Platelet Transfusion for Treatment of Patent Ductus Arteriosus in Thrombocytopenic Preterm Neonates

Summary

Patent ductus arteriosus (PDA) is a common problem in preterm babies. Recently there have been various studies for and against an association between thrombocytopenia and PDA. A meta-analysis published in 2015 showed a marginally significant positive association between PDA and thrombocytopenia but these were all observational studies and there are no randomized controlled trials (RCT) on it. The investigators decided to conduct an RCT to determine whether liberal platelet transfusion criteria achieve earlier PDA closure rates than standard restrictive platelet transfusion criteria among thrombocytopenic preterm neonates (\<35 weeks' gestation) with hemodynamically significant PDA presenting within the first 14 days of life. The investigators primary objective is to determine whether liberal platelet transfusion criteria achieve earlier PDA closure rates within 120 hours compared to standard restrictive platelet transfusion criteria among thrombocytopenic preterm neonates (\<35 weeks' gestation) with hemodynamically significant PDA presenting within the first 14 days of life. The investigators will stratify the study population based on platelet count, i.e \< 50000 and 50000-100000 per microlitre, and will randomly allocate participants to control and intervention group. Babies in the intervention group will receive platelet transfusion to maintain the platelet count above 100,000 per microlitre. Babies in control group will receive platelets only when clinically indicated and as per current standard indications. The investigators will perform an echocardiogram at baseline to document a hemodynamically significant PDA (hsPDA) and then serially to look for the closure of PDA. Medical management of PDA will be as per unit policy. The investigators will follow the baby till PDA closes or 120 hours post randomization.

Timeline

Start

2016-03

Primary completion

2017-03-20

Completion

2017-03-20

Publications

• Background Bancalari E, Claure N, Gonzalez A. Patent ductus arteriosus and respiratory outcome in premature infants. Biol Neonate. 2005;88(3):192-201. doi: 10.1159/000087582.
• Background Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR, Walsh MC, Hale EC, Newman NS, Schibler K, Carlo WA, Kennedy KA, Poindexter BB, Finer NN, Ehrenkranz RA, Duara S, Sanchez PJ, O'Shea TM, Goldberg RN, Van Meurs KP, Faix RG, Phelps DL, Frantz ID 3rd, Watterberg KL, Saha S, Das A, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics. 2010 Sep;126(3):443-56. doi: 10.1542/peds.2009-2959. Epub 2010 Aug 23.
• Background Adrouche-Amrani L, Green RS, Gluck KM, Lin J. Failure of a repeat course of cyclooxygenase inhibitor to close a PDA is a risk factor for developing chronic lung disease in ELBW infants. BMC Pediatr. 2012 Jan 27;12:10. doi: 10.1186/1471-2431-12-10.
• Background Echtler K, Stark K, Lorenz M, Kerstan S, Walch A, Jennen L, Rudelius M, Seidl S, Kremmer E, Emambokus NR, von Bruehl ML, Frampton J, Isermann B, Genzel-Boroviczeny O, Schreiber C, Mehilli J, Kastrati A, Schwaiger M, Shivdasani RA, Massberg S. Platelets contribute to postnatal occlusion of the ductus arteriosus. Nat Med. 2010 Jan;16(1):75-82. doi: 10.1038/nm.2060. Epub 2009 Dec 6.
• Background Simon SR, van Zogchel L, Bas-Suarez MP, Cavallaro G, Clyman RI, Villamor E. Platelet Counts and Patent Ductus Arteriosus in Preterm Infants: A Systematic Review and Meta-Analysis. Neonatology. 2015;108(2):143-51. doi: 10.1159/000431281. Epub 2015 Jul 7.
• Background Stoller JZ, Demauro SB, Dagle JM, Reese J. Current Perspectives on Pathobiology of the Ductus Arteriosus. J Clin Exp Cardiolog. 2012 Jun 15;8(1):S8-001. doi: 10.4172/2155-9880.S8-001.
• Background Loftin CD, Trivedi DB, Tiano HF, Clark JA, Lee CA, Epstein JA, Morham SG, Breyer MD, Nguyen M, Hawkins BM, Goulet JL, Smithies O, Koller BH, Langenbach R. Failure of ductus arteriosus closure and remodeling in neonatal mice deficient in cyclooxygenase-1 and cyclooxygenase-2. Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):1059-64. doi: 10.1073/pnas.98.3.1059. Epub 2001 Jan 23.
• Background Yu Y, Funk CD. A novel genetic model of selective COX-2 inhibition: comparison with COX-2 null mice. Prostaglandins Other Lipid Mediat. 2007 Jan;82(1-4):77-84. doi: 10.1016/j.prostaglandins.2006.05.021. Epub 2006 Jul 7.
• Background Reese J, Paria BC, Brown N, Zhao X, Morrow JD, Dey SK. Coordinated regulation of fetal and maternal prostaglandins directs successful birth and postnatal adaptation in the mouse. Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9759-64. doi: 10.1073/pnas.97.17.9759.
• Background Reese J, Waleh N, Poole SD, Brown N, Roman C, Clyman RI. Chronic in utero cyclooxygenase inhibition alters PGE2-regulated ductus arteriosus contractile pathways and prevents postnatal closure. Pediatr Res. 2009 Aug;66(2):155-61. doi: 10.1203/PDR.0b013e3181aa07eb.
• Background Derzbach L, Treszl A, Balogh A, Vasarhelyi B, Tulassay T, Rigo J J. Gender dependent association between perinatal morbidity and estrogen receptor-alpha Pvull polymorphism. J Perinat Med. 2005;33(5):461-2. doi: 10.1515/JPM.2005.082.
• Background Bokodi G, Derzbach L, Banyasz I, Tulassay T, Vasarhelyi B. Association of interferon gamma T+874A and interleukin 12 p40 promoter CTCTAA/GC polymorphism with the need for respiratory support and perinatal complications in low birthweight neonates. Arch Dis Child Fetal Neonatal Ed. 2007 Jan;92(1):F25-9. doi: 10.1136/adc.2005.086421. Epub 2006 Jun 5.
• Background Gonzalez A, Sosenko IR, Chandar J, Hummler H, Claure N, Bancalari E. Influence of infection on patent ductus arteriosus and chronic lung disease in premature infants weighing 1000 grams or less. J Pediatr. 1996 Apr;128(4):470-8. doi: 10.1016/s0022-3476(96)70356-6.
• Background Rojas MA, Gonzalez A, Bancalari E, Claure N, Poole C, Silva-Neto G. Changing trends in the epidemiology and pathogenesis of neonatal chronic lung disease. J Pediatr. 1995 Apr;126(4):605-10. doi: 10.1016/s0022-3476(95)70362-4.
• Background Waleh N, Hodnick R, Jhaveri N, McConaghy S, Dagle J, Seidner S, McCurnin D, Murray JC, Ohls R, Clyman RI. Patterns of gene expression in the ductus arteriosus are related to environmental and genetic risk factors for persistent ductus patency. Pediatr Res. 2010 Oct;68(4):292-7. doi: 10.1203/PDR.0b013e3181ed8609.
• Background BORN GV, DAWES GS, MOTT JC, RENNICK BR. The constriction of the ductus arteriosus caused by oxygen and by asphyxia in newborn lambs. J Physiol. 1956 May 28;132(2):304-42. doi: 10.1113/jphysiol.1956.sp005526. No abstract available.
• Background KOVALCIK V. THE RESPONSE OF THE ISOLATED DUCTUS ARTERIOSUS TO OXYGEN AND ANOXIA. J Physiol. 1963 Nov;169(1):185-97. doi: 10.1113/jphysiol.1963.sp007249. No abstract available.
• Background MOSS AJ, EMMANOUILIDES GC, ADAMS FH, CHUANG K. RESPONSE OF DUCTUS ARTERIOSUS AND PULMONARY AND SYSTEMIC ARTERIAL PRESSURE TO CHANGES IN OXYGEN ENVIRONMENT IN NEWBORN INFANTS. Pediatrics. 1964 Jun;33:937-44. No abstract available.
• Background Fay FS. Guinea pig ductus arteriosus. I. Cellular and metabolic basis for oxygen sensitivity. Am J Physiol. 1971 Aug;221(2):470-9. doi: 10.1152/ajplegacy.1971.221.2.470. No abstract available.
• Background Smith GC. The pharmacology of the ductus arteriosus. Pharmacol Rev. 1998 Mar;50(1):35-58. No abstract available.
• Background Ward JP. Oxygen sensors in context. Biochim Biophys Acta. 2008 Jan;1777(1):1-14. doi: 10.1016/j.bbabio.2007.10.010. Epub 2007 Nov 1.
• Background Fleming I. Vascular cytochrome p450 enzymes: physiology and pathophysiology. Trends Cardiovasc Med. 2008 Jan;18(1):20-5. doi: 10.1016/j.tcm.2007.11.002.
• Background Baragatti B, Schwartzman ML, Angeloni D, Scebba F, Ciofini E, Sodini D, Ottaviano V, Nencioni S, Paolicchi A, Graves JP, Zeldin DC, Gotlinger K, Luin S, Coceani F. EDHF function in the ductus arteriosus: evidence against involvement of epoxyeicosatrienoic acids and 12S-hydroxyeicosatetraenoic acid. Am J Physiol Heart Circ Physiol. 2009 Dec;297(6):H2161-8. doi: 10.1152/ajpheart.00576.2009. Epub 2009 Oct 2.
• Background Roulet MJ, Coburn RF. Oxygen-induced contraction in the guinea pig neonatal ductus arteriosus. Circ Res. 1981 Oct;49(4):997-1002. doi: 10.1161/01.res.49.4.997.
• Background Nakanishi T, Gu H, Hagiwara N, Momma K. Mechanisms of oxygen-induced contraction of ductus arteriosus isolated from the fetal rabbit. Circ Res. 1993 Jun;72(6):1218-28. doi: 10.1161/01.res.72.6.1218.
• Background Tristani-Firouzi M, Reeve HL, Tolarova S, Weir EK, Archer SL. Oxygen-induced constriction of rabbit ductus arteriosus occurs via inhibition of a 4-aminopyridine-, voltage-sensitive potassium channel. J Clin Invest. 1996 Nov 1;98(9):1959-65. doi: 10.1172/JCI118999.
• Background Weir EK, Lopez-Barneo J, Buckler KJ, Archer SL. Acute oxygen-sensing mechanisms. N Engl J Med. 2005 Nov 10;353(19):2042-55. doi: 10.1056/NEJMra050002. No abstract available.
• Background Michelakis E, Rebeyka I, Bateson J, Olley P, Puttagunta L, Archer S. Voltage-gated potassium channels in human ductus arteriosus. Lancet. 2000 Jul 8;356(9224):134-7. doi: 10.1016/S0140-6736(00)02452-1.
• Background Archer SL, Wu XC, Thebaud B, Moudgil R, Hashimoto K, Michelakis ED. O2 sensing in the human ductus arteriosus: redox-sensitive K+ channels are regulated by mitochondria-derived hydrogen peroxide. Biol Chem. 2004 Mar-Apr;385(3-4):205-16. doi: 10.1515/BC.2004.014.
• Background Arcilla RA, Thilenius OG, Ranniger K. Congestive heart failure from suspected ductal closure in utero. J Pediatr. 1969 Jul;75(1):74-8. doi: 10.1016/s0022-3476(69)80103-4.
• Background Zuckerman H, Reiss U, Rubinstein I. Inhibition of human premature labor by indomethacin. Obstet Gynecol. 1974 Dec;44(6):787-92. No abstract available.
• Background Coceani F, Olley PM. The response of the ductus arteriosus to prostaglandins. Can J Physiol Pharmacol. 1973 Mar;51(3):220-5. doi: 10.1139/y73-031. No abstract available.
• Background Coceani F, Olley PM, Bodach E. Lamb ductus arteriosus: effect of prostaglandin synthesis inhibitors on the muscle tone and the response to prostaglandin E2. Prostaglandins. 1975 Feb;9(2):299-308. doi: 10.1016/0090-6980(75)90034-9.
• Background Sharpe GL, Thalme B, Larsson KS. Studies on closure of the ductus arteriosus. XI. Ductal closure in utero by a prostaglandin synthetase inhibitor. Prostaglandins. 1974 Dec 10;8(5):363-8. doi: 10.1016/0090-6980(74)90110-5. No abstract available.
• Background Starling MB, Elliott RB. The effects of prostaglandins, prostaglandin inhibitors, and oxygen on the closure of the ductus arteriosus, pulmonary arteries and umbilical vessels in vitro. Prostaglandins. 1974 Nov 10;8(3):187-203. doi: 10.1016/0090-6980(74)90042-2. No abstract available.
• Background Friedman WF, Hirschklau MJ, Printz MP, Pitlick PT, Kirkpatrick SE. Pharmacologic closure of patent ductus arteriosus in the premature infant. N Engl J Med. 1976 Sep 2;295(10):526-9. doi: 10.1056/NEJM197609022951003.
• Background Heymann MA, Rudolph AM, Silverman NH. Closure of the ductus arteriosus in premature infants by inhibition of prostaglandin synthesis. N Engl J Med. 1976 Sep 2;295(10):530-3. doi: 10.1056/NEJM197609022951004.
• Background Coceani F, Olley PM, Bishai I, Bodach E, Heaton J, Nashat M, White E. Prostaglandins and the control of muscle tone in the ductus arteriosus. Adv Exp Med Biol. 1977;78:135-42. doi: 10.1007/978-1-4615-9035-4_10.
• Background Coceani F, White E, Bodach E, Olley PM. Age-dependent changes in the response of the lamb ductus arteriosus to oxygen and ibuprofen. Can J Physiol Pharmacol. 1979 Aug;57(8):825-31. doi: 10.1139/y79-126.
• Background Schneider DJ, Moore JW. Patent ductus arteriosus. Circulation. 2006 Oct 24;114(17):1873-82. doi: 10.1161/CIRCULATIONAHA.105.592063. No abstract available.
• Background Clyman RI, Chan CY, Mauray F, Chen YQ, Cox W, Seidner SR, Lord EM, Weiss H, Waleh N, Evans SM, Koch CJ. Permanent anatomic closure of the ductus arteriosus in newborn baboons: the roles of postnatal constriction, hypoxia, and gestation. Pediatr Res. 1999 Jan;45(1):19-29. doi: 10.1203/00006450-199901000-00005.
• Background Keck M, Resnik E, Linden B, Anderson F, Sukovich DJ, Herron J, Cornfield DN. Oxygen increases ductus arteriosus smooth muscle cytosolic calcium via release of calcium from inositol triphosphate-sensitive stores. Am J Physiol Lung Cell Mol Physiol. 2005 May;288(5):L917-23. doi: 10.1152/ajplung.00403.2004. Epub 2005 Feb 4.
• Background Weir EK, Obreztchikova M, Vargese A, Cabrera JA, Peterson DA, Hong Z. Mechanisms of oxygen sensing: a key to therapy of pulmonary hypertension and patent ductus arteriosus. Br J Pharmacol. 2008 Oct;155(3):300-7. doi: 10.1038/bjp.2008.291. Epub 2008 Jul 21.
• Background Thebaud B, Michelakis ED, Wu XC, Moudgil R, Kuzyk M, Dyck JR, Harry G, Hashimoto K, Haromy A, Rebeyka I, Archer SL. Oxygen-sensitive Kv channel gene transfer confers oxygen responsiveness to preterm rabbit and remodeled human ductus arteriosus: implications for infants with patent ductus arteriosus. Circulation. 2004 Sep 14;110(11):1372-9. doi: 10.1161/01.CIR.0000141292.28616.65. Epub 2004 Sep 7.
• Background Thebaud B, Wu XC, Kajimoto H, Bonnet S, Hashimoto K, Michelakis ED, Archer SL. Developmental absence of the O2 sensitivity of L-type calcium channels in preterm ductus arteriosus smooth muscle cells impairs O2 constriction contributing to patent ductus arteriosus. Pediatr Res. 2008 Feb;63(2):176-81. doi: 10.1203/PDR.0b013e31815ed059.
• Background Kajimoto H, Hashimoto K, Bonnet SN, Haromy A, Harry G, Moudgil R, Nakanishi T, Rebeyka I, Thebaud B, Michelakis ED, Archer SL. Oxygen activates the Rho/Rho-kinase pathway and induces RhoB and ROCK-1 expression in human and rabbit ductus arteriosus by increasing mitochondria-derived reactive oxygen species: a newly recognized mechanism for sustaining ductal constriction. Circulation. 2007 Apr 3;115(13):1777-88. doi: 10.1161/CIRCULATIONAHA.106.649566. Epub 2007 Mar 12.
• Background Hong Z, Hong F, Olschewski A, Cabrera JA, Varghese A, Nelson DP, Weir EK. Role of store-operated calcium channels and calcium sensitization in normoxic contraction of the ductus arteriosus. Circulation. 2006 Sep 26;114(13):1372-9. doi: 10.1161/CIRCULATIONAHA.106.641126. Epub 2006 Sep 18.
• Background Coceani F, Kelsey L. Endothelin-1 release from lamb ductus arteriosus: relevance to postnatal closure of the vessel. Can J Physiol Pharmacol. 1991 Feb;69(2):218-21. doi: 10.1139/y91-033.
• Background Fineman JR, Takahashi Y, Roman C, Clyman RI. Endothelin-receptor blockade does not alter closure of the ductus arteriosus. Am J Physiol. 1998 Nov;275(5):H1620-6. doi: 10.1152/ajpheart.1998.275.5.H1620.
• Background Weiss H, Cooper B, Brook M, Schlueter M, Clyman R. Factors determining reopening of the ductus arteriosus after successful clinical closure with indomethacin. J Pediatr. 1995 Sep;127(3):466-71. doi: 10.1016/s0022-3476(95)70084-6.
• Background Fujioka K, Morioka I, Miwa A, Morikawa S, Shibata A, Yokoyama N, Matsuo M. Does thrombocytopenia contribute to patent ductus arteriosus? Nat Med. 2011 Jan;17(1):29-30; author reply 30-1. doi: 10.1038/nm0111-29. No abstract available.
• Background Shah NA, Hills NK, Waleh N, McCurnin D, Seidner S, Chemtob S, Clyman R. Relationship between circulating platelet counts and ductus arteriosus patency after indomethacin treatment. J Pediatr. 2011 Jun;158(6):919-923.e1-2. doi: 10.1016/j.jpeds.2010.11.018. Epub 2010 Dec 30.
• Background Alyamac Dizdar E, Ozdemir R, Sari FN, Yurttutan S, Gokmen T, Erdeve O, Emre Canpolat F, Uras N, Suna Oguz S, Dilmen U. Low platelet count is associated with ductus arteriosus patency in preterm newborns. Early Hum Dev. 2012 Oct;88(10):813-6. doi: 10.1016/j.earlhumdev.2012.05.007. Epub 2012 Jun 18.
• Background Sallmon H, Weber SC, Huning B, Stein A, Horn PA, Metze BC, Dame C, Buhrer C, Felderhoff-Muser U, Hansmann G, Koehne P. Thrombocytopenia in the first 24 hours after birth and incidence of patent ductus arteriosus. Pediatrics. 2012 Sep;130(3):e623-30. doi: 10.1542/peds.2012-0499. Epub 2012 Aug 6.
• Background Bas-Suarez MP, Gonzalez-Luis GE, Saavedra P, Villamor E. Platelet counts in the first seven days of life and patent ductus arteriosus in preterm very low-birth-weight infants. Neonatology. 2014;106(3):188-94. doi: 10.1159/000362432. Epub 2014 Jul 5.
• Background Weiser TG, Regenbogen SE, Thompson KD, Haynes AB, Lipsitz SR, Berry WR, Gawande AA. An estimation of the global volume of surgery: a modelling strategy based on available data. Lancet. 2008 Jul 12;372(9633):139-144. doi: 10.1016/S0140-6736(08)60878-8. Epub 2008 Jun 24.
• Background Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev. 2013 Apr 30;(4):CD003481. doi: 10.1002/14651858.CD003481.pub5.
• Background O'Riordan JM, Fitzgerald J, Smith OP, Bonnar J, Gorman WA; National Blood Users Group. Transfusion of blood components to infants under four months: review and guidelines. Ir Med J. 2007 Jun;100(6):suppl 1-24 following 496. No abstract available.
• Kumar J, Dutta S, Sundaram V, Saini SS, Sharma RR, Varma N. Platelet Transfusion for PDA Closure in Preterm Infants: A Randomized Controlled Trial. Pediatrics. 2019 May;143(5):e20182565. doi: 10.1542/peds.2018-2565. Epub 2019 Apr 2.

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Indications