Anthony K. C. Chan Professor, Department of Pediatrics McMaster Children’s Hospital/Hamilton Health Sciences Foundation Chair in Pediatric Thrombosis and Hemostasis Associate Chair of Research (Pediatrics) McMaster University, Hamilton, Canada How low can they go: Thrombocytopenia in Children so we need to treat

Concept Fibrinogen Fibrin FDP Thrombin Thrombomodulin Thrombin Thrombomodulin PC TAFI APC TAFIa Thrombin Prothrombin Plasmin Plasminogen Coagulation Cascade Fibrinolytic Cascade AT  2-M  2-AP AT  2-M Modified from Bajzar L Arterioscler. Thromb. Vasc. Biol. 2000;20; Platelet

FX FXa FX FV FVa prothrombin THROMBIN fibrinogen fibrin fibrin polymer FXIIIa FXIII Ca 2+ fibrin cross-linked FVII/VIIa TF Ca 2+ platelet Tissue Factor Pathway FVII/VIIa TF subendothelium FIX FIXaFVIIIa FVIII FXIa FXI FXIIa FXII Contact Pathway K PK HWMK

FX FXa FX FV FVa Tissue Factor Pathway prothrombin THROMBIN fibrinogen fibrin fibrin polymer FXIIIa FXIII Ca 2+ fibrin cross-linked FVII/VIIa TF FVII/VIIa TF Ca 2+ platelet Phospholipid Surface subendothelium FIX FIXaFVIIIa FVIII FXIa FXI FXIIa FXII Contact Pathway K PK HWMK

FX FV Tissue Factor Pathway prothrombin THROMBIN fibrinogen fibrin fibrin polymer FXIIIa FXIII Ca 2+ fibrin cross-linked FVII/VIIa TF FVII/VIIa TF subendothelium FIX FVIII FXIa FXI FXIIa FXII Contact Pathway K PK HWMK Ca 2+ platelet Tenase Complex FIXaFVIIIa FXa FVa Ca 2+ Prothrombinase Complex

Platelet function Primary Haemostasis ADHESION SECRETION PROCOAGULANT SURFACE AGGREGATION ACTIVATION

Platelet Count

Platelet Function Israels Sem Thromb Hemost 2009

vWF Katz et al., Blood 1989; 73:

AgeNo. of patients Bleeding Time (seconds) Adults90320 Bleeding Time Aversa et al., JPHO 1995; 17:25-8.

Platelets Function: Primary role is in hemostasis and thrombosis. Platelet Transfusion: Platelet transfusion is indicated to prevent hemorrhage in patients with thrombocytopenia or platelet dysfunction Platelet transfusion is indicated to treat a hemorrhage related to thrombocytopenia or platelet dysfunction Contraindications to Platelet Transfusion: TTP HIT ITP ( relative )

Neunert et al. Blood 2011; 117(16):

Initial Management of ITP Bleeding Events: No RCT using significant bleeding events (i.e. ICH) as clinical outcomes Extrapolation of available data indicate that the vast majority of children do not experience significant bleeding at follow-up Furthermore, children may develop severe bleeding despite treatment at presentation

Initial Management of ITP (Recommendation) Neunert et al. Blood 2011; 117(16):

Patient Populations Neonate Critically ill patients Children with myelosuppression Patient requiring anticoagulation

Platelet Transfusion in Adults Sharma et al. Am Fam Physician 2011, 83:719-24

Andrew et al. J Pediatr 1993, 123:285-91

Overview A multicenter prospective, RCT was conducted to determine whether early use of platelet concentrates would reduce the incidence and/or extension of ICH in sick preterm infants with thrombocytopenia. The effects on bleeding as reflected by the amount of blood product support administered and a shortened bleeding time were assessed as secondary outcomes. Andrew et al. J Pediatr 1993, 123:285-91

Method Premature infants with a platelet count <150x10 9 /L within the first 72 hours of life were randomly assigned to receive either conventional therapy or conventional therapy plus platelet concentrates (10 ml/kg). The platelet count was maintained >150x10 9 /L until day 7 of life by one to three platelet transfusions. Andrew et al. J Pediatr 1993, 123:285-91

Conclusions Although early infusion of platelet concentrates increased platelet counts and shortened bleeding times, it did not reduce the incidence or extent of ICH in premature infants. Andrew et al. J Pediatr 1993, 123:285-91

Complications The complications arising from platelet transfusions include: –febrile reactions –viral and bacterial infections –hemolysis –allergic manifestations –alloimmunization, platelet refractories –transfusion-related lung injury –death Paes et al. Nova Science Publishers Inc.

Curley et al. Neonatology 2014, 106:102-6

Objectives Platelets for Neonatal Transfusion – Study 2 (PlaNeT-2) aims to assess whether a higher prophylactic platelet transfusion threshold is superior to the lower thresholds in current standard practice in reducing the proportion of patients who have a major bleed or die up to study day 28. Curley et al. Neonatology 2014, 106:102-6

Methods PlaNet-2 compares clinical outcomes in preterm neonates (<34 weeks’ gestation at birth) randomised to receive prophylactic platelet transfusions to maintain platelet counts at or above either 25 ×10 9 /L or 50 ×10 9 /L. Curley et al. Neonatology 2014, 106:102-6

Methods The primary outcome measure is the proportion of patients who either die or experience a major bleed up to and including study day 28. A total of 660 infants will be randomised. Patients eligible for the study will be stable, non- bleeding neonates. Curley et al. Neonatology 2014, 106:102-6

Follow-up Neurodevelopmental at 2 years of corrected gestational age. Disability will be classified into three groups: –Mild –Moderate –Severe. Record of all deaths within 2 years after randomisation will be kept. Curley et al. Neonatology 2014, 106:102-6

Results and Conclusions This trial will help define optimal platelet transfusion support for severely thrombocytopenic preterm neonates by evaluating the risks and benefits of two different prophylactic neonatal platelet transfusion thresholds. Curley et al. Neonatology 2014, 106:102-6

Lieberman et al. Blood 2014, 123:

Methods Once the systematic review was complete, it became evident that there was insufficient evidence to develop recommendations for or against platelet transfusions in this setting. Conclusions were reached by consensus. Lieberman et al. Blood 2014, 123:

Results Initial literature search yielded 1471 citations. 21 studies in –neonates (n=15) –adults (n=5) –children (n=1) Lieberman et al. Blood 2014, 123:

Critically Ill Adults Lieberman et al. Blood 2014, 123:

Critically Ill Children Lieberman et al. Blood 2014, 123:

Critically Ill Preterm Neonates Lieberman et al. Blood 2014, 123:

What shall we do without recommendations derived from data Transfuse platelet for bleeding patients with thrombocytopenia Transfuse platelet for a non – bleeding pre-term neonates with platelet count 25 ×10 9 /L or 50 ×10 9 /L –With consent from the patient or parents and local circumstances

Lieberman et al. Transfusion 2014, 54:

Objectives Primary Objective: To assess RBC and platelet (PLT) utilization rates and transfusion thresholds in pediatric oncology patients. Secondary Objective: To describe transfusion-related complications including RBC alloantibody development and transfusion reactions. Lieberman et al. Transfusion 2014, 54:

Methods Epidemiologic cohort study involved pediatric oncology patients at a McMaster Children’s Hospital between April 2002 and December Demographic, clinical, laboratory, and transfusion variables were collected from the Transfusion Registry for Utilization Statistics and Tracking database. Lieberman et al. Transfusion 2014, 54:

Transfusion Thresholds Median PLT count before ordering a PLT transfusion was 16 ×10 9 /L (IQR, 10 × × 10 9 /L). Median PLT increase after a PLT transfusion was 24 ×10 9 /L (IQR, 12 × ×10 9 /L). Lieberman et al. Transfusion 2014, 54:

Transfusion Thresholds For the majority of PLT transfusions, the patients’ PLT counts were less than 25 ×10 9 /L. Lieberman et al. Transfusion 2014, 54:

Conclusion The descriptive results from this epidemiologic study provide baseline information to generate hypotheses to be tested in future interventional studies. Lieberman et al. Transfusion 2014, 54:

Crighton et al. Cochrane Database Syst Rev 2015, 9:CD010981

Conclusions Low- to moderate-grade evidence that a therapeutic-only platelet transfusion policy is associated with increased risk of bleeding when compared with a prophylactic platelet transfusion policy in haematology patients who are thrombocytopenic due to myelosuppressive chemotherapy or HSCT. Crighton et al. Cochrane Database Syst Rev 2015, 9:CD010981

Conclusions There is insufficient evidence to determine any difference in mortality rates and no evidence of any difference in adverse events between a therapeutic-only vs. prophylactic platelet transfusion policy. A therapeutic-only platelet transfusion policy is associated with a clear reduction in the number of platelet components administered. Crighton et al. Cochrane Database Syst Rev 2015, 9:CD010981

Estcourt et al. Cochrane Database Syst Rev 2012, (5) CD004269

Conclusions Platelet dose does not affect the number of patients with significant bleeding, but whether it affects number of days each patient bleeds for is as yet undetermined. No evidence that platelet dose affects the incidence of WHO grade 4 bleeding. Prophylactic platelet transfusions were more effective than platelet-poor plasma at preventing bleeding. Estcourt et al. Cochrane Database Syst Rev 2012, (5) CD004269

Conclusions No evidence that a prophylactic platelet transfusion policy prevents bleeding. No evidence, at the moment, to suggest a change from the current practice of using a platelet count of 10 x 10 9 /L. However, the evidence for a platelet count threshold of 10 x 10 9 /L being equivalent to 20 x 10 9 /L is not as definitive as it would first appear and further research is required. Estcourt et al. Cochrane Database Syst Rev 2012, (5) CD004269

Role of Platelet in Hemostasis Slichter SJ et al., Clin Haematol 1978; 7:

Thrombocytopenic Patients requiring anticoagulation therapy Most of the adult literature suggest using 50 x10 9 /L Suggest to use 30 x10 9 /L for initiation of anticoagulation therapy in children

Transfusion Platelet transfusion threshold for prophylaxis remains to be determined –Depends on etiology of thrombocytopenia –Depends on the circumstances Type of surgery ; tolerance of risk Clinical status Much research is required in the area of transfusion