PLATELET TRANSFUSIONS IN NEONATES AND BRAIN DEVELOPMENT:  THE NEW FRONTIER

MANUSCRIPT CITATION

Moore CM, D’Amore A, Fustolo-Gunnink S, Hudson C, Newton A, Lopez Santamaria B, et al.  Two-year outcomes following a randomised platelet transfusion trial in preterm infants. Arch Dis Child Fetal Neonatal Ed 2023;doi:10.1136/archdischild-2022-324915. PMID 36810309

REVIEWED BY

Martha Sola-Visner, MD
Boston Children’s Hospital
Harvard Medical School
Martha.sola-visner@childrens.harvard.edu

Patricia Davenport, MD
Boston Children’s Hospital
Harvard Medical School
Patricia.davenport@childrens.harvard.edu

Cassidy Delaney, MD
Children’s Hospital Colorado
University of Colorado Anschutz Medical Campus
Cassidy.delaney@childrenscolorado.org

TYPE OF INVESTIGATION

Treatment

QUESTION

(P) Among 660 preterm infants previously enrolled in the PlaNeT-2/MATISSE trial, (I) did a higher platelet transfusion threshold (platelet count <50×10⁹/L) (C) compared to a lower transfusion threshold (<25×10⁹/L) (O) result in a higher rate of death or neurodevelopmental impairment (T) at two years of corrected age?

METHODS

• Design: Randomized multicenter clinical trial that enrolled between June 2011 and August 2017.
• Allocation: A Web-based service assigned infants randomly in a 1:1 ratio to a high transfusion threshold or a low threshold group.
• Blinding: Caregivers during the trial were not blinded, but outcome assessors were blinded to treatment group.
• Follow-up period: Two year follow up, completed by 2020.
• Setting: 43 level II/III/IV neonatal intensive care units (NICUs) across UK, Netherlands and Ireland
• Patients: Preterm neonates born at <34 weeks gestation with a platelet count <50×10⁹/L.  Exclusion criteria were a major or life-threatening congenital malformation, major bleeding within the previous 72 hours, fetal intracranial hemorrhage, immune thrombocytopenia, no administration of parenteral vitamin K, or a low probability of survival beyond several hours.
• Intervention: Infants were randomized to receive a platelet transfusion (15 mL/Kg) at platelet count thresholds of 50×10⁹/L (high threshold group) or 25×10⁹/L (low threshold group).
• Outcomes: The prespecified long-term follow-up outcome was a composite of death or neurodevelopmental impairment at 2 years corrected age.
  • Primary outcome: The primary outcome was a composite of death or neurodevelopmental impairment, defined as developmental delay >9 months behind expected for age, cerebral palsy that impaired independent walking, severe seizure disorder, profound hearing loss, or severe visual impairment at 2 years corrected age.
  • Secondary outcomes: Secondary outcomes were the component parts of the composite long-term outcome.  In addition, a post-hoc analysis of death or dependence on respiratory support at 2 years corrected age was conducted.
• Analysis and Sample Size: The outcome for this follow-up study was analyzed using a mixed logistic regression model.  All models were risk-adjusted for gestational age and intrauterine growth restriction as covariates, and center of recruitment as a random effect.  This study was powered for the primary outcome of the original study (mortality or major bleed at 28 days post-randomization), not for death or adverse neurodevelopmental outcome at 2 years.
• Patient follow-up: Of 653 infants in the PlaNeT-2 trial, 601 (92%) were available for analysis of the primary long-term composite outcome of death or neurodevelopmental impairment.

MAIN RESULTS

Primary Outcome:

• Infants randomized to the higher platelet transfusion threshold of 50×10⁹/L compared with 25×10⁹/L had a higher rate of death or significant neurodevelopmental impairment at two years corrected age (50% vs. 39%, OR 1.54 (95% CI 1.09-2.17, p=0.017).
  • The number of infants who would need to be assigned to a lower transfusion threshold to prevent one unfavorable neurodevelopmental outcome was 9 (95% CI 5 to 48).

Secondary Outcomes:

• The individual components of the composite primary outcome (death and adverse neurological outcome) were not significantly different between the two trial arms, but both favored the lower platelet transfusion threshold group.
• 38% of children in the higher threshold group died or required respiratory support at 2 years of age, compared with 28% in the lower threshold group (OR= 1.62, 95% CI 1.12 to 2.34).
• 11% of children in the high threshold group required oxygen or respiratory support at 2 years, compared with 4% in the low threshold group (OR=2.86, 95% CI 1.25 to 6.51, excluding infants who had died).

CONCLUSION

The PlaNet-2 Trial found that infants randomized to a higher platelet transfusion threshold of 50×10⁹/L had an increased rate of mortality or major bleeding 28 days after randomization (the primary outcome) and an increased incidence of bronchopulmonary dysplasia (secondary outcome).

This long-term follow up study revealed that children previously randomized to the higher platelet transfusion threshold also had a higher composite rate of death or adverse neurodevelopmental outcome at a corrected age of 2 years.   A post-hoc exploratory analysis (given the findings of the primary trial) also found a significantly higher rate of death or need for respiratory support among children randomized to the high threshold group.  These findings further support the potential for short- and long-term harm associated with high prophylactic platelet thresholds in the NICU.

COMMENTARY

Preterm neonates have a high incidence of thrombocytopenia and intraventricular hemorrhage (IVH). Because of this, they are traditionally transfused at higher platelet count (PC) thresholds compared to older children and adults, under the premise that higher PCs decrease bleeding risk (1).  Paradoxically, the largest randomized platelet transfusion threshold trial in preterm neonates (PlaNeT-2), found a higher incidence of death or major bleeding within 28 days of randomization (primary outcome) and a higher incidence of bronchopulmonary dysplasia (BPD) among neonates randomized to a higher platelet transfusion threshold (<50×10⁹/L), compared to those randomized to a lower threshold (<25×10⁹/L) (2).  Neonates with a high baseline risk of bleeding and/or death benefited from the lower platelet transfusion threshold as much as low-risk neonates (3).

 

In this manuscript, Moore and collaborators provide evidence that high platelet transfusion thresholds are associated with increased mortality and neurodevelopmental impairment (NDI) at 2 years corrected age (4).  The study had a high follow up rate (92%), combining results from formal neurodevelopmental (ND) assessment tools (41% of participants), review of medical records, practitioners’ notes and early intervention services.  Participants were dichotomized as having a favorable or unfavorable outcome (death or severe CP, developmental delay or visual or hearing loss).  The combination of different methods to assess ND outcomes is a limitation of the study and restricted the ability of investigators to evaluate subtle deficits or specific neurologic domains.   Future trials should include standardized ND assessments at 2 years and be powered for this outcome.  Nevertheless, the fact that only severe deficits were included made the findings even more concerning.

 

Given the initial finding that neonates randomized to a higher platelet transfusion threshold had a higher incidence of BPD, the authors performed a post-hoc analysis that found a higher need for respiratory support at 2 years among children randomized to the high threshold group.  While BPD is common among preterm infants, oxygen dependence or need for respiratory support at 2 years of age is not.  Thus, the higher incidence of this outcome among children randomized to the higher threshold suggests platelet transfusions given to high-risk preterm neonates might trigger or enhance pathways leading to severe lung disease.

 

The mechanisms underlying increased morbidity and mortality associated with platelet transfusions are likely related to non-hemostatic effects of platelets.  Platelets are critical regulators of immune and inflammatory responses, and it has been hypothesized that adult (transfused) platelets are more pro-inflammatory than neonatal platelets (5-8). In support of this hypothesis, pre-clinical studies suggest platelet transfusions trigger inflammation or dysregulated immune responses in neonates, in a context-dependent manner (9). Whether NDI results from direct effects of transfused platelets on the developing brain or is mediated by higher rates of IVH and BPD observed in infants randomized to the high threshold group (both of which are associated with NDI), is unknown.  Additional studies are needed to define the mechanisms underlying the deleterious and beneficial effects of platelet transfusions, which remain lifesaving in neonates with bleeding or severe thrombocytopenia. In the meantime, this study further supports the use of a restrictive, evidence-based approach to neonatal platelet transfusions.

REFERENCES

1. Patel RM, Hendrickson JE, Nellis ME, Birch R, Goel R, Karam O, et al. Variation in Neonatal Transfusion Practice. J Pediatr 2021; 235:92-9 e4.

2. Curley A, Stanworth SJ, Willoughby K, Fustolo-Gunnink SF, Venkatesh V, Hudson C, et al. Randomized Trial of Platelet-Transfusion Thresholds in Neonates. N Engl J Med 2019; 380 3:242-51.

3. Fustolo-Gunnink SF, Fijnvandraat K, van Klaveren D, Stanworth SJ, Curley A, Onland W, et al. Preterm neonates benefit from low prophylactic platelet transfusion threshold despite varying risk of bleeding or death. Blood 2019; 134 26:2354-60.

4. Moore CM, D’Amore A, Fustolo-Gunnink S, Hudson C, Newton A, Santamaria BL, et al. Two-year outcomes following a randomised platelet transfusion trial in preterm infants. Arch Dis Child Fetal Neonatal Ed 2023.

5. Maouia A, Rebetz J, Kapur R, Semple JW. The Immune Nature of Platelets Revisited. Transfus Med Rev2020; 34 4:209-20.

6. Davizon-Castillo P, Allawzi A, Sorrells M, Fisher S, Baltrunaite K, Neeves K, et al. Platelet activation in experimental murine neonatal pulmonary hypertension. Physiol Rep 2020; 8 5:e14386.

7. Davenport P, Sola-Visner M. Platelets in the neonate: Not just a small adult. Res Pract Thromb Haemost 2022; 6 3:e12719.

8. Delaney C, Davizon-Castillo P, Allawzi A, Posey J, Gandjeva A, Neeves K, et al. Platelet activation contributes to hypoxia-induced inflammation. Am J Physiol Lung Cell Mol Physiol 2021; 320 3:L413-L21.

9. Davenport P, Fan HH, Nolton E, Feldman HA, Lorenz V, Canas J, et al. Platelet transfusions in a murine model of neonatal polymicrobial sepsis: Divergent effects on inflammation and mortality. Transfusion 2022; 62 6:1177-87.