The Role of Fibrinogen in Reducing Transfusion
C. David Mazer, MD, FRCPC
Objectives:
After attending this session, the participant will be better able to
1. discuss the pathophysiology of fibrinogen in the setting of massive bleeding and transfusion
2. explain the rationale for clinical trials involving administration of fibrinogen in these situations.
Significant bleeding after cardiac surgery is common clinical problem. Allogeneic transfusion rates are
variable but may approach 100% in some centers and for some procedures. Because of the risks, costs
and adverse outcomes associated with transfusion (especially massive transfusion), there is an urgent
need to evaluate the use of hemostatic agents and coagulation concentrates in this setting. Potential
advantages could include low volume, pathogen inactivated, readily available and easily administered
products which could be dose titrated.
Fibrinogen is an essential component of the clotting system. The normal plasma concentration is
between 1.5 and 4.0 g/L, although it can be higher in some clinical settings. It is a soluble, 340 kDa
plasma glycoprotein which is cleaved to produce fibrin monomers, the basis of the clot. It also facilitates
platelet aggregation, and is an acute phase reactant. Fibrinogen levels decrease in cardiac surgery
patients because of bleeding, fibrinolysis, hemodilution, and consumption; low levels are associated
with increased bleeding and transfusion. Fibrinogen is one of the first clotting factors to fall to critical
levels in the surgical or trauma setting and low preoperative levels have also been found to be predictive
of bleeding and transfusion. Recent guidelines recommend administration of fibrinogen in a bleeding
patient when the concentration falls below 1.5–2.0 g/L. Plasma levels of fibrinogen can be assessed
using spectroscopic (Clauss) techniques or by viscoelastic rotational thromboelastometry (eg ROTEM).
There are 3 main sources of fibrinogen for perioperative use: Frozen plasma (FP), cryoprecipitate and
fibrinogen concentrate. FP is obtained from centrifugation of donated blood and thus contains all
proteins in human plasma in the same concentration as blood. Because of the complications associated
with plasma administration, its use is increasingly being replaced with other products. Cryoprecipitate is
made by thawing, centrifugation and separation of fresh frozen plasma. Each 15 ml unit of ‘cryo’
contains about 250-400 mg of fibrinogen. Fibrinogen concentrates are purified, heat-treated,
lyophilized concentrates of human plasma fibrinogen which can be stored at room temperature.
Different preparations are available in different jurisdictions. Fibrinogen concentrates are approved for
treatment of fibrinogen deficiency in Europe and North America.
Retrospective and prospective studies have documented the ability to raise fibrinogen levels with
fibrinogen replacement. To increase fibrinogen concentration by ~1 gm/L in the typical patient would
require about 3 gm of fibrinogen (or the equivalent of 1500-2000 ml FP, 8-10 units of cryoprecipitate or
100-300 ml of reconstituted fibrinogen concentrate). Recent randomized controlled trials have studied
fibrinogen concentrate in patients undergoing cardiovascular surgery. In these studies, ROTEM guided
fibrinogen concentrate administration in bleeding patients after aortic surgery significantly reduced the
amount of allogeneic transfusion. A multicenter international RCT of Fibrinogen concentrate during
complex cardiovascular surgery is currently in progress. While the relatively small amount of data so far
is promising, recent systematic reviews and meta-analyses of the clinical trials to date highlight the need
for more research to establish the optimal dosing, method, monitoring, efficacy, safety and cost-benefit
of fibrinogen replacement for reducing transfusion in cardiac surgery.
Selected References:
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Anesthesiology 2010;113:1205–19
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systematic review and meta-analysis. Interact Cardiovasc Thorac Surg. 2013 doi: 10.1093/icvts/ivt506
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cell transfusion in cardiac surgery: an observational study. Anesth Analg. 2013 Jul;117(1):14-22.
Karkouti K, et al. The influence of perioperative coagulation status on postoperative blood loss in complex cardiac
surgery: a prospective observational study. Anesth Analg. 2010 Jun 1;110(6):1533-40
Karlsson M, et al. Prophylactic fibrinogen infusion reduces bleeding after coronary artery bypass surgery. A
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of Anaesthesiology. Eur J Anaesthesiol. 2013;30(6):270-382
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surgery: a randomized, placebo-controlled trial. Anesthesiology. 2013 Jan;118(1):40-50.
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replacement surgery: preliminary data of purified lyophilized human fibrinogen concentrate versus conventional
transfusion. Transfusion. 2014;54(1):109-18.
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surgery and the effect of fibrinogen replacement therapy remains uncertain. J Thromb Haemost. 2013
Aug;11(8):1519-26.
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surgery patients. Anesthesiology. 2012 Sep;117(3):531-47.
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29;8:CD008864. doi: 10.1002/14651858.CD008864.pub2.