Few studies have reported on the off-label use of rFVIIa in aortic surgery, with no previous study focusing on the safety of rFVIIa in ASHCA.10,11 However, the high possibility of massive bleeding necessitates an evaluation of the safety of off-label rFVIIa use in ASHCA. The crucial findings of the present study were as follows: (i) preoperative shock, coagulopathic state in laboratory tests, higher JapanSCORE II 30-day mortality rate, and longer ACC time might be associated with excessive bleeding in ASHCA and (ii) rFVIIa application did not result in a significant increase in the postoperative 30-day mortality and AEs in ASHCA.
Preoperative shock and coagulopathy increased the risk of intraoperative bleeding, which might require rFVIIa administration. Preoperative shock in our patients was primarily caused by AAD or ruptured TAA. The aforementioned pathologies cause coagulopathy. Guan et al. reported that intense prothrombin generation and excessive systemic fibrinolysis occur in AAD before surgery, thereby leading to prolonged consumption coagulopathy, excessive bleeding, and complications . Researchers have also described coagulopathy in aortic aneurysms with increased intensity upon rupture . The rFVIIa group demonstrated significantly lower Plt and fibrinogen levels, prolonged aPTT, and PT-INR before PSM. This resulted in a significantly greater amount of intraoperative bleeding and transfusion.
JapanSCORE II is a calculated operative risk similar to EuroSCORE. However, it is based on JCVSD. JapanSCORE II more precisely reflects operative risk in Japan than EuroSCORE . In the present study, the higher frequency of AAD, emergent surgery, and shock might result in higher operative risk in the rFVIIa group. Despite a lower actual mortality rate than the calculated value, JapanSCORE II appeared to be a reliable risk predictor.
The clinical impact of HCA-induced coagulopathy is well known. However, the underlying mechanism is still unclear. Hypothermia and CPB are factors that cause coagulopathy. However, several studies have reported that the lowest body temperature is not associated with bleeding [2, 4]. In the present study, the lowest temperature was significantly higher in the rFVIIa group. Nevertheless, intraoperative bleeding was significantly higher in the rFVIIa group than that in the control group. In other words, the lowest temperature was not strongly associated with coagulopathy. Meanwhile, the ACC time in the present study was significantly longer and supposedly associated with excessive bleeding. There are few reports on the relationship between coagulopathy and ACC. Moreover, longer ACC reportedly causes both fibrinogen consumption and accumulation of tissue plasminogen activator. Nonetheless, the underlying mechanism is unclear .
The efficacy of off-label rFVIIa use has been repeatedly reported. However, most of the latter studies involved patients who underwent cardiac surgery [7–10], where the efficacy was demonstrated with respect to the amount of perioperative bleeding, transfusion, and re-exploration [7–10]. However, a previous study on AAD surgery reported on significantly greater perioperative bleeding, transfusion, and re-exploration, following rFVIIa administration . In the present study, the rFVIIa group demonstrated significantly higher intraoperative bleeding and transfusion, in addition to significantly lower postoperative Plt. The severity of coagulopathy in ASHCA is expectedly much higher than that in general cardiac surgery. Therefore, consumption coagulopathy may have persisted even after rFVIIa treatment. According to Paparella et al., intense thrombin generation in patients with AAD stimulates platelet activation and dysfunction, and promotes coagulation factor consumption and excessive fibrinolysis, which collectively result in excessive bleeding . Consumption coagulopathy and platelet dysfunction have been not only reported in AAD but also in TAA . Patients in the rFVIIa group in ASHCA might continue to suffer from life-threatening bleeding and require a greater amount of transfusion if not treated with rFVIIa. Therefore, rFVIIa in ASHCA plays an important role in rescue therapy.
The safety of rFVIIa is still unclear and depends on several factors, such as patient characteristics, transfusion, and the dose of rFVIIa applied. A randomized trial reported on no significant increase in mortality, rather a numeric increase in AEs . Alferevic et al. reported on higher mortality and renal morbidity in the rFVIIa group . The aforementioned studies focused on complex cardiac surgery. Other studies on AAD or aortic surgery demonstrated no significant increase in postoperative mortality or AEs [11, 12]. Intense thrombin generation in ASHCA causes platelet dysfunction, consumptive coagulopathy, and excessive fibrinolysis. Based on the above-mentioned factors, a low frequency of thromboembolic AEs might result from rFVIIa therapy in aortic surgery.
The safety dose or optimal protocol for rFVIIa in cardiac surgery is still unknown. Researchers have reported on the safety and efficacy of a dose ranging between 35 µg/kg to 70 µg/kg in general cardiac surgery . Several studies have described the efficacy of low-dose rFVIIa <20 µg/kg . However, considering the severity of coagulopathy in ASHCA, a higher dose may also be acceptable. A dose <90 µg/kg is considered safe in patients without hemophilia . In the present study, the median dose of rFVIIa was 56 µg/kg, and patients did not demonstrate an increase in mortality or thromboembolic AEs. We administered rFVIIa following the correction of other hemostatic parameters, which was in compliance with current recommendations .
Our study had several limitations. This was a single-center, retrospective, observational study with a small sample size. We performed PSM based on different characteristics before rFVIIa treatment. Nevertheless, there were several unmeasured confounders. In addition, we observed a difference in intraoperative transfusions, which might have affected the amount of intraoperative bleeding and rFVIIa administration. However, it was impossible to equalize the number of intraoperative transfusions because of the retrospective observational study design. Despite the aforementioned limitations, this is the first study to focus on the use of rFVIIa in ASHCA.