Clinical Significance of Soluble Fibrin in Coagulopathy Caused by Highly Invasive Surgery

This study aims to examine the clinical significance of SF and conventional coagulofibrinolytic markers in coagulopathy (SAC and DIC) caused by highly invasive surgery.

In total, 44 highly invasive surgeries conducted in our department from April 2011 to April 2014 were evaluated: hepatectomy (segmental resection or more severe cases, including biliary duct reconstruction; 23 cases), pancreaticoduodenectomy (9 cases), distal pancreatectomy (5 cases), hepatectomy for living-donor liver transplantation (5 cases), and splenectomy (splenomegaly/portal hypertension; 2 cases).

The DIC score was calculated according to the diagnostic criteria for acute DIC.^6–8  Peripheral venous blood was drawn preoperatively and on postoperative days (PODs) 1, 2, 3, 5, 7, and 10 to determine the SF level (latex immune nephelometry; normal level, <7 μg/mL: LSI Medience Corporation, Tokyo, Japan), platelet count, fibrinogen degradation products (FDPs), prothrombin time (PT), and SIRS parameters (body temperature, heart rate, respiration rate, and white blood cell count). A SIRS score of 1 to 3 points was defined as SAC, and a score of ≥4 points was defined as DIC.

After excluding 2 patients with splenectomy with postoperative DIC scores of 0 points and 5 patients with donor hepatectomy who did not develop DIC, 37 patients remained and were classified into 2 groups: the SAC group, in which SAC remained after surgery (n = 16), and the DIC group, which developed DIC (n = 21; Fig. 1).

Examination 1: Changes in SF and other markers over time in the SAC and DIC groups.

Examination 2: Statistical examination of risk factors in the DIC group using univariate and multivariate analyses

For the statistical analysis, the t-test, χ² test, receiver-operating characteristic (ROC) analysis, and logistic regression analysis were performed using the medical statistical software EZR,⁹  with significance defined as P < 0.05.

This study was approved by the medical faculty's ethics committee.

As shown by the changes in the DIC scores, all patients received a diagnosis of SAC on POD1 and of DIC on POD2 (Fig. 2). On POD1, the SF level, FDP, platelet count, and PT–international normalized ratio (INR) were significantly higher in the DIC group than in the SAC group (Fig. 3).

There were no significant differences in the patient- or surgery-related factors between the groups (Table 1). Univariate analysis of the vital signs, 2 inflammatory markers, and 4 coagulofibrinolytic markers revealed significant differences in the SF level, FDP, and PT-INR between the 2 groups (Table 2).

Multivariate analysis with cutoff values based on the ROC analysis of the 3 factors revealed significant differences only in the SF level and FDP (Fig. 4). The SF level had the highest odds ratio at 14.4 (Table 3). A prediction formula was then prepared based on the β value: P = 1 / [1 + exp {–(2.665 × SF + 2.049 × FDP – 1.309)}].

In the ROC analysis based on the prediction formula, the area under the curve with the formula was 0.875, and the cutoff value was set to 94.5 (Fig. 5).

Next, multivariate analysis was performed for SF, FDP, and the prediction formula based on the cutoff value. A significant difference was observed only for the prediction formula (odds ratio, 17.2). The sensitivity and specificity of the prediction formula were 71% and 94%, respectively (Table 4).

These results showed that the risk factors in the DIC group were SF and FDP on POD1, with SF being the stronger risk factor.

It is believed that inflammatory cytokines cause a series of excessive responses¹⁰  and SAC.¹  The more invasive the surgery, the more frequently coagulofibrinolytic abnormalities induce the progression of SAC to DIC.¹¹  The rates of mortality and morbidity for highly invasive surgery, such as major hepatectomy and pancreaticoduodenectomy, have still been about 10 times higher than those of those of standard gastrointestinal surgery. There have been no molecular markers that can quantify postoperative surgical stress early.

The clinical use of SF as a coagulation marker is increasing.²  SF is a polymer of fibrin monomers that directly reflects clotting, but its role during the perioperative period has not been examined, despite its use in diagnosing deep vein thrombosis³  and DIC.⁴  Therefore, we evaluated changes in SF and other conventional markers, and statistical examination of risk factors in the DIC.

This study has 3 main findings. First, postoperative SAC occurred in 95% of patients who underwent highly invasive surgery, and the fact that half of the patients developed DIC on POD2 demonstrates the significantly high occurrence of coagulopathy after highly invasive surgery. Interestingly, among the operations performed, although DIC was most frequent in patients who underwent hepatectomy, including subsegmental resection, DIC did not occur in patients who underwent hepatectomy for living-donor liver transplantation, which involves essentially the same technique and amount of resection (data not shown). This finding suggests that even the same operative method has significantly different effects on the coagulofibrinolytic system. The difference in invasiveness might have been affected by differences in patient factors, such as injured versus normal livers; further consideration of this point is required. Second, SF and FDP appear to predict postoperative DIC after highly invasive surgery, especially SF. Hematologically, FDP is a fibrinolysis marker, whereas SF is a coagulation marker, reflecting early hypercoagulation before clotting. Third, operative stress can be quantified using the SF level on POD1, enabling more specific perioperative management from the perspective of postoperative coagulopathy control. Figure 6 shows a chart for initiating treatment of coagulopathy at the time of SAC. According to the chart, there is a 94% risk of remaining SAC if the predictive formula value on POD1 is less than or equal to the cutoff value; otherwise, there is a 71% risk of the development of DIC. Therefore, we believe that it is useful to treat SAC earlier using urinastatin¹²  or sivelestat sodium hydrate.¹³  However, there is no evidence of improvement in survival with treatment-induced improvement in the DIC score, unlike the effect of AT-III¹⁴  and recombinant human soluble thrombomodulin¹⁵  to septic DIC. Prospective clinical examinations of these agents must be performed in the future.

In conclusion, SF as a coagulation marker can predict postoperative DIC after highly invasive surgery, and it may quantify operative stress, enabling more specific perioperative management from the perspective of operative coagulopathy control.

The authors would like to specially thank T. Nishiyama, vice-head medical technologist of the Department of Clinical Laboratories; and T. Taguchi for excellent technologic support. The English in this document has been checked by at least two professional editors, both native speakers of English. For a certificate, please see: http://www.textcheck.com/certificate/EWBq3a. The article has been checked by a statistician. None of authors has any financial or personal conflicts of interest of any kind.