Effectiveness of prothrombin complex concentrate (PCC) in neonates and infants with bleeding or risk of bleeding: a systematic review and meta-analysis
To systematically evaluate the effectiveness of prothrombin complex concentrate (PCC) in neonates and infants, we performed a systematic review and meta-analysis based on current evidence. Quality of studies was assessed by Cochrane Collaboration’s risk of bias tool and Newcastle-Ottawa quality assessment scale. For dichotomous data, we obtained the number of events and total number and calculated the relative risk (RR) with 95% confidence intervals (CI). For continuous variables, we obtained mean and standard deviation (SD) values and calculated mean difference (MD) with 95% CI. We identified six trials and two cohort studies. For trials, selection bias and performance bias were high, while detection bias, attrition bias, and reporting bias were relatively low. For cohort studies, selection bias was low. Both individual studies and meta-analysis failed to find any benefit of PCC on mortality. Meta-analysis also failed to show any benefit in reducing intracranial hemorrhage. The effectiveness of PCC on the correction of hemostatic defects was inconsistent among studies. In addition, PCC was not more effective than fresh frozen plasma (FFP) in correcting hemostatic defects.
What is Known:
• Prothrombin Complex Concentrate is becoming increasingly used off-label for treatment of neonates and infants with severe bleeding or risk of severe bleeding.
• Some case reports showed PCC seemed to be effective for infants and children with coagulation factor deficiency, but evidence about the effectiveness of PCC to reverse serious Vitamin K Deficiency Bleeding is limited.
What is New:
• As far as we know, this is the first systematic review that evaluates the effectiveness of PPC in neonates with bleeding or risk of bleeding.
• There is insufficient evidence to allow a recommendation for use of PCCs in neonates and infants.
KeywordsProthrombin complex concentrate Neonates Infants Systematic review Meta-analysis
Activated partial thromboplastin time
Chinese Biomedical Literature Database
China Dissertation Database
China Doctoral Dissertations and Master’s Theses Full-text Databases
China National Knowledge Infrastructure
Food and Drug Administration
Fresh frozen plasma
Hypoxic ischemic encephalopathy
International Clinical Trials Registry Platform
Prothrombin complex concentrate
ProQuest Digital Dissertation
World Health Organization
We thank Program for Yangtze River Scholars and Innovative Research Team in University (No. IRT0935) and the Group of People with Highest Risk of Drug Exposure of International Network for the Rational Use of Drugs, China, for its support.
Linan Zeng searched and selected the literatures, assessed the quality of studies, and wrote the paper. Imti Choonara analyzed the data and wrote the paper. Lingli Zhang extracted the data and revised the paper. Youping Li wrote and revised the paper. Jing Shi selected the literature and analyzed the data.
Compliance with ethical standards
This study was funded by the Natural Science Foundation of China (No. 81373381) and the National Science Foundation for Young Scholars of China (No. 71503177).
Conflict of interest
The authors declare that they have no conflict of interest.
Research involving human participants and/or animals
This article does not contain any studies with human participants performed by any of the authors.
For this type of study, formal consent is not required.
- 2.Andrew M, Paes B, Milner R (1988) Development of the human coagulation. System in the healthy premature infant. Blood 80:1998–2005Google Scholar
- 4.Cochrane and book for Systematic Reviews of Interventions. Version 5.1.0.updated 2011. Editors: Julian PT Higgins and Sally Green. Available from: http://handbook.cochrane.org/
- 7.Department of Health and Human Services Food and Drug Administration Center for Biologics Evaluation and Research (2012) FDA pharmacovigilance plan review: prothrombin complex concentrateGoogle Scholar
- 9.Gu Q, Ma YJ, Yang CY (2004) The effection of prothrombin complex on the coagulation of neonatal hypoxic-ischemic encephalopathy. J Appl Clin Pedia-tri 19:464–465Google Scholar
- 11.Hanke AA, Joch C, Gorlinger K (2013) Long-term safety and efficacy of a pasteurized nanofiltrated prothrombin complex concentrate (Beriplex P/N): a pharmacovigilance study. Br J Anaesth.:1–9Google Scholar
- 12.Higgins JPT, Altman DG, Sterne JAC (2011) Assessing risk of bias in included studies. In: Higgins JPT, Green S (eds) Cochrane handbook for systematic reviews of interventions. Version 5.1.0.Cochrane CollaborationGoogle Scholar
- 13.Huang CH, Zeng L (2013) The effection of prothrombin complex on intracranial hemorrhage caused by late onset vitamin K deficiency bleeding. Contemporary Medicine 19:57Google Scholar
- 15.Kuperman AA, Brenner B, Kenet G Intraventricular haemorrhage in preterm infants—can we improve outcome by addressing coagulation? J Matern Fetal Neonatal Med. Early Online:1–3Google Scholar
- 17.Li W, Chen J (2004) Efficacy of prothrombin complex on premature children of gastrointestinal hemorrhage. Sichuan Medical Journal 25:1131–1132Google Scholar
- 18.Lin GX, Luo YM, Chen L (2010) 32 cases of intracranial hemorrhage caused by late onset vitamin K deficiency bleeding treated with prothrombin complex. Fujian Med J 32:6–8Google Scholar
- 20.National advisory committee on blood and blood products (2011) Recommendations for use of prothrombin complex concentrates in CanadaGoogle Scholar
- 21.Nova Scotia Provincial Blood Coordinating Program (2013) Utilization guidelines for prothrombin complex concentrates in Nova ScotiaGoogle Scholar
- 23.Review Manager(RevMan)[Computer program] 2008. Version 5.0.Copenhagen: The Nordic Cochrane Centre, The Cochrane CollaborationGoogle Scholar
- 28.Von KR, Hanawa Y (1993) Neonatal VK prophylaxis. Report of scientific and standardization subcommittee on perinatal haemostasis. Thromb Haemost 69:293–295Google Scholar
- 30.Wells GA, Shea B, O'Connell D, Peterson J, Welch V, Losos M,Tugwell P. The Newcastle- Ottawa Scale (NOS) for assessing the quality of non-randomized studies in meta-analysis. www.ohri.ca/programs/clinical_epidemiology/oxford.asp
- 31.Yang J, Li YX (2011) Prevention and treatment of intraventricular haemorrhage in premature using prothrombin complex combined with phenobarbital. World Health Digest Medical Periodiea 8:57–58Google Scholar