In the Journals

Higher platelet transfusion threshold increased risk for death among neonates with severe thrombocytopenia

Higher platelet transfusion threshold appeared to increase risk for death and major bleeding among preterm infants with severe thrombocytopenia, according to results of a randomized trial published in The New England Journal of Medicine.

“Our trial highlights the importance of trials of platelet transfusion involving patients with conditions other than hematologic cancers,” Anna Curley, MD, consultant neonatologist at National Maternity Hospital in Dublin, and colleagues wrote. “It [also] adds to previous data indicating a tenuous relationship between platelet count and bleeding.”

An estimated 73% of infants with birth weight less than 1,000 g develop thrombocytopenia during their stay in neonatal ICUs.

Platelet transfusions often are used to prevent bleeding among preterm infants who have thrombocytopenia. However, limited data exist about appropriate thresholds for prophylactic platelet transfusions, according to study background.

Curley and colleagues conducted a multicenter trial that included 660 infants born at less than 34 weeks of gestation who developed severe thrombocytopenia. Median gestational age was 26.6 weeks (range, 22.7-33.9) and median birth weight was 740 g (range, 360-2,490).

Researchers randomly assigned 329 infants to platelet transfusion at a platelet-count threshold of 50,000 per cubic millimeter (high-threshold group). They assigned the other 331 infants to transfusion with platelet-count threshold of 25,000 per cubic millimeter (low-threshold group).

Death or new major bleeding within 28 days after randomization served as the primary outcome measure.

Investigators used a validated bleeding assessment tool to prospectively document bleeding daily for 14 days after randomization. Thereafter, they collected data weekly for infants who were not discharged or transferred. Data for infants transferred to another hospital were collected through a minimum of 28 days after randomization.

A higher percentage of infants in the high-threshold group than low-threshold group received at least one platelet transfusion (90% vs. 53%).

Researchers reported a significantly higher incidence of new major bleeding episodes or death in the high-threshold group (26% vs. 19%; OR = 1.57; 95% CI, 1.06-2.32; P = .02).

Forty-eight (15%) infants in the high-threshold group and 33 (10%) in the low-threshold group died (OR = 1.56; 95% CI, 0.95-2.55).

Incidence of serious adverse events did not differ significantly between the high-threshold and low-threshold groups (25% vs. 22%; OR = 1.14; 95% CI, 0.78-1.67).

Aside from major bleeding, 81 infants in the high-threshold group experienced a combined 91 serious adverse events, whereas 74 infants in the low-threshold group experienced a combined 92 serious adverse events. These events included necrotizing enterocolitis, multiorgan failure, renal failures, sepsis and respiratory failure.

Researchers determined one serious adverse event — respiratory deterioration attributed to transient acute lung inflammation — could have been related to transfusion.

Investigators acknowledged potential study limitations, including the fact that 3.2% of platelet transfusions (n = 45 of 1,393) were additional transfusions not indicated by protocol.

Also, only 37% of infants enrolled in the study underwent randomization on or before their fifth day of life. However, Curley and colleagues noted necrotizing enterocolitis and late-onset sepsis — both of which are clinically significant causes of severe neonatal thrombocytopenia — are more common at later ages than during the first postnatal week.

The explanations for the between-group differences in mortality and major bleeding are not known, according to researchers.

“Inflammatory consequences after transfusion of platelet components as biologic agents, hemodynamic shifts related to platelet-transfusion volume or both — coupled with fragility of the germinal matrix and disturbances in organ and brain blood flow — could have contributed to an increased risk of hemorrhage,” Curley and colleagues wrote. “Preterm lungs, with a large capillary bed and abundant immune cells, may be vulnerable to proinflammatory injury mediated by platelet transfusion-derived bioreactive components. ... Other potential causes of adverse outcomes include platelet-derived reactive oxygen species and proangiogenic factors that may aggravate the aberrant angiogenesis characterizing bronchopulmonary dysplasia, a common complication of prematurity. Vessel occlusion by platelet microthrombi could also compromise collateral blood flow.”

The only other randomized trial to compare platelet-transfusion thresholds among preterm neonates had been published 25 years ago. That trial included 152 premature neonates with birth weight less than 1,500 g and platelet counts less than 150,000 per cubic millimeter.

Investigators in that trial randomly assigned neonates to platelet transfusions in their first week of life at platelet-count threshold of 150,000 per cubic millimeter or no platelet transfusion unless their platelet count was less than 50,000 per cubic millimeter or the neonate had bleeding.

Results showed no significant differences between groups with regard to intracranial hemorrhage or worsening of existing intracranial hemorrhages.

“These results led neonatologists to embrace 50,000 per cubic millimeter as the most frequently used threshold for platelet transfusions in preterm neonates, although limitations in this single randomized trial left room for uncertainty and several unanswered questions, including which transfusion thresholds to use beyond the first week of life and whether platelet counts lower than 50,000 per cubic millimeter were safe in preterm neonates,” Martha C. Sola-Visner, MD, director of the newborn medicine clinical research program at Boston Children’s Hospital and associate professor in pediatrics at Harvard Medical School, wrote in an accompanying editorial. “In the absence of additional trials, surveys and observational studies over the past decade revealed a striking worldwide variability in thresholds for platelet transfusions in neonates.”

Although the mechanisms for the findings in the trial by Curley and colleagues have not been established, they represent “a major advance in neonatal hematology,” Sola-Visner wrote.

“This long-awaited trial provides neonatologists with high-level evidence that should translate into a shift toward restrictive thresholds for prophylactic platelet transfusions in neonates who have not had recent major bleeding ([because] this trial excluded infants with major bleeding within the previous 72 hours which was either already known or detected on cranial ultrasonography performed within 6 hours before randomization),” she wrote.

“In clinical practice, recent cranial ultrasonographic findings are not always available when decisions are made regarding platelet transfusions. This raises concerns, particularly for infants during the first week of life,” she added. “Nevertheless, it is now clear that platelet transfusions may have deleterious effects in preterm neonates, and the evidence from this trial strongly suggests that less is more when it comes to the management of neonatal thrombocytopenia.” – by Mark Leiser

Disclosures: Curley reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures. Sola-Visner reports grants, personal fees and nonfinancial support from Sysmex America Inc. outside of the submitted work.

Higher platelet transfusion threshold appeared to increase risk for death and major bleeding among preterm infants with severe thrombocytopenia, according to results of a randomized trial published in The New England Journal of Medicine.

“Our trial highlights the importance of trials of platelet transfusion involving patients with conditions other than hematologic cancers,” Anna Curley, MD, consultant neonatologist at National Maternity Hospital in Dublin, and colleagues wrote. “It [also] adds to previous data indicating a tenuous relationship between platelet count and bleeding.”

An estimated 73% of infants with birth weight less than 1,000 g develop thrombocytopenia during their stay in neonatal ICUs.

Platelet transfusions often are used to prevent bleeding among preterm infants who have thrombocytopenia. However, limited data exist about appropriate thresholds for prophylactic platelet transfusions, according to study background.

Curley and colleagues conducted a multicenter trial that included 660 infants born at less than 34 weeks of gestation who developed severe thrombocytopenia. Median gestational age was 26.6 weeks (range, 22.7-33.9) and median birth weight was 740 g (range, 360-2,490).

Researchers randomly assigned 329 infants to platelet transfusion at a platelet-count threshold of 50,000 per cubic millimeter (high-threshold group). They assigned the other 331 infants to transfusion with platelet-count threshold of 25,000 per cubic millimeter (low-threshold group).

Death or new major bleeding within 28 days after randomization served as the primary outcome measure.

Investigators used a validated bleeding assessment tool to prospectively document bleeding daily for 14 days after randomization. Thereafter, they collected data weekly for infants who were not discharged or transferred. Data for infants transferred to another hospital were collected through a minimum of 28 days after randomization.

A higher percentage of infants in the high-threshold group than low-threshold group received at least one platelet transfusion (90% vs. 53%).

Researchers reported a significantly higher incidence of new major bleeding episodes or death in the high-threshold group (26% vs. 19%; OR = 1.57; 95% CI, 1.06-2.32; P = .02).

Forty-eight (15%) infants in the high-threshold group and 33 (10%) in the low-threshold group died (OR = 1.56; 95% CI, 0.95-2.55).

Incidence of serious adverse events did not differ significantly between the high-threshold and low-threshold groups (25% vs. 22%; OR = 1.14; 95% CI, 0.78-1.67).

Aside from major bleeding, 81 infants in the high-threshold group experienced a combined 91 serious adverse events, whereas 74 infants in the low-threshold group experienced a combined 92 serious adverse events. These events included necrotizing enterocolitis, multiorgan failure, renal failures, sepsis and respiratory failure.

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Researchers determined one serious adverse event — respiratory deterioration attributed to transient acute lung inflammation — could have been related to transfusion.

Investigators acknowledged potential study limitations, including the fact that 3.2% of platelet transfusions (n = 45 of 1,393) were additional transfusions not indicated by protocol.

Also, only 37% of infants enrolled in the study underwent randomization on or before their fifth day of life. However, Curley and colleagues noted necrotizing enterocolitis and late-onset sepsis — both of which are clinically significant causes of severe neonatal thrombocytopenia — are more common at later ages than during the first postnatal week.

The explanations for the between-group differences in mortality and major bleeding are not known, according to researchers.

“Inflammatory consequences after transfusion of platelet components as biologic agents, hemodynamic shifts related to platelet-transfusion volume or both — coupled with fragility of the germinal matrix and disturbances in organ and brain blood flow — could have contributed to an increased risk of hemorrhage,” Curley and colleagues wrote. “Preterm lungs, with a large capillary bed and abundant immune cells, may be vulnerable to proinflammatory injury mediated by platelet transfusion-derived bioreactive components. ... Other potential causes of adverse outcomes include platelet-derived reactive oxygen species and proangiogenic factors that may aggravate the aberrant angiogenesis characterizing bronchopulmonary dysplasia, a common complication of prematurity. Vessel occlusion by platelet microthrombi could also compromise collateral blood flow.”

The only other randomized trial to compare platelet-transfusion thresholds among preterm neonates had been published 25 years ago. That trial included 152 premature neonates with birth weight less than 1,500 g and platelet counts less than 150,000 per cubic millimeter.

Investigators in that trial randomly assigned neonates to platelet transfusions in their first week of life at platelet-count threshold of 150,000 per cubic millimeter or no platelet transfusion unless their platelet count was less than 50,000 per cubic millimeter or the neonate had bleeding.

Results showed no significant differences between groups with regard to intracranial hemorrhage or worsening of existing intracranial hemorrhages.

“These results led neonatologists to embrace 50,000 per cubic millimeter as the most frequently used threshold for platelet transfusions in preterm neonates, although limitations in this single randomized trial left room for uncertainty and several unanswered questions, including which transfusion thresholds to use beyond the first week of life and whether platelet counts lower than 50,000 per cubic millimeter were safe in preterm neonates,” Martha C. Sola-Visner, MD, director of the newborn medicine clinical research program at Boston Children’s Hospital and associate professor in pediatrics at Harvard Medical School, wrote in an accompanying editorial. “In the absence of additional trials, surveys and observational studies over the past decade revealed a striking worldwide variability in thresholds for platelet transfusions in neonates.”

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Although the mechanisms for the findings in the trial by Curley and colleagues have not been established, they represent “a major advance in neonatal hematology,” Sola-Visner wrote.

“This long-awaited trial provides neonatologists with high-level evidence that should translate into a shift toward restrictive thresholds for prophylactic platelet transfusions in neonates who have not had recent major bleeding ([because] this trial excluded infants with major bleeding within the previous 72 hours which was either already known or detected on cranial ultrasonography performed within 6 hours before randomization),” she wrote.

“In clinical practice, recent cranial ultrasonographic findings are not always available when decisions are made regarding platelet transfusions. This raises concerns, particularly for infants during the first week of life,” she added. “Nevertheless, it is now clear that platelet transfusions may have deleterious effects in preterm neonates, and the evidence from this trial strongly suggests that less is more when it comes to the management of neonatal thrombocytopenia.” – by Mark Leiser

Disclosures: Curley reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures. Sola-Visner reports grants, personal fees and nonfinancial support from Sysmex America Inc. outside of the submitted work.