Fibrinogen and Bleeding: Old Molecule—New Ideas

Abstract

Hydroxyethyl starches (HES) are often administered to surgical patients as a colloid intravascular volume expander. Although all volume expanders administered to a bleeding patient may produce dilutional coagulopathy, HES solutions can also produce platelet inhibition and decreased clot strength (1,2). However, hemodilution with HES of all molecular weights significantly decreases whole blood and plasma clot strength in a fibrinogen-reversible manner (3–8). Fenger-Eriksen et al. (3) were the first to demonstrate in vitro that addition of fibrinogen to HES-diluted whole blood restored clot strength, an observation subsequently confirmed (4) and mechanistically defined as inhibition of thrombin-Factor XIII-fibrinogen interactions (5). Specifically, HES-mediated decreases in the speed of clot formation and strength were attenuated the most by addition of fibrinogen/Factor XIII compared with addition of either Factor XIII or thrombin alone (5). Further, given that the clot strength due to Factor XIII crosslinking of fibrin polymers was not significantly changed following dilution of plasma with HES (9), the most likely molecular explanation would be that HES species prevent thrombin interactions with Factor XIII and fibrinogen. In subsequent preclinical rabbit (6,7) and porcine (8) models involving in vivo hemodilution with various HES preparations, adding concentrated fibrinogen solutions (which invariably contain Factor XIII activity) markedly improved clot strength. The first translation of these observations (3–9) in a clinical study is reported by Mittermayer et al. (10) in this issue of Anesthesia & Analgesia. This investigation included patients undergoing spine surgery that were randomized to groups administered lactated Ringer's solution, gelatin solution or a HES (Voluven®, Fresenius, Austria). Administration of fibrinogen in the form of concentrates available in Europe was based not on plasma fibrinogen concentrations determined by standard laboratory methods but, rather, by the observation of a minimum plasma clot strength value (<25% the lower normal value) obtained by thrombelastography (10). Although patients receiving colloids required more red cell transfusions than the patients receiving crystalloid solutions, this was potentially secondary to the colloid-exposed groups having a lower baseline hematocrit (10). Importantly, there was no significant difference in blood loss or plasma fibrinogen concentration between the groups, and only the groups administered colloid required fibrinogen concentrate treatment (10). Thus, by following a Thrombelastograph®-based transfusion algorithm, the authors likely minimized HES-mediated bleeding in this particular patient population (10). Another important question raised by this investigation is the level of plasma fibrinogen required to maintain optimal hemostasis in the perioperative period. Most transfusion algorithms do not treat fibrinogen levels unless they are <100–150 mg/dL (1–1.5 g/L), levels that are below normal values for fibrinogen (11–13). Mittermayer et al.'s (10) investigation shows that similar fibrinogen concentrations may result in very different clot strengths. Further, increases in fibrinogen increase plasma clot strength linearly up to 300 mg/dL (14), and result in plasma clot strength equal to whole blood at 625 mg/dL (9), and plasma clots with 1000 mg/dL of fibrinogen have a strength three-fold greater than whole blood (15). Thus, further investigation is required to determine what concentration of fibrinogen (and plasma clot strength) provides optimal hemostasis without hypercoagulability, and if there are patient-specific and clinical setting-specific factors that affect the efficacy of fibrinogen administration. Will “optimal” fibrinogen administration adequately prevent or treat HES-mediated bleeding in all patients and clinical settings? Probably not, for although fibrinogen administration markedly improves the rate of clot growth and strength in blood diluted with HES, there are other pathologic states that may interact with HES to cause bleeding. In particular, HES enhances the onset of fibrinolysis in human plasma in vitro and in plasma obtained from rabbits administered HES (16). Given the multiple perioperative settings involving fibrinolysis (e.g., cardiac surgery, liver transplantation), further identification of mechanism(s) of HES-mediated bleeding and a continued search for effective therapies will likely continue for years to come.