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 (TAXI-CAB)
Lani Lieberman, MD, FRCPC
1; Oliver Karam, MD, PhD
2; Simon J. Stanworth, MD
3; Susan M.
Goobie, MD, FRCPC
4; Gemma Crighton, MD
5; Ruchika Goel, MD, MPH
6; Jacques Lacroix, MD
7; Marianne E. Nellis, MD, MS
8; Robert I. Parker, MD
9; Katherine Steffen, MD
10; Paul Stricker MD
11; Stacey L. Valentine, MD, MPH
12; Marie E. Steiner
13, MD for the Pediatric Critical
Care Transfusion and Anemia Expertise Initiative – Control/Avoidance of Bleeding (TAXI- CAB), in collaboration with the Pediatric Critical Care Blood Research Network (BloodNet), and
the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network
1
Department of Clinical Pathology, University Health Network Hospitals. Department of Laboratory Medicine & Pathobiology; University of Toronto, Toronto, Canada.
2
Division of Pediatric Critical Care Medicine, Children’s Hospital of Richmond at VCU, Richmond, VA, USA.
3
NHS Blood and Transplant; Oxford University Hospitals NHS Foundation Trust; Radcliffe Department of Medicine and Oxford BRC Haematology Theme, University of Oxford, UK.
4
Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.
5
Department of Haematology, Royal Children’s Hospital, Melbourne, Australia.
6
Division of Transfusion Medicine, Department of Pathology, Johns Hopkins University,
Baltimore, MD and Simmons Cancer Institute, Division of Hematology Oncology at SIU School of Medicine, Springfield, IL, USA.
7
Division of Pediatric Critical Care Medicine, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, QC, Canada.
8
Division of Pediatric Critical Care Medicine, Department of Pediatrics, NY Presbyterian
Hospital – Weill Cornell Medicine, New York, NY, USA.
9
Department of Pediatric Hematology/Oncology, Renaissance School of Medicine, State University of New York at Stony Brook, Stony Brook, NY, USA.
10
Division of Pediatric Critical Care Medicine, Department of Pediatrics, Stanford University, Palo Alto, CA, USA.
11
Department of Anesthesiology and Critical Care, The Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, PA, USA.
12
Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA, USA.
13
Divisions of Hematology and Critical Care, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
Transfusion and Anemia EXpertise Initiative – Control/Avoidance of Bleeding (TAXI-CAB) Members are listed in Appendix 1
Correspondence: Dr. Lani Lieberman MD, FRCPC
Transfusion Medicine Specialist, University Health Network 200 Elizabeth Street Room 306, Toronto, ON M5G 2C4 416 340 5390 (office); 416 340 5410(fax)
lani.lieberman@uhn.ca
Financial Support: The Transfusion and Anemia EXpertise Initiative – Control/Avoidance of Bleeding (TAXI-CAB) was supported, in part, by the National Institutes of Health National Heart, Lung and Blood Institute under award number R13 HL154544-01.
Conflicts of Interest: None
MeSH Terms: platelet transfusion, plasma, transfusion, hemostasis, critical illness, child, sepsis, oncology, malignancy, liver transplant, evidence based guidelines
Abbreviations: DIC - disseminated intravascular coagulopathy; HSCT - hematologic stem cell transplant; MOF - multi-organ failure; Neonatal intensive care unit - NICU; Pediatric intensive care unit - PICU; RCT - randomized control study; Transfusion and Anemia Expertise Initiative – Control/Avoidance of Bleeding (TAXI-CAB); ATR - acute transfusion reaction
Word Count: 4136
Supplemental Table 1: Characteristics and risk of bias of studies included in the analysis of critically ill children with malignancy
Year of publicatio
n
1st author Study design
Stud y year
s
Settin g
Sampl e size
(n)
Population
Mean/
Media n age, yr (SD/IQ
R)
Male (%)
Interventio n
Blood products document
ed
Primary outcome
Secondary
outcomes Conclusions Risk of bias
2016
Du Pont- Thibodea u [S1]
Prospective cohort and survey
2009 - 2010
PICU 60
Mixed PICU population receiving platelet transfusion
60.2
(75.2) 52 None Platelets
Organ dysfunctio n
Mortality, sepsis, nosocomial infections, length of stay
Platelet transfusions associated with increased frequency and severity of organ dysfunction, sepsis, nosocomial infections, prolonged PICU stay, and increased risk of mortality
Low
2017 Alsheikh
[37]
Retrospectiv
e cohort NR PICU 64
Mixed PICU population receiving platelet transfusion
8 (2,
15.5) 56 None Platelets
Pre- transfusion platelet count
Laboratory parameters post transfusion, mortality
Most common indication was underlying hematologic condition and threshold for transfusion varied with clinical condition (higher among surgical patients)
Moderat e
2018 Nellis [1] Prospective cohort
2016 - 2017
PICU 559
Mixed PICU population receiving platelet transfusion
4.1 (0.5, 10.8)
55 None Platelets Mortality
Length of stay, Length mechanical ventilation, organ dysfunction, laboratory parameters post transfusion
Platelet transfusions independently associated with mortality
Low
2018 Saini [S2] Retrospectiv e cohort
2010 - 2016
PICU 232 Mixed
PICU population receiving
2.3 (0.1, 11.2)
50 None Platelets Mortality Indication
for platelet transfusion, transfusion
Predicted probability of dying change in patients who
Low- modera te
platelet transfusion
related adverse events
received platelet transfusions based on underlying disease severity
2019 Nellis [S3]
Prospective cohort (secondary analysis)
2016 - 2017
PICU 503
Mixed PICU population receiving platelet transfusion of varying ABO compatibili ty
4.3 (0.8, 10.8) and 3.1 (0.3, 10.2) and 3.1 (0.2, 10.7)
57 None Platelets
Laboratory parameter s post transfusion
Transfusion reactions, organ dysfunction
No differences observed in incremental platelet count or transfusion reactions based on ABO compatible vs incompatible transfusions
Low
2019 Nellis [2]
Prospective cohort (secondary analysis)
2016 - 2017
PICU 237
Critically ill children with oncologic diagnosis receiving platelet transfusion
7.5 (2.3, 12.3)
58 None Platelets
Laboratory parameter s post transfusion
Length of stay, mortality, total dose platelet transfusions
Children with oncologic diagnosis receive nearly half of all platelet transfusions in PICU at thresholds generally higher than 20x109/L.
Low
IQR = interquartile range; LPs = lumbar punctures; NR = not recorded; PICU = Pediatric Intensive Care Unit; SD = standard deviation; yr = year
Supplemental Table 2: Characteristics and risk of bias of studies included in the analysis of critically ill children with acute liver failure and/or liver transplantation
Year of publicatio n
1st autho r
Study design
Stud y year s
Settin g
Sampl e size (n)
Populatio n
Age, yr (IQR)
Male (%)
Interventio n
Blood products document ed
Primary outcome
Secondary
outcomes Conclusions Risk of bias
2012 Wu
[S4]
Retrospectiv e cohort
1994 - 2009
OR and Liver ICU
522
Liver transplan t recipients
47
(4,55) 67 None
Plasma, platelets, RBC
Bleeding None
Plasma independently associated with bleeding requiring re-exploration
Low- Moderate
2017 Nacoti
[54]
Prospective cohort
2002 - 2013
PICU 232 Liver
transplan t recipients
1.1 (0.1,17 )
50 None Platelets,
RBC
Complicatio n-free survival
Mortality, organ failure, thrombosis
Intraoperative RBC and platelet transfusions independent risk factors for developing one or
Low
more major complications in first year after transplant
2018 Arni
[52]
Prospective cohort
2014 - 2015
PICU
18 (20 Transf usions )
Liver transplan t recipients
11.6 (2.8, 14.7)
72 None Plasma Antithrombi
n (AT) levels
Thrombosi s, transfusion reactions, mortality
Plasma transfusions marginally increase AT levels in children after liver transplant
Low
AT = antithrombin; ICU = intensive care unit; IQR = interquartile range; OR = Operating room; PICU = pediatric intensive care unit; RBC = red blood cells; yr = year
Supplemental Table 3: Characteristics and risk of bias of studies included in the analysis of critically ill children with sepsis and/or disseminated intravascular coagulation (DIC)
Year of publicatio n
1st author Study design
Stud y year s
Settin g
Sampl e size (n)
Population Mean / Media n age, yr (SD/I QR)
Male (%)
Interventio n
Blood products document ed
Primary outcome
Secondary
outcomes Conclusions Risk of bias
1982 Gross
[S5] RCT
1978 - 1981
NICU 33
Preterm infants with DIC
In weeks (1) 29.7 +/- 4.5 (2) 31.2 +/-4.8 (3) 31 +/2 2.4
NR (1) Exchange transfusion
; (2) Standing plasma and platelet transfusion s; (3) control
Plasma and platelets
Resolution of DIC
Mortality, laboratory parameter s post transfusion
Improvement in coagulation and survival not improved by exchange transfusion or standing transfusion of plasma and platelet
Low
1996
Northern Neonatal Trial Group [63]
RCT
1990 - 1992
NICU 776
Preterm infants <32 weeks GA
NR NR
(1) FFP (2) Gelatin plasma substitute (3) Dextrose/
dextrose saline
Plasma and platelets
Survival without neurologic disability at 2 years
Outcome at hospital discharge including ICH
Proportion dying and survival with severe disability did not differ between randomized groups Similar developmental quotients at age 2
Moderate
1998 Kabra
[S6]
Prospecti ve cohort
1996 Pediat ric
37 Children with
6.65 (2.87)
48 Platelet transfusion
Plasma and
Mortality Bleeding No effect of platelet
High
wards
dengue hemorrhag ic fever
and 7.41
(2.32) s platelets transfusions seen
2015 Karam [3] Prospecti
ve cohort 2014 PICU 443
Mixed PICU population receiving plasma transfusion
1 (0.2,
6.4) 43 None Plasma
Indication for transfusion
Laboratory parameter s post transfusion
1/3 transfused patients were not bleeding and had no planned procedure and plasma corrected coagulation tests only for patients with severe coagulopathy
Low
2016
Du Pont- Thibodea u [S1]
Prospecti ve cohort and survey
2009 - 2010
PICU 60
Mixed PICU population receiving platelet transfusion
60.2
(75.2) 52 None Platelets Organ
dysfunction
Mortality, sepsis, nosocomia l infections, length of stay
Platelet transfusions associated with increased frequency and severity of organ dysfunction, sepsis, nosocomial infections, prolonged PICU stay, and increased risk of mortality
Low
2018 Nellis [1] Prospecti ve cohort
2016 - 2017
PICU 559
Mixed PICU population receiving platelet transfusion
4.1 (0.5, 10.8)
55 None Platelets Mortality
Length of stay, Length mechanica l ventilation, organ dysfunctio n, laboratory parameter s post transfusion
Platelet transfusions independently associated with mortality
Low
2020 El-
Nawawy [S7]
Open label randomiz ed trial
2015 - 2016
PICU 80 Critically ill children with severe sepsis or septic shock and
5.0 (3.3,2 2.5) and 12.5 (3.3,2 0.5)
55 and 30
Plasma, low-dose heparin, and tranexamic acid
Plasma No
progression to overt
Shock reversal time, PICU length of stay, developme nt of
A bundle of plasma transfusion, low- dose heparin, and tranexamic acid decreased the progression from
Low
non-overt disseminat ed Intravascul arCoagulo pathy (DIC)
complicati ons, occurrence of bleeding events, and mortality.
non-overt to overt DIC. It was also associated with improved survival and shorter length of stay
2020 Go [S8] Retrospec
tive
2010 - 2017
NICU 366;
DIC scores
> 3 = 103;
DIC scores
< 3 = 263
Compare neonates with and without DIC scores
> 3
GA group 1:
29.4 weeks Group 2:
36.4 weeks
NR
Plasma, Platelet, antithrom bin 3, recombina nt human soluble thrombom odulin
Plasma, platelets, AT3
Investigate underlying conditions affecting DIC at birth
Assess effectivene ss of rTM and plasma
DIC scores improved following treatment (limitation – not controlled for one product)
Low
AT3 = antithrombin 3; FFO = ; GA = gestational age; DIC = disseminated intravascular coagulopathy; NICU = neonatal intensive care unit; NR = not recorded; PICU = pediatric intensive care unit; RCT = randomized control trial; rTM = recombinant human soluble thrombomodulin (rTM)
