Australian and New Zealand consensus guideline for paediatric newly diagnosed immune thrombocytopaenia endorsed by Australian New Zealand Children's Haematology and Oncology Group.

In children, the majority of cases are self-limiting and thus many paediatric patients can be managed conservatively with minimal complications. This varies considerably compared to adult newly diagnosed immune thrombocytopaenia (NDITP) where, in most cases, thrombocytopaenia persists with higher risk of moderate to severe bleeding complications. In the past decade, local and international guidelines have emerged to support approaches to the investigation and management of NDITP, with a focus primarily on adult immune thrombocytopaenia (ITP). International consensus guidelines on paediatric NDITP have been developed, however gaps remain, and approaches vary between North American, Asia, Europe and the UK. There are no current Australian or New Zealand paediatric ITP guidelines readily available, rather differing guidelines for each state, territory or island. These inconsistencies cause uncertainty for patients, families and physicians managing cases. Subsequently, physicians, including paediatric haematologists and general paediatricians, have come together to provide a consensus approach guideline specific to paediatric NDITP for Australian or New Zealand. Persistent or chronic paediatric ITP remains a complex and separate entity and are not discussed here.

International guidelines regarding the role of IVIG in the management of Rh- and ABO-mediated haemolytic disease of the newborn.

Haemolytic disease of the newborn (HDN) can be associated with significant morbidity. Prompt treatment with intensive phototherapy (PT) and exchange transfusions (ETs) can dramatically improve outcomes. ET is invasive and associated with risks. Intravenous immunoglobulin (IVIG) may be an alternative therapy to prevent use of ET. An international panel of experts was convened to develop evidence-based recommendations regarding the effectiveness and safety of IVIG to reduce the need for ETs, improve neurocognitive outcomes, reduce bilirubin level, reduce the frequency of red blood cell (RBC) transfusions and severity of anaemia, and/or reduce duration of hospitalization for neonates with Rh or ABO-mediated HDN. We used a systematic approach to search and review the literature and then develop recommendations from published data. These recommendations conclude that IVIG should not be routinely used to treat Rh or ABO antibody-mediated HDN. In situations where hyperbilirubinaemia is severe (and ET is imminent), or when ET is not readily available, the role of IVIG is unclear. High-quality studies are urgently needed to assess the optimal use of IVIG in patients with HDN.

Plasma and Platelet Transfusion Strategies in Critically Ill Children Following Noncardiac Surgery and Critically Ill Children Undergoing Invasive Procedures Outside the Operating Room: From the Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding.

OBJECTIVES: To present consensus statements and supporting literature for plasma and platelet transfusions in critically ill children following noncardiac surgery and critically ill children undergoing invasive procedures outside the operating room from the Transfusion and Anemia EXpertise Initiative - Control/Avoidance of Bleeding. DESIGN: Systematic review and consensus conference of international, multidisciplinary experts in platelet and plasma transfusion management of critically ill children. SETTING: Not applicable. PATIENTS: Critically ill children undergoing invasive procedures outside of the operating room or noncardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A panel of 10 experts developed evidence-based and, when evidence was insufficient, expert-based statements for plasma and platelet transfusions in critically ill children following noncardiac surgery or undergoing invasive procedures outside of the operating room. These statements were reviewed and ratified by the 29 Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding experts. A systematic review was conducted using MEDLINE, EMBASE, and Cochrane Library databases, from inception to December 2020. Consensus was obtained using the Research and Development/University of California, Los Angeles Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. We developed eight expert consensus statements focused on the critically ill child following noncardiac surgery and 10 expert consensus statements on the critically ill child undergoing invasive procedures outside the operating room. CONCLUSIONS: Evidence regarding plasma and platelet transfusion in critically ill children in this area is very limited. The Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding Consensus Conference developed 18 pediatric specific consensus statements regarding plasma and platelet transfusion management in these critically ill pediatric populations.

Plasma and Platelet Transfusion Strategies in Critically Ill Children With Malignancy, Acute Liver Failure and/or Liver Transplantation, or Sepsis: From the Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding.

OBJECTIVES: To present the consensus statements with supporting literature for plasma and platelet transfusions in critically ill neonates and children with malignancy, acute liver disease and/or following liver transplantation, and sepsis and/or disseminated intravascular coagulation from the Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding. DESIGN: Systematic review and consensus conference of international, multidisciplinary experts in platelet and plasma transfusion management of critically ill children. SETTING: Not applicable. PATIENTS: Critically ill neonates and children with malignancy, acute liver disease and/or following liver transplantation, and sepsis and/or disseminated intravascular coagulation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A panel of 13 experts developed evidence-based and, when evidence was insufficient, expert-based statements for plasma and platelet transfusions in critically ill neonates and children with malignancy, acute liver disease and/or following liver transplantation, and sepsis and/or disseminated intravascular coagulation. These statements were reviewed and ratified by the 29 Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding experts. A systematic review was conducted using MEDLINE, EMBASE, and Cochrane Library databases, from inception to December 2020. Consensus was obtained using the Research and Development/University of California, Los Angeles Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. We developed 12 expert consensus statements. CONCLUSIONS: In the Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding program, the current absence of evidence for use of plasma and/or platelet transfusion in critically ill children with malignancy, acute liver disease and/or following liver transplantation, and sepsis means that only expert consensus statements are possible for these areas of practice.

Research Priorities for Plasma and Platelet Transfusion Strategies in Critically Ill Children: From the Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding.

OBJECTIVES: To present a list of high-priority research initiatives for the study of plasma and platelet transfusions in critically ill children from the Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding. DESIGN: Systematic review and consensus conference of international, multidisciplinary experts in platelet and plasma transfusion management of critically ill children. SETTING: Not applicable. PATIENTS: Critically ill pediatric patients at risk of bleeding and receiving plasma and/or platelet transfusions. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A panel of 13 experts developed research priorities for the study of plasma and platelet transfusions in critically ill children which were reviewed and ratified by the 29 Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding experts. The specific priorities focused on the following subpopulations: severe trauma, traumatic brain injury, intracranial hemorrhage, cardiopulmonary bypass surgery, extracorporeal membrane oxygenation, oncologic diagnosis or stem cell transplantation, acute liver failure and/or liver transplantation, noncardiac surgery, invasive procedures outside of the operating room, and sepsis and/or disseminated intravascular coagulation. In addition, tests to guide plasma and platelet transfusion, as well as component selection and processing, were addressed. We developed four general overarching themes and 14 specific research priorities using modified Research and Development/University of California, Los Angeles methodology. CONCLUSIONS: Studies are needed to focus on the efficacy/harm, dosing, timing, and outcomes of critically ill children who receive plasma and/or platelet transfusions. The completion of these studies will facilitate the development of evidence-based recommendations.

Executive Summary of Recommendations and Expert Consensus for Plasma and Platelet Transfusion Practice in Critically Ill Children: From the Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding (TAXI-CAB).

OBJECTIVES: Critically ill children frequently receive plasma and platelet transfusions. We sought to determine evidence-based recommendations, and when evidence was insufficient, we developed expert-based consensus statements about decision-making for plasma and platelet transfusions in critically ill pediatric patients. DESIGN: Systematic review and consensus conference series involving multidisciplinary international experts in hemostasis, and plasma/platelet transfusion in critically ill infants and children (Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding [TAXI-CAB]). SETTING: Not applicable. PATIENTS: Children admitted to a PICU at risk of bleeding and receipt of plasma and/or platelet transfusions. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A panel of 29 experts in methodology, transfusion, and implementation science from five countries and nine pediatric subspecialties completed a systematic review and participated in a virtual consensus conference series to develop recommendations. The search included MEDLINE, EMBASE, and Cochrane Library databases, from inception to December 2020, using a combination of subject heading terms and text words for concepts of plasma and platelet transfusion in critically ill children. Four graded recommendations and 49 consensus expert statements were developed using modified Research and Development/UCLA and Grading of Recommendations, Assessment, Development, and Evaluation methodology. We focused on eight subpopulations of critical illness (1, severe trauma, intracranial hemorrhage, or traumatic brain injury; 2, cardiopulmonary bypass surgery; 3, extracorporeal membrane oxygenation; 4, oncologic diagnosis or hematopoietic stem cell transplantation; 5, acute liver failure or liver transplantation; 6, noncardiac surgery; 7, invasive procedures outside the operating room; 8, sepsis and/or disseminated intravascular coagulation) as well as laboratory assays and selection/processing of plasma and platelet components. In total, we came to consensus on four recommendations, five good practice statements, and 44 consensus-based statements. These results were further developed into consensus-based clinical decision trees for plasma and platelet transfusion in critically ill pediatric patients. CONCLUSIONS: The TAXI-CAB program provides expert-based consensus for pediatric intensivists for the administration of plasma and/or platelet transfusions in critically ill pediatric patients. There is a pressing need for primary research to provide more evidence to guide practitioners.

Pediatric Fibrinogen PART I-Pitfalls in Fibrinogen Evaluation and Use of Fibrinogen Replacement Products in Children.

Fibrinogen is a key coagulation protein, playing a critical role in hemostasis. It is the first factor to decrease to critical levels during bleeding. Hypofibrinogenemia is an important risk factor for bleeding in clinical settings, including pediatric surgery. Yet, the optimal measurement of fibrinogen levels is subject to debate, as is the critical threshold for intervention. Fibrinogen replacement may be provided by cryoprecipitate and fibrinogen concentrate. Whilst both products contain fibrinogen, they are not equivalent, each has its own advantages and disadvantages, especially for pediatric use. Unfortunately, medical literature to support fibrinogen replacement in children is limited. In this article we review the current diagnostic tools to measure fibrinogen, with respect to their use in the pediatric critical care setting. Secondly, we evaluate the different fibrinogen replacement therapies, focusing on cryoprecipitate and fibrinogen concentrate and examine their individual product characteristics, associated risks and benefits, different dosing strategies and specific pitfalls for use in children. We summarize by highlighting current knowledge gaps and areas for future research.

Pediatric Fibrinogen PART II-Overview of Indications for Fibrinogen Use in Critically Ill Children.

Bleeding is frequently seen in critically ill children and is associated with increased morbidity and mortality. Fibrinogen is an essential coagulation factor for hemostasis and hypofibrinogenemia is an important risk factor for bleeding in pediatric and adult settings. Cryoprecipitate and fibrinogen concentrate are often given to critically ill children to prevent bleeding and improve fibrinogen levels, especially in the setting of surgery, trauma, leukemia, disseminated intravascular coagulopathy, and liver failure. The theoretical benefit of fibrinogen supplementation to treat hypofibrinogenemia appears obvious, yet the evidence to support fibrinogen supplementation in children is sparce and clinical indications are poorly defined. In addition, it is unknown what the optimal fibrinogen replacement product is in children and neonates or what the targets of treatment should be. As a result, there is considerable variability in practice. In this article we will review the current pediatric and applicable adult literature with regard to the use of fibrinogen replacement in different pediatric critical care contexts. We will discuss the clinical indications for fibrinogen supplementation in critically ill children and the evidence to support their use. We summarize by highlighting current knowledge gaps and areas for future research.

Changes in emergency department blood product use for major paediatric trauma following the implementation of a major haemorrhage protocol.

OBJECTIVE: Fixed ratio blood product administration may improve outcomes in trauma patients with massive blood loss. The present study aimed to describe the impact of a major haemorrhage protocol (MHP) on the ratio of blood products administered for paediatric major trauma. METHODS: Retrospective observational study in a state-designated paediatric major trauma centre in Melbourne, Australia. Children with major trauma who received blood products in the ED were identified from a hospital trauma registry. Blood product ratios before, during and after implementation of a hospital MHP were compared in consecutive 2 year blocks. RESULTS: Over a 6 year period, 767 major trauma patients were identified, of whom 47 received blood products in the ED and were included in the analysis; 14 pre-MHP implementation, 24 during-MHP implementation and nine post-MHP implementation. No patients received blood products at a ratio of 1:1:1 for red blood cells:fresh frozen plasma:platelets, respectively, during any time period. In this cohort of predominantly blunt trauma, blood products were infrequently administered in the ED because of the low prevalence of massive blood loss. Coagulopathy and hypofibrinogenaemia were commonly observed, nearly half of included patients were managed operatively and one quarter did not survive their injuries. CONCLUSION: The implementation of a MHP did not change the ratio of blood product administration in this cohort of patients because of the infrequency of massive blood loss. Future studies may focus on the impact of treating coagulopathy and hypofibrinogenaemia on patient-centred outcomes.

Blood transfusion following major orthopaedic surgery in cerebral palsy: a retrospective analysis.

BACKGROUND: Progressive musculoskeletal pathology is ubiquitous among children with cerebral palsy (CP). Corrective surgery places them at risk of major blood loss and red blood cell (RBC) transfusion. Significant variability exists in uptake of perioperative patient blood management (PBM) strategies. This study aimed to examine factors contributing to RBC transfusion and assist in future development of care pathways. METHODS: A retrospective review at a tertiary paediatric hospital was undertaken to identify patients with CP undergoing either primary spinal fusion or single event, multilevel surgery (SEMLS) between 2010 and 2015. Solely soft tissue procedures were excluded. Data collected included demographics, Gross Motor Function Classification System level, surgical details, perioperative PBM and transfusion rates. Univariable analysis was performed to assess contributing factors to RBC transfusion. RESULTS: A total of 36 spinal fusion and 98 SEMLS patients were included. Preoperatively, 12% were anaemic, but only 19% had a ferritin checked. Overall, 49 patients (37%) received RBC transfusions. Intraoperative usage of tranexamic acid and cell salvage was 89% and 81%, respectively, for the spine cohort, and 22% and 3% for the SEMLS cohort. Successively higher Gross Motor Function Classification System levels, sodium valproate usage, longer surgical times, spinal fusion, pelvis instrumentation and more osteotomies were associated with RBC transfusion. CONCLUSION: More than one-third of CP patients who underwent major orthopaedic surgery received RBC transfusion. As expected, the more severely affected patients undergoing longer procedures were at highest risk. Significant improvements can be made in PBM to help optimize patients for surgery and minimize the need for transfusion.

Optimal Dose, Timing and Ratio of Blood Products in Massive Transfusion: Results from a Systematic Review.

Optimal dose, timing and ratio to red blood cells (RBC) of blood component therapy (fresh frozen plasma [FFP], platelets, cryoprecipitate or fibrinogen concentrate) to reduce morbidity and mortality in critically bleeding patients requiring massive transfusion is unknown. We performed a systematic review for randomized controlled trials (RCT) in MEDLINE, The Cochrane Library, Embase, CINAHL, PubMed the Transfusion Evidence Library and using multiple clinical trials registries to 21 February 2017. Sixteen RCTs were identified: six completed (five in adult trauma patients, one pediatric burn patients) and ten ongoing trials. Of the completed trials: three were feasibility trials, comparing a FFP, platelets and RBC ratio of 1:1:1 to laboratory-guided transfusion practice [n=69], early cryoprecipitate compared to standard practice [n=41], and early fibrinogen concentrate compared to placebo [n=45]; one trial compared the effect of FFP, platelets and RBC ratio of 1:1:1 with 1:1:2 on 24-hour and 30-day mortality [n=680]; one compared whole blood to blood component therapy on 24-hour blood use [n=107]; one compared a FFP to RBC ratio of 1:1 with 1:4 [n=16]. Data from two trials were pooled in a meta-analysis for 28-day mortality because the transfusion ratios achieved were similar. Results from these two trials suggest higher transfusion ratios were associated with transfusion of more FFP and platelets without evidence of significant difference with respect to mortality or morbidity. On the limited evidence available, there is insufficient basis to recommend a 1:1:1 over a 1:1:2 ratio or standard care for adult patients with critical bleeding requiring massive transfusion.

Contemporary management of neonatal alloimmune thrombocytopenia: good outcomes in the intravenous immunoglobulin era: results from the Australian neonatal alloimmune thrombocytopenia registry.

OBJECTIVE: To describe the natural history, antenatal and postnatal therapy, and clinical outcomes of Australian patients with fetomaternal/neonatal alloimmune thrombocytopenia (NAIT) recorded in the Australian NAIT registry. METHODS: Analysis of registry data of Australian mothers treated antenatally for NAIT and any fetus/newborn with thrombocytopenia (TCP) and maternal human platelet antigen (HPA) antibodies. RESULTS: Ninety four potential cases (91 pregnancies; three twin pregnancies) were registered between December 2004 and September 2015 with 76 confirmed or treated as NAIT. NAIT was frequently unanticipated (44 cases, 58%), whilst 32 cases (42%) were anticipated due to personal or family history. In 70/76 cases, the diagnosis of NAIT was made based on HPA antibody results; anti-HPA-1a was most commonly detected (58/70, 82%), followed by anti-HPA-5b (5/70, 7%). Intracranial haemorrhage (ICH) was detected in seven cases (9%). Maternal antenatal therapy resulted in improved clinical outcomes. For antenatally treated cases, whilst 10/29 (34%) neonates had severe TCP, only one ICH was detected. CONCLUSIONS: This study provides data on contemporary "real world" management of Australian mothers and babies with NAIT. Antenatal IVIG therapy was associated with better neonatal outcomes. Maternal side-effects and treatment costs were substantial.

Platelet Transfusions in Patients with Hypoproliferative Thrombocytopenia: Conclusions from Clinical Trials and Current Controversies.

Patients with hematologic malignancies frequently become thrombocytopenic as a result of their underlying malignancy or treatments, including cytotoxic chemotherapy and hematopoietic stem cell transplantation and are at increased risk of hemorrhage. Prophylactic platelet transfusions are aimed at preventing severe or life-threatening hemorrhage. This review summarizes recent evidence, including the need for prophylactic platelet transfusions, the optimal dose, platelet transfusion triggers, and risk factors for bleeding. It also discusses controversies surrounding platelet transfusions in this population.