Myocardial infarction (MI) usually originates from thrombosis of atherosclerotic plaque rupture.1 Circulating markers of thrombosis, activated coagulation and fibrinolysis may be linked to the pathogenesis of coronary artery disease (CAD).1,2 D-dimers are a specific product of fibrin degradation that results from thrombin activation, activated factor XIII, and plasmin.3 It has been demonstrated that higher levels of D-dimer in plasma are one of the most useful biomarkers for acute MI due to plaque rupture induced coronary thrombosis, which plays an important role in the pathophysiology of acute MI.4 Moreover, D-dimer levels may reflect a systemic prothrombotic state and focal vessel wall-related fibrin formation with unstable atherosclerotic plaque activity.5 Recent studies have also shown that elevated D-dimer levels are associated with in-hospital and mid-term mortality in patients with ST elevation myocardial infarction (STEMI).6

The SYNTAX score (SS) is an angiographic lesion-based scoring system originally designed to assess the complexity of CAD.7 The SYNTAX score II (SSII) includes clinical variables determined by applying a Cox proportional hazards model to the results of the SYNTAX trial.8 In a study investigating the predictive value of the SSII compared to the SS, SSII had better prognostic accuracy for patients with CAD.9 Furthermore, both SS and SSII were associated with long-term mortality and major adverse cardiac events in patients with STEMI.10,11

In the present study, we investigated the association between D-dimers and the severity of CAD using the SS and SSII in patients with STEMI treated with primary percutaneous coronary intervention (PCI).

The baseline clinical, laboratory, echocardiographic and angiographic characteristics of the study population are listed in Table 1. According to our findings, initial Syntax score, final Syntax score, thrombus score, initial TIMI flow grade 0-1 and no-reflow phenomenon parameters were significantly higher in the high SSII group than in the low SSII group (p<0.05). LVEF was also lower in the high SSII group than in the low SSII group (p<0.001).

Predictors of CAD severity based on SSII are shown in Table 2. The following were found to be the independent predictors of SSII: D-dimer (β=2.06, CI 95%: 1.142–3.712, p =0.016), thrombus score (β=3.23, CI 95%: 2.015–5.160, p<0.001), LVEF (β=0.696, CI 95%: 0.623–0.777, p<0.001), no-reflow phenomenon (β=4.39, CI 95%: 1.267-15.243, p=0.02), GFR (β=0.981, CI 95%: 0.966-0.996, p=0.02), age (β=1.286, CI 95%: 1.192-1.389, p<0.001), and gender (β=146.5, CI 95%: 22.716-944.964, p<0.001).

Patients in the high SSII group had higher levels of D-dimers than the low SSII group. The ROC curve analysis provided a cutoff value of 0.26 μg/ml for D-dimers to predict the severity of CAD with 69.8% sensitivity and 65.6% specificity, with the area under the ROC curve being 0.725 (CI 95%: 0.667-0.782, P<0.001) (Figure 1).

Figure 1.

D-dimers to predict CAD severity based on receiver operating characteristic curve analysis.

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To the best of our knowledge, our study is the first in the literature to assess the association between admission D-dimer levels and the severity of CAD by using SSII in patients with STEMI who underwent primary PCI. We demonstrated that high D-dimer levels were an independent predictor of high SSII in STEMI patients treated with primary PCI. The primary findings of the present study are that D-dimer level, thrombus score, no-reflow phenomenon, LVEF, GFR, age and gender are independent predictors of CAD severity.

Rupture of a vulnerable plaque, which subsequently induces platelet aggregation, triggers acute coronary syndrome (ACS) and coagulation at this site, blocks coronary blood flow and causes myocardial ischemic injury. D-dimer in ACS serves as a direct marker of ongoing fibrinolysis at the site of coronary artery occlusion. Several studies have shown that D-dimers might be helpful in the diagnosis and prognosis of patients with acute chest pain, unstable angina pectoris, and non-ST elevation myocardial infarction (NSTEMI).17,18 Moreover, D-dimer levels rise earlier than cardiac injury markers, including myoglobin in acute ischemic events, because D-dimers are involved at an earlier stage in the pathophysiology of ACS.19 However, data concerning the role of D-dimer testing in STEMI are still unclear. In a previous study, it was reported that when compared with primary PCI, thrombolytic treatment for STEMI was associated with higher levels of D-dimer.20 Besides, Choi et al. observed that the myocardial infarct size of the left ventricle was significantly larger in patients with high D-dimer levels.21 According to these studies, STEMI patients treated with thrombolysis have higher D-dimer levels and a larger myocardial infarct area. Similar to the abovementioned results, we observed that higher CK-MB and troponin levels were correlated with larger infarct size. We also demonstrated that D-dimer levels were significantly higher in the high SSII group.

A growing thrombus partially or completely blocks coronary blood flow during STEMI. High thrombus burden at the site of the infarct-related artery is predictive of distal embolization, which is accepted as the leading cause of no-reflow.22 Since there is a high thrombus burden caused by the coagulation and aggregation process in myocardial infarction, D-dimers, a product of coagulation, are higher in coronary no-reflow or slow-flow phenomenon. Besides, thrombus burden and distal embolization can complicate the success of the operation and patients with a high thrombus burden have poor prognosis. Sarli et al. also reported that D-dimer levels measured at admission might be a predictor of postinterventional no-reflow and in-hospital major adverse cardiovascular events (MACE) in patients with STEMI undergoing primary PCI.23 Accordingly, in the present study, no-reflow phenomenon, which was associated with high D-dimer levels and high thrombus burden, was observed to be an independent predictor of CAD severity.

Akgul et al. showed that six-month cardiovascular mortality was significantly higher in patients with STEMI and high D-dimer levels at admission.6 Additionally, fatal reinfarction, advanced heart failure and MACE were more frequently observed in the high D-dimer group at the mid-term follow-up. Several studies reported that in patients with NSTEMI, D-dimer levels are positively correlated with TIMI and GRACE risk scores, which predict the risk of mortality in NSTEMI.24,25 In the present study, we observed that admission D-dimer levels are an independent predictor of CAD severity based on SSII. Since the severity of CAD correlates with increased cardiovascular mortality, we can speculate that patients with STEMI and higher D-dimer levels on admission are at high risk for cardiovascular mortality and morbidity.

Besides the abovementioned advantages of D-dimer assays, there are some limitations. D-dimer levels are elevated in most patients with acute thrombosis. However, D-dimer levels are also increased following recent surgery, with trauma, advanced age, during pregnancy, puerperium, in malignancy and chronic inflammatory conditions.26 Therefore, D-dimers are a sensitive marker for detection of thrombosis in spite of low specificity. In the present study, D-dimer levels may be found to be elevated as a result of some clinical variables included in SSII, such as age. We performed logistic regression analysis in order to avoid this confusion, and we observed that high D-dimer levels are independently correlated with high SSII.

SYNTAX score, the most commonly used anatomical scoring system worldwide, has been found to be associated with STEMI patient prognosis. SSII is a new scoring system, which includes clinical variables. Karabag et al. reported that SSII was better than SS in the prediction of in-hospital and long-term mortality.27 Therefore, we preferred to use this scoring system in our study.

Recent studies revealed that initial SS is associated with no-reflow phenomenon and long-term mortality in STEMI. Higher SS indicates high thrombus burden, no-reflow risk and higher mortality. Duman et al. reported that SS was higher in patients with STEMI undergoing primary PCI and high thrombus burden.28 Moreover, Yesin et al. showed that SSII might be more useful than SS in prediction of the no-reflow phenomenon.29 Similarly, we observed that thrombus score and no-reflow phenomenon were independent predictors of severe CAD.

ACS occurs three to four times more often in men than in women under the age of 60, however, over the age of 75 women represent the majority of patients.30 In our study, ACS occurs 4.5 times more in men than in women. Female gender was recently reported to be an independent predictor of long-term mortality in the PCI group of the SYNTAX trial, despite adjustment for risk factors.31 Six of the eight SSII variables — anatomical SS, age, LVEF, LMCA disease, COPD, and female gender — showed a moderate to strong interaction effect in predicting long-term mortality in patients with CABG and PCI.8 The authors also demonstrated that female gender has a higher SSII than male gender. Our results were similar to the abovementioned studies in terms of gender and cardiovascular risk.

Several limitations of the present study should be mentioned. First, our study is limited by its retrospective and observational design, which may diminish its potency. Second, it was a single-center study and the number of patients was limited. Our study focused on the relationship between D-dimer levels and CAD severity as assessed solely by visual assessment of coronary angiograms. Finally, patients with subclinical deep vein thrombosis may have been excluded from the study as we did not routinely perform duplex ultrasound.

Increased D-dimer levels are associated with CAD severity based on Syntax Score II in patients with STEMI who successfully underwent revascularization with a primary PCI. Moreover, coronary thrombus score, LVEF, no-reflow phenomenon and GFR were other independent predictors of CAD severity.

The authors have no conflicts of interest to declare.

Externally peer-reviewed.