EDITORIAL Platelet transfusion volume reduction: it can be done, but why do it?
I
n this issue of TRANSFUSION, Dutch investigators report1 the posttransfusion blood platelet (PLT) count increments in neonates who received at least one PLT transfusion (PTX) prepared by different methods from apheresis PLT units: 1) volume-reduced and concentrated PLTs (VRP), 2) PLT additive solution PLTs (PASP), or 3) plasma-PLTs. Because the plasma-PLT group was too small to permit reasonable conclusions, all of my comments will pertain to the retrospective analysis of VRP versus PASP. As the major finding, the authors documented that when twice the dose of VRP was transfused versus PASP, the mean posttransfusion increments measured within 8 hours posttransfusion were, respectively, 111 × 109/L versus 62 × 109/L and, when measured 16 to 24 hours posttransfusion, were 60 × 109/L versus 38 × 109/L. The finding that if one transfuses twice the number of PLTs, the posttransfusion increments will be approximately twice as high, is not surprising. However, it is important that the results document that the Dutch method of volume reduction did not noticeably damage the PLTs (i.e., after transfusion, PLTs from VRP units circulated and increased the blood PLT count of neonates with thrombocytopenia). Over the years, several methods to volume reduce PLT units have been published, with quality of the PLTs in the volume-reduced units assessed by in vitro methods and/or with limited in vivo posttransfusion PLT increment data.2,3 The Dutch report is noteworthy because of the in vivo posttransfusion increment data in a fairly large number of human neonates, comparing VRP with PASP PLTs that were not exposed to the “stresses” of centrifugation and concentration.1 Although I believe that the findings can be confidently accepted in a “qualitative” or general sense, several shortcomings of the study do not permit the findings to be accepted “quantitatively” (i.e., one must be cautious and not assume that the actual posttransfusion increments reported will be achieved by every neonate transfused with VRP, when prepared by local blood banks or centers adopting the Dutch methods). The shortcomings, some of which are acknowledged by the authors, include: 1.
The study was retrospective with VRP transfused at one neonatal intensive care unit and PASP at another location—rather than being designed as a prospective clinical trial in which all neonates at both intensive care units were randomly allocated to receive either TRANSFUSION 2013;53:3029-3031.
2.
3.
4.
VRP or PASP. Thus, environmental or institutional differences or variables might influence results independently of whether VRP or PASP were transfused (i.e., the type of PLT product transfused was not, necessarily, the single experimental variable being studied). As evident in their Table 1, neonates transfused with VRP were more mature, larger, and less seriously ill in many respects than neonates given PASP. Undoubtedly, this difference led to variability in medical management between the two intensive care units. Thus, multiple biologic and management differences or variables in heterogeneous study subjects or neonates existed that might influence responses to PTXs independently of whether VRP or PASP were transfused—again, not one single experimental variable being studied. The actual dose and number of PLTs transfused was estimated for VPR, rather than being known, and the techniques of transfusion or infusion per se differed between the two groups of neonates being studied. VRP were infused in 15 minutes with no mention of a filter being used—compared to an infusion time of 30 minutes through a blood filter for PASP. Although these differences may have had little effect on posttransfusion PLT count increments, the actual effect is unknown—thus, another variable was introduced to possibly confound the results. Not every eligible neonate was analyzed and, as is typical for retrospective studies, data were missing for some transfusions. Moreover, there was no mention of a method to validate the completeness and accuracy of the data. Thus, it is difficult to exclude the possibility of bias.
In fairness to the authors, as reported in the article, the authors expended considerable efforts carefully attempting to minimize or offset these confounding factors by use of several statistical techniques. However, statistical “corrections” are unlikely to be 100% effective in eliminating experimental imbalances or possible bias, and these retrospective efforts are inferior to a study with prospective, randomized, and blinded design. As a case in point, a better experimental design for the Dutch study—if it had been possible—would have been: 1) to randomly allocate all eligible neonates at all intensive care unit locations to receive PTXs with either VRP or PASP; 2) to know, rather than estimate, the number of PLTs contained in every VRP and PASP unit transfused; 3) to prescribe PLT transfusions using uniform clinical Volume 53, December 2013 TRANSFUSION
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EDITORIAL
guidelines or indications; 4) to perform all PTXs using techniques that were as identical as possible; 5) to collect “real-time” data on standard data collection forms designed to collect all information needed to address the primary endpoint of posttransfusion increments; 6) to validate completeness and accuracy of data collected; 7) to “blind” as many investigators and caregivers as possible to the type of PTX product given; and 8) to report observations of clinical outcomes (e.g., transfusion reactions, changes in vital signs, effects on bleeding that might be present) during and after PTXs. Regardless, it seems clear that transfusion of VRP, when prepared per the Dutch method, will result in a substantial increase in the posttransfusion blood PLT count of transfused neonates1—but a key question is “Why spend the time, effort, and money to volume reduce PLT units or aliquots before transfusing them, when the usual goals and expectations of PTXs can be achieved without doing so?” To explain why this question is relevant. . . . The vast majority of neonatal PTX are given prophylactically—more than 98% in the current study1— with the belief that overt bleeding will be prevented or minimized1,3 and, although bleeding is more likely to occur in patients with severe thrombocytopenia, the risk of bleeding, generally, cannot be related directly to the degree of thrombocytopenia present in infants3-5 or in older patients.6,7 In the only randomized trial reported to date in neonates,4 there was no difference in the rate of severe intraventricular intracranial bleeding when the PLT count was maintained greater than 150 × 109/L versus giving PTX when the PLT count fell to less than 50 × 109/L. Thus, it is a reasonable goal or expectation of neonatal PTXs to achieve a posttransfusion blood PLT count of 100 × 109/L—rather than demanding some higher value. Although PTX practices vary widely, with some neonatologists or pediatricians giving PTX with pretransfusion blood PLT counts of 100 × 109/L, there are no data to support maintaining posttransfusion PLT counts of more than 100 × 109/L.3,4 Accepting posttransfusion blood PLT counts of 100 × 109/L to be satisfactory for prophylactic PTX, it is well established that this goal can be achieved by transfusing 10 mL/kg of an unmodified PLT unit taken straight from the blood bank PLT rotator (i.e., there is NO need to volume reduce). The rationale is as follows: 1. 2. 3.
3030
PLT concentrates, whether apheresis or whole blood derived, contain approximately 1 × 109 PLTs/mL.1,2 Transfusion of 10 mL/kg PLT concentrate provides approximately 10 × 109 PLTs per kg infant body weight. If an infant’s blood volume is 70 mL/kg and plasma volume is 40 mL/kg, a PTX of 10 mL/kg can be calculated to increase the PLT count by 100 × 109 to 150 × 109/L, assuming a posttransfusion PLT recovery of 60%.2 TRANSFUSION Volume 53, December 2013
4.
5.
Importantly, these calculations have been validated by in vivo clinical trial data4 in which a posttransfusion PLT increment of 95 × 109/L followed a transfusion of 10 mL/kg of unmodified (M. Andrew, personal communication, 1993) PLT concentrates. My personal unpublished experience is similar to that of Dr Andrew’s. For most neonates, a PTX infusion volume of 10 mL/kg is not excessive—providing the neonatologist or pediatrician is mindful of the intake of other intravenous fluids, medications, and nutrients.
Another reason often mentioned to justify volume reduction of PLT products is to limit quantities of anti-A and/or anti-B transfused to non-group O neonates. Recognizing that hemolysis from passive antibody has been reported, very rarely, it should not be a problem for several reasons: 1.
2.
3.
4.
It is strongly recommended that the ABO group of transfused PLTs be identical with the ABO group of neonatal recipients.3 If clinical circumstances are such that donor– recipient ABO groups cannot be identical, the amount of passive anti-A or anti-B transfused is very likely to be limited because most neonates receive only one PTX,1,3 and some blood centers collecting PLTs select only group O donors with low titers of anti-A or anti-B. Even if transfused, only small quantities of anti-A and/or anti-B bind to neonatal RBCs because expression of A and B antigens is developmentally weak on neonatal RBCs, and the transfused antibodies can bind to non-RBC A and B antigens on other tissues and in secretions. Thus, the direct antiglobulin test may become positive due to anti-A or anti-B, but reports of clinically significant hemolysis are extremely uncommon.
In summary, although the Dutch method of volume reduction provides PLT concentrates that will produce a satisfactory posttransfusion response in neonatal recipients, there is little justification to expend the time, resources, and money to transfuse VRP as a routine to neonates. CONFLICT OF INTEREST None.
Ronald G. Strauss, MD e-mail: [email protected] Professor Emeritus of Pathology & Pediatrics University of Iowa College of Medicine Iowa City, IA Associate Medical Director, LifeSource/ITxM Blood Center Chicago, IL
EDITORIAL
REFERENCES
5. von Lindern JS, van den Bruele T, Lopriore E, et al. Thrombocytopenia in neonates and the risk of intraventricular
1. Honohan A, van’t Ende E, Hulzebos C, et al. Posttransfusion platelet increments after different platelet products in neonates: a retrospective cohort study. Transfusion 2031;53:3100-9. 2. Morroff G, Friedman A, Robkine L, et al. Reduction of the volume of stored platelet concentrates for use in neonatal patients. Transfusion 1984;24:144-6. 3. Strauss RG. Platelet transfusion in neonates and children. In: Sweeny JD, Lozano M, editors. Platelet transfusion therapy. Bethesda (MD): American Association of Blood
hemorrhage: a retrospective cohort study. BMC Pediatr 2011;11:16-21. 6. Slichter SJ, Kaufman RM, Assman SF, et al. Dose of prophylactic platelet transfusions and prevention of hemorrhage. N Engl J Med 2010;362:600-13. 7. Josephson CD, Su LL, Christensen RD, et al. Platelet transfusion practices among neonatologists in the United States and Canada: results of a survey. Pediatrics 2009;123:278-85.
Banks; 2013. p. 359-69. 4. Andrew M, Vegh P, Caco C, et al. A randomized, controlled trial of platelet transfusions in thrombocytopenic premature infants. J Pediatr 1993;123:285-91.
Volume 53, December 2013 TRANSFUSION
3031
I
n this issue of TRANSFUSION, Dutch investigators report1 the posttransfusion blood platelet (PLT) count increments in neonates who received at least one PLT transfusion (PTX) prepared by different methods from apheresis PLT units: 1) volume-reduced and concentrated PLTs (VRP), 2) PLT additive solution PLTs (PASP), or 3) plasma-PLTs. Because the plasma-PLT group was too small to permit reasonable conclusions, all of my comments will pertain to the retrospective analysis of VRP versus PASP. As the major finding, the authors documented that when twice the dose of VRP was transfused versus PASP, the mean posttransfusion increments measured within 8 hours posttransfusion were, respectively, 111 × 109/L versus 62 × 109/L and, when measured 16 to 24 hours posttransfusion, were 60 × 109/L versus 38 × 109/L. The finding that if one transfuses twice the number of PLTs, the posttransfusion increments will be approximately twice as high, is not surprising. However, it is important that the results document that the Dutch method of volume reduction did not noticeably damage the PLTs (i.e., after transfusion, PLTs from VRP units circulated and increased the blood PLT count of neonates with thrombocytopenia). Over the years, several methods to volume reduce PLT units have been published, with quality of the PLTs in the volume-reduced units assessed by in vitro methods and/or with limited in vivo posttransfusion PLT increment data.2,3 The Dutch report is noteworthy because of the in vivo posttransfusion increment data in a fairly large number of human neonates, comparing VRP with PASP PLTs that were not exposed to the “stresses” of centrifugation and concentration.1 Although I believe that the findings can be confidently accepted in a “qualitative” or general sense, several shortcomings of the study do not permit the findings to be accepted “quantitatively” (i.e., one must be cautious and not assume that the actual posttransfusion increments reported will be achieved by every neonate transfused with VRP, when prepared by local blood banks or centers adopting the Dutch methods). The shortcomings, some of which are acknowledged by the authors, include: 1.
The study was retrospective with VRP transfused at one neonatal intensive care unit and PASP at another location—rather than being designed as a prospective clinical trial in which all neonates at both intensive care units were randomly allocated to receive either TRANSFUSION 2013;53:3029-3031.
2.
3.
4.
VRP or PASP. Thus, environmental or institutional differences or variables might influence results independently of whether VRP or PASP were transfused (i.e., the type of PLT product transfused was not, necessarily, the single experimental variable being studied). As evident in their Table 1, neonates transfused with VRP were more mature, larger, and less seriously ill in many respects than neonates given PASP. Undoubtedly, this difference led to variability in medical management between the two intensive care units. Thus, multiple biologic and management differences or variables in heterogeneous study subjects or neonates existed that might influence responses to PTXs independently of whether VRP or PASP were transfused—again, not one single experimental variable being studied. The actual dose and number of PLTs transfused was estimated for VPR, rather than being known, and the techniques of transfusion or infusion per se differed between the two groups of neonates being studied. VRP were infused in 15 minutes with no mention of a filter being used—compared to an infusion time of 30 minutes through a blood filter for PASP. Although these differences may have had little effect on posttransfusion PLT count increments, the actual effect is unknown—thus, another variable was introduced to possibly confound the results. Not every eligible neonate was analyzed and, as is typical for retrospective studies, data were missing for some transfusions. Moreover, there was no mention of a method to validate the completeness and accuracy of the data. Thus, it is difficult to exclude the possibility of bias.
In fairness to the authors, as reported in the article, the authors expended considerable efforts carefully attempting to minimize or offset these confounding factors by use of several statistical techniques. However, statistical “corrections” are unlikely to be 100% effective in eliminating experimental imbalances or possible bias, and these retrospective efforts are inferior to a study with prospective, randomized, and blinded design. As a case in point, a better experimental design for the Dutch study—if it had been possible—would have been: 1) to randomly allocate all eligible neonates at all intensive care unit locations to receive PTXs with either VRP or PASP; 2) to know, rather than estimate, the number of PLTs contained in every VRP and PASP unit transfused; 3) to prescribe PLT transfusions using uniform clinical Volume 53, December 2013 TRANSFUSION
3029
EDITORIAL
guidelines or indications; 4) to perform all PTXs using techniques that were as identical as possible; 5) to collect “real-time” data on standard data collection forms designed to collect all information needed to address the primary endpoint of posttransfusion increments; 6) to validate completeness and accuracy of data collected; 7) to “blind” as many investigators and caregivers as possible to the type of PTX product given; and 8) to report observations of clinical outcomes (e.g., transfusion reactions, changes in vital signs, effects on bleeding that might be present) during and after PTXs. Regardless, it seems clear that transfusion of VRP, when prepared per the Dutch method, will result in a substantial increase in the posttransfusion blood PLT count of transfused neonates1—but a key question is “Why spend the time, effort, and money to volume reduce PLT units or aliquots before transfusing them, when the usual goals and expectations of PTXs can be achieved without doing so?” To explain why this question is relevant. . . . The vast majority of neonatal PTX are given prophylactically—more than 98% in the current study1— with the belief that overt bleeding will be prevented or minimized1,3 and, although bleeding is more likely to occur in patients with severe thrombocytopenia, the risk of bleeding, generally, cannot be related directly to the degree of thrombocytopenia present in infants3-5 or in older patients.6,7 In the only randomized trial reported to date in neonates,4 there was no difference in the rate of severe intraventricular intracranial bleeding when the PLT count was maintained greater than 150 × 109/L versus giving PTX when the PLT count fell to less than 50 × 109/L. Thus, it is a reasonable goal or expectation of neonatal PTXs to achieve a posttransfusion blood PLT count of 100 × 109/L—rather than demanding some higher value. Although PTX practices vary widely, with some neonatologists or pediatricians giving PTX with pretransfusion blood PLT counts of 100 × 109/L, there are no data to support maintaining posttransfusion PLT counts of more than 100 × 109/L.3,4 Accepting posttransfusion blood PLT counts of 100 × 109/L to be satisfactory for prophylactic PTX, it is well established that this goal can be achieved by transfusing 10 mL/kg of an unmodified PLT unit taken straight from the blood bank PLT rotator (i.e., there is NO need to volume reduce). The rationale is as follows: 1. 2. 3.
3030
PLT concentrates, whether apheresis or whole blood derived, contain approximately 1 × 109 PLTs/mL.1,2 Transfusion of 10 mL/kg PLT concentrate provides approximately 10 × 109 PLTs per kg infant body weight. If an infant’s blood volume is 70 mL/kg and plasma volume is 40 mL/kg, a PTX of 10 mL/kg can be calculated to increase the PLT count by 100 × 109 to 150 × 109/L, assuming a posttransfusion PLT recovery of 60%.2 TRANSFUSION Volume 53, December 2013
4.
5.
Importantly, these calculations have been validated by in vivo clinical trial data4 in which a posttransfusion PLT increment of 95 × 109/L followed a transfusion of 10 mL/kg of unmodified (M. Andrew, personal communication, 1993) PLT concentrates. My personal unpublished experience is similar to that of Dr Andrew’s. For most neonates, a PTX infusion volume of 10 mL/kg is not excessive—providing the neonatologist or pediatrician is mindful of the intake of other intravenous fluids, medications, and nutrients.
Another reason often mentioned to justify volume reduction of PLT products is to limit quantities of anti-A and/or anti-B transfused to non-group O neonates. Recognizing that hemolysis from passive antibody has been reported, very rarely, it should not be a problem for several reasons: 1.
2.
3.
4.
It is strongly recommended that the ABO group of transfused PLTs be identical with the ABO group of neonatal recipients.3 If clinical circumstances are such that donor– recipient ABO groups cannot be identical, the amount of passive anti-A or anti-B transfused is very likely to be limited because most neonates receive only one PTX,1,3 and some blood centers collecting PLTs select only group O donors with low titers of anti-A or anti-B. Even if transfused, only small quantities of anti-A and/or anti-B bind to neonatal RBCs because expression of A and B antigens is developmentally weak on neonatal RBCs, and the transfused antibodies can bind to non-RBC A and B antigens on other tissues and in secretions. Thus, the direct antiglobulin test may become positive due to anti-A or anti-B, but reports of clinically significant hemolysis are extremely uncommon.
In summary, although the Dutch method of volume reduction provides PLT concentrates that will produce a satisfactory posttransfusion response in neonatal recipients, there is little justification to expend the time, resources, and money to transfuse VRP as a routine to neonates. CONFLICT OF INTEREST None.
Ronald G. Strauss, MD e-mail: [email protected] Professor Emeritus of Pathology & Pediatrics University of Iowa College of Medicine Iowa City, IA Associate Medical Director, LifeSource/ITxM Blood Center Chicago, IL
EDITORIAL
REFERENCES
5. von Lindern JS, van den Bruele T, Lopriore E, et al. Thrombocytopenia in neonates and the risk of intraventricular
1. Honohan A, van’t Ende E, Hulzebos C, et al. Posttransfusion platelet increments after different platelet products in neonates: a retrospective cohort study. Transfusion 2031;53:3100-9. 2. Morroff G, Friedman A, Robkine L, et al. Reduction of the volume of stored platelet concentrates for use in neonatal patients. Transfusion 1984;24:144-6. 3. Strauss RG. Platelet transfusion in neonates and children. In: Sweeny JD, Lozano M, editors. Platelet transfusion therapy. Bethesda (MD): American Association of Blood
hemorrhage: a retrospective cohort study. BMC Pediatr 2011;11:16-21. 6. Slichter SJ, Kaufman RM, Assman SF, et al. Dose of prophylactic platelet transfusions and prevention of hemorrhage. N Engl J Med 2010;362:600-13. 7. Josephson CD, Su LL, Christensen RD, et al. Platelet transfusion practices among neonatologists in the United States and Canada: results of a survey. Pediatrics 2009;123:278-85.
Banks; 2013. p. 359-69. 4. Andrew M, Vegh P, Caco C, et al. A randomized, controlled trial of platelet transfusions in thrombocytopenic premature infants. J Pediatr 1993;123:285-91.
Volume 53, December 2013 TRANSFUSION
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