In the present retrospective analysis, administration of a mean dose of 6.5 g of fibrinogen concentrate in cardiovascular surgery patients with diffuse bleeding after weaning from CPB was followed by an 89% increase in the fibrinogen plasma level and in vivo
recovery of 114%. Our results showed that the administration of a mean dose of fibrinogen concentrate of 6.5 g increased plasma fibrinogen levels by a mean of 1.7 g litre−1
, with an increment of 2.3 g litre−1
per substituted mg kg−1
bodyweight. This finding is not in agreement with other studies investigating the administration of fibrinogen concentrate for haemostatic therapy in acquired fibrinogen deficiency. In the observational study performed by Danes and colleagues8
investigating 69 patients suffering from various forms of acquired severe hypofibrinogenaemia, a mean absolute increase of 1.09 g litre−1
of plasma fibrinogen was measured 24 h after a median dose of 4 g of fibrinogen concentrate (Table ). In another retrospective study of 43 patients, Fenger-Eriksen and colleagues22
showed an increase in fibrinogen of 1.01 g litre−1
with only half the dose (median 2 g) of fibrinogen concentrate (Table ). The differences in the increase of fibrinogen plasma concentration may reflect differences between the study populations such as underlying clinical conditions (e.g. sepsis, haematological malignancy, and liver insufficiency),8
mean age (52 and 49.5 yr in the studies by Danes and colleagues8
and Fenger-Eriksen and colleagues,22
respectively), and the proportion of paediatric patients (2.9% and 9.3% in the studies by Danes and colleagues8
and of Fenger-Eriksen and colleagues,22
respectively). The patients included in our study were all aged >18 yr [mean age 58 (sd
11) yr], and cardiovascular surgery was the only clinical condition. Furthermore, our retrospective analysis excluded patients receiving additional medication containing fibrinogen (i.e. FFP) between the pre- and post-therapy analysis of fibrinogen concentration. Administration of haemostatic products containing fibrinogen in addition to fibrinogen concentrate between the pre- and post-therapy time could have influenced the fibrinogen recovery parameters reported previously. It is difficult to estimate whether recovery values would have been higher or lower in the previous reports in the absence of FFP administration. The concentration of fibrinogen in FFP varies between units but is generally lower than the plasma concentrations reached in our patients. Above a target level of 2.25 g litre−1
, which is the mean concentration of fibrinogen in plasma thawed after more than 24 h of storage,26
FFP is likely to act as a diluent and decreases the plasma fibrinogen concentration.
Previously published data on plasma fibrinogen recovery in patients with acquired hypofibrinogenaemia. N/R, not reported
Recovery values >100% (e.g. 109% reported by Danes and colleagues8
and 114% in the present study) can be explained by the slightly hypovolaemic conditions that commonly occur after surgery. Prolonged bleeding in the ICU or a postoperative increase in fibrinogen as part of the acute phase reaction can also influence plasma fibrinogen over a time frame of hours.8,15,22
Earlier measurement (e.g. within 1 h of administration, as in the present study) might overcome this limitation. Values of recovery above 100% also raise the question whether the amount of fibrinogen present in the vials was higher than 1 g, the amount indicated on the label. Batches of Haemocomplettan P vary slightly in fibrinogen content, since this concentrate is a biological product fractionated from FFP (cryoprecipitate). The packet insert indicates a range of 900–1300 mg per 1 g vial. However, this does not represent the actual variation in the amount of fibrinogen; instead, this is the theoretical variation allowed. We performed a review of the certificates of analysis of fibrinogen concentrate batches and found a high degree of consistency in fibrinogen content: vials were overfilled by a mean 8.75% at the beginning of the shelf-life to compensate for several factors that lead to loss of fibrinogen during administration: fibrinogen solution remaining in the vial, transfer from the glass vial into syringes, fluid remaining in the perfusion line, etc. In the present report, recovery was calculated according to the label (1 g per vial) and not according to the actual amount of fibrinogen administered, because in clinical practice, the concentrate is generally dosed according to the label.
In our clinic, fibrinogen concentrate is administered considerably more rapidly (e.g. 6 g in 1–2 min) for severe bleeding occurring intraoperatively than in a non-acute setting (e.g. congenital deficiency) in order to obtain a prompt haemostatic response. This infusion rate is higher than the rate recommended in the package insert (5 ml min−1, representing a 60 min infusion time for 6 g). However, it is unclear how different infusion rates influence the increase in fibrinogen concentration measured after 1 h; further investigations are warranted for the perioperative setting where rapid correction of severe bleeding is required.
The mean dose of 6.5 g fibrinogen concentrate administered here was higher than the doses administered in acquired hypofibrinogenaemia in other studies, including cardiac surgery patients.8,10,15,23
In the guidelines recently published by the German Medical Association, it is suggested that adults will generally require a single dose of 3–6 g of fibrinogen concentrate.27
Importantly, the mean level of fibrinogen after administration of fibrinogen concentrate was comparable with baseline levels, which correspond to levels reported for healthy subjects of similar age.28
The high-normal target level of fibrinogen was chosen based on observations regarding the protective role of high fibrinogen concentration against bleeding in cardiac and non-cardiac settings.3–5
On the basis of the results of previous in vitro
high fibrinogen concentration might have compensated for decreased platelet counts with regard to clot firmness.
The administration of fibrinogen concentrate and the calculation of recovery parameters is generally based on the plasma fibrinogen level measured using the Clauss method (turbidimetric read-out). In our department, however, administration of fibrinogen concentrate is most often guided by the thromboelastometric FIBTEM test because of its rapidity and its reflection of the mechanical strength of the clot. There are reports on the use of FIBTEM to guide haemostatic therapy in several settings, including orthopaedic surgery, trauma, and cardiovascular surgery.10,13,14,29
MCF target levels above 7 mm have been considered for orthopaedic surgery,10
whereas in cardiovascular surgery, a considerably higher target has been discussed (22 mm).13,14
There is currently no evidence for these target levels, and randomized controlled trials investigating this therapeutic approach appear desirable. Nevertheless, FIBTEM appears to be a valuable means of guiding fibrinogen concentrate therapy in the perioperative setting. Although a correlation between plasma fibrinogen concentration and FIBTEM MCF has been reported,30
neither FIBTEM nor the Clauss method measure fibrinogen concentration directly. The Clauss method measures the time to fibrin formation and compares it with a calibration curve.31
The result is therefore a clotting time, from which the concentration of fibrinogen can be derived. When obtained using a photo-optical technique, as in the present report, the result may be affected by many functional fibrinogen-independent factors, such as fibrinogen degradation products that have an anticoagulant effect, fibrin degradation products, haemodilution with hydroxyethyl starches,32
or factors that influence turbidity (e.g. lipid concentration in the plasma sample, bile pigment, and free haemoglobin). Fibrinogen values obtained when using the Clauss method are therefore prone to inaccuracy. FIBTEM, a test for assessing the elasticity of the fibrin clot under platelet inhibition by cytochalasin D, is more a measurement of fibrin quality rather than a fibrinogen measurement. FIBTEM MCF is mainly dependent on fibrinogen concentration, but as with the Clauss assay, it is subject to the influence of fibrinogen-independent factors. FXIII appears to be one of these factors.33
The present data show that after therapy, the mean fibrinogen increased to 189% of the pre-therapy value, whereas the mean FIBTEM MCF increased to 200%. The apparently higher increase in FIBTEM MCF may have been related to small amounts of FXIII in the fibrinogen concentrate (i.e. 50 IU FXIII per 1 g fibrinogen concentrate). As FXIII has been shown to help maintain clot firmness in haemodilution,34
it appears necessary to investigate further its haemostatic role in the present setting.
The records of the patients included in the study showed no venous thromboses or arterial ischaemic events. Regarding the safety of fibrinogen concentrate administration, a 22 yr pharmacovigilance programme and a systematic review of clinical studies indicated that the thrombogenic potential of Haemocomplettan®
P is low.35
In fact, given its role as a substrate for formation of the fibrin net, fibrinogen may play an important antithrombotic role. Fibrin, known as antithrombin I, acts by sequestering thrombin in the incipient clot, reducing the activity of the bound thrombin, and localizing the subsequent processes of clot formation.36
Sufficient formation of the fibrin net may be beneficial at the end of CPB, when antithrombin levels are decreased,37
and reversal of heparinization is induced with protamine.
Nevertheless, caution is required when administering fibrinogen concentrate for the treatment of bleeding after ACB, because there are few data on the influence of this therapy on graft patency or on its safety in this setting. In a prospective study of 10 ACB patients, prophylactic administration of fibrinogen concentrate increased baseline fibrinogen concentration of 2.9 by 0.7 g litre−1
, and no clinically relevant postoperative thrombotic events were observed.24
High preoperative fibrinogen values (>3.5 g litre−1
) in ACB have been shown to predict postoperative mortality of all cause, but not the mortality from cardiac cause or the need for myocardial vascularization,38
supporting the hypothesis that fibrinogen was a marker of inflammation, rather than a cause of thrombosis in these patients. On the other hand, decreased preoperative fibrinogen values have been shown to correlate with bleeding after ACB,5
possibly because they lead to low fibrinogen values when weaning from CPB. In contrast to the prophylactic approach, some clinicians favour administration of fibrinogen concentrate only for therapy of overt bleeding, as in the present study. It remains to be established whether administering fibrinogen concentrate as prophylaxis or for correction of bleeding in a dosage adjusted according to bodyweight, actual fibrinogen level or fibrin-based clot firmness is a more viable strategy when using fibrinogen concentrate as haemostatic therapy for severe bleeding post-CPB.
One limitation of the current study is variation in the type of cardiac surgery. Also, bleeding and necessity for transfusion were judged clinically, which could introduce bias. A further limitation of the study is that the fibrinogen recovery parameters were calculated from values obtained towards the end of surgery, and not immediately after administration of fibrinogen concentrate. Infusion of colloids, crystalloids, or blood from cell-saver could have influenced the recovery parameters. However, with bleeding already corrected by the haemostatic therapy, the patients were in a stable condition at this time, and the impact of plasma loss or replacement would have been limited. Furthermore, it is important to keep in mind that the comparability of pharmacokinetic data presented in different reports is limited if different methods of fibrinogen measurement are used.39
A number of different assays based on the Clauss method are commercially available, and they vary in thrombin strength, buffer composition, inclusion of inhibitors of heparin and fibrinogen degradation products, calibration method, and dilution range. Even when calibrated correctly, Clauss assays can differ up to 50%.32,40
Recently, Fenger-Eriksen and colleagues41
showed that the results of Clauss measurement differ significantly in the presence of colloid plasma expander when using different automated coagulation analysers. Variability can also be introduced by different commercially available calibrators,42
or by heterogeneity of fibrinogen (high molecular weight fraction/low molecular weight fraction) in different patient groups compared with the calibration material.43,44
Each of these factors alone might not be clinically relevant in the perioperative setting, but taken together they could invalidate comparisons between studies.
In conclusion, this retrospective analysis showed that fibrinogen concentrate administered for haemostatic therapy in cardiovascular surgery was effective in increasing the plasma fibrinogen level and contributed to the correction of bleeding. Prospective investigation of this therapeutic approach appears warranted.