The Supply Side of Coagulation: Fibrinogen and Bleeding in Liver Disease and Transplantation.

Abstract

In this issue of Transplantation, Carrier et al1 describe a study that assesses the effect of preoperative fibrinogen levels on perioperative bleeding and outcomes. In 613 patients with end-stage liver disease who underwent liver transplantation between 2008 and 2019, preoperative low fibrinogen levels were associated with more blood loss but not worse 1-y survival in univariate and multivariate statistical models. This effect was most prominent when fibrinogen levels were below 3 g/L before surgery. In any model of coagulation, fibrinogen is the substrate required to create an effective clot and provide hemostasis. Like most components of hemostasis, fibrinogen is synthesized by the liver and reduced in severe liver disease. Additionally, and maybe more commonly‚ dysfibrinogenemia occurs in liver disease resulting in defects of the fibrinogen structure with undetermined effects on hemostasis.2 The coagulation abnormalities associated with liver disease result in dysbalanced hemostasis that can cause impaired clot formation or excessive thrombosis. Conventional coagulation tests cannot detect this dysbalanced hemostasis‚ as they measure only (a part of) the procoagulant side of hemostasis. Viscoelastic testing, now routinely used in many transplant centers‚ may provide a better assessment of all aspects of clot formation by creating a visual representation of changes in the viscosity of blood when a clot forms. Viscoelastic testing can guide transfusion management in many clinical scenarios‚ including liver transplantation‚ but possibly, more importantly, allows us to identify patients who are hypercoagulable even when the conventional coagulation tests are abnormally high. The results of Carrier et al suggest that low preoperative fibrinogen levels may be an indicator that a patient is at risk for increased intraoperative bleeding. This may be particularly useful if perioperative viscoelastic testing is not used or available as with the study center. This risk of bleeding increased when fibrinogen levels were below 3 g/L before surgery, a level that is far higher than what has traditionally been considered a concerning threshold. Most experts and societies, for example, the review on perioperative coagulation management in liver transplant recipients by Bezinover et al here in Transplantation in 2018,3 recommend fibrinogen concentrate and/or cryoprecipitate transfusion for fibrinogen levels below 1.5 to 2 g/L. Although raising new questions, the present study does not provide enough evidence to change this recommendation at this time. An association with bleeding (even in a multivariate model) does not necessarily mean that replacing fibrinogen with levels over 3 g/L will reduce the risk of bleeding. The assumption is that fibrinogen levels that are below 3 g/L before surgery may decrease more during transplantation to a level that actually impairs hemostasis. Excessive transfusion of cryoprecipitate (and, to a lesser degree, fibrinogen concentrates) is not without risk and may increase the risk of thromboembolic complications.4 The results by Carrier et al are raising new questions about fibrinogen thresholds and may provide the impetus for future (prospective) studies but should not necessarily change our current management. The Centre Hospitalier de L’Universite de Montreal (CHUM) has demonstrated for many years with great success what can be achieved with a concerted effort to reduce blood transfusion5: More than 70% of the patients in the present study did not receive any red blood cell transfusion at all! The center undertakes a number of interventions to achieve these remarkable results. For example, over 50% of the patients in this study underwent phlebotomy at the beginning of surgery. I am not aware of any other center that implemented such a vigorous and successful program to reduce blood transplantation. Unfortunately, this also limits the generalizability of the present study (and reduces the statistical power of the study). Furthermore, because viscoelastic testing was not used in this study, we do not know if lower preoperative fibrinogen levels result in deficient fibrinogen contribution to clot strength later during surgery (assessed, for example, using fibrinogen assays such as FIBTEM with rotational thromboelastometry, ROTEM). In summary, Carrier et al provide important insight into the role of fibrinogen in achieving hemostasis during and good outcomes after liver transplantation. Their data encourage us to check for fibrinogen levels whenever we measure conventional or viscoelastic coagulation tests and design future randomized trials of fibrinogen replacement in liver transplantation.