Platelets and PlaNeT-2

Platelets and coagulation Damaged endothelium PLATELETS Adenosine diphosphate (calling effect) CollagenFibrinogen ↓ ↓ PLATELETS ↓ ↓

Thrombocytopenia: Platelet count of <150x10 9 /L in a neonate of any gestational age Severe thrombocytopenia: Platelet count of <50x10 9 /L Thrombocytopenia

Neonatal Thrombocytopenia Prevalence: 1 - 5% of all newborns 25% NICU admissions 5-10% severe thrombocytopenia

Neonatal Thrombocytopenia: Main causes Fetal: Alloimmune Congenital infection Aneuploidy Early-onset (<72 hours): Chronic fetal hypoxia Perinatal asphyxia Perinatal infection Late-onset (>72 hours): Late-onset sepsis NEC

Neonatal Thrombocytopenia Why don’t neonates up-regulate platelet production when they have consumptive disorders? ? ? ? ? ? ? ? ? ? Developmental deficiency ? Disease process ? Cell-intrinsic differences ? Hematopoietic environment

Neonatal Thrombocytopenia: In 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)

PlaNeT-1 Prospective observational study of NICU admissions with platelet counts <60x10 9 /L 7 NICUs 169 neonates studied for 7 days, or until platelets >60x10 9 /L  Platelet count  Haemorrhage  Platelet transfusions  Outcome Stanworth et al (2009)

PlaNeT-1: Haemorrhage

PlaNeT-1: Lowest Platelet Counts (++) indicates group median and (- -) IQR

2/3 received platelet transfusion Most transfusions given as prophylaxis often well after “risk period” for haemorrhage has passed PlaNeT-1: Transfusions

Moving forward!

PlaNeT-2 Platelets for Neonatal Transfusion - Study 2

PlaNeT-2 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.

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

PlaNeT-2: Choosing platelet thresholds Last RCT done by Andrew et al (1993) assessed x10 9 /L vs. >150x10 9 /L PlaNeT-1 (2009): Most transfusions given at platelets 10–50x10 9 /L. 50 th and 90 th centile pre-transfusion platelet counts 27 and 48x10 9 /L. 42% transfusions <25x10 9 /L and 92% <50x10 9 /L

Arm A Standard: transfuse platelets at <25x10 9 /L (330 neonates) Arm B Intervention: transfuse platelets at <50x10 9 /L (330 neonates) Dose: 15ml/kg for both arms PlaNeT-2: Platelet thresholds

PlaNeT-2: Additional Platelet Transfusions May be considered under the following circumstances: Therapeutically to treat moderate, major or severe bleeding 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.

Admission to a participating NICU (includes postnatal transfers) <34 weeks GA at birth Platelet count of <50 x10 9 /L Cranial ultrasound scan: undertaken <6 hours before randomisation to exclude recent major IVH PlaNeT-2: Inclusion criteria

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

PlaNeT-2: Consent and randomisation Consent:  Parents/ guardians will be counselled when platelets <100x10 9 /L.  Written, informed consent will be obtained. Randomisation: only when platelet count <50x10 9 /L. For neonates with an initial platelet count of <50x10 9 /L, parents will be approached for consideration of immediate study participation.

PlaNeT-2: Data collection schedule

PlaNeT-2: Data collection (I) When the consent is signed and platelets <50x10 9 /L:  Pre-randomisation form (F1)  Eligibility for randomisation (F2)  Current medical conditions & previous major bleeds (F3)  Randomisation (F4)

Daily Bleeding Assessment Tool (BAT) (F5)  During Ward Round  Daily until Study Day (SD) 14 Daily Platelet Count (F6) until SD28 Weekly Data Collection (F7)  Weekly from SD14 until the end of the study Cranial Ultrasounds: Weekly for 4 weeks At SD7, SD14, SD21 and SD28 PlaNeT-2: Data collection (II)

PlaNeT-2: BAT Completed for 14 days during Ward Round Nursing records and communication

PlaNeT-2: Data collection (II) For randomised babies:  Study day 7: Cranial USS  Study day 14: Cranial USS Last day for BAT (F5)  Study day 21: Cranial USS  Study day 28:Cranial USS Last day for Daily Platelet Count (F6)  Weekly Data Collection (F7) until end of study

PlaNeT-2: Data collection (III) Forms for completion as required:  Platelet Transfusion Data (F8)  NEC/Sepsis Form (F9)  Discontinuation of Treatment Allocation (F10)  Major/Severe Bleed (F13)  Serious Adverse Event (F14)  Serious Platelet Transfusion Related Adverse Event (F15)

PlaNeT-2: Serious Adverse Events (SAE) in death is life-threatening and 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 A SAE is an adverse event that results:

Data collection will cease and an End of Study Form will be completed at 38 weeks gestational age or time of discharge home PlaNeT-2: End of study

PlaNeT-2: Data collection (cont.) End of study:  Cranial Ultrasound at End of Study (F11)  End of Study (F12)

PlaNeT-2: Weekly Assessment Tool

Summary Platelets are responsible for the initial cessation of bleeding Thrombocytopenia in NICU is common and its reasons unknown PlaNeT-2 is a trial to compare two platelet count threshold for prophylactic transfusion PlaNeT-2 aims to improve platelet transfusion practice

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. 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. Manco-Jonhson M, Rodden DJ, Collins SM. ‘Newborn hematology’, in Merenstein GB, Gardner SL. Handbook of Neonatal Intensive Care. 6 th ed. Mosby Elsevier: St. Louis, pp Roberts I, Stanworh S, Murray NA. (2008) Thrombocytopenia in the neonate. Blood reviews Roberts I, Murray NA. (2003) Neonatal thrombocytopenia: causes and management. Archives of diseases in childhood - Fetal and neonatal edition 88 F359-F364. Sola-Visner M, Sallmon H, Brown R. (2009) New insights into the mechanisms of nonimmune thrombocytopenia in neonates. Seminars in Perinatology 33(1) Sola-Visner M, Saxonhouse MA, Brown R. (2008) Neonatal thrombocytopenia: what we do and don’t know. Early Human Development 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. 4 th ed. Norwich: The Stationary Office. [online]. Available from:

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