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Does fibrinogen really result in reduction in transfusion requirements ?
- jean-luc hanouz, Marc olivier Fischer, Christelle Charpentier (16 April 2009)
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Re: Coagulation tests in future studies: What to use?
- Christian Fenger-Eriksen, Jørgen Ingerslev, Benny Sørensen (7 March 2009)
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Coagulation tests in future studies: What to use?
- Paul Moor, Tom Woolley, T Woolley, Tom Woolley Mark Midwinter, M Midwinter, Mark Midwinter (22 December 2008)
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jean-luc hanouz, Professor of Anaesthesia an Intensive Care , Marc olivier Fischer, Christelle Charpentier
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Dear Charles S Reilly, Dear C. Fenger-Eriksen, M. Lindberg-Larsen, A. Q. Christensen, J. Ingerslev, and B. Sørensen Does fibrinogen really result in reduction in transfusion requirements ? We read with interest the study by Fenger-Eriksen and colleagues about fibrinogen concentrate substitution therapy in patients with massive haemorrhage and low plasma fibrinogen concentration.1 However, we do not fully agree with the authors conclusion stating that “The main finding from this retrospective study is that substitution therapy with fibrinogen concentrate was associated with a significant reduction in transfusion requirements for RBC, FFP, and pooled platelets concentrates and a significant reduction in blood loss.…the present study suggest that substitution therapy with fibrinogen concentrate, as a supplementary intervention in bleeding patients with low level of fibrinogen, may contribute to reduce transfusion requirements, decrease blood loss, and lead to an overall improvement of laboratory coagulation tests”. We think that there are major flaws in the study which do not enable to draw such assertions. First, based on the study design and statistical analysis the sole conclusion that can be drawn is that there was a significant difference in the number of units of packed red blood cells, fresh frozen plasma, and platelets pools transfused before and after administration of fibrinogen concentrate (figure 1 in the manuscript), as well as a significant difference in laboratory coagulation tests before and after administration of fibrinogen concentrate. Definitely, the differences shown does not prove a relationship between fibrinogen concentrate administration and the results observed. Second, as indicated in table 2, bleeding was stopped in adult patients before the second period named “after fibrinogen substitution”. We doubt that patients did not benefit from haemostatic interventions such as selective embolisation, surgical haemostasis or both. The authors must provide information on these major haemostatic interventions. We strongly think that the differences reported (fig. 1 and Table 2) were related mainly to haemostatic interventions rather than fibrinogen substitution. We strongly think that rapid surgical or radiological haemostasis should have been discussed in the discussion section of the manuscript, at least to provide this important educational message. At least, the reference of the recently published European Guidelines for management of bleeding following major trauma should have been cited.2 Third, the heterogeneity of the small population studied including obstetric haemorrhage (known to involved hyperfibrinolysis), haemorrhage in infants presenting congestive heart failure (from 15 days old to 2 months old), cardiothoracic and intra-abdominal bleeding of unknown aetiology (postoperative bleeding ? bleeding related to anticoagulant or antiplatelet therapies ?…), trauma haemorrhage, and other (see table 1; unknown aetiology ?) did not enable to draw any conclusion. There are major differences in pathophysiology of haemorrhage between these aetiology. Clearly, the authors must detailed the aetiology of haemorrhage more precisely. Fourth, the authors must report the total volume of cristalloids and colloids infused in these patients as well as the presence of shock and therapy used to treat this shock (norepinephrine, vasopressine, epinephrine, recombinant factor VIIa…). This is important because the authors correctly pointed out that synthetic colloids interfere with fibrinogen assays.3 Finally, I would like to make some minor comments which should have been corrected during proofs readings. In table 1 the units for age reporting is not indicated (“year” I presume). In figure 1 the first columns indicated “PRBC” appear as RBC in the text and legend. In table 2 blood loss must be reported in ml.kg-1 for paediatric patients. Conflict of Interest:None declared |
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Christian Fenger-Eriksen , Jørgen Ingerslev, Benny Sørensen
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Editor – We cordially thank for the interest forwarded by Moor and colleagues. Laboratory monitoring of haemostatic capacity in the setting of peri-operative bleeding management is challenging. As outlined by Moor and co-workers, the overall haemostatic capacity depends on a concerted action of plasma pro-coagulant and anti-coagulant proteins, as well as platelets and other blood cells. In particular in management of peri- operative bleeding bedside whole blood coagulation analysis such as thromboelastography or thromboelastometry appear more rational modalities for assessing the overall haemostatic capacity than standard plasma tests. As briefly mentioned in our manuscript, in particular standard laboratory measurement of levels of fibrinogen, using the Clauss method may result in underestimating the importance of fibrinogen as a heamostatic agent in management of peri-operative and traumatic haemorrhage.(1;2) There may be several reasons for fibrinogen concentrate being overlooked as potent haemostatic intervention. For decades, haematologists have set the lower threshold level of fibrinogen at 1 g/L. Unfortunately, this level has never been clinically validated, yet mentioned again and again, although a series of publications have indicated that the critical level of fibrinogen may be significantly higher. A majority of patients experiencing excessive bleeding are treated with colloid plasma expanders for volume substitution. The presence of colloid plasma expanders or high levels of fibrin degradation products have been reported to induce artificial false high levels of fibrinogen when measure by the Clauss method. These phenomena may further have masked the recognizing and understanding the importance of fibrinogen in management of peri- operative/traumatic bleeding. Finally, the use of plasma expanders such as colloids, gelatine, or dextrans, is now known to induce a coagulopathy characterised by acquired hypo-fibrinogenemia and abnormal fibrin polymerisation.(3-5) Moreover, experimental studies, animal studies, retrospective clinical surveys, as well as prospective randomised clinical studies have demonstrated excellent haemostatic effect of substitution with a fibrinogen concentrate. (3;6-8) Haemostatic functional levels of fibrinogen can be evaluated by TEG or ROTEM using commercially available tests, such as the FibTEM® or Functional fibrinogen® tests. In contrast to standard Clauss measurements, the FibTEM test (and likely also the Functional fibrinogen test) has been shown to clearly reveal abnormal fibrinogen following haemodilution. In conclusion, we agree with Moor et al, that systematic bedside use of TEG or ROTEM will induce a more rational use of blood products and guide in selection of effective coagulation factor concentrates. In particular, the fibrinogen sensitive assays seem important to early recognize acquired fibrinogen deficiency. On behalf of all co-authors, Christian Fenger-Eriksen Jørgen Ingerslev Benny Sørensen References (1) Hiippala ST. Dextran and hydroxyethyl starch interfere with fibrinogen assays. Blood Coagul Fibrinolysis 1995 Dec;6(8):743-6. (2) Hellstern P, Muntean W, Schramm W, Seifried E, Solheim BG. Practical guidelines for the clinical use of plasma. Thromb Res 2002 Oct 31;107 Suppl 1:S53-7.:S53-S57. (3) Fenger-Eriksen C, Anker-Moller E, Heslop J, Ingerslev J, Sorensen B. Thrombelastographic whole blood clot formation after ex vivo addition of plasma substitutes: improvements of the induced coagulopathy with fibrinogen concentrate. Br J Anaesth 2005 Mar;94(3):324-9. (4) Fries D, Innerhofer P, Klingler A, Berresheim U, Mittermayr M, Calatzis A, et al. The effect of the combined administration of colloids and lactated Ringer's solution on the coagulation system: an in vitro study using thrombelastograph coagulation analysis (ROTEG. Anesth Analg 2002 May;94(5):1280-7. (5) Mittermayr M, Streif W, Haas T, Fries D, Velik-Salchner C, Klingler A, et al. Hemostatic changes after crystalloid or colloid fluid administration during major orthopedic surgery: the role of fibrinogen administration. Anesth Analg 2007 Oct;105(4):905-17, table. (6) Fenger-Eriksen C, Lindberg-Larsen M, Christensen AQ, Ingerslev J, Sorensen B. Fibrinogen concentrate substitution therapy in patients with massive haemorrhage and low plasma fibrinogen concentrations. Br J Anaesth. 2008 Dec;101(6):769-73. (7) Fries D, Krismer A, Klingler A, et al. Effect of fibrinogen on reversal of dilutional coagulopathy: a porcine model. Br J Anaesth 2005;(92(2)):172-7. (8) Danes AF, Cuenca LG, Bueno SR, Mendarte BL, Ronsano JB. Efficacy and tolerability of human fibrinogen concentrate administration to patients with acquired fibrinogen deficiency and active or in high-risk severe bleeding. Vox Sang 2008 Apr;94(3):221-6. Conflict of Interest:None declared |
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Paul Moor , Tom Woolley, T Woolley, Tom Woolley Mark Midwinter, M Midwinter, Mark Midwinter
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Editor- We read with interest the work of Fenger-Eriksen and his colleagues, regarding fibrinogen concentrate substitution therapy in patients with massive haemorrhage and hypofibrinogenaemia1. The authors reported an improvement of varying significance in the serum clotting tests and recommended further prospective work to further evaluate the haemostatic potential of fibrinogen. As our understanding of coagulocompetence and our knowledge of the interaction between the serine protease cascade, platelet activation and the role of fibrinolysis, increases2; we require a test that reflects overall coagulation status to individualise blood component prescription. With the increasing use of platelets and haemostatic resuscitation3 to treat massive haemorrhage, plasma tests could be increasingly misleading. It is our opinion that thromboelastometry (ROTEM) and thromboelastography (TEG) would be best suited to measure coagulocompetence in future studies, where coagulation factor depletion and fibrinolysis may be a significant contributor to any perceived coagulopathy. These techniques would allow accurate monitoring of whole blood coagulation in a wide range of conditions, where typically, serum tests , PT and APTT, may not be as sensitive4-7. During progressive blood loss, TEM and TEG provide point of care testing and are easily interpreted with minimal delay, differentiating between a functional loss in factors, platelets or fibrinogen or indeed demonstrating hyperfibrinolysis. Such tests are a safe and cost effective8 surveillance of coagulation, and expedite/assist with the most appropriate blood component therapy, thereby minimising donor exposures and inappropriate blood bank stock use9-10. What do the authors feel would be the most appropriate test for coagulation in future studies? P. Moor* T. Woolley M. Midwinter *E-mail: moorpaul@hotmail.com 1Fenger-Eriksen C, Lindberg-Larsen M, Christensen A Q, Ingerslev J, Sørensen B Fibrinogen concentrate substitution therapy in patients with massive haemorrhage and low plasma fibrinogen concentrations Br J Anaes 101 (6):769 – 73 2Brohi K, Cohen M, Ganter MT, Matthay MA, Mackersie RC, Pittet JF. Acute traumatic coagulopathy: initiated by hypoperfusion: modulated through the protein C pathway? Ann Surg 2007;245:812-18 3 Holcomb JB, Jenkins D, Rhee P, Johannigman J, Mahoney P, Mehta S et al. Damage Control Resuscitation: Directly Addressing the Early Coagulopathy of Trauma. J Traum 2007;62:307-10 4Kheirabadi B, Crissey J, Deguzman R, Holcomb J. In vivo bleeding time and in vitro thromboelastography measurements are better indicators of dilutional hypothermic coagulopathy than prothrombin time. J Traum 2007;62(6):1352-1361 5Rugeri L, Levrat A, David J et al. Diagnosis of early coagulation abnormalities in trauma patients by rotation thromboelastography. J Thromb Haemostasis 2006;5:289-295 6Martini WZ, Cortez DS, Dubick MA, et al. Thromboelastography is better than PT.aPTT and activated clotting time in detecting clinically relevant clotting abnormalities after hypothermia, hemorrhagic shock and resuscitation in pigs. J Traum 2008;65(3):535-543 7Rugeri L, Levrat A, David J, et al. Diagnosis of early coagulation abnormalities in trauma patients by rotation elastography. J Thromb Haemostasis 2006;5:289-295 8Craig J, Aguiar-Ibanez R, Bhattacharya S, Downie S, Duffy S, Kohli H, Nimmo A, Trueman P, Wilson S, Yunni Y. The clinical and cost effectiveness of thromboelastography/thromboelastometry. HTA Programme: Health Technology Assessment Report 11 9Johansson P. Treatment of massively bleeding patients: introducing real time monitoring, transfusion packages and thrombelastography (TEG®). ISBT Science Series 2007;2(1):159-67 10Spalding GJ, Hartrumpf M, Oesberg N, Kirsche CG, Albes JM. Cost reduction of perioperative coagulation management in cardiac surgery: value of ‘bedside’ thromboelastography (ROTEM). Eur J Cardiothorac Surg 2007;31:1052-1057 Conflict of Interest:None declared |
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