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Two-year outcomes following a randomised platelet transfusion trial in preterm infants
Moore CM, D'Amore A, Fustolo-Gunnink S, Hudson C, Newton A, Santamaria BL, Deary A, Hodge R, Hopkins V, Mora A, et al
Archives of disease in childhood. Fetal and neonatal edition. 2023
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Editor's Choice
Abstract
OBJECTIVE Assess mortality and neurodevelopmental outcomes at 2 years of corrected age in children who participated in the PlaNeT-2/MATISSE (Platelets for Neonatal Transfusion - 2/Management of Thrombocytopenia in Special Subgroup) study, which reported that a higher platelet transfusion threshold was associated with significantly increased mortality or major bleeding compared to a lower one. DESIGN Randomised clinical trial, enrolling from June 2011 to August 2017. Follow-up was complete by January 2020. Caregivers were not blinded; however, outcome assessors were blinded to treatment group. SETTING 43 level II/III/IV neonatal intensive care units (NICUs) across UK, Netherlands and Ireland. PATIENTS 660 infants born at less than 34 weeks' gestation with platelet counts less than 50×10(9)/L. INTERVENTIONS Infants were randomised to undergo a platelet transfusion at platelet count thresholds of 50×10(9)/L (higher threshold group) or 25×10(9)/L (lower threshold group). MAIN OUTCOMES MEASURES Our prespecified long-term follow-up outcome was a composite of death or neurodevelopmental impairment (developmental delay, cerebral palsy, seizure disorder, profound hearing or vision loss) at 2 years of corrected age. RESULTS Follow-up data were available for 601 of 653 (92%) eligible participants. Of the 296 infants assigned to the higher threshold group, 147 (50%) died or survived with neurodevelopmental impairment, as compared with 120 (39%) of 305 infants assigned to the lower threshold group (OR 1.54, 95% CI 1.09 to 2.17, p=0.017). CONCLUSIONS Infants randomised to a higher platelet transfusion threshold of 50×10(9)/L compared with 25×10(9)/L had a higher rate of death or significant neurodevelopmental impairment at a corrected age of 2 years. This further supports evidence of harm caused by high prophylactic platelet transfusion thresholds in preterm infants. TRIAL REGISTRATION NUMBER ISRCTN87736839.
PICO Summary
Population
Preterm infants enrolled in the PlaNeT-2/MATISSE trial, at 43 neonatal intensive care units across UK, Netherlands and Ireland (n= 660).
Intervention
Higher platelet transfusion threshold (n= 296).
Comparison
Lower platelet transfusion threshold (n= 305).
Outcome
The prespecified long-term follow-up outcome was a composite of death or neurodevelopmental impairment (developmental delay, cerebral palsy, seizure disorder, profound hearing or vision loss) at 2 years of corrected age. Follow-up data were available for 601 of 653 (92%) eligible participants. Of the 296 infants assigned to the higher threshold group, 147 (50%) died or survived with neurodevelopmental impairment, as compared with 120 (39%) of 305 infants assigned to the lower threshold group (OR: 1.54; 95% CI [1.09, 2.17]).
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Effect of platelet storage duration on clinical outcomes and incremental platelet change in critically ill children
Nellis, M. E., Spinella, P. C., Tucci, M., Stanworth, S. J., Steiner, M. E., Cushing, M. M., Davis, P. J., Karam, O.
Transfusion. 2020;60(12):2849-2858
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Abstract
The safety of platelet (PLT) concentrates with longer storage duration has been questioned due to biochemical and functional changes that occur during blood collection and storage. Some studies have suggested that transfusion efficacy is decreased and immune system dysfunction is worsened with increased storage age. We sought to describe the effect of PLT storage age on laboratory and clinical outcomes in critically ill children receiving PLT transfusions. STUDY DESIGN AND METHODS We performed a secondary analysis of a prospective, observational point-prevalence study. Children (3 days to 16 years of age) from 82 pediatric intensive care units in 16 countries were enrolled if they received a PLT transfusion during one of the predefined screening weeks. Outcomes (including PLT count increments, organ dysfunction, and transfusion reactions) were evaluated by PLT storage age. RESULTS Data from 497 patients were analyzed. The age of the PLT transfusions ranged from 1 to 7 days but the majority were 4 (24%) or 5 (36%) days of age. Nearly two-thirds of PLT concentrates were transfused to prevent bleeding. The indication for transfusion did not differ between storage age groups (P = .610). After patient and product variables were adjusted for, there was no association between storage age and incremental change in total PLT count or organ dysfunction scoring. A significant association between fresher storage age and febrile transfusion reactions (P = .002) was observed. CONCLUSION The results in a large, diverse cohort of critically ill children raise questions about the impact of storage age on transfusion and clinical outcomes which require further prospective evaluation.
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Dynamics of Platelet Counts in Major Trauma: The Impact of Haemostatic Resuscitation and Effects of Platelet Transfusion-A Sub-Study of the Randomized Controlled RETIC Trial
Tauber H, Innerhofer N, von Langen D, Ströhle M, Fries D, Mittermayr M, Hell T, Oswald E, Innerhofer P
J Clin Med. 2020;9(8)
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Editor's Choice
Abstract
Although platelets play a central role in haemostasis, the dynamics of platelet counts during haemostatic resuscitation, the response to platelet transfusion, and effects on clinical outcome are poorly described for trauma patients. As a sub-study of the already published randomized controlled RETIC Study "Reversal of Trauma-induced Coagulopathy using First-line Coagulation Factor Concentrates or Fresh-Frozen Plasma" trial, we here analysed whether the type of first-line haemostatic resuscitation influences the frequency of platelet transfusion and determined the effects of platelet transfusion in coagulopathic patients with major trauma. Patients randomly received first-line plasma (FFP) or coagulation factor concentrates (CFC), mainly fibrinogen concentrate. In both groups, platelets were transfused to maintain platelet counts between 50 and 100 × 10(9) /L. Transfusion rates were significantly higher in the FFP (n = 44) vs. CFC (n = 50) group (FFP 47.7% vs. CFC 26%); p = 0.0335. Logistic regression analysis adjusted for the stratification variables injury severity score (ISS) and brain injury confirmed that first-line FFP therapy increases the odds for platelet transfusion (odds ratio (OR) 5.79 (1.89 to 20.62), p = 0.0036) and this effect was larger than a 16-point increase in ISS (OR 4.33 (2.17 to 9.74), p =0.0001). In conclusion, early fibrinogen supplementation exerted a platelet-saving effect while platelet transfusions did not substantially improve platelet count and might contribute to poor clinical outcome.
PICO Summary
Population
Trauma patients with trauma-induced coagulopathy (TIC) enrolled in the RETIC trial (n= 94).
Intervention
First-line plasma (FFP), (n= 44).
Comparison
Coagulation factor concentrates (CFC), (n= 50).
Outcome
Transfusion rates were significantly higher for FFP 47.7% than CFC 26%. Logistic regression analysis adjusted for the stratification variables injury severity score and brain injury confirmed that first-line FFP therapy increases the odds for platelet transfusion.
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Platelet transfusion thresholds in premature neonates (PlaNeT-2 trial)
Estcourt LJ
Transfusion Medicine. 2019;29(1):20-22
Abstract
CLINICAL QUESTION Does transfusing platelets to preterm infants (< 34 weeks) at a higher platelet count threshold count (< 50 x 109 /L) reduce the risk of major bleeding or death compared to only transfusing platelets when the platelet count drops below 25 x 109 /L. EVIDENCE FROM TRIAL Preterm infants with a low platelet count who were transfused platelets at the higher platelet count threshold had a higher risk of dying or having a major bleed than those who were not. The reasons why this occurred are currently unclear. Copyright © 2019 British Blood Transfusion Society.
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Randomized Trial of Platelet-Transfusion Thresholds in Neonates
Curley A, Stanworth SJ, Willoughby K, Fustolo-Gunnink SF, Venkatesh V, Hudson C, Deary A, Hodge R, Hopkins V, Lopez Santamaria B, et al
The New England Journal of Medicine. 2019;380:242-251
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Editor's Choice
Abstract
BACKGROUND Platelet transfusions are commonly used to prevent bleeding in preterm infants with thrombocytopenia. Data are lacking to provide guidance regarding thresholds for prophylactic platelet transfusions in preterm neonates with severe thrombocytopenia. METHODS In this multicenter trial, we randomly assigned infants born at less than 34 weeks of gestation in whom severe thrombocytopenia developed to receive a platelet transfusion at platelet-count thresholds of 50,000 per cubic millimeter (high-threshold group) or 25,000 per cubic millimeter (low-threshold group). Bleeding was documented prospectively with the use of a validated bleeding-assessment tool. The primary outcome was death or new major bleeding within 28 days after randomization. RESULTS A total of 660 infants (median birth weight, 740 g; and median gestational age, 26.6 weeks) underwent randomization. In the high-threshold group, 90% of the infants (296 of 328 infants) received at least one platelet transfusion, as compared with 53% (177 of 331 infants) in the low-threshold group. A new major bleeding episode or death occurred in 26% of the infants (85 of 324) in the high-threshold group and in 19% (61 of 329) in the low-threshold group (odds ratio, 1.57; 95% confidence interval [CI], 1.06 to 2.32; P=0.02). There was no significant difference between the groups with respect to rates of serious adverse events (25% in the high-threshold group and 22% in the low-threshold group; odds ratio, 1.14; 95% CI, 0.78 to 1.67). CONCLUSIONS Among preterm infants with severe thrombocytopenia, those randomly assigned to receive platelet transfusions at a platelet-count threshold of less than 50,000 per cubic millimeter had a significantly higher rate of death or major bleeding within 28 days after randomization than those in the group that received less than 25,000 per cubic millimeter. (Funded by the National Health Service Blood and Transplant Research and Development Committee and others; Current Controlled Trials number, ISRCTN87736839 .).
PICO Summary
Population
Infants born at less than 34 weeks of gestation in whom severe thrombocytopenia developed, from centres in Ireland, The Netherlands and UK (n= 660).
Intervention
platelet-count thresholds of 50,000 per cubic millimeter (high-threshold group, n= 328).
Comparison
25,000 per cubic millimeter (low-threshold group, n= 331).
Outcome
In the high-threshold group, 90% of the infants (296 of 328 infants) received at least one platelet transfusion, as compared with 53% (177 of 331 infants) in the low-threshold group. A new major bleeding episode or death occurred in 26% of the infants (85 of 324) in the high-threshold group and in 19% (61 of 329) in the low-threshold group (odds ratio, 1.57; 95% confidence interval [CI], 1.06 to 2.32). There was no significant difference between the groups with respect to rates of serious adverse events (25% in the high-threshold group and 22% in the low-threshold group; odds ratio, 1.14; 95% CI, 0.78 to 1.67).
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Elevated Syndecan-1 after Trauma and Risk of Sepsis: A Secondary Analysis of Patients from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial
Wei S, Rodriguez EG, Chang R, Holcomb JB, Kao LS, Wade CE
Journal of the American College of Surgeons. 2018;227((6):):587-595.
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Abstract
BACKGROUND Endotheliopathy of trauma is characterized by breakdown of the endothelial glycocalyx. Elevated biomarkers of endotheliopathy, such as serum syndecan-1 (Synd-1) ≥ 40 ng/mL, have been associated with increased need for transfusions, complications, and mortality. We hypothesized that severely injured trauma patients who exhibit elevated Synd-1 levels shortly after admission have an increased likelihood of developing sepsis. STUDY DESIGN We analyzed a subset of PROPPR patients that survived at least 72 hours after hospital admission and determined elevated Synd-1 levels (≥ 40 ng/mL) 4 hours after hospital arrival. Sepsis was defined a priori as meeting systemic inflammatory response criteria and having a known or suspected infection. Univariate analysis was performed to identify variables associated with elevated Synd-1 levels and sepsis. Significant variables at a p-value <0.2 in the univariate analysis were chosen by purposeful selection and analyzed in a mixed effects multivariate logistic regression model to account for the 12 different study sites. RESULTS We included 512 patients. Of these, 402 (79%) had elevated Synd-1 levels, and 180 (35%) developed sepsis. Median Synd-1 levels at 4 hours after admission were 70 ng/dL (IQR 36 - 157 ng/dL) in patients who did not develop sepsis, and 165 ng/dL (IQR 67 - 336 ng/dL) in those who did (p < 0.001). Adjusting for treatment arm and site, multivariable analyses revealed that elevated Synd-1 status, injury severity score (ISS), and total blood transfused were significantly associated with an increased likelihood of developing sepsis. CONCLUSIONS Elevated Synd-1 levels 4 hours after admission in severely injured adult trauma patients who survived the initial 72 hours after hospital admission is associated with subsequent sepsis.
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Platelet transfusions improve hemostasis and survival in a substudy of the prospective, randomized PROPPR trial
Cardenas JC, Zhang X, Fox EE, Cotton BA, Hess JR, Schreiber MA, Wade CE, Holcomb JB
Blood Advances. 2018;2((14)):1696-1704.
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Abstract
Transfusing platelets during massive hemorrhage is debated because of a lack of high-quality evidence concerning outcomes in trauma patients. The objective of this study was to examine the effect of platelet transfusions on mortality in severely injured trauma patients. This work analyzed PROPPR (Pragmatic, Randomized Optimal Platelet and Plasma Ratios) trial patients who received only the first cooler of blood products, which either did or did not contain platelets. Primary outcomes were all-cause mortality at 24 hours and 30 days and hemostasis. Secondary outcomes included cause of death, complications, and hospital-, intensive care unit (ICU)-, and ventilator-free days. Continuous variables were compared using Wilcoxon rank sum tests. Categorical variables were compared using Fisher's exact tests. There were 261 PROPPR patients who achieved hemostasis or died before receiving a second cooler of blood products (137 received platelets and 124 did not). Patients who received platelets also received more total plasma (median, 3 vs 2 U; P < .05) by PROPPR intervention design. There were no differences in total red blood cell transfusions between groups. After controlling for plasma volume, patients who received platelets had significantly decreased 24-hour (5.8% vs 16.9%; P < .05) and 30-day mortality (9.5% vs 20.2%; P < .05). More patients in the platelet group achieved hemostasis (94.9% vs 73.4%; P < .01), and fewer died as a result of exsanguination (1.5% vs 12.9%; P < .01). Patients who received platelets had a shorter time on mechanical ventilation (P < .05); however, no differences in hospital- or ICU-free days were observed. In conclusion, early platelet administration is associated with improved hemostasis and reduced mortality in severely injured, bleeding patients. This trial was registered at www.clinicaltrials.gov as # NCT01545232.
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Outcomes after concomitant traumatic brain injury and hemorrhagic shock: a secondary analysis from the Pragmatic, Randomized Optimal Platelets and Plasma Ratios trial
Galvagno SM Jr, Fox EE, Appana SN, Baraniuk S, Bosarge PL, Bulger EM, Callcut RA, Cotton BA, Goodman M, Inaba K, et al
The Journal of Trauma and Acute Care Surgery. 2017;83((4)):668-674.
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BACKGROUND Often the clinician is faced with a diagnostic and therapeutic dilemma in patients with concomitant traumatic brain injury (TBI) and hemorrhagic shock (HS), as rapid deterioration from either can be fatal. Knowledge about outcomes after concomitant TBI and HS may help prioritize the emergent management of these patients. We hypothesized that patients with concomitant TBI and HS (TBI + HS) had worse outcomes and required more intensive care compared with patients with only one of these injuries. METHODS This is a post hoc analysis of the Pragmatic, Randomized Optimal Platelets and Plasma Ratios (PROPPR) trial. TBI was defined by a head Abbreviated Injury Scale score greater than 2. HS was defined as a base excess of -4 or less and/or shock index of 0.9 or greater. The primary outcome for this analysis was mortality at 30 days. Logistic regression, using generalized estimating equations, was used to model categorical outcomes. RESULTS Six hundred seventy patients were included. Patients with TBI + HS had significantly higher lactate (median, 6.3; interquartile range, 4.7-9.2) compared with the TBI group (median, 3.3; interquartile range, 2.3-4). TBI + HS patients had higher activated prothrombin times and lower platelet counts. Unadjusted mortality was higher in the TBI + HS (51.6%) and TBI (50%) groups compared with the HS (17.5%) and neither group (7.7%). Adjusted odds of death in the TBI and TBI + HS groups were 8.2 (95% confidence interval, 3.4-19.5) and 10.6 (95% confidence interval, 4.8-23.2) times higher, respectively. Ventilator, intensive care unit-free and hospital-free days were lower in the TBI and TBI + HS groups compared with the other groups. Patients with TBI + HS or TBI had significantly greater odds of developing a respiratory complication compared with the neither group. CONCLUSION The addition of TBI to HS is associated with worse coagulopathy before resuscitation and increased mortality. When controlling for multiple known confounders, the diagnosis of TBI alone or TBI+HS was associated with significantly greater odds of developing respiratory complications. LEVEL OF EVIDENCE Prognostic study, level II.
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Platelet mass index: is it a hope for reduction of platelet transfusion in NICU?
Yavuzcan Ozturk D, Ercin S, Gursoy T, Karatekin G, Ovali F
Journal of Maternal-Fetal & Neonatal Medicine. 2016;29((12)):1926-9.
Abstract
OBJECTIVE Thrombocytopenia is a very common problem in neonatal intensive care unit whose only specific treatment is platelet (PLT) transfusion which has well-known risks. Our aim is to test whether using PLT mass-based transfusion guideline would result in fewer transfusions or not. METHODS One hundred neonates with PLT count <100000/mul were randomized into two groups: Group 1 (n=50) was transfused according to PLT count-based guideline, whereas Group 2 (n=50) was transfused according to PLT mass-based guideline. Subjects receiving one or more PLT transfusions and total number of PLT transfusions, hemorrhages, morbidity and mortality in both groups were recorded. RESULTS Demographic characteristics, PLT counts of the infants and clinical conditions associated with thrombocytopenia in both groups were not different. There was no reduction in the number of subjects receiving PLT transfusions (54% in Group 1, 50% in Group 2; p=0.69) and in the number of PLT transfusions per infant (0.82+/-1.13 versus 0.8+/-1.23; p=0.95). There was also no difference with respect to bleeding, morbidity and mortality between the groups. CONCLUSION Transfusion according to PLT mass or PLT count-based guideline does not seem to influence number of transfusions or the number of infants who were transfused.
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Transfusing neonates based on platelet count vs. platelet mass: A randomized feasibility-pilot study
Zisk JL, Mackley A, Clearly G, Chang E, Christensen RD, Paul DA
Platelets. 2014;25((7):):513-6.
Abstract
Abstract The objective of this study was to obtain pilot data on which to judge the feasibility and sample size needed for a future comparative-effectiveness trial of platelet transfusions in the NICU. We conducted a limited-scope pilot trial in which neonates were randomized to receive platelet transfusions based on platelet mass vs. platelet count, using preset "transfusion-trigger" values. Analysis included parental consent rate, number of platelet transfusions given, bleeding episodes recorded, and mortality rate. Statistical analysis included ANOVA and Chi-square. A convenience sample of 30 were randomized; 15 per group. No differences were found between groups in gestational age, birth weight, race, gender or clinical diagnoses. The study consent rate was 52% (30/58). No differences were found in number of platelet transfusions received, bleeding episodes, or mortality. Lack of a trend in transfusion-reduction resulted in inability to estimate the number needed in a future comparative-effectiveness trial. Using platelet mass, rather than platelet count, for a NICU platelet transfusion trigger is feasible. However, any future comparative-effectiveness trial, testing the hypothesis that a platelet mass-based trigger reduces the transfusion rate will likely require a very large sample size.