Fibrinopeptide-A and fibrinopeptide-B may help to D-dimer as early diagnosis markers for acute mesenteric ischemia

Introduction

Acute mesenteric ischemia (AMI) has a poor prognosis when accompanied by concomitant diseases. Delayed diagnosis increases mortality. Prognosis is improved when intestinal revascularization and operational intervention can be achieved within 6 h after ischemia development [1], [2], [3], [4].

Serum biomarkers have limited sensitivity and specificity in the diagnosis of AMI. To diagnose intestinal ischemia, elevated levels of biomarkers can only be detected when transmural intestinal infarct has developed [5], [6], [7], [8], [9]. Neopterin usually plays a role in cellular immune activation and vascular endothelial damage. Ischemic or septic damages cause elevation of neopterin levels. In a study, neopterin, creatine phosphokinase (CPK), lactate dehydrogenase (LDH), amylase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and leukocytes levels have been increased according to intestinal wall changes. This elevation was significant at 6–12 h after the occlusion of superior mesenteric arter (SMA) [10], [11]. In another study, serum LDH and lactate levels with a rising due to prolonged ischemia were significantly higher in all ischemia groups rather than sham. D-dimer, lactate, neopterin and LDH values were investigated in these studies, and concluded that together with radiological examinations, they might help in the early diagnosis of AMI [12], [13].

In the last two decades, D-dimer measurement has become more important when thrombotic pathologies are suspected. D-dimer is a fibrin degradation product. Fibrin polymer generation requires two enzymatic pathways, whereas fibrin degradation products require only one. Thrombin cleaves fibrinogen into fibrinopeptide A, B, and E, known as fibrin monomers [14], [15], [16], [17].

The aim of the study was to evaluate the fibrin monomer synthesis intermediate products fibrinopeptide A and B in the early phase (first 6 h) of mesenteric ischemia and to investigate their correlation with D-dimer levels.

Materials and methods

Pathological assessment

Small intestines are evaluated blindly, whereas all tissues were coded earlier. Tissues were considered normal (Figure 1) or ischemic (Figure 2). Ischemic damage of the small intestines was classified using microscopic evaluation, hematoxylin-eosin staining and the Chiu/Park scale [18].

Figure 1:

Normal intestinal mucosa.

Figure 2:

Ischemic intestinal mucosa.

Results

There were significant differences in fibrinopeptide-A (p=0.0001), fibrinopeptide-B (p=0.0001) and D-dimer levels in the IG according to time. As a result of Dunn’s multiple comparison tests, it was observed that the levels of fibrinopeptide A and B in the IG were significantly higher at 3 and 6 h than they were at 0 h. Fibrinopeptide A and B levels between 0 and 3 h (p=0.022 and p=0.003, respectively) and between 0 and 6 h (p=0.0001 and p=0.0001, respectively) were significantly elevated.

It was observed that D-dimer levels differed significantly between 1 and 3 h (p=0.016) and between 1 and 6 h (p=0.0016). The concentration values of D-dimer at 3 and 6 h were found to be higher than those at 1 h (Table 1).

Differences in fibrinopeptide-A concentration values in all-time combination without 0 h–1 h were observed to be statistically significant between the CG and the IG (p<0.05). 1st, 3rd, 6th h concentration values of fibrinopeptide-A between the SG and the IG were found to be statistically significant compared to values at 0 h. These data are summarized in Table 2.

Differences of fibrinopeptide-B concentration values in all time combinations without 3rd–6th h were observed to be statistically significant between the IG and the CG (p<0.05), and between the IG and the SG (p<0.05). These data are summarized in Table 3.

D-dimer concentration values between the 1st and 6th h were observed to be statistically significant between the CG and the IG (p=0.005) (Table 4).

Discussion

Acute mesenteric ischemia is a lethal vascular disease. Mortality is reported as 50%–80%, whereas early diagnosis and treatment decrease mortality. D-dimer has a sensitivity between 93% and 95% and a specificity of 50% for the diagnosis of thromboembolism [2], [19], [20], [21], [22], [23]. Negative results of D-dimer can exclude thrombosis, [24], [25] but early or delayed venipuncture, liver diseases, inflammation, malignancy, trauma, pregnancy, recent surgical operations, high levels of rheumatoid factor and aging may cause false-negative results.

Further investigations are needed regarding the relation between positive D-dimer levels and phases of AMI. Our study aimed to evaluate the usefulness of fibrinopeptide-A and B levels and D-dimer levels at 6 h of AMI.

When each marker was evaluated by itself, significant increases in all groups and times of fibrinopeptide-A and fibrinopeptide-B were detected, while D-dimer level variations at 6 h of AMI were not significant. A statistically significant difference was observed between the 1st and 6th h of the control and the ischemic group’s D-dimer levels, but this difference was not as substantial as the statistical change in fibrinopeptide-A and fibrinopeptide-B.

Early diagnosis is highly important in AMI, where the mortality rate can be reduced from between 70% and 90% to 50%. It is not known exactly how helpful the most commonly used D-dimer is in the first 6 h of diagnosis. As mentioned above, negativity of D-dimer can be observed in early blood samples taken at the beginning of AMI, which is the result of this experimental study. According to the data in our study, this negativity risk was not observed for fibrinopeptide-A and fibrinopeptide-B. We determined that fibrinopeptide-A and fibrinopeptide-B may supplement D-dimer as an AMI detection marker. Moreover, fibrinopeptides may be more valuable than D-dimer in the early phase of AMI. Furthermore, D-dimer levels may not be elevated, despite the early phase of mesenteric ischemia (hence it is called negativity), though severe mesenteric ischemia may result later in the day. Also, in a prospective study by Ghafouri et al. ischemia was not determined by computed tomography (CT) angiography in 43 patients while it was in 27 patients. D-dimer levels were not elevated in AMI compared to non-AMI (p=0.256). This study supports that AMI may not cause significant D-dimer elevations. Furthermore Aydin et al. revealed that the D-dimer levels were not increased according to mesenteric ischemia and D-dimer is not suitable for early diagnosis of AMI [26], [27].

This animal study provides noticeable finding for the clinical assessment of AMI. Combined laboratory findings of some markers as neopterin, D-dimer, fibrinopeptides may be more valuable for the early diagnosis of AMI [10].

Our study had some limitations including hemolysis, coagulation and the amount of in taking blood according to surgical stress during the blood intake from rats’ vein. They solved in time and the operation was completed successfully.

D-dimer is routinely used in diagnosis of mesenteric ischemia, but our results suggest that the combination of D-dimer and fibrinopeptide is more effective. Although fibrinopeptide analyses are more expensive than D-dimer and the combination will increase the costs, the diagnosis and treatment of mesenteric ischemia cost higher than laboratory analyses. It is expected that costs for diagnosis of mesenteric ischemia will decrease, when fibrinopeptide levels are measured routinely in clinical laboratories.

The results of our work cannot be confirmed in humans by prospective randomized trials. Nevertheless, this experimental study clearly demonstrates that fibrinopeptide-A and fibrinopeptide-B can be used in combination with D-dimer and that they are useful for the early detection of AMI, particularly in the early phase of AMI when AMI is not clinically severe.

Conclusion

Fibrinopeptide-A and fibrinopeptide-B may be markers that can be used for early diagnosis of mesenteric ischemia, and early diagnosis is highly important for decreasing mortality and morbidity.