- Email: [email protected]
Platelet transfusion thresholds in neonatal medicine
Early Human Development xxx (xxxx) xxxx
Contents lists available at ScienceDirect
Early Human Development journal homepage: www.elsevier.com/locate/earlhumdev
Platelet transfusion thresholds in neonatal medicine ⁎
Carmel Maria Moore , Anna Curley National Maternity Hospital, Holles Street, Dublin 2, Ireland
A R T I C LE I N FO
A B S T R A C T
Keywords: Thrombocytopenia Neonatal platelet transfusion Transfusion associated adverse event Major haemorrhage
Thrombocytopenia is common in preterm neonates. Thresholds for prophylactic platelet transfusion vary widely due to lack of evidence. The results of the PlaNet-2/MATISSE Study identified harm in the form of mortality and major bleed in babies prophylactically transfused below a platelet count of 50 × 109/L compared to 25 × 109/L. Neonatal platelet transfusions are administered at volumes based on historical practice which greatly exceed those routinely used in adults. Rate of transfusion is also based around practice in trauma and does not take into account the physiology of the preterm infant. There are multiple ways in which platelets may be mediating harm and this review discusses these potential mechanisms including immunological, inflammatory and blood group incompatibility. Much of the difficulty in assessing harm relates to problems in classification of transfusionassociated adverse events in babies. Thrombocytopenia and timing, efficacy and adverse effects of platelet transfusion are poorly understood. Further research is essential.
1. Background incidence Thrombocytopenia (platelet count < 150 × 109/L) is common in the neonatal intensive care unit (NICU) population, especially in babies born extremely low birth weight and/or small for gestational age [1]. Platelet transfusions are often used prophylactically in these infants to reduce the potential risk of bleeding, in particular intraventricular haemorrhage (IVH), the most common form of major haemorrhage and a leading cause of death and disability in preterm babies [2]. As a result, up to 15% of preterm babies receive platelet transfusions, with a quarter of very low birth weight (VLBW) infants receiving a platelet transfusion in one case series [2]. There are no evidence based recommendations for platelet transfusion thresholds in neonates, leading to a wide variation in transfusion practices between clinicians, institutions, and countries, with thresholds often ranging from 20 to 150 × 109/L. [3–5] Recent studies have suggested a role for thrombocytopenia in other preterm conditions such as delayed ductal closure or retinopathy of prematurity (ROP) which might promote a more aggressive approach to treatment of thrombocytopenia [6]. A randomised controlled trial (RCT) assessing the role of platelet transfusions in preventing patent ductus arteriosus (PDA) demonstrated no difference in time to closure but interestingly revealed a higher incidence of IVH in the transfused group [7]. Thrombocytopenia has been suggested in many case control studies to be a risk factor for retinopathy of prematurity [8], and one mouse model has suggested that transfusion may interrupt progression
⁎
to severe retinopathy [9]. Potential benefits of platelet therapy need to be balanced however, against the risks of transfusion. A large retrospective review of 1600 thrombocytopenic patients in the NICU from 2007 reported that at all levels of platelet count, those babies that received platelet transfusions had a higher mortality rate [10]. Sicker babies are more likely to be transfused and in retrospective studies it can be difficult to ascertain which outcomes can be attributed to baseline risk characteristics and which may be mediated by platelets. Sensitivity analysis of the study by Baer et al. suggested that transfusions themselves were likely responsible for some of this harm [10]. A further analysis by the same group in 2009 of babies with platelet counts < 50 × 109/L showed that mortality was not predicted by the lowest platelet count but by the number of platelet transfusions administered [11]. It also demonstrated that intraventricular, pulmonary and gastrointestinal haemorrhages were not predicted by the lowest platelet count. This was borne out in the observational study PlaNet-1 where there was no correlation between platelet count nadir in thrombocytopenic infants and incidence of major bleed [12]. 2. Evidence base for platelet transfusion In 1993 a randomised controlled trial by Andrew et al. demonstrated that prophylactic platelet transfusion to maintain a platelet count > 150 × 109/L compared to 50 × 109/L did not reduce the incidence or severity of any new onset IVH (22 vs 19 haemorrhages, treatment vs control group) in preterm neonates [13]. Of note the rate
Corresponding author. E-mail addresses: [email protected] (C.M. Moore), [email protected] (A. Curley).
https://doi.org/10.1016/j.earlhumdev.2019.104845
0378-3782/ © 2019 Elsevier B.V. All rights reserved.
Please cite this article as: Carmel Maria Moore and Anna Curley, Early Human Development, https://doi.org/10.1016/j.earlhumdev.2019.104845
Early Human Development xxx (xxxx) xxxx
C.M. Moore and A. Curley
5. The role of ABO incompatibility
of new major IVH however, was increased in the higher threshold group (IVH: 12 vs 5, treatment vs control). There were no further RCTs of platelet transfusion until recently when the PlaNet-2/MATISSE study demonstrated that a lower threshold; 25 × 109/L versus 50 × 109/L for platelet transfusion showed a reduced composite outcome of death and/or major bleeding within 28 days of randomisation [14]. Another recent randomised trial reported (although not as a primary outcome) that there was a significantly higher rate of IVH in a group of babies liberally transfused to a target platelet concentration of 100 × 109/L: 41% of infants had any grade of IVH in the liberal transfusion group compared with 4.5% in the restrictive group [7].
Although the ABO blood group system is crucial in the transfusion of red blood cells its role in platelet transfusion is less clear. ABO incompatible platelets are often given for logistic reasons of availability. As type O platelets and plasma have anti-A and anti-B antigens non ABO-matched platelet transfusions can cause ABO immune complexes to be formed [18]. There is limited evidence regarding the ABO matching of platelets transfused to neonates. Studies have shown that any ABO incompatible platelets transfused contribute to platelet refractoriness in adults [18]. A prospective randomised trial in adults showed that ABO matched platelets provided a greater platelet increment than ABO mismatched platelets [19] and studies suggest the negative effect on platelet count and function of non-ABO-matched transfusions may be cumulative [18]. This has yet to be demonstrated in the paediatric or neonatal critical care population [20].
3. Neonatal transfusion practices Although neonatologists vary in their approach as to when to transfuse there is relative consistency in volumes given and speed of transfusion. Consensus guidelines on platelet transfusion vary but the majority list 10–15 ml per kilogram of body weight as the recommended dose of platelets to transfuse in neonatal and paediatric patients [15]. This figure appears to derive from established practice and also perhaps similarity to red cell volumes rather than having a good physiologic basis. Guidelines for adult transfusions suggest that one unit of platelets (approximately 300mls and 2.6 × 10 [11] platelets) constitutes an appropriate treatment dose for adult patients. The average adult weighing 70 kg, would therefore receive approximately 4 ml per kilogram of body weight. In adults, although many factors can affect post-transfusion platelet increments, on average one unit of platelets will cause an immediate increase in platelet count by 20–40 × 109/L. Neonates receiving a platelet transfusion at 10–15 mls/ kg would therefore receive greater than threefold the volume of platelets given to adults. In the 1993 RCT by Andrew et al., 10mls/kg volume of platelets given to neonates demonstrated an increment of 95 × 10 in platelet count [13]. As exogenous platelets last about four days in the human body [16], there may not be any benefit to raising the platelet count greater than that which is immediately needed. This is likely to be less than what is suggested by many current guidelines. It is possible that dose reduction could temper, in a dose response fashion, some of the risks associated with platelet transfusion.
6. Adverse effects of transfusion Platelets, like other blood products, can cause transfusion associated adverse effects including transfusion related acute lung injury (TRALI) and transfusion associated circulatory overload (TACO). Both these conditions have the potential to cause significant morbidity and mortality. Platelets are more likely than red cell concentrates to cause TRALI, due to higher volume of plasma in the transfusate. TRALI in adults is defined as a new acute lung injury occurring during or within six hours after a transfusion, with a clear temporal relationship to the transfusion, the absence of circulatory overload or other likely causes, or in the presence of human leucocyte antigen (HLA) or human neutrophil antigen (HNA) antibodies cognate with the recipient. TACO is defined by the NHS Serious Hazards of Transfusion Agency (SHOT) as acute or worsening respiratory compromise or evidence of acute or worsening pulmonary oedema based on clinical physical examination, radiographic chest imaging or other non-invasive assessment of cardiac within 12–24 h of transfusion [21]. Studies suggest that paediatric patients may be at higher risk of TRALI than adults [21]. There are limited data on TRALI and TACO in neonates, probably related to the difficulty in defining these conditions in this population. Other types of adverse reactions to transfusion include febrile, allergic and hypotensive reactions (FAHR). There were no FAHR reported to NHS SHOT following neonatal transfusions in 2018 possibly related to under recognition rather than true incidence. The PlaNeT-2/MATISSE study [14] demonstrated an increased rate of death or major bleeding in babies assigned to a higher platelet transfusion threshold (> 50 × 109/L). This group also showed a higher rate of bronchopulmonary dysplasia at 36 weeks. Although this was an unexpected finding, recent adult studies have also highlighted potential harm from liberal platelet transfusion. These studies have shown an association between platelet transfusion, venous and arterial thromboembolism and mortality and an association between pre-procedure prophylactic platelet transfusions and an increased risk of thrombosis, 30-day mortality and ICU admission [22,23]. A study investigating platelet transfusion in adults with intracranial haemorrhages whilst on anti-platelet therapy showed that prophylactic platelet transfusion was associated with increased mortality or significant neurological impairment [24] in recipients. There are many potential explanations why platelet transfusions in their current form may be causing harm in the neonatal population. The volume and rapidity of the transfusion alone may mediate harm through direct haemodynamic effects. We also know that in-vitro neonatal platelets appear to be hyporeactive relative to adult platelets. We do not know, however, if transfusing adult more active platelets into the neonate promote excess microthrombosis. Platelets also have significant immunologic and inflammatory effects [18,25]. Studies have shown that there can be higher levels of proinflammatory mediators in the lungs of preterm infants with bronchopulmonary dysplasia, and there is a risk that bioreactive components
4. Platelet characteristics, collection, storage and administration Platelets used in neonatal transfusion are typically collected by apheresis from a single donor, compared to pooled platelets which are derived from whole blood donations from multiple donors. Platelets are stored in bags that are permeable to oxygen in order to allow aerobic respiration and In hospital blood banks, platelets are stored at between 20 and 24 degrees Celsius on an agitator to prevent platelet clumping [17]. There are some suggestions that storage, time off the agitator and time in closed containers may affect platelet count as well as platelet function [17]. Platelets are normally stored for no longer than one week. Platelets are traditionally infused over 30 to 60 min. This leads to a large volume bolus in a potentially critically ill acidotic infant with a pressure passive cerebral circulation. This practice most likely derives from adult practice relating to acute major bleeding where limited intravenous access also necessitates rapid administration of product. Current evidence suggests that platelets can safely tolerate up to 8 h at a time without agitation [17]. Guidelines suggest that they should be transfused as soon as released from the laboratory due to concerns over platelet clumping. There is no clear evidence for the rate of infusion typically used and although there are studies looking at infusion rates in adults, as mentioned above, the much larger volumes per kilogram in each neonatal platelet transfusion must be taken into consideration.
2
Early Human Development xxx (xxxx) xxxx
C.M. Moore and A. Curley
[6] H. Sallmon, S.C. Weber, B. Huning, et al., Thrombocytopenia in the first 24 hours after birth and incidence of patent ductus arteriosus, Pediatrics 130 (2012) e623–e630. [7] J. Kumar, S. Dutta, V. Sundaram, S.S. Saini, R.R. Sharma, N. Varma, Platelet transfusion for PDA closure in preterm infants: a randomized controlled trial, Pediatrics 143 (2019). [8] A.K. Jensen, G.S. Ying, J. Huang, G.E. Quinn, G. Binenbaum, Longitudinal study of the association between thrombocytopenia and retinopathy of prematurity, Journal of AAPOS : The Official Publication of the American Association for Pediatric Ophthalmology and Strabismus 22 (2018) 119–123. [9] B. Cakir, R. Liegl, G. Hellgren, et al., Thrombocytopenia is associated with severe retinopathy of prematurity, JCI Insight 3 (2018). [10] V.L. Baer, D.K. Lambert, E. Henry, G.L. Snow, M.C. Sola-Visner, R.D. Christensen, Do platelet transfusions in the NICU adversely affect survival? Analysis of 1600 thrombocytopenic neonates in a multihospital healthcare system, J Perinatol: Official Journal of the California Perinatal Association 27 (2007) 790–796. [11] V.L. Baer, D.K. Lambert, E. Henry, R.D. Christensen, Severe thrombocytopenia in the NICU, Pediatrics 124 (2009) e1095–e1100. [12] S.J. Stanworth, P. Clarke, T. Watts, et al., Prospective, observational study of outcomes in neonates with severe thrombocytopenia, Pediatrics 124 (2009) e826–e834. [13] M. Andrew, P. Vegh, C. Caco, et al., A randomized, controlled trial of platelet transfusions in thrombocytopenic premature infants, J. Pediatr. 123 (1993) 285–291. [14] A. Curley, S.J. Stanworth, K. Willoughby, et al., Randomized trial of platelettransfusion thresholds in neonates, N. Engl. J. Med. 380 (2019) 242–251. [15] H.V. New, J. Berryman, P.H. Bolton-Maggs, et al., Guidelines on transfusion for fetuses, neonates and older children, Br. J. Haematol. 175 (2016) 784–828. [16] J.A. Cohen, C.H. Leeksma, Determination of the life span of human blood platelets using labelled diisopropylfluorophosphonate, J. Clin. Invest. 35 (1956) 964–969. [17] S. Thomas, Platelets: handle with care, Transfusion Medicine (Oxford, England) 26 (2016) 330–338. [18] M. Stolla, M.A. Refaai, J.M. Heal, et al., Platelet transfusion - the new immunology of an old therapy, Front. Immunol. 6 (2015) 28. [19] J.M. Heal, J.M. Rowe, A. McMican, D. Masel, C. Finke, N. Blumberg, The role of ABO matching in platelet transfusion, Eur. J. Haematol. 50 (1993) 110–117. [20] Nellis ME, Goel R, Karam O, et al. Effects of ABO matching of platelet transfusions in critically ill children. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the world Federation of Pediatric Intensive and Critical Care Societies 2019;20:e61-e9. [21] S Narayan (Ed) D Poles et al on behalf of the Serious Hazards of Transfusion Steering group. The 2018 Annual SHOT Report (2019). UK: NHS; 2019. [22] A.A. Khorana, C.W. Francis, N. Blumberg, E. Culakova, M.A. Refaai, G.H. Lyman, Blood transfusions, thrombosis, and mortality in hospitalized patients with cancer, Arch. Intern. Med. 168 (2008) 2377–2381. [23] A.E. Schmidt, K.F. Henrichs, S.A. Kirkley, M.A. Refaai, N. Blumberg, Prophylactic Preprocedure platelet transfusion is associated with increased risk of thrombosis and mortality, Am. J. Clin. Pathol. 149 (2017) 87–94. [24] M.I. Baharoglu, C. Cordonnier, R. Al-Shahi Salman, et al., Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, Phase 3 Trial. Lancet (London, England) 387 (2016) 2605–2613. [25] J.D. McFadyen, Z.S. Kaplan, Platelets are not just for clots, Transfus. Med. Rev. 29 (2015) 110–119.
from platelet transfusions could also contribute to this type of injury, potentially explaining the higher rate of bronchopulmonary dysplasia in recent studies [14]. 7. Summary Recent neonatal and adult studies of platelet transfusion suggest harm when higher prophylactic transfusion thresholds are used. There are many unanswered questions about platelet transfusion in neonates: when should we transfuse, which volume is necessary, how fast should we give platelets and what is the role of platelet donor characteristics such as ABO matching in mitigating harm. Further research is essential to advance our knowledge in this important area affecting up to one in four very low birth weight infants in neonatal intensive care. Declaration of competing interest Carmel Maria Moore has no conflicts of interest to declare. Anna Curley has no conflicts of interest to declare. Acknowledgements Anna Curley received funding from the National Health Service Blood and Transplant Research and Development Committee (Ref No: BS06/1); Sanquin Research, Amsterdam (grant PPOC-12-012027); Adden-brooke's Charitable Trust; the Neonatal Breath of Life Fund 9145; and the National Institute for Health Research Clinical Research Network. References [1] R.D. Christensen, E. Henry, S.E. Wiedmeier, et al., Thrombocytopenia among extremely low birth weight neonates: data from a multihospital healthcare system, J Perinatol: Official Journal of the California Perinatal Association 26 (2006) 348–353. [2] K.A. Sparger, S.F. Assmann, S. Granger, et al., Platelet transfusion practices among very-low-birth-weight infants, JAMA Pediatr. 170 (2016) 687–694. [3] C.D. Josephson, L.L. Su, R.D. Christensen, et al., Platelet transfusion practices among neonatologists in the United States and Canada: results of a survey, Pediatrics 123 (2009) 278–285. [4] M. Cremer, M. Sola-Visner, S. Roll, et al., Platelet transfusions in neonates: practices in the United States vary significantly from those in Austria, Germany, And Switzerland. Transfusion 51 (2011) 2634–2641. [5] Chaudhary R, Clarke P. Current transfusion practices for platelets and fresh, frozen plasma in UK tertiary level neonatal units. Acta paediatrica (Oslo, Norway : 1992) 2008;97:135.
3
Contents lists available at ScienceDirect
Early Human Development journal homepage: www.elsevier.com/locate/earlhumdev
Platelet transfusion thresholds in neonatal medicine ⁎
Carmel Maria Moore , Anna Curley National Maternity Hospital, Holles Street, Dublin 2, Ireland
A R T I C LE I N FO
A B S T R A C T
Keywords: Thrombocytopenia Neonatal platelet transfusion Transfusion associated adverse event Major haemorrhage
Thrombocytopenia is common in preterm neonates. Thresholds for prophylactic platelet transfusion vary widely due to lack of evidence. The results of the PlaNet-2/MATISSE Study identified harm in the form of mortality and major bleed in babies prophylactically transfused below a platelet count of 50 × 109/L compared to 25 × 109/L. Neonatal platelet transfusions are administered at volumes based on historical practice which greatly exceed those routinely used in adults. Rate of transfusion is also based around practice in trauma and does not take into account the physiology of the preterm infant. There are multiple ways in which platelets may be mediating harm and this review discusses these potential mechanisms including immunological, inflammatory and blood group incompatibility. Much of the difficulty in assessing harm relates to problems in classification of transfusionassociated adverse events in babies. Thrombocytopenia and timing, efficacy and adverse effects of platelet transfusion are poorly understood. Further research is essential.
1. Background incidence Thrombocytopenia (platelet count < 150 × 109/L) is common in the neonatal intensive care unit (NICU) population, especially in babies born extremely low birth weight and/or small for gestational age [1]. Platelet transfusions are often used prophylactically in these infants to reduce the potential risk of bleeding, in particular intraventricular haemorrhage (IVH), the most common form of major haemorrhage and a leading cause of death and disability in preterm babies [2]. As a result, up to 15% of preterm babies receive platelet transfusions, with a quarter of very low birth weight (VLBW) infants receiving a platelet transfusion in one case series [2]. There are no evidence based recommendations for platelet transfusion thresholds in neonates, leading to a wide variation in transfusion practices between clinicians, institutions, and countries, with thresholds often ranging from 20 to 150 × 109/L. [3–5] Recent studies have suggested a role for thrombocytopenia in other preterm conditions such as delayed ductal closure or retinopathy of prematurity (ROP) which might promote a more aggressive approach to treatment of thrombocytopenia [6]. A randomised controlled trial (RCT) assessing the role of platelet transfusions in preventing patent ductus arteriosus (PDA) demonstrated no difference in time to closure but interestingly revealed a higher incidence of IVH in the transfused group [7]. Thrombocytopenia has been suggested in many case control studies to be a risk factor for retinopathy of prematurity [8], and one mouse model has suggested that transfusion may interrupt progression
⁎
to severe retinopathy [9]. Potential benefits of platelet therapy need to be balanced however, against the risks of transfusion. A large retrospective review of 1600 thrombocytopenic patients in the NICU from 2007 reported that at all levels of platelet count, those babies that received platelet transfusions had a higher mortality rate [10]. Sicker babies are more likely to be transfused and in retrospective studies it can be difficult to ascertain which outcomes can be attributed to baseline risk characteristics and which may be mediated by platelets. Sensitivity analysis of the study by Baer et al. suggested that transfusions themselves were likely responsible for some of this harm [10]. A further analysis by the same group in 2009 of babies with platelet counts < 50 × 109/L showed that mortality was not predicted by the lowest platelet count but by the number of platelet transfusions administered [11]. It also demonstrated that intraventricular, pulmonary and gastrointestinal haemorrhages were not predicted by the lowest platelet count. This was borne out in the observational study PlaNet-1 where there was no correlation between platelet count nadir in thrombocytopenic infants and incidence of major bleed [12]. 2. Evidence base for platelet transfusion In 1993 a randomised controlled trial by Andrew et al. demonstrated that prophylactic platelet transfusion to maintain a platelet count > 150 × 109/L compared to 50 × 109/L did not reduce the incidence or severity of any new onset IVH (22 vs 19 haemorrhages, treatment vs control group) in preterm neonates [13]. Of note the rate
Corresponding author. E-mail addresses: [email protected] (C.M. Moore), [email protected] (A. Curley).
https://doi.org/10.1016/j.earlhumdev.2019.104845
0378-3782/ © 2019 Elsevier B.V. All rights reserved.
Please cite this article as: Carmel Maria Moore and Anna Curley, Early Human Development, https://doi.org/10.1016/j.earlhumdev.2019.104845
Early Human Development xxx (xxxx) xxxx
C.M. Moore and A. Curley
5. The role of ABO incompatibility
of new major IVH however, was increased in the higher threshold group (IVH: 12 vs 5, treatment vs control). There were no further RCTs of platelet transfusion until recently when the PlaNet-2/MATISSE study demonstrated that a lower threshold; 25 × 109/L versus 50 × 109/L for platelet transfusion showed a reduced composite outcome of death and/or major bleeding within 28 days of randomisation [14]. Another recent randomised trial reported (although not as a primary outcome) that there was a significantly higher rate of IVH in a group of babies liberally transfused to a target platelet concentration of 100 × 109/L: 41% of infants had any grade of IVH in the liberal transfusion group compared with 4.5% in the restrictive group [7].
Although the ABO blood group system is crucial in the transfusion of red blood cells its role in platelet transfusion is less clear. ABO incompatible platelets are often given for logistic reasons of availability. As type O platelets and plasma have anti-A and anti-B antigens non ABO-matched platelet transfusions can cause ABO immune complexes to be formed [18]. There is limited evidence regarding the ABO matching of platelets transfused to neonates. Studies have shown that any ABO incompatible platelets transfused contribute to platelet refractoriness in adults [18]. A prospective randomised trial in adults showed that ABO matched platelets provided a greater platelet increment than ABO mismatched platelets [19] and studies suggest the negative effect on platelet count and function of non-ABO-matched transfusions may be cumulative [18]. This has yet to be demonstrated in the paediatric or neonatal critical care population [20].
3. Neonatal transfusion practices Although neonatologists vary in their approach as to when to transfuse there is relative consistency in volumes given and speed of transfusion. Consensus guidelines on platelet transfusion vary but the majority list 10–15 ml per kilogram of body weight as the recommended dose of platelets to transfuse in neonatal and paediatric patients [15]. This figure appears to derive from established practice and also perhaps similarity to red cell volumes rather than having a good physiologic basis. Guidelines for adult transfusions suggest that one unit of platelets (approximately 300mls and 2.6 × 10 [11] platelets) constitutes an appropriate treatment dose for adult patients. The average adult weighing 70 kg, would therefore receive approximately 4 ml per kilogram of body weight. In adults, although many factors can affect post-transfusion platelet increments, on average one unit of platelets will cause an immediate increase in platelet count by 20–40 × 109/L. Neonates receiving a platelet transfusion at 10–15 mls/ kg would therefore receive greater than threefold the volume of platelets given to adults. In the 1993 RCT by Andrew et al., 10mls/kg volume of platelets given to neonates demonstrated an increment of 95 × 10 in platelet count [13]. As exogenous platelets last about four days in the human body [16], there may not be any benefit to raising the platelet count greater than that which is immediately needed. This is likely to be less than what is suggested by many current guidelines. It is possible that dose reduction could temper, in a dose response fashion, some of the risks associated with platelet transfusion.
6. Adverse effects of transfusion Platelets, like other blood products, can cause transfusion associated adverse effects including transfusion related acute lung injury (TRALI) and transfusion associated circulatory overload (TACO). Both these conditions have the potential to cause significant morbidity and mortality. Platelets are more likely than red cell concentrates to cause TRALI, due to higher volume of plasma in the transfusate. TRALI in adults is defined as a new acute lung injury occurring during or within six hours after a transfusion, with a clear temporal relationship to the transfusion, the absence of circulatory overload or other likely causes, or in the presence of human leucocyte antigen (HLA) or human neutrophil antigen (HNA) antibodies cognate with the recipient. TACO is defined by the NHS Serious Hazards of Transfusion Agency (SHOT) as acute or worsening respiratory compromise or evidence of acute or worsening pulmonary oedema based on clinical physical examination, radiographic chest imaging or other non-invasive assessment of cardiac within 12–24 h of transfusion [21]. Studies suggest that paediatric patients may be at higher risk of TRALI than adults [21]. There are limited data on TRALI and TACO in neonates, probably related to the difficulty in defining these conditions in this population. Other types of adverse reactions to transfusion include febrile, allergic and hypotensive reactions (FAHR). There were no FAHR reported to NHS SHOT following neonatal transfusions in 2018 possibly related to under recognition rather than true incidence. The PlaNeT-2/MATISSE study [14] demonstrated an increased rate of death or major bleeding in babies assigned to a higher platelet transfusion threshold (> 50 × 109/L). This group also showed a higher rate of bronchopulmonary dysplasia at 36 weeks. Although this was an unexpected finding, recent adult studies have also highlighted potential harm from liberal platelet transfusion. These studies have shown an association between platelet transfusion, venous and arterial thromboembolism and mortality and an association between pre-procedure prophylactic platelet transfusions and an increased risk of thrombosis, 30-day mortality and ICU admission [22,23]. A study investigating platelet transfusion in adults with intracranial haemorrhages whilst on anti-platelet therapy showed that prophylactic platelet transfusion was associated with increased mortality or significant neurological impairment [24] in recipients. There are many potential explanations why platelet transfusions in their current form may be causing harm in the neonatal population. The volume and rapidity of the transfusion alone may mediate harm through direct haemodynamic effects. We also know that in-vitro neonatal platelets appear to be hyporeactive relative to adult platelets. We do not know, however, if transfusing adult more active platelets into the neonate promote excess microthrombosis. Platelets also have significant immunologic and inflammatory effects [18,25]. Studies have shown that there can be higher levels of proinflammatory mediators in the lungs of preterm infants with bronchopulmonary dysplasia, and there is a risk that bioreactive components
4. Platelet characteristics, collection, storage and administration Platelets used in neonatal transfusion are typically collected by apheresis from a single donor, compared to pooled platelets which are derived from whole blood donations from multiple donors. Platelets are stored in bags that are permeable to oxygen in order to allow aerobic respiration and In hospital blood banks, platelets are stored at between 20 and 24 degrees Celsius on an agitator to prevent platelet clumping [17]. There are some suggestions that storage, time off the agitator and time in closed containers may affect platelet count as well as platelet function [17]. Platelets are normally stored for no longer than one week. Platelets are traditionally infused over 30 to 60 min. This leads to a large volume bolus in a potentially critically ill acidotic infant with a pressure passive cerebral circulation. This practice most likely derives from adult practice relating to acute major bleeding where limited intravenous access also necessitates rapid administration of product. Current evidence suggests that platelets can safely tolerate up to 8 h at a time without agitation [17]. Guidelines suggest that they should be transfused as soon as released from the laboratory due to concerns over platelet clumping. There is no clear evidence for the rate of infusion typically used and although there are studies looking at infusion rates in adults, as mentioned above, the much larger volumes per kilogram in each neonatal platelet transfusion must be taken into consideration.
2
Early Human Development xxx (xxxx) xxxx
C.M. Moore and A. Curley
[6] H. Sallmon, S.C. Weber, B. Huning, et al., Thrombocytopenia in the first 24 hours after birth and incidence of patent ductus arteriosus, Pediatrics 130 (2012) e623–e630. [7] J. Kumar, S. Dutta, V. Sundaram, S.S. Saini, R.R. Sharma, N. Varma, Platelet transfusion for PDA closure in preterm infants: a randomized controlled trial, Pediatrics 143 (2019). [8] A.K. Jensen, G.S. Ying, J. Huang, G.E. Quinn, G. Binenbaum, Longitudinal study of the association between thrombocytopenia and retinopathy of prematurity, Journal of AAPOS : The Official Publication of the American Association for Pediatric Ophthalmology and Strabismus 22 (2018) 119–123. [9] B. Cakir, R. Liegl, G. Hellgren, et al., Thrombocytopenia is associated with severe retinopathy of prematurity, JCI Insight 3 (2018). [10] V.L. Baer, D.K. Lambert, E. Henry, G.L. Snow, M.C. Sola-Visner, R.D. Christensen, Do platelet transfusions in the NICU adversely affect survival? Analysis of 1600 thrombocytopenic neonates in a multihospital healthcare system, J Perinatol: Official Journal of the California Perinatal Association 27 (2007) 790–796. [11] V.L. Baer, D.K. Lambert, E. Henry, R.D. Christensen, Severe thrombocytopenia in the NICU, Pediatrics 124 (2009) e1095–e1100. [12] S.J. Stanworth, P. Clarke, T. Watts, et al., Prospective, observational study of outcomes in neonates with severe thrombocytopenia, Pediatrics 124 (2009) e826–e834. [13] M. Andrew, P. Vegh, C. Caco, et al., A randomized, controlled trial of platelet transfusions in thrombocytopenic premature infants, J. Pediatr. 123 (1993) 285–291. [14] A. Curley, S.J. Stanworth, K. Willoughby, et al., Randomized trial of platelettransfusion thresholds in neonates, N. Engl. J. Med. 380 (2019) 242–251. [15] H.V. New, J. Berryman, P.H. Bolton-Maggs, et al., Guidelines on transfusion for fetuses, neonates and older children, Br. J. Haematol. 175 (2016) 784–828. [16] J.A. Cohen, C.H. Leeksma, Determination of the life span of human blood platelets using labelled diisopropylfluorophosphonate, J. Clin. Invest. 35 (1956) 964–969. [17] S. Thomas, Platelets: handle with care, Transfusion Medicine (Oxford, England) 26 (2016) 330–338. [18] M. Stolla, M.A. Refaai, J.M. Heal, et al., Platelet transfusion - the new immunology of an old therapy, Front. Immunol. 6 (2015) 28. [19] J.M. Heal, J.M. Rowe, A. McMican, D. Masel, C. Finke, N. Blumberg, The role of ABO matching in platelet transfusion, Eur. J. Haematol. 50 (1993) 110–117. [20] Nellis ME, Goel R, Karam O, et al. Effects of ABO matching of platelet transfusions in critically ill children. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the world Federation of Pediatric Intensive and Critical Care Societies 2019;20:e61-e9. [21] S Narayan (Ed) D Poles et al on behalf of the Serious Hazards of Transfusion Steering group. The 2018 Annual SHOT Report (2019). UK: NHS; 2019. [22] A.A. Khorana, C.W. Francis, N. Blumberg, E. Culakova, M.A. Refaai, G.H. Lyman, Blood transfusions, thrombosis, and mortality in hospitalized patients with cancer, Arch. Intern. Med. 168 (2008) 2377–2381. [23] A.E. Schmidt, K.F. Henrichs, S.A. Kirkley, M.A. Refaai, N. Blumberg, Prophylactic Preprocedure platelet transfusion is associated with increased risk of thrombosis and mortality, Am. J. Clin. Pathol. 149 (2017) 87–94. [24] M.I. Baharoglu, C. Cordonnier, R. Al-Shahi Salman, et al., Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, Phase 3 Trial. Lancet (London, England) 387 (2016) 2605–2613. [25] J.D. McFadyen, Z.S. Kaplan, Platelets are not just for clots, Transfus. Med. Rev. 29 (2015) 110–119.
from platelet transfusions could also contribute to this type of injury, potentially explaining the higher rate of bronchopulmonary dysplasia in recent studies [14]. 7. Summary Recent neonatal and adult studies of platelet transfusion suggest harm when higher prophylactic transfusion thresholds are used. There are many unanswered questions about platelet transfusion in neonates: when should we transfuse, which volume is necessary, how fast should we give platelets and what is the role of platelet donor characteristics such as ABO matching in mitigating harm. Further research is essential to advance our knowledge in this important area affecting up to one in four very low birth weight infants in neonatal intensive care. Declaration of competing interest Carmel Maria Moore has no conflicts of interest to declare. Anna Curley has no conflicts of interest to declare. Acknowledgements Anna Curley received funding from the National Health Service Blood and Transplant Research and Development Committee (Ref No: BS06/1); Sanquin Research, Amsterdam (grant PPOC-12-012027); Adden-brooke's Charitable Trust; the Neonatal Breath of Life Fund 9145; and the National Institute for Health Research Clinical Research Network. References [1] R.D. Christensen, E. Henry, S.E. Wiedmeier, et al., Thrombocytopenia among extremely low birth weight neonates: data from a multihospital healthcare system, J Perinatol: Official Journal of the California Perinatal Association 26 (2006) 348–353. [2] K.A. Sparger, S.F. Assmann, S. Granger, et al., Platelet transfusion practices among very-low-birth-weight infants, JAMA Pediatr. 170 (2016) 687–694. [3] C.D. Josephson, L.L. Su, R.D. Christensen, et al., Platelet transfusion practices among neonatologists in the United States and Canada: results of a survey, Pediatrics 123 (2009) 278–285. [4] M. Cremer, M. Sola-Visner, S. Roll, et al., Platelet transfusions in neonates: practices in the United States vary significantly from those in Austria, Germany, And Switzerland. Transfusion 51 (2011) 2634–2641. [5] Chaudhary R, Clarke P. Current transfusion practices for platelets and fresh, frozen plasma in UK tertiary level neonatal units. Acta paediatrica (Oslo, Norway : 1992) 2008;97:135.
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