Fibrinogen is a plasma glycoprotein synthesised by the liver which plays a critical role in haemostasis by acting as an endogenous substrate for fibrin formation and by inducing clot formation and platelet aggregation

Franchini, Massimo

Gentili, Sara

Liumbruno, Giancarlo M.

Marano, Giuseppe

Mengoli, Carlo

Pupella, Simonetta

Vaglio, Stefania

English

VAGLIO, Stefania

Archivio della ricerca- Università di Roma La Sapienza

215Blood Transfus 2017; 15: 215-7  DOI 10.2450/2017.0362-16© SIMTI Servizi SrlCਏ਍਍ਅ਎ਔਁ਒ਙFibrinogen concentrate in surgeryGiuseppe Marano1, Carlo Mengoli1, Massimo Franchini1,2, Stefania Vaglio1,3, Sara Gentili1, Simonetta Pupella1, Giancarlo M. Liumbruno11Italian National Blood Centre, National Institute of Health, Rome; 2Department of Haematology and Transfusion Medicine, "Carlo Poma" Hospital, Mantua; 3Department of Clinical and Molecular Medicine, "Sapienza" University of Rome, Rome, ItalyFibrinogen is a plasma glycoprotein synthesised by the liver which plays a critical role in haemostasis by acting as an endogenous substrate for fibrin formation and by inducing clot formation and platelet aggregation1. A deficiency in fibrinogen may be inherited or acquired, the latter condition developing predominantly in association with trauma-related or peri-operative major bleeding2,3. Fibrinogen supplementation can be achieved using fresh-frozen plasma, cryoprecipitate or plasma-derived, virally-inactivated, fibrinogen concentrate4-8.Although a number of studies have reported the use of fibrinogen concentrate for the treatment and prevention of acquired bleeding, its beneficial effect is still debated, mainly due to the low quality of the published clinical evidence9. For instance, a Cochrane review published in 2013 by Wikkelsø and Colleagues10, which evaluated fibrinogen concentrate in 248 bleeding patients enrolled in six randomised controlled trials, concluded that, besides an apparent effect on the reduction of transfusion requirements, the heterogeneity and the high risk of bias of these studies prevented a proper evaluation of any beneficial effect of fibrinogen concentrate. The topic of the beneficial effects of fibrinogen concentrate in surgical patients was recently reviewed by another meta-analysis published by Fominskiy and Colleagues11. This review paper pooled 14 original studies12-24, all with a prospective, randomised controlled design. The end-points focused on in the meta-analysis were all-cause mortality, volume of bleeding, and red blood cell units transfused. Data regarding the first end-point, which were drawn from ten studies, showed a consistently lower cumulative rate of fatal events in the pooled arm of fibrinogen-treated patients than in the placebo-treated control arm, as evaluated by the risk ratio (0.26) with a 95% confidence interval (95% CI) of 0.09 to 0.78 (p=0.02). The authors, however, included data on all-cause mortality obtained in a multicentre study conducted by Rahe-Meyer (oral presentation during the 2015 Annual Congress of the European Society of Anaesthesiology, Berlin, May 30-June 2, 2015), still unpublished on the date of submission of the meta-analysis. These data were subsequently published by the same author, albeit with minor changes (a total of 152 patients enrolled instead of 142)25.The use of fibrinogen concentrate was also associated with a significantly less bleeding (nine studies included) and a lower number of red blood cell units transfused (nine studies included), but the mean differences of these quantitative indices were modest (−127 mL and −0.93 units, respectively). Differences in other indices were of borderline statistical significance, but were not significant when Bonferroni's correction was applied (the number of patients receiving red blood cell transfusions and the number of patients receiving any blood components). Moreover, the number of surgical revisions for bleeding, the rate of thrombotic events, and the incidence of myocardial infarction were not statistically significantly different between the patients who received fibrinogen concentrate and those who did not.Considering this meta-analysis11 in greater detail, a number of criticisms can be levelled against it. The first is that it seems improper to put together studies dealing with different clinical diseases, with patients being submitted to a very wide variety of surgical procedures. Most patients had coronary artery disease and were submitted to cardiopulmonary shunting with anticoagulant treatment. Two studies concerned paediatric patients with severe congenital heart disease12,14, one study collected liver transplant recipients (in whom the basal severe liver failure could have caused deficient synthesis of clotting factors)21, one study was on women with severe post-partum haemorrhages24, and one study was on patients undergoing total cystectomy13. In addition, two studies used active comparators, in one instance platelet transfusion23, and in the other cryoprecipitate14. Another concern is the use of "all-cause mortality at the longest follow-up available" as a proper index of efficacy in the context of surgery. Fibrinogen is a clotting factor, and in a surgical context a pro-haemorrhagic effect in the control arm is expected to happen early. So, early deaths (in the first 7-10 days after surgery) would have been a more suitable index than later mortality, which seems due mostly to the © SIMTI Servizi SrlAll rights reserved - For personal use only No other use without premission216Marano G et alBlood Transfus 2017; 15: 215-7  DOI 10.2450/2017.0362-16baseline clinical condition. Unfortunately, only the study by Rahe-Meyer and Colleagues published in 2016 distinguished early deaths from later ones25, whereas most studies neither indicated the time of deaths, nor mentioned the time limits of surveillance for untoward events. Interestingly, while this latter study reported one death in the fibrinogen arm and five deaths in the control arm, the early deaths ("between 1 and 10 days after study medication") as well as the treatment-related adverse events were balanced (1:1 and 4:4, respectively). Notably, most of the deaths in the review11 were reported in the two subsequent studies published by Rahe-Meyer and Colleagues in 2013 and 201619,25. The all-cause mortality appeared significant. However, this large effect size (reducing the risk by almost three-quarters in fibrinogen-treated patients) was hardly justified by the modest reduction in the fibrinogen arm of the other two quantitative end-points reported in detail: post-operative bleeding (mean difference, −127 mL), and number of transfused red blood cell units (mean difference, −0.93 units). Differences in the latter end-points were statistically significant, but quantitatively modest. A likely explanation for this incongruity could be the comparative index chosen for mortality cumulative incidence, relative risk. First, this choice of index excludes all eventless studies from the quantitative evaluation (6 studies out 10)26. Moreover, since the relative risk is a ratio between incidences, it masks the substantive rareness of deaths. Indeed, fatal events were uncommon, with 19 deaths among 872 patients (about 2.2%). We would have preferred another comparative index, the risk difference, which does not suffer from these drawbacks. In addition, the risk difference enables calculation of an important pharmaco-economic index, the number-needed-to-treat. We calculated the pooled inverse-variance risk difference on the same ten papers considered in the meta-analysis. Using the method of Mantel-Haenszel the index was significant, with a mean −2.5% (95% CI: −4.7% to −0.3%, p=0.024). However, with the inverse variance method, a lower mean was found, 0.07% (95% CI: −2% to 0.7%, p: not significant). Clearly, these estimates suffer of a degree of instability. Indeed, all classical meta-analytical methods are less than satisfactory with rare events27,28. A remedy could consist in logistic or Poisson regression for hierarchical data, taking into account the studies as grouping variable29,30. With the former method, the estimated mean risk difference was −1.4% (95% CI: −5.0% to −0.4%, p=0.016), and the results were very similar with the latter. The estimates were statistically significant, but the effect sizes were low. Another method that appears suitable for determining risk difference when events are rare was recently developed by Tian and Colleagues31. This method is based on the combination of the study-level risk difference distributions32,33. Using this procedure, the mean risk difference was estimated as −1.6% (95% CI: −5.8% to 0.1%, p=0.086) and the corresponding number-needed-to-treat (i.e., the number of patients who need to be treated with fibrinogen in order to save one life) was 61.In conclusion, for a series of methodological aspects, the evidence collected by the above-cited meta-analysis11 seems weak and insufficient as a basis for therapeutic or prophylactic guidelines, as highlighted in the previously published Cochrane meta-analysis10.Disclosure of conflicts of interestGML is the Editor-in-Chief of Blood Transfusion and this manuscript has undergone additional external review as a result. The other Authors declare no conflicts of interest.References1) Mosesson MW. Fibrinogen and fibrin structure and function. J Thromb Haemost 2005; 3: 1894-904.2) Levy JH, Szlam F, Tanaka KA, Sniecienski RM. Fibrinogen and hemostasis: a primary hemostatic target for the management of acquired bleeding. Anesth Analg 2012; 114: 261-74.3) Levy JH, Welsby I, Goodnough LT. Fibrinogen as a therapeutic target for bleeding: a review of critical levels and replacement therapy. Transfusion 2014; 54: 1389-405.4) Franchini M, Lippi G. Fibrinogen replacement therapy: a critical review of the literature. Blood Transfus 2012; 10: 23-7.5) Vaglio S, Prisco D, Biancofiore G, et al. Recommendations for the implementation of a Patient Blood Management programme. Application to elective major orthopaedic surgery in adults. Blood Transfus 2016; 14: 23-65. 6) Liumbruno GM, Bennardello F, Lattanzio A, et al. Italian Society of Transfusion Medicine and Immunohaematology (SIMTI) Working Party. Recommendations for the transfusion management of patients in the peri-operative period. I. The pre-operative period. Blood Transfus 2011; 9: 19-40.7) Liumbruno GM, Bennardello F, Lattanzio A, et al. Italian Society of Transfusion Medicine and Immunohaematology (SIMTI) Working Party. Recommendations for the transfusion management of patients in the peri-operative period. II. The intra-operative period. Blood Transfus 2011; 9: 189-217. 8) Liumbruno GM, Bennardello F, Lattanzio A, et al. Italian Society of Transfusion Medicine and Immunohaematology Working Party. Recommendations for the transfusion management of patients in the peri-operative period. III. The post-operative period. Blood Transfus 2011; 9: 320-35.9) Liumbruno GM, Vaglio S, Capuzzo E, Franchini M. Fibrinogen concentrate as haemostatic therapy in acquired bleeding disorders: not only a question of dosing strategies and thresholds. Blood Transfus 2015; 13: 159-60. 10) Wikkelsø A, Lunde J, Johansen M, et al. Fibrinogen concentrate in bleeding patients. Cochrane Database Syst Rev 2013; 8: CD008864.11) Fominskiy E, Nepomniashchikh VA, Lomivorotov VV, et al. Efficacy and safety of fibrinogen concentrate in surgical patients: a meta-analysis of randomized controlled trials. J Cardiothorac Vasc Anesth 2016; 30: 1196-204.12) Cui Y, Hei F, Long C, et al. Perioperative monitoring of thromboelastograph on blood protection and recovery for severely cyanotic patients undergoing complex cardiac surgery. Artif Organs 2010; 34: 955-60.©SIMTI Servizi SrlAll rights reserved - For personal use only No other use without premission217Blood Transfus 2017; 15: 215-7  DOI 10.2450/2017.0362-16Fibrinogen concentrate in surgery13) Fenger-Eriksen C, Jensen TM, Kristensen BS, et al. Fibrinogen substitution improves whole blood clot firmness after dilution with hydroxyethyl starch in bleeding patients undergoing radical cystectomy: a randomized, placebo-controlled clinical trial. J Thromb Haemost 2009; 7: 795-802.14) Galas FR, de Almeida JP, Fukushima JT, et al. Hemostatic effects of fibrinogen concentrate compared with cryoprecipitate in children after cardiac surgery: a randomized pilot trial. J Thorac Cardiovasc Surg 2014; 148: 1647-55.15) Jeppsson A, Waldén K, Roman-Emanuel C, et al. Preoperative supplementation with fibrinogen concentrate in cardiac surgery: a randomized controlled study. Br J Anaesth 2016; 116: 208-14.16) Karlsson M, Ternström L, Hyllner M, et al. Prophylactic fibrinogen infusion reduces bleeding after coronary artery bypass surgery. A prospective randomised pilot study. Thromb Haemost 2009; 102: 137-44.17) Lancé MD, Ninivaggi M, Schols SE, et al. Perioperative dilutional coagulopathy treated with fresh frozen plasma and fibrinogen concentrate: a prospective randomized intervention trial. Vox Sang 2012; 103: 25-34.18) Najafi A, Shariat Moharari R, Orandi AA, et al. Prophylactic administration of fibrinogen concentrate in perioperative period of total hip arthroplasty: a randomized clinical trial study. Acta Med Iran 2014; 52: 804-10.19) Rahe-Meyer N, Solomon C, Hanke A, et al. Effects of fibrinogen concentrate as first-line therapy during major aortic replacement surgery: a randomized, placebo-controlled trial. Anesthesiology 2013; 118: 40-50.20) Ranucci M, Baryshnikova E, Crapelli GB, et al. Randomized, double-blinded, placebo-controlled trial of fibrinogen concentrate supplementation after complex cardiac surgery. J Am Heart Assoc 2015; 4: e002066.21) Sabate A, Gutierrez R, Beltran J, et al. Impact of pre-emptive fibrinogen concentrate on transfusion requirements in liver transplantation: a multicenter, randomized, double-blind, placebo-controlled trial. Am J Transplant 2016; 16: 2421-9.22) Sadeghi M, Atefyekta R, Azimaraghi O, et al. A randomized, double blind trial of prophylactic fibrinogen to reduce bleeding in cardiac surgery. Braz J Anesthesiol 2014; 64: 253-7.23) Tanaka KA, Egan K, Szlam F, et al. Transfusion and hematologic variables after fibrinogen or platelet transfusion in valve replacement surgery: preliminary data of purified lyophilized human fibrinogen concentrate versus conventional transfusion. Transfusion 2014; 54: 109-18.24) Wikkelsø AJ, Edwards HM, Afshari A, et al. Pre-emptive treatment with fibrinogen concentrate for postpartum haemorrhage: Randomized controlled trial. Br J Anaesth 2015; 114: 623-33.25) Rahe-Meyer N, Levy JH, Mazer CD, et al. Randomized evaluation of fibrinogen vs placebo in complex cardiovascular surgery (REPLACE): a double-blind phase III study of haemostatic therapy. Br J Anaesth 2016; 117: 41-51.26) Friedrich JO, Adhikari NK, Beyene J. Inclusion of zero total event trials in meta-analyses maintains analytic consistency and incorporates all available data. BMC Med Res Methodol 2007; 7: 5.27) Validity of methods of meta-analysis for rare events. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 (2011). Higgins JPT, Green S. Eds. Available at: http://handbook.cochrane.org/chapter_16/16_9_5_validity_of_methods_of_meta_analysis_for_rare_events.htm. Accessed on 15/12/2016.28) Bradburn MJ, Deeks JJ, Berlin JA, Localio AR. Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events. Statist Med 2007; 26: 53-77. 29) Cai T, Parast L, Ryan L. Meta-analysis for rare events. Stat Med 2010; 29: 2078-89.30) Boehning D, Mylona K, Kimber A. Meta-analysis of clinical trials with rare events. Biom J 2015; 57: 633-48.31) Tian L, Cai T, Pfeffer MA, et al. Exact and efficient inference procedure for meta-analysis and its application to the analysis of independent 2x2 tables with all available data but without artificial continuity correction. Biostatistics 2009; 10: 275-81.32) Chen DG, Peace KE. Applied Meta-analysis with R. Boca Raton: CRC Press; 2013. p. 266.33) Liu D. Combining information for heterogeneous studies and rare events studies: a confidence distribution approach. Dissertation submitted to Rutgers, The State University of New Jersey; 2012. Available at: https://rucore.libraries.rutgers.edu/rutgers-lib/37435/. Accessed on 15/12/2016.Arrived: 16 December 2016 - Accepted: 11 January 2017Correspondence: Massimo FranchiniDepartment of Haematology and Transfusion MedicineASST Carlo PomaStrada Lago Paiolo 1046100 Mantova, Italye-mail: massimo.franchini@asst-mantova.it© SIMTI Servizi SrlAll rights reserved - For personal use only No other use without premission

Fibrinogen concentrate in surgery

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Fibrinogen concentrate in surgery

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