According to this survey, many patients with massive hemorrhage who were transferred to our center had coagulopathy, especially due to trauma and maternal hemorrhage. Trauma and volume of crystalloid solution were factors independently associated with coagulopathy. Patients with coagulopathy had higher 24-h mortality, and required more blood transfusions within 24 h.
In trauma patients without brain injury, permissive hypotension to achieve a target systolic blood pressure of 80–90 mmHg is recommended until major bleeding has been stopped in the initial phase following trauma [4, 12]. In prehospital settings, intravenous fluid administration is recommended to be titrated for a palpable radial pulse using small boluses of fluid (250 ml) rather than fixed volumes or continuous administration [13]. In this survey, median systolic blood pressure at the time of arrival to our center was 100 mmHg (IQR 80–117 mmHg) overall and 99 mmHg (IQR 84–120 mmHg) for trauma, all of which were within standard values, but were high from the perspective of permissive hypotension. Both trauma and maternal hemorrhage cases received large volumes of crystalloid infusion before reaching our center and many showed coagulopathy at the time of visit, so there was considered to be some room to limit infusion volumes before arrival at our center.
Regarding prehospital administration of blood products, both RBCs and FFP have been reported to show improvements in mortality and coagulopathy among trauma cases [5–7, 14]. This study targeted transfer cases from hospitals that can administer blood products, not direct transport from the field. However, the rate of blood product administration was 23.5% for RBCs and 7.6% for FFP in all cases, and 32.4% for RBCs and 8.1% for FFP in trauma cases. In Europe, viscoelastic methods (VEMs), like thromboelastography and rotational thromboelastometry, are recommended for the diagnosis of trauma-induced coagulopathy because of the ability to provide rapid assessment of hemostasis to support clinical decision-making [4]. In Japan, VEM is usually restricted to experimental and research settings in academic hospitals, and VEM equipment is rarely present in most primary-care hospitals. Coagulopathy due to trauma occurs early after trauma [15, 16], and in severe trauma such as multiple injuries, the frequency of established coagulopathy on emergency room admission is high [11, 17]. In patients with massive hemorrhage, early administration of FFP is rational to prevent coagulopathy. In fact, early administration [18] and high-ratio administration [19, 20] of FFP are recommended. In our area, even in environments in which testing for coagulopathy is not possible, blood products including FFP should be administered more often at the time of transfer to a hospital.
On the other hand, patients experiencing massive hemorrhage are under severe time constraints, because transfer to a hospital that can achieve definitive hemostasis is required as soon as possible. One of the reasons why the rate of FFP administration was low may be that a longer time is needed to thaw the product. In that respect, fibrinogen concentrate does not require thawing or cross-matching and allows rapid administration [21], and is useful in prehospital settings [22]. Furthermore, because fibrinogen levels decrease earlier than any other hemostatic factors in the case of massive hemorrhage [23], supplementation of fibrinogen is required from early in trauma. Conversely, FFP requires high volumes to maintain fibrinogen levels [24], so fibrinogen concentrate can be supplemented with fibrinogen even in small amounts [21]. This is also advantageous from the perspective of restricted volume replacement for permissive hypotension and prevention of hypocalcemia resulting from the citrate chelation of serum Ca2+. Fibrinogen concentrate reportedly carries lower risks of massive transfusion or multiple organ failure than FFP [25]. Fibrinogen concentrate has also been reported to reduce blood loss and total amount of FFP when treating coagulopathy from postpartum hemorrhage [26]. At present, although fibrinogen concentrate is only approved for bleeding episodes in patients with congenital fibrinogen deficiency in Japan, due to the above-mentioned advantages, some facilities use fibrinogen concentrate for trauma and obstetric bleeding with the approval of the hospital ethics committee. If administration of fibrinogen concentrate for patients with bleeding becomes approved in Japan as in many European countries, early correction of coagulopathy should be possible.
Tranexamic acid should be given to bleeding trauma patients as early as possible [27, 28], but administration at the referring hospital was limited to 13.5% in our region. In the obstetric setting, tranexamic acid has been shown to be effective, particularly when given early after bleeding onset [29], but administration was limited to 6.1%. On the other hand, routine use of tranexamic acid is not recommended for upper gastrointestinal bleeding [30], and tranexamic acid was used in 14.6% of gastrointestinal bleeding cases. Early treatment with tranexamic acid for trauma and maternal hemorrhage should thus be promoted in our region.
The mechanisms of coagulopathy following trauma are considered to involve tissue hypoperfusion and hypoxia, which in turn induce endothelial damage and activation [31–33], and an iatrogenic factor that occurs secondary to uncritical volume therapy leading to acidosis, hypothermia, and hemodilution [33]. Maternal hemorrhage is also associated with a high risk of early coagulopathy, because loss of clotting factors by placental separation and atonic bleeding causes early progression, so dilute coagulopathy is more likely to occur with a small amount of bleeding compared to intraoperative bleeding in other diseases, and obstetric disseminated intravascular coagulation with premature separation of the placenta and amniotic fluid embolism shows a very high bleeding tendency [34]. Both trauma and maternal hemorrhage are prone to a high degree of coagulopathy, since the properties cause coagulopathy as well as consequences of bleeding and dilution. In the present study, many coagulopathies were observed due to trauma and maternal hemorrhage.
On the other hand, coagulopathy due to gastrointestinal hemorrhage was not observed. Although many facilities use massive transfusion protocols for early replacement of coagulation factors in cases other than trauma [35, 36], the results of this study suggest that administration of a high ratio of FFP to RBCs for gastrointestinal bleeding may not be effective. Many reports have described restriction of blood transfusion as showing better prognosis for gastrointestinal bleeding [37–39]. However, since many reports exclude massive bleeding or do not consider severity, transfusion strategies for severe gastrointestinal hemorrhage warrant closer consideration.
This study showed several limitations that merit consideration when interpreting the results. First, this study was a single-center, retrospective study, and the number of subjects was limited, so our results cannot be generalized. However, the results that a large infusion volume of crystalloid solution is associated with coagulopathy and that the presence of early coagulopathy is associated with poor prognosis were the same as reported elsewhere. Few reports have examined whether DCR is performed in prehospital settings, so the result of low compliance with DCR seems to be a problem that is not exclusive to our region. Second, the judgement of the doctor from the referring hospital was adopted in the definition of massive hemorrhage, because blood pressure or estimated blood loss is difficult to determine due to intra- or retroperitoneal hemorrhage in some cases. Although this involved the inclusion of subjective judgments from doctors at the referring hospital, there was not considered to be any difference in treatment content or prognosis after transfer, because this study did not identify the doctor from the referring hospital or the doctor in charge at that time. Third, this study involved a review of medical records, so if the details of treatment by the doctor from the referring hospital remain unclear, missing values may occur, and results may differ. Fourth, the 30-day mortality rate was 9.1% in the overall study cohort and 13.5% in trauma cases. No deaths due to ruptured aortic aneurysm were identified. Mortality rates in studies of massive hemorrhage due to trauma reportedly vary from 8.4–37.5% [5, 7, 12], but were generally higher than the mortality rates in this survey. This was thought to be due to the exclusion of more severe patients, such as those who experienced cardiac arrest before arrival at our center or those in an unstable condition and could not be transferred to the hospital. Preventing coagulopathy may stabilize the patient into a transferable condition, which does not change the conclusion that early response to coagulopathy is warranted.