Our study specifically described changes in the coagulation system and platelet activation among patients with AAD from symptom onset to the first postoperative day. In this study, we analyzed several molecular biomarkers of the coagulation system and platelet function using ELISA and we analyzed clotting factors, platelet function and fibrinogen function by TEG in patients with AAD who underwent emergent aortic arch surgery. The principal finding of the present study is that AAD itself activates the coagulation system and consumes a large amount of clotting factors and fibrinogen even before surgery. The ELISA results demonstrated that the perioperative procoagulant state is associated with intense thrombin generation (as demonstrated by elevated TAT). In addition, the TEG results also demonstrated consumption coagulopathy (consumption of clotting factors and fibrinogen) in patients with AAD. In contrast, we found that platelet function was not more severely impaired (as demonstrated by soluble CD40L levels and MA) in patients with AAD.
Excessive bleeding is still a common complication that is encountered in aortic arch surgery and often leads to the need for blood transfusions [5, 6]. Thus, surgical treatment of patients with AAD is required to further clarify changes in the coagulation system and platelet functions. The use of CPB in the treatment of AAD has been reported to be responsible for coagulation disorders [7, 8]. Nevertheless, other reports have focused their attention on changes in the perioperative coagulation system during emergent aortic surgery [3, 8], but none of them included a control group to highlight the differences in the coagulation system between patients with AAD and patients requiring complex CPB surgery.
Preoperatively, a low R time suggests clotting factor consumption and, ultimately, coagulopathy in the early phase of AAD. As the final substrate in the coagulation cascade and the ligand of platelet glycoprotein IIb/IIIa receptors, low preoperative fibrinogen levels also demonstrated an initial burst in the consumption of clotting factors. The time from symptom onset to intervention was inversely correlated with the preoperative fibrinogen level (r = 0.63; p < 0.01). This is in line with previous findings and may also explain why fibrinogen levels are not always reduced in patients with AAD. Thus, we demonstrated that blood flow contact with the nonendothelialized false lumen results in the release of large amounts of cytokines, which activate the coagulation system and lead to the consumption of many clotting factors before surgery in patients with AAD. This procoagulant state and subsequent consumption coagulopathy at the onset of AAD have been demonstrated, and it eventually results in disseminated intravascular coagulation (DIC)-like coagulopathy in patients with AAD.
As expected, in this study, significantly higher levels of perioperative TAT were observed in AAD patients who underwent aortic arch surgery compared with those with thoracic aortic aneurysms. Therefore, the findings suggest that the procoagulant state and coagulopathy may persist even after the repair of the dissection. This observation suggests a systemic activation of coagulation that potentially lead to impaired hemostasis, which is frequently observed in aortic arch surgery. Through activation of the coagulation cascade, thrombin generation was greatly amplified during CPB despite full heparinization [9, 10]. Because thrombin generation regulates various biochemical and physiological processes involved in coagulation and inflammation, it has a central role in the clotting process [11, 12]. This procoagulant state is a possible underlying mechanism that contributes to microvascular thrombosis, clotting factor consumption and bleeding tendency in patients with AAD [13].
In addition, our TEG results also suggested that the consumption of clotting factors and fibrinogen ultimately lead to coagulopathy and DIC, which was consistent with our previous findings [14]. Thrombus remains in contact with systemic blood flow in AAD through the reverse flow after surgery. This indicates that prolonged contact with a thrombosed area leads to more severe consumption coagulopathy. If bleeding is prolonged, consumption coagulopathy can cause serious complications, such as DIC and multiple organ failure. Thus, we may speculate that massive clotting factor consumption is one of the causes of coagulopathy and bleeding in this type of surgery.
At the same time, our data showed that platelet activation, which was evaluated by measuring the soluble CD40L concentration, was significantly increased in patients with AAD during surgery. The CD40 molecule belongs to the tumor necrosis factor receptor super family that is located at 20q11-13.2. Soluble CD40L is the product of CD40L hydrolysis and is not expressed in non-disease states [15]. CD40L stimulates platelet activation and stabilizes arterial thrombi through a glycoprotein IIb/IIIa ligand-dependent mechanism [16]. At least 95% of circulating soluble CD40L comes from platelets [17]. However, soluble CD40L levels in patients with AAD had a tendency to significantly decline after CPB compared with that in patients with thoracic aortic aneurysms. Moreover, our research confirmed that there was no significant difference in platelet function between the 2 groups during the operation by TEG. This finding revealed that obvious platelet activation and consumption were not observed in patients with AAD. It is possible that the number of platelet glycoprotein IIb/IIIa receptors on the surface of the platelet remained relatively stable after CPB, which is consistent with the findings of previous studies [14, 18]. Indeed, platelet counts and platelet function are separate entities. Additionally, reducing the platelet infusion quantity might also affect clinical prognosis. Thus, we believe that there is no need for excessive platelet transfusion if platelet functions are within normal levels.
Several reports have already reported that that clinical presentations of AAD including anemia, depleting clotting factors and intravascular coagulopathy, result from the consumption of clotting factors in the false lumen [19, 20]. We also confirmed this DIC-like coagulopathy in the acute phase of AAD by ELISA and TEG in this study. Thus, we speculate that the standard guidelines of hemostatic therapy are relatively inadequate for patients with AAD [21]. Based on the different periods of coagulopathy, a suitable medical treatment should involve dealing with the DIC-like coagulopathy. Taking all these factors into consideration, we considered the patients with AAD to be at high risk for perioperative coagulopathy, and their clotting factors and fibrinogen concentrations should be further increased to ameliorate consumption coagulopathy in patients with AAD. Theoretically, thrombin generation should be reduced during the operation, but anticoagulation in patients with an elevated hemorrhagic risk is a difficult task. Therefore, basic scientific principles for this DIC-like state appear to suggest the use of different medications for different phases of AAD.
Study limitations
A major limitation of our study is that it is still difficult to separate the effects of different pathologies and mechanisms as well as, extended CPB and hypothermia on the coagulation system of the 2 groups. Another important study limitation is that the number of patients and adverse clinical outcomes is small. This small number limited our power of analysis to identify changes in the coagulation system among patients with AAD. In addition, with the experience gained in previous years and with the results of this study, the present authors designed a randomized clinical trial to determine the role of hemostasis in aortic arch surgery.