy of Platelets Treated with Pathogen Inactivation Process)

MethodsMulti-centre (9 centres in France), non-inferiority, randomised, double-blind, controlled trial

Participants810 adult patients hospitalised for bone marrow aplasia expected to become thrombocytopenic

InterventionsIntercept® pathogen-reduced platelet concentrates versus standard platelet concentrates (in Intersol® additive solution)

OutcomesPrimary Outcome Measure: Incidence of grade 2 or higher (WHO) haemorrhagic episodes.
Secondary Outcome Measures: Frequency incidence of haemorrhagic episodes (grade 1 and higher); Number of serious grade 3-4 haemorrhagic episodes; Number of minor grade 1 haemorrhagic episodes; Transfusion outcome in platelets (CCI) at 24 hours
Number of transfusions of platelet concentrates and red blood cells; Transfusion intervals; Safety; Occurrence of anti-platelet antibodies (Anti-HLA, anti-HPA); Occurrence of platelet transfusions refractoriness; Validation of a new haemorrhagic evaluation: EFS scale; Variation in hematocrit and hemoglobin levels.

Starting dateApril 2013

Contact informationContact: Pierre Tiberghien, MD, PhD. pierre.tiberghien@efs.sante.fr

NotesEstimated end date: December 2015

Supported by Etablissement Français du Sang

ClinicalTrials.gov ID: NCT01789762.

 
Comparison 1. Pathogen-reduced platelets versus standard platelets

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Number of participants with 'any bleeding' event(s) (WHO grade 1-4 or equivalent) - follow-up < 48 hrs3309Risk Ratio (Fixed, 95% CI)0.86 [0.63, 1.19]

    1.1 Intercept plts vs standard plts - single platelet transfusion studies
3309Risk Ratio (Fixed, 95% CI)0.86 [0.63, 1.19]

 2 Number of participants with 'any bleeding' event(s) (WHO grade 1-4 or equivalent) - follow-up > 7 days51085Risk Ratio (M-H, Fixed, 95% CI)1.09 [1.02, 1.15]

    2.1 Intercept plts vs standard plts - multiple platelet transfusion studies
4975Risk Ratio (M-H, Fixed, 95% CI)1.07 [1.01, 1.13]

    2.2 Mirasol plts vs standard plts - multiple platelet transfusion studies
1110Risk Ratio (M-H, Fixed, 95% CI)1.38 [0.95, 2.02]

 3 Number of participants with a 'clinically significant' bleeding event(s) (WHO grade ≥ 2 of equivalent) - follow-up > 7 days4982Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.93, 1.21]

    3.1 Intercept plts vs standard plts - multiple platelet transfusion studies
3872Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.91, 1.18]

    3.2 Mirasol plts vs standard plts - multiple platelet transfusion studies
1110Risk Ratio (M-H, Fixed, 95% CI)1.65 [0.70, 3.88]

 4 Number of participants with a 'severe' bleeding event(s) (WHO grade ≥ 3 of equivalent) - follow-up > 7 days51085Risk Ratio (M-H, Fixed, 95% CI)1.27 [0.76, 2.12]

    4.1 Intercept plts vs standard plts - multiple platelet transfusion studies
4975Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.67, 2.06]

    4.2 Mirasol plts vs standard plts - multiple platelet transfusion studies
1110Risk Ratio (M-H, Fixed, 95% CI)1.93 [0.51, 7.33]

 5 All-cause mortality post-transfusion (follow-up 0 to 12 weeks)61296Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.41, 1.29]

    5.1 Intercept plts vs standard plts - single platelet transfusion studies
1211Risk Ratio (M-H, Fixed, 95% CI)0.14 [0.01, 2.76]

    5.2 Intercept plts vs standard plts - multiple platelet transfusion studies
4975Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.39, 1.35]

    5.3 Mirasol plts vs standard plts - multiple platelet transfusion studies
1110Risk Ratio (M-H, Fixed, 95% CI)2.89 [0.31, 26.96]

 6 Number of participants with an acute transfusion reaction61226Risk Ratio (Fixed, 95% CI)0.96 [0.74, 1.25]

    6.1 Intercept plts vs standard plts - single platelet transfusion studies
2251Risk Ratio (Fixed, 95% CI)1.57 [0.71, 3.48]

    6.2 Intercept plts vs standard plts - multiple platelet transfusion studies
4975Risk Ratio (Fixed, 95% CI)0.91 [0.69, 1.20]

 7 Number of participants experiencing platelet refractoriness61115Risk Ratio (M-H, Fixed, 95% CI)2.74 [1.84, 4.07]

    7.1 Intercept plts vs standard plts - multiple platelet transfusion studies
51005Risk Ratio (M-H, Fixed, 95% CI)2.83 [1.88, 4.26]

    7.2 Mirasol plts vs standard plts - multiple platelet transfusion studies
1110Risk Ratio (M-H, Fixed, 95% CI)1.45 [0.25, 8.32]

 8 Number of participants experiencing platelet refractoriness and platelet alloimmunisation5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    8.1 Intercept plts vs standard plts - multiple platelet transfusion studies
51005Risk Ratio (M-H, Fixed, 95% CI)1.53 [0.80, 2.95]

 9 Number of participants with an adverse event61156Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.98, 1.03]

    9.1 Intercept plts vs standard plts - single platelet transfusion studies
2255Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.87, 1.09]

    9.2 Intercept plts vs standard plts - multiple platelet transfusion studies
3791Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.99, 1.02]

    9.3 Mirasol plts vs standard plts - multiple platelet transfusion studies
1110Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.97, 1.07]

 10 Number of participants with a serious adverse event71340Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.88, 1.35]

    10.1 Intercept plts vs standard plts - single platelet transfusion studies
2255Risk Ratio (M-H, Fixed, 95% CI)1.21 [0.55, 2.68]

    10.2 Intercept plts vs standard plts - multiple platelet transfusion studies
4975Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.84, 1.36]

    10.3 Mirasol plts vs standard plts - multiple platelet transfusion studies
1110Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.56, 2.32]

 11 Lab response - 1-hour count increment [x 109/L]6Mean Difference (IV, Fixed, 95% CI)Subtotals only

    11.1 Intercept plts vs standard plts - single platelet transfusion studies
2219Mean Difference (IV, Fixed, 95% CI)-1.39 [-4.81, 2.02]

    11.2 Intercept plts vs standard plts - multiple platelet transfusion studies
4975Mean Difference (IV, Fixed, 95% CI)-12.53 [-14.44, -10.62]

 12 Lab response - 1-hour corrected count increment (CCI) [x 103/L]7Mean Difference (IV, Fixed, 95% CI)Subtotals only

    12.1 Intercept plts vs standard plts - single platelet transfusion studies
2219Mean Difference (IV, Fixed, 95% CI)-0.89 [-2.35, 0.58]

    12.2 Intercept plts vs standard plts - multiple platelet transfusion studies
4975Mean Difference (IV, Fixed, 95% CI)-4.67 [-5.53, -3.81]

    12.3 Mirasol plts vs standard plts - multiple platelet transfusion studies
1110Mean Difference (IV, Fixed, 95% CI)-3.87 [-6.26, -1.48]

 13 Lab response - 24-hour count increment [x 109/L]5Mean Difference (IV, Fixed, 95% CI)Subtotals only

    13.1 Intercept plts vs standard plts - single platelet transfusion studies
1186Mean Difference (IV, Fixed, 95% CI)-4.1 [-7.16, -1.04]

    13.2 Intercept plts vs standard plts - multiple platelet transfusion studies
4975Mean Difference (IV, Fixed, 95% CI)-8.75 [-10.36, -7.14]

 14 Lab response - 24-hour corrected count increment (CCI) [x 103/L]61271Mean Difference (IV, Fixed, 95% CI)-3.09 [-3.71, -2.46]

    14.1 Intercept plts vs standard plts - single platelet transfusion studies
1186Mean Difference (IV, Fixed, 95% CI)-1.96 [-3.24, -0.68]

    14.2 Intercept plts vs standard plts - multiple platelet transfusion studies
4975Mean Difference (IV, Fixed, 95% CI)-3.61 [-4.37, -2.85]

    14.3 Mirasol plts vs standard plts - multiple platelet transfusion studies
1110Mean Difference (IV, Fixed, 95% CI)-1.98 [-4.25, 0.29]

 15 Number of platelet transfusions per patient per day of platelet support3798Mean Difference (IV, Fixed, 95% CI)0.07 [0.03, 0.11]

    15.1 Intercept plts vs standard plts - multiple platelet transfusion studies
2688Mean Difference (IV, Fixed, 95% CI)0.09 [0.04, 0.13]

    15.2 Mirasol plts vs standard plts - multiple platelet transfusion studies
1110Mean Difference (IV, Fixed, 95% CI)0.04 [-0.03, 0.11]

 16 Platelet transfusion interval (days to next platelet transfusion)7Mean Difference (IV, Fixed, 95% CI)Subtotals only

    16.1 Intercept plts vs standard plts - single platelet transfusion studies
2194Mean Difference (IV, Fixed, 95% CI)0.10 [-0.13, 0.34]

    16.2 Intercept plts vs standard plts - multiple platelet transfusion studies
4969Mean Difference (IV, Fixed, 95% CI)-0.51 [-0.66, -0.37]

    16.3 Mirasol plts vs standard plts - multiple platelet transfusion studies
1110Mean Difference (IV, Fixed, 95% CI)-0.14 [-0.73, 0.45]

 17 Number of red cell transfusions per patient per day of platelet support51112Mean Difference (IV, Fixed, 95% CI)0.00 [-0.02, 0.03]

    17.1 Intercept plts vs standard plts - single platelet transfusion studies
1211Mean Difference (IV, Fixed, 95% CI)-0.02 [-0.27, 0.23]

    17.2 Intercept plts vs standard plts - multiple platelet transfusion studies
3791Mean Difference (IV, Fixed, 95% CI)-0.00 [-0.03, 0.03]

    17.3 Mirasol plts vs standard plts - multiple platelet transfusion studies
1110Mean Difference (IV, Fixed, 95% CI)0.02 [-0.02, 0.06]

 
Summary of findings for the main comparison. Pathogen-reduced platelets versus standard platelets for the prevention of bleeding in thrombocytopenia

Pathogen-reduced platelets versus standard platelets for the prevention of bleeding in thrombocytopenia

Patient or population: thrombocytopenia
Settings: hospital
Intervention: pathogen-reduced platelets

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlPathogen-reduced platelets

Number of participants with 'any bleeding' event(s) (WHO grade 1 to 4 or equivalent) - follow-up > 7days
Follow-up: 8 to 70 days
Study populationRR 1.09
(1.02 to 1.15)
1085
(5 studies)
⊕⊕⊕⊕
high
Random-effects analysis: RR 1.14, 95% CI 0.93 to 1.38; I² = 59%

696 per 1000793 per 1000
(647 to 960)

Moderate

800 per 1000912 per 1000
(744 to 1000)

Number of participants with 'clinically significant' bleeding event(s) (WHO grade ≥ 2 or equivalent) - follow-up > 7 days
Follow-up: 8 to 70 days
LowRR 1.06
(0.93 to 1.21)
983
(4 studies)
⊕⊕⊕⊕
high
Assumed risks from published data1,2,3

570 per 1000604 per 1000
(530 to 690)

Moderate

700 per 1000742 per 1000
(651 to 847)

High

790 per 1000837 per 1000
(735 to 956)

Number of participants with a 'severe' bleeding event(s) (WHO grade ≥ 3 or equivalent) - follow-up > 7 days
Follow-up: 8 to 70 days
ModerateRR 1.27
(0.76 to 2.12)
1085
(5 studies)
⊕⊕⊕⊝
moderate4
Medium-risk data taken from PLADO trial (Slichter 2010)

100 per 1000194 per 1000
(66 to 570)

All-cause mortality post-transfusion
Follow-up: 0 to 12 weeks
Study populationRR 0.73
(0.41 to 1.29)
1294
(6 studies)
⊕⊕⊕⊝
moderate5

41 per 100030 per 1000
(17 to 53)

Moderate

24 per 100018 per 1000
(10 to 31)

Number of participants with a serious adverse event
Follow-up: 15 to 84 days
Study populationRR 1.09
(0.88 to 1.35)
1253
(5 studies)
⊕⊕⊕⊝
moderate6

192 per 1000209 per 1000
(169 to 259)

Moderate

204 per 1000222 per 1000
(180 to 275)

Number of patients experiencing platelet refractoriness
Follow-up: 0 to 24 hours
Study populationRR 2.74
(1.84 to 4.07)
1115
(6 studies)
⊕⊕⊕⊕
high
Refractoriness was defined as 2 successive 1-hour CCIs below 5 x 103 in 4 studies (Cazenave 2010; Janetzko 2005; McCullough 2004; van Rhenen 2003), while Kerkhoffs 2010 defined refractoriness as 2 successive 1-hour CCIs below 7.5 x 103 or 24-hour CCIs below 4.5 x 103 and presence of antibodies against platelets

53 per 1000146 per 1000
(98 to 217)

Moderate


Lab response - 24-hour corrected count increment (CCI)
Follow-up: 10 to 28 hours
The mean lab response - 24-hour corrected count increment (CCI) ranged across control groups from
6.55 to 12.8 (x 10^3/L)
The mean lab response - 24-hour corrected count increment (CCI) in the intervention groups was
3.09 lower
(3.71 to 2.46 lower)
1271
(6 studies)
⊕⊕⊕⊕
high

*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.

 1Low risk = data taken from autologous transplantation patients from PLADO (PLAtelet DOse) trial (Slichter 2010).
2Medium risk = overall bleeding rate for all patients in the PLADO trial (Slichter 2010).
3High risk = data taken from allogeneic transplantation patients in PLADO trial (Slichter 2010).
4One large study (McCullough 2004) had proportionately more events in the control group than the other five studies. Although the studies within this subgroup had similar follow-up periods and to our knowledge there are no other major differences between them, the difference in the event rate may nevertheless be due to undetected methodological differences between the studies.
5Follow-up periods for mortality varied from 24 hours post-transfusion to up to 12 weeks post-transfusion.
6Follow-up periods for serious adverse events varied from 15 days post-transfusion to up to 84 days post-transfusion.
 
Table 1. Trial characteristics

StudyPublicationStudy designType of platelet componentNo. of participantsUnderlying diseaseType of treatment received

for underlying

disease (%)
Follow-up periods

for mortality

(days)
Approx mean

plt storage duration

(days)
Platelet dose

 

[Mean plt Tx dose] [(1011/unit)]



DesignAnalysisTotalPCT PltsStd PltsPCT PltsStd Plts

Single transfusion studies - Intercept®

De Francisci 2004AP2NRNR442222Adult liver transplant/

paediatric cardiac surgery
Liver: 14

Cardiac: 8
Liver: 14

Cardiac: 8
 NR NR NR

Lozano 2011FP2Non-IBC 86%

Aph 14%
211105106Adult haemato-

oncological disease
Auto: 42

Allo: 29

Ch: 27

Other: 3
Auto:40

Allo: 25

Ch: 34

Other: 2
156.8 Intermediate

 

[4.2] 

Simonsen 2006FC-ONon-IBC25 (20)PCT-STDSTD-PCTAdult haemato-

oncological disease
PCT-STDSTD-PCT 

1
 

7
Low/intermediate

 

[2.9]

911Allo: 33

Ch: 67 
Allo: 64

Ch: 36 

Slichter 2006FC-OEAph50 (32)PCT-STDSTD-PCTAdult haemato-

oncological disease
 NR NR 42$ 3 High

 

[7.5]

NRNR

Multiple transfusion studies – Intercept®

Agliastro 2006AP2NRPCT Plts: BC

Std Plts: Aph
301911Paediatric haemato-

oncological disease
 NR NR NRLow/intermediate

 

[2.9]













Janetzko 2005FP2EAph432221Adult haemato-

oncological disease
SCT: 68

Ch: 27

Other: 5 
SCT: 62

Ch: 38
 35 3.1Intermediate

 

[4.0]

Kerkhoffs 2010FP3Non-IBC1848599Adult haemato-

oncological disease
Auto:  39

Allo: 7

Ch: 49

Other: 5
Auto:32

Allo: 12

Ch: 53

Other: 3
42 

4

 
 Intermediate

 

[3.7*]

McCullough 2004FP2Non-IAph645318327Paediatric + adult  haemato-oncological

disease
Auto:  48

Allo:  28

Ch: 21

Other: 3
Auto: 52

Allo: 28

Ch: 18

Other: 2
 35 3.5£ Intermediate

 

[3.9*]

van Rhenen 2003FP2EBC1035251Paediatric + adult haemato-oncological

disease
SCT: 37

Ch: 63
SCT: 37

Ch:63
 84 3.5 Intermediate

 

[4.1*]

Multiple transfusion studies – Mirasol®

Cazenave 2010FP2Non-I25%  BC

75% Aph
1105654Adult haemato-

oncological disease
NR562.7Intermediate

 

[5.2]

 Key:
A: abstract only
Allo: treated with allogeneic stem cell transplantation
Aph: apheresis
Auto: treated with autologous stem cell transplantation
BC: buffy coats
Ch: treated with chemotherapy, but without stem cell transplantation
C-O: cross-over trial
E: equivalence trial
F: full paper
Non-I: non-inferiority
NR: not reported
P2:  parallel 2 arms
P3: parallel, 3 arms
Plt: platelet
SCT: treated with stem cell transplantation (undifferentiated)
*: Statistically significant lower mean platelet doses were issued for PCT versus standard platelet transfusions (P < 0.001 for Kerkhoffs 2010, McCullough 2004 and van Rhenen 2003). However, the doses in both arms were within the intermediate dose category of the PLADO study (Slichter 2010) in all of these studies. Although these differences were statistically significant overall there was less than a 10% difference in dose between the study arms in the three trials (range 8% (McCullough 2004) to 15% (Kerkhoffs 2010)).
#: Platelet dose has been categorised according to the low-dose, intermediate-dose and high-dose categories in the PLADO study (Slichter 2010). Low/intermediate means that the dose was between the low and intermediate categories of PLADO.
$: Cross-over design means adverse events (including mortality) were not assigned as specifically related to either PCT or standard transfusion.
£: Statistically significant difference between treatment arms for duration of platelet storage in McCullough 2004 (P = 0.03).
 
Table 2. Platelet transfusion data

StudyPlatelet Tx Protocol No of Plt Txs/patient

(mean ± SD)
Total % (No) of

off-protocol Txs


PCT pltsSTD pltsPCT pltsSTD plts

Single transfusion studies - Intercept®

De Francisci 2004P (NR)11NRNR

Lozano 2011P (10 to 20)1

 
1NANA

 

Simonsen 2006P (10 to 20)11(2/25)(1/25)

Slichter 2006P (20)11NANA

Multiple transfusion studies - Intercept ®

Agliastro 2006TNRNRNRNR

Janetzko 2005P (20); PP (NR) or T4.7 ± 3.35.5 ± 4.716.5% (17/103)7% (8/115)

Kerkhoffs 2010P (10 to 40); PP (40 to 100) or T5 ± 2*4 ± 2*34% (134/391)18% (65/357)

McCullough 2004P (NR) or T8.4 ± 8.6*6.2 ± 7.02*8.5% (232/2715)4.8% (101/2092)

van Rhenen 2003P (20) or T7.5 ± 5.85.6 ± 5.520.3% (79/390)10.5% (30/286)

 Multiple transfusion studies - Mirasol®

Cazenave 2010P (10 to 20); PP (50) or T5.41 ± 3.43#

1.16 ± 2.25@
4.41 ± 3.37#

1.33 ± 3.58@
17.7% (65/368)23.2% (72/310)

 Key:       
NA: not applicable
NR: not reported
P: prophylactic transfusion (threshold plt count x 109/L)
PCT: photochemically treated
plt: platelet
PP: pre-procedure transfusion (threshold plt count x 109/L)
STD: standard
T: therapeutic transfusion
Tx: transfusion
*: statistically significant difference in the number of platelet transfusions received per patient
#: on-protocol transfusions only
@: off-protocol transfusions only                 
 
Table 3. Bleeding assessment

StudyBleeding

scale used
Duration of

bleeding

assessment
Timing of bleeding assessment(s)Maximum number of

days of on-study

plt transfusion support
Bleeding results

reported in meta-analysis

Single transfusion studies - Intercept®

De Francisci 2004NRSNR1NR

Lozano 2011WHO1S6 hrs pre- and 6 hrs post-Tx1Post-Tx bleeding score

Simonsen 2006WHO1 (m)S≤ 12 hrs post-Tx1Post-Tx bleeding score

Slichter 2006WHO1 (m)S6 hrs pre- and 6 hrs post-Tx

 
1

 
Post-Tx bleeding score

Multiple transfusion studies - Intercept®

Agliastro 2006NRLNRNRNR

Janetzko 2005WHO1L6 hrs pre- and post- each plt Tx + daily35Max bleeding score/patient 

Kerkhoffs 2010CTCAE2LPost-1st Tx + daily42Max bleeding score/patient 

McCullough 2004WHO1 (e)L12 hrs post-Tx + daily28

 
Max bleeding score/patient 

van Rhenen 2003WHO1 (m)L6 hrs pre- and 6 hrs post-Tx56

 
Max bleeding score/patient 

Multiple transfusion studies - Mirasol®

Cazenave 2010WHO1L1 hr pre and post Tx

+ 24 hrs post-Tx +  final follow-up visit*
28Max bleeding score/patient 

 Key:
(e) = scale expanded (defined WHO grades more specifically, including sites of bleeding)
L: long-term bleeding assessment (> 7 days) post-transfusion
(m) = scale modified(only 3 scores: none = 0, minor = 1 (equivalent  to WHO grades 1 and 2), major = 2 (equivalent to WHO grades 3 and 4))
NA = not applicable
NR = not reported
plt: platelet
S: short-term bleeding assessment (up to 48 hours) post-transfusion
* = on-protocol platelet transfusions only
References:
1. WHO scale – WHO. WHO Handbook for Reporting Results of Cancer Treatment. Geneva: World Health Organisation; 1979.
2. U.S. Dept of Health and Human Services (National Institutes of Health & National Cancer Institute). Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0, September 2006.
 
Table 4. Laboratory data

StudyTiming of pre-Tx

plt count from Tx
Timing of 1-hr post-Tx

plt count (mins)
Timing of 24-hr post-Tx

plt count (hrs)
 

Timing of plt dose

measurement
CCI calculation

Single transfusion studies - Intercept®

De Francisci 2004NRNRNRNRNR

Lozano 2011Same day10 to 24016 to 24Day 5 of storageNR

Simonsen 2006≤ 6 hrs OR same day10 to 90NRPrior to storageCI x BSA/Plt dose

Slichter 2006NR60 to 12018 to 24NRCI x BSA/Plt dose

Multiple transfusion studies - Intercept®

Agliastro 2006NRNRNRNRNR

Janetzko 2005≤ 6 hrsNRNRAt issueCI x BSA/Plt dose

Kerkhoffs 2010≤ 6 hrs10 to 12016 to 28Prior to storageCI x BSA/Plt dose

McCullough 2004Same day10 to 24010 to 24NRCI x BSA/Plt dose

van Rhenen 2003NR10 to 24018 to 24At issueCI x BSA/Plt dose

Multiple transfusion studies - Mirasol®

Cazenave 2010≤ 12 hrs30 to 9018 to 26At issueCI x BSA/Plt dose

 BSA: body surface area
CCI: corrected count increment          
CI: count increment
NR: not reported
Plt: platelet
Tx: transfusion