Therapy with fibrinogen concentrate: clinical and ethical considerations

We are concerned that a recent report of Solomon and colleagues regarding changes in fibrinogen concentration through administration of fibrinogen concentrate utilized approaches not in harmony with appropriate guidelines. The study compared different methods of fibrinogen concentration analysis and correlated these with rotational thrombelastometry, a functional test measuring the mechanical properties of the fibrin clot. The correlation was good, but became less significant with increasing fibrinogen concentration; one reason for this may have been confusion between plasma and blood concentrations in some instances. The authors also appear to be confused about the normal concentration of fibrinogen, mentioning fibrinogen values “up to approximately the limit of normal values (4.5 g/L)” or “at concentrations to and above normal value 4.5 g/L.” However, in fact, the normal range for plasma fibrinogen concentration is (related to different methods) 1.5 to 4.0 g/L with a mean of 2.75 g/L. Aliberti and coworkers found in 4116 normal value outpatients a mean fibrinogen concentration of 3.24 (2.3-3.9) g/L. Solomon and colleagues surprisingly do not comment on their own findings demonstrating fibrinogen concentrations in four volunteers between 2 and 3 g/L (their Fig. 4) and 1.8 g/L (mean) in 33 cardiac patients. In addition, as stated by Urwyler and colleagues, if fibrinogen concentration were determined by point-of-care thrombelastometry (ROTEM) instead of the standard method according to Clauss, “the use of fibrinogen concentrate would increase significantly.” The study of Solomon and colleagues reported the effects of the use of fibrinogen concentrate in their patients. We want to emphasize that fibrinogen concentrate is extremely expensive and not completely harmless; its indiscriminate use should be avoided as there is no solid evidence for any benefit when given prophylactically. The applicable regulation for the study of Solomon and colleagues are the German guidelines, which state in issue 2008, Chapter 7.1.7. that “After fibrinogen substitution plasma concentration should be at least 1.0 g/L. In the adult normally 3-6 g fibrinogen concentrate are necessary.” For us, the reported use of fibrinogen concentrate in 33 cardiac surgical patients is a matter of concern. The clinical need for fibrinogen concentrate therapy may be assumed in special trauma cases with massive bleeding, but is a rare exception in cardiac surgical patients. The authors do not explain the indication for fibrinogen concentrate based on the appropriate guidelines or comprehensible evidence. Instead we learn that 6 g was given to 33 consecutive patients with “diffuse bleeding” after bypass, increasing the fibrinogen plasma concentration up to 3.3 g/L; the clinical situations were not explained any further, and they were not mentioned in the discussion either. In fact, the initial mean fibrinogen level in these 33 patients was 1.8 g/L, which is comfortably within normal range, as described above. In addition they had been treated with aprotinin, an antifibrinolytic agent. Platelet (PLT) count, aPTT, and PT were also within acceptable range after bypass, without being affected by fibrinogen administration. We doubt therefore that fibrinogen concentrate was given with legitimate indication. Diffuse bleeding after bypass is not unknown, but up to now there is no evidence that this situation is mainly related to fibrinogen deficiency; hemodilution, PLT dysfunction, or inadequate heparin reversal also have to be considered. As stated in the article, one patient required 2 units of red blood cells (RBCs), 6 units of plasma, and 3 units of PLTs; one patient required a single unit of RBCs, and the remaining 31 patients had no need for transfusions at all! This does not sound like urgent need for treatment of coagulation disorder. The authors should have described the clinical situations in more detail, such as the amount of blood loss and the site(s) of bleeding, for example, vents, sternum, and pericardium. Additionally, the authors should have discussed the potential hazardous side effects of fibrinogen concentrate infusion, such as venous thromboembolism, anaphylactic reaction, or transmission of viral diseases. The authors appropriately note the approval of their ethics committee and the patients’ informed consent. May we ask if the patients had been informed about the possibility of fibrinogen application, and did they know about the potential side effects of this medication? This is not an unfair question since 33 cases needing fibrinogen concentrate after bypass within a period of 10 months exceeds the likely number of unpredictable emergencies and thus suggests that the routine consent of all patients for fibrinogen use should be obtained when they are scheduled for cardiac surgery. TRANSFUSION appropriately requires authors to state their conflicts of interest. Five of the eight authors of the article by Solomon and colleagues reported conflicts with various manufacturers related to the study, and one was an employee of the company manufacturing the fibrinogen concentrate. This observation makes us even more wary of the approaches described.