The role of fibrinogen in cardiac surgery

Excessive bleeding is one of the most common complications in cardiac surgery and is caused most frequently by insufficient surgical hemostasis or impairments of the coagulation system or a combination of both. A substantial number of patients consume disproportionately high amounts of blood products. Transfusion of blood products is associated with negative outcomes such as early and late mortality, increased risk for infections, prolonged hospital stay and decrease of long term quality of life. At the start of this project, the procoagulant fibrinogen concentrate was increasingly infused in cardiac surgery without solid evidence on its effect. This lack of evidence and the questions that were raised on the effects of fibrinogen in cardiac surgery, together with the aspiration to optimize hemostasis in this domain, have led to the formulation of this thesis project. In Chapter 2, a large retrospective cohort of high-risk cardiac surgery procedures revealed that administering fibrinogen concentrate did not reduce postoperative blood loss and transfusion. There was also no increase in clinical adverse events such as 30-day mortality, myocardial infarction, stroke, renal insufficiency or failure, infections and prolonged mechanical ventilation. In Chapter 3, the implementation of a cardiac surgery specific transfusion protocol is described in order to systematically direct the use of blood products and pro-hemostatic medication to prevent excessive transfusion of blood products and reduce the number of transfused patients. The new cardiac surgery specific transfusion protocol resulted in fewer patients transfused with red blood cells (RBC) and fresh frozen plasma (FFP) and a lower risk for myocardial infarction. In Chapter 4, a prediction model was developed using the widely used EuroSCORE variables to predict intraoperative and postoperative blood loss in cardiac surgery. The EuroSCORE variables proved to be very solid and accurate in predicting intraoperative blood loss with good calibration and a discrimination (an area under the curve (AUC)) of 0.84. For the postoperative period the discriminative ability was lower (AUC 0.74). In Chapter 5, end cardiopulmonary bypass (end-CPB) plasma fibrinogen levels were related to postoperative blood loss and transfusion. The purpose of this study was to determine the critical plasma fibrinogen levels for excessive bleeding. Interestingly, there was no critical fibrinogen level that resulted in excessive bleeding. However, end-CPB plasma fibrinogen levels higher than ≥ 2.5 g/L reduced the risk for excessive postoperative bleeding. The target fibrinogen concentration was set at this level (2.5 g/L) in the randomized clinical trial. Chapter 6, the randomized clinical trial is described. In this trial, targeted fibrinogen concentrate infusion did not reduce intraoperative blood loss. However, postoperative blood loss at 24 hours after surgery was reduced significantly. Also, after 24 hours less patients had received postoperative RBC transfusion. We observed more cases of stroke in the fibrinogen group compared to the placebo group. It must be emphasized that this study was not powered to assess statistical differences in adverse events between the fibrinogen and the control group. Further research is needed to assess the risk/benefit ratio of fibrinogen concentrate infusion in cardiac surgery