Continuous intraoperative bleeding causes a reduction in coagulation factor levels. Pathological conditions such as hypothermia and acidosis complicate coagulation reactions based on enzyme-substrate reactions. Coagulation factor levels decrease as the amount of bleeding increases, leading to a vicious cycle of further bleeding and difficulty in stopping the bleeding . Our previous study revealed a negative correlation between the fibrinogen levels and bleeding volume before cryoprecipitate administration, and the amount of blood loss and transfusion tended to increase when the fibrinogen levels were < 100 mg/dL . In the present study, the operative time was significantly prolonged in the group with higher blood loss, which was expected to lead to further blood loss and difficulty in stopping the bleeding. In a systematic review comparing the fibrinogen concentrate with FFP, 5 out of 91 eligible studies reported the outcome of fibrinogen concentrate versus a comparator . The evidence was consistently positive (70% of all outcomes), with no negative effects reported (0% of all outcomes). Fibrinogen concentrate was compared directly with FFP in three high-quality studies and was found to be superior for > 50% of outcomes in terms of reducing blood loss, allogeneic transfusion requirements, length of intensive care unit and hospital stay, and increasing the plasma fibrinogen levels. However, it was concluded that the trigger value for fibrinogen administration in acquired fibrinogen deficiency, a common coagulation factor deficiency condition associated with surgical bleeding, remains unclear. Many guidelines and mass transfusion protocols recommend the administration of cryoprecipitate when the plasma fibrinogen levels are below 100–150 mg/dL; however, this threshold is not based on established clinical evidence . In addition to the increased consumption of clotting factors in the setting of persistent bleeding, the difficulty in obtaining a timely measurement of the fibrinogen levels has led to the argument that fibrinogen levels should not be used as a guide for the management of bleeding . Besides measuring fibrinogen levels, viscoelastic devices such as thromboelastography (TEG) and rotational thromboelastometry (ROTEM) are useful as they can provide real-time data regarding severe bleeding, especially in relation to cardiovascular surgery; the measurement of blood viscosity by viscoelastic devices in the operating room (point-of-care monitoring) is ideal. This strategy has the potential to reduce the risk of complications such as transfusion-associated circulatory overload (TACO), transfusion-related acute lung injury (TRALI), and thromboembolic adverse events . Our previous study concluded that plasma fibrinogen levels should be maintained between 100 and 150 mg/dL and should be > 100 mg/dL to prevent clotting factor deficiency . To prevent hypofibrinogenemia, plasma fibrinogen levels should be maintained > 100–150 mg/dL and not < 100 mg/dL. Kikura et al. reported that a fibrinogen level < 130 mg/dL is the cutoff value for fibrin polymerization (FIBTEM A10) measured by ROTEM as < 6 mm, and that postoperative blood loss and transfusion volume significantly increased when FIBTEM A10 was < 6 mm . They also found that the effect of fibrinogen concentrate on reducing blood loss and transfusion volume was clear in patients with FIBTEM A10 < 6 mm at the time of weaning from cardiopulmonary bypass, while in patients with FIBTEM A10 > 6 mm, hemostatic capacity was high and FFP was sufficient . In addition to these viscoelastic devices, new techniques for rapid measurement and estimation of fibrinogen levels have recently been developed in Japan [12, 13]. Although there are limitations in the interpretation and these rapid measurements of fibrinogen levels, it is hoped that rapid measurement of fibrinogen levels will become more widespread in the future, as fibrinogen levels themselves remain an important guideline for evaluating patients with bleeding .
In the present study, group C, who experienced significant bleeding and fibrinogen concentrations of approximately < 100 mg/dL before cryoprecipitate administration, demonstrated significantly greater fibrinogen recovery than group A, who experienced relatively little bleeding and maintained the fibrinogen levels. However, the dose of cryoprecipitate administered in relation to the amount of bleeding must be considered, since the percentage of the four packs of cryoprecipitate used in group C was significantly higher. In addition, a high initial fibrinogen concentration at the start of fibrinogen supplementation limits further increments in fibrinogen concentration . These findings suggest that the timing of cryoprecipitate administration is important to maximize the effect of cryoprecipitate, taking into account the amount of bleeding and the decrease in fibrinogen level due to bleeding.
In situations where viscoelastic devices or rapid fibrinogen measurement devices have not been introduced, the decision to administer cryoprecipitate must be made comprehensively based on the amount of blood loss, the rate of blood loss, the progress of the surgery, and vital signs. Our findings might help determine the timing of cryoprecipitate administration using the amount of intraoperative blood loss as an indicator. In our study, most patients showed fibrinogen levels > 100 mg/dL and approximately 60% of the patients showed fibrinogen levels > 150 mg/dL in group A, whereas half of the cases in group B and 70% of those in group C had fibrinogen levels < 100 mg/dL. Since most patients in group B had fibrinogen levels < 150 mg/dL which improved to > 150 mg/dL after cryoprecipitate administration in approximately 70% of patients, this observation might support the hypothesis that cryoprecipitate administration should be considered when bleeding exceeds 5000 ml and rapid cryoprecipitate administration is necessary for hemostasis when bleeding is > 10,000 mL.
The present study has several limitations. The surgeries were classified according to the amount of blood loss, and the surgical site was not considered. The background may be different for obstetric hemorrhage, wherein coagulation factors are lost early, and cardiovascular surgery, wherein the consumption of coagulation factors by artificial heart-lung, hemodilution, hypothermia, and effects on platelet aggregation function are taken into account. In addition, a multicenter prospective study is desirable in the future, since this was a single-center retrospective study.