1. Platelets for Neonatal Transfusion Study 2 (PlaNeT-2):
Training Update
A randomised controlled trial of platelet transfusion thresholds
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2. Neonatal Thrombocytopenia
Prevalence: 1 - 5% of all newborns
25% NICU admissions
5-10% severe thrombocytopenia
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3. Neonatal Thrombocytopenia: Current Evidence (I)
RCT; n= 152
<1500g; GA < 33weeks; Platelet count
Arm 1: Plt Tx to keep platelet count >150x109/L
Arm 2: Plt Tx at threshold count x109/L
No evidence ‘aggressive’ prophylaxis influenced incidence or extension of IVH
Andrew et al (1993)
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4. Neonatal Thrombocytopenia: Current Evidence (II)
No increased haemorrhage irrespective of whether platelets were administered
Murray et al (2002)
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5. Neonatal Thrombocytopenia: Current Evidence (III)
Retrospective Cohort Analysis of neonates with NEC and platelets <100x109/L
Results suggested platelet transfusions in infants with NEC associated with greater morbidity
Kenton et al (2005)
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6. Neonatal Thrombocytopenia: Current Evidence (IV)
Baer et al (2007)
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7. Neonatal Thrombocytopenia: Current Practice
Current national transfusion guidance based on consensus rather than evidence
British Committee for Standards in Haematology (2004)
United Kingdom Blood Services (2007)
Survey in the UK showed wide variation in platelet transfusion practice
Chaudhary and Clarke (2008)
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8. PlaNeT-1: A Study of Outcomes
Prospective observational study of NICU admissions with platelet counts <60x109/L
7 NICUs
169 neonates studied for 7 days, or until platelets >60x109/L
Platelet count
Haemorrhage
Platelet transfusions
Outcome
Stanworth et al (2009)
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9. PlaNeT-1: Haemorrhage
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10. (++) indicates group median and (- -) IQR
PlaNeT-1: Lowest Platelet Counts
(++) indicates group median and (- -) IQR
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(++) indicates group median and (- -) IQR

11. PlaNeT-1: Transfusions
2/3 received platelet transfusion
Most transfusions given as prophylaxis often well after “risk period” for haemorrhage has passed
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12. Moving forward!
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13. PlaNeT-2 Platelets for Neonatal Transfusion - Study 2
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14. PlaNeT-2: Study design (I)
Two-stage, randomised, parallel group, superiority trial.
Aim: to compare two different platelet count thresholds for prophylactic platelet transfusion to preterm neonates.
Primary Outcome:
Proportion of patients who either die or experience a major bleed up to and including study day 28.
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15. PlaNeT-2: Study design (II)
Secondary Outcomes:
Proportion of neonates surviving to home following a major bleed
Mortality prior to day 28
Major bleeds by day 28
Platelets transfused to study day 28
Length of hospital stay
Transfusion-related adverse events
Neuro-developmental outcome
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16. PlaNeT-2: Platelet thresholds
Arm A Standard: transfuse platelets at <25x109/L
(330 neonates)
Arm B Intervention: transfuse platelets at <50x109/L
Dose: 15 ml/kg
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17. PlaNeT-2: Additional platelet transfusions
May be considered under the following circumstances:
Therapeutically to treat major bleeding, following objective and documented signs of clinically relevant bleeding graded as moderate, major or severe, but not for minor bleeding.
Prior to planned invasive procedures as below only
Suprapubic aspiration
Lumbar puncture
Major surgery where haemostasis may be critical to outcome.
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18. Modified WHO Bleeding Assessment Score
Grade 1 – Minor Haemorrhage
Any bleed from the
skin, umbilical cord, skin around stoma, surgical scar, mucosa.
Any pink frothy or old bleed from the ET tube.
H1 haemorrhage on cranial US (Germinal Layer Haemorrhage, GLH)
Grade 2 – Moderate Haemorrhage
Any frank bleed from
the stoma
macroscopic haematuria,
IVH (H2 or H3) without dilatation (V0),
Acute fresh bleed through ETT without ventilatory changes
Grade 3 – Major Haemorrhage any:
Frank Rectal
Acute fresh bleed through ETT with ventilatory change.
Intracranial bleed An intracranial bleed is defined as a major bleed if any of the following apply: Neurosurgical intervention is required; Scans show a midline shift; Clinical signs and symptoms of neurolgical deficit with significant derangement of laboratory investigations
Major IVH is defined as H2 or H3 with ventricular dilatation (V1); H1, H2, H3 with parenchymal involvement (P3) ; Any evolution of intracranial haemorrhage to H2V1, H3V1, or (H1, H2, H3) with parenchymal involvement (P3)
Grade 4 – Severe Haemorrhage
Shock defined as life threatening major bleed associated with hypotension, hyopovolaemia or any other haemodynamic instability and/or bleeding requiring volume boluses, red cell transfusion in the same 24 hours, fatal major bleeding
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19. PlaNeT-2: Inclusion criteria
Admission to a participating NICU (includes postnatal transfers)
<34 weeks GA at birth
Platelet count of <50 x109/L
Cranial ultrasound scan: undertaken <6 hours before randomisation to exclude recent major IVH
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20. PlaNeT-2: Exclusion criteria
Major/life-threatening congenital malformations
Recent major haemorrhage within the last 72 hours
All fetal intracranial haemorrhages
Known immune thrombocytopenia
Neonates unlikely to survive
Neonates not given parenteral vitamin K
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21. PlaNeT-2: Consent When platelets <100x109/L
Parents will be counselled
Written, informed consent will be obtained
Documented in the clinical notes
Three copies signed:
For parents
For the clinical notes with Parent Information Sheet
For the study file
When platelets <50x109/L
Parents will be approached for consideration of immediate study participation.
Show <100 PLT pack
Document on PlaNeT-2 log book
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22. PlaNeT-2: Randomisation
When the consent is signed and platelets <50x109/L:
Pre-randomisation Platelet transfusion information (FA)
Pre-randomisation form (F1)
Eligibility for randomisation (F2)
Current medical conditions & previous major bleeds (F3)
Randomisation (F4)
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23. FA – Platelet transfusion information
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24. F1 – Pre-randomisation
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25. F2 – Eligibility for randomisation
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26. F3 – Current medical conditions And previous major bleeds
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27. F4 – Randomisation
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28. PlaNeT-2: Data collection (I)
SD1
BAT
SD2
SD3
SD4
SD5
SD6
SD7
USS
SD8
SD9
SD10
SD11
SD12
SD13
SD14
SD15
BAT
SD16
SD17
SD18
SD19
SD20
SD21
USS
SD22
SD23
SD24
SD25
SD26
SD27
SD28
SD29
SD30
SD31
SD32
SD33
SD34
SD35
Weekly
SD36
SD37 …
END
USS
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29. F5 – Bleeding Assessment Tool (BAT)
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30. F7 – Weekly Data Collection
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31. PlaNeT-2: Data collection (II)
Platelet Transfusion Data (F8)
Necrotising enterocolitis (NEC) /Sepsis Form (F9)
Discontinuation of Treatment Allocation (F10)
Major/Severe Bleed (F13)
Serious Adverse Event (F14)
Serious Platelet Transfusion Related Adverse Event (F15) F8 F9
F10
F13
F14
F15
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32. F8 – Platelet Transfusion Data
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33. PlaNeT-2: NEC/Sepsis form
Necrotising enterocolitis ≥ Stage 2 defined as per Bells Criteria (Bell et al,1978)
Sepsis: culture positive sepsis or culture negative sepsis where a course of at least 5 days of antibiotics is to be administered for proven or clinically-suspected sepsis.
All episodes of NEC and sepsis must be recorded on the adverse event form
A listing of adverse events will be reported six monthly to the Independent Data Monitoring Committee.
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34. F9 – NEC/Sepsis form
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35. F10 – Discontinuation of Treatment Allocation
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36. PlaNeT-2: Major/Severe bleed form
All new major bleeding events will be reported to the CSU without disclosing allocation arm.
Each report will be forwarded to the Independent Data Monitoring Committee for review as soon as it is received at the CSU.
In cases of uncertainty the local team may contact one of the CIs or neonatal medical experts.
MAJOR BLEED FORM
Within one working day of becoming aware of an Major Bleed, please fax a completed Major Bleed form to the NHSBT/MRC CSU
Fax:

37. F13 – Major/Severe Bleed
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38. PlaNeT-2: Serious Adverse Event (SAE)
A SAE is an adverse event that results:
in death
is life-threatening
requires hospitalisation or prolongation of existing hospitalisation (including readmission within 28 study days if discharged home earlier)
there is a likelihood of persistent or significant disability or incapacity
SAE NOTIFICATION
Within one working day of becoming aware of an SAE, please fax a completed SAE form to the NHSBT/MRC CSU
Fax:

39. F14 – Serious Adverse Event
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40. transfusion related adverse event
PlaNeT-2: Serious platelet
transfusion related adverse event
Data collected on serious transfusion related adverse reactions/events will be based on current definitions used by hospitals reporting to UK national haemovigilance reporting schemes (SHOT and MHRA).
These definitions cover the following:
Incorrect blood component transfused
Acute transfusion reactions
Transfusion Related Acute Lung Injury (TRALI)
Transfusion transmitted infections, including bacterial transmission
Transfusion Associated Circulatory Overload (TACO)
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41. transfusion related adverse event
F15 – Serious platelet
transfusion related adverse event
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42. PlaNeT-2: End of study
Data collection will cease when the baby is 38 weeks corrected gestational age or time of discharge home
Cranial Ultrasound at End of Study (F11)
End of Study (F12)
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43. F11 – Cranial USS at the end of study
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44. F12 – End of study
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45. PlaNeT-2: Transfer out of recruiting unit
Inform the local PlaNeT-2 team if neonate transferred out of recruiting unit
Keep all the forms, do not send them with the patient
Receiving hospital should:
Collect information as required by the protocol thereafter until 38 weeks CGA or discharge.
Continue to give any required platelet transfusions according to the randomised platelet threshold.
Do not send any PlaNeT-2 forms
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46. PlaNeT-2: Data Quality NHSBT CTU Black ink
For platelet count use the date and time the sample is received in the lab
Do not leave blank fields, enter leading zeros
Any data incorrectly recorded must be crossed through with a single line and the correct value documented by the side. All corrections must be initialled and dated by the individual making the changes
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47. PlaNeT-2: Two years follow up
Thames Regional Perinatal Outcome Group/ Standard Electronic Neonatal Database/ National Neonatal Audit Programme (TRPG/SEND/NNAP) 2- year corrected age outcome form
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48. PlaNeT-2: Research & Development and Ethics approval
Ethics approval obtained from the regional ethics committee
NIHR adopted
CLRN adopted
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49. PlaNeT-2: Trial Governance
The Trial Management Group (TMG) will be responsible for the daily management of the trial.
The TMG is responsible to the Trial Steering Committee which has oversight of the trial and provides advice as needed
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50. PlaNeT-2: TMG Group Louise Choo Priya Muthukumar Paul Clarke Helen New
Anna Curley
Alison Deary
Rizwan Khan
Renate Hodge
Priya Muthukumar
Helen New
Simon Stanworth
Vidheya Venkatesh
Tim Watts
Karen Willoughby
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51. PlaNeT-2: Trial Steering Committee
This trial will be overseen by a Trial Steering Committee
Prof Colin Morley Independent Chair and Retired Professor of Neonatology
Dr Sandy Calvert Independent Consultant Neonatologist
Dr Anthony Emmerson Independent Consultant Neonatologist
Dr Anna Curley Consultant Neonatologist and joint CI
Dr Simon Stanworth Consultant Haematologist and joint CI
Dr Louise Choo CSU Statistician
TBA Parent Representative(s)
Dr Charlotte Llewelyn CSU Manager
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52. PlaNeT-2: Independent Data Monitoring Committee
An Independent Data Monitoring Committee will review safety data and trial progress on a six monthly basis.
In addition, all SAEs and major bleeds will be reviewed as they are reported to the CSU.
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53. PlaNeT-2: Finance
The trial is funded by a Project Grant from the NHSBT which is administered by the National Research & Development Committee.
Any payments will be made to participating centres to cover costs associated with the undertaking of this trial, as specified in Individual Investigator Site Agreements.
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54. PlaNeT-2: Communications
For general trial queries: contact
Karen Willoughby copy to
For medical queries regarding transfusions, SAEs, grading major/severe bleeds or transfusion reactions contact
Simon Stanworth: or
Anna Curley:
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55. References
Andrew M, Vegh P, Caco C, Kirpalani H, Jeffries A, Ohlsson A, Watts J, Sagial S, Milner R, Wang EA. (1993) Randomised controlled trial of platelet transfusions in thrombocytopenic premature infants. Journal of Pediatrics –291.
Baer VL, Lambert DK, Henry E, Snow GL, Sola-Visner MC, Christensen RD (2007) Do platelet transfusions in the NICU adversely affect survival? Analysis of 1600 thrombocytopenic neonates in a multihospital healthcare systemMultiple platelet transfusions and survival. Journal of Perinatology
British Committee for Standards in Haematology (2004) Transfusion Guidelines for neonates and older children. British Journal of Haematology
Chaudhary R, Clarke P. (2008) Current transfusion practices for platelets and fresh, frozen plasma in UK tertiary level neonatal units. Acta Pædiatrica 97(1) 135.
Kenton AB, Hegemier S, Smith EO, O'Donovan DJ, Brandt ML, Cass DL, Helmrath MA, Washburn K, Weihe EK, Fernandes CJ (2005) Platelet transfusions in infants with necrotizing enterocolitis do not lower mortality but may increase morbidity. Journay of Perinatology 25(3) 173–177
Murray NA, Howarth LJ, McCloy MP, Letsky EA, Roberts IAG (2002) Platelet transfusion in the management of severe thrombocytopenia in neonatal intensive care unit patients. Transfusion Medicine 12(1)
Stanworth S, Clarke P, Watts T, Ballard S, Choo L, Morris T, Murphy MF, Roberts I (2009) Prospective, observational study of outcomes in neonates with severe thrombocytopenia. Pediatrics
United Kingdom Blood Services (2007) Handbook of Transfusion Medicine. 4th ed. Norwich: The Stationary Office. [online]. Available from:
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56. Thank you!
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