Research Article: Factor XIa and Thrombin Generation Are Elevated in Patients with Acute Coronary Syndrome and Predict Recurrent Cardiovascular Events

Date Published: July 15, 2016

Publisher: Public Library of Science

Author(s): Rinske Loeffen, René van Oerle, Mathie P. G. Leers, Johannes A. Kragten, Harry Crijns, Henri M. H. Spronk, Hugo ten Cate, Ingo Ahrens.


In acute coronary syndrome (ACS) cardiac cell damage is preceded by thrombosis. Therefore, plasma coagulation markers may have additional diagnostic relevance in ACS. By using novel coagulation assays this study aims to gain more insight into the relationship between the coagulation system and ACS.

We measured plasma thrombin generation, factor XIa and D-dimer levels in plasma from ACS (n = 104) and non-ACS patients (n = 42). Follow-up measurements (n = 73) were performed at 1 and 6 months. Associations between coagulation markers and recurrent cardiovascular events were calculated by logistic regression analysis.

Thrombin generation was significantly enhanced in ACS compared to non-ACS patients: peak height 148±53 vs. 122±42 nM. There was a significantly diminished ETP reduction (32 vs. 41%) and increased intrinsic coagulation activation (25 vs. 7%) in ACS compared to non-ACS patients. Furthermore, compared to non-ACS patients factor XIa and D-dimer levels were significantly elevated in ACS patients: 1.9±1.1 vs. 1.4±0.7 pM and 495(310–885) vs. 380(235–540) μg/L. Within the ACS spectrum, ST-elevated myocardial infarction patients had the highest prothrombotic profile. During the acute event, thrombin generation was significantly increased compared to 1 and 6 months afterwards: peak height 145±52 vs. 100±44 vs. 98±33 nM. Both peak height and factor XIa levels on admission predicted recurrent cardiovascular events (OR: 4.9 [95%CI 1.2–20.9] and 4.5 [1.1–18.9]).

ACS patients had an enhanced prothrombotic profile, demonstrated by an increased thrombin generation potential, factor XIa and D-dimer levels. This study is the first to demonstrate the positive association between factor XIa, thrombin generation and recurrent cardiovascular events.

Partial Text

Thrombotic occlusion of a coronary artery resulting in myocardial underperfusion is the key event in the development of the acute coronary syndrome (ACS) [1, 2]. The principal cause is the rupture of a coronary atherosclerotic plaque, which triggers thrombosis through the activation of the hemostatic system [3, 4]. According to Virchow’s triad, the risk of atherothrombosis is depending on plaque vulnerability, shear stress, and systemic factors in the circulating blood (i.e. hemostatic and cellular blood components) [5]. Besides the well-established role of platelets [6], there is substantial evidence suggesting the involvement of the coagulation system in the pathogenesis of ACS [7, 8]. Several studies showed that during the acute phase of ACS the coagulation system is activated and elevated levels of markers of activated coagulation, such as thrombin-antithrombin complexes (TAT), prothrombin fragment 1.2 and D-dimer, have been demonstrated in those patients [9–13]. Moreover, a persistent hypercoagulable state after clinical stabilization has also been demonstrated in ACS patients [10]. However, whether increased coagulation is the cause or consequence of thrombotic events remains difficult to establish in clinical research.

In total, 104 patients diagnosed with ACS were enrolled in the study, of which 73 ACS patients signed informed consent for follow-up appointments at 1 and 6 months. These ACS patients were compared to 42 non-ACS patients, who did not meet the ACS criteria and were discharged from the hospital without (cardiological) follow-up. Table 1 presents the baseline characteristics for ACS baseline, non-ACS and ACS follow-up patients. There were no significant differences in baseline variables between the total ACS cohort and the subgroup that completed the 6 months’ follow-up. The mean age on admission in the ACS cohort was 67 years (range 42–100) and 68% (n = 71) were male. The group of non-ACS patients comprised 55% males (n = 23) with a mean age of 62 years (range 31–88) and was significantly younger than the ACS cohort (p = 0.035, Table 1). The distribution of classical cardiovascular risk factors was similar between ACS and non-ACS patients. Also, there was no significant difference in the distribution of cardiovascular medication between ACS and non-ACS patients. As expected, there were important differences in cardiac markers, with increased troponins, creatinine kinase (CK) and aspartate aminotransferase (ASAT) in the ACS patients compared to the non-ACS patients (p<0.0001, Table 1). Furthermore, at baseline glucose and CRP levels were significantly higher in ACS versus non-ACS patients. In the present study we compared the coagulation profile of ACS patients to non-ACS patients. Overall, ACS patients had an enhanced prothrombotic phenotype as demonstrated by an increased thrombin generation potential with enhanced activation of the intrinsic pathway of coagulation and attenuated anticoagulant function of the protein C pathway. Furthermore, at the acute moment ACS patients had ongoing coagulation activity demonstrated by increased levels of circulating factor XIa and D-dimer. In accordance with the degree of coronary occlusion, STEMI patients had the highest prothrombotic profile. During follow-up thrombin generation was attenuated at 1 and 6 months, whereas D-dimer and factor XIa levels were not significantly different from baseline levels. Both, maximum thrombin generation and circulating factor XIa levels, predicted recurrent cardiovascular events with an odds ratio of approximately 5, suggesting potential clinical applicability of these laboratory assays.   Source: