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

Abstract

Objective: 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.

Methods: 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.

Results: 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]).

Conclusion: 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.

Fig 1. Baseline plasma thrombin generation levels in ACS versus non-ACS patients.

Thrombin generation analysis (1 pM TF) of plasma collected from 104 ACS and 42 non-ACS patients during the acute event. Upper panel: time to peak in min (A), and peak height in nM (B). Lower panel: velocity index in nM/min (C), and ETP reduction in % (D). Panel D represents thrombin generation analysis upon addition of thrombomodulin titrated at an ETP reduction of 50% in normal pooled plasma (horizontal dotted line). Depicted are the percentage reductions in ETP. Horizontal lines indicate means ± SD (A, B, D), or medians ± IQR (C). Differences between the groups were tested with a one-way ANOVA or Kruskal-Wallis test with multiple comparison analysis. * p<0.05.

Fig 2. Baseline factor XIa and D-dimer levels in ACS versus non-ACS patients.

D-dimer (A) and factor XIa (B) measurements of plasma collected from 104 ACS and 42 non-ACS patients. The horizontal dotted lines represent the D-dimer cut-off value of 500 μg/L (A) and the mean factor XIa level ± SD in a group of healthy individuals, n = 30 (B). Horizontal lines indicate means ± SD (B), or medians ± IQR (A). Differences between groups were tested with a one-way ANOVA or Kruskal-Wallis test with multiple comparison analysis. * p<0.05.

Fig 3. Plasma thrombin generation levels in ACS patients during follow-up.

Thrombin generation analysis (1 pM TF) of plasma collected from 73 ACS patients during the acute event and after 1 and 6 months follow-up. Upper panel: peak height in nM (A), and ETP in nM.min (B). Lower panel: velocity index in nM/min (C), and ETP reduction in % (D). Panel D represents thrombin generation analysis upon addition of thrombomodulin titrated at an ETP reduction of 50% in normal pooled plasma (horizontal dotted line). Depicted are the percentage reductions in ETP. Horizontal lines indicate means ± SD (A, B, D), or medians ± IQR (C). Differences between baseline and follow-up measurements were established by repeated measured ANOVA or Friedman test with multiple comparison analysis. * p<0.05.

Fig 4. Factor XIa and D-dimer levels in ACS patients during follow-up.

D-dimer (A) and factor XIa (B) measurements of plasma collected from 73 ACS patients during the acute event and after 1 and 6 months follow-up. The horizontal dotted lines represent the D-dimer cut-off value of 500 μg/L (A) and the mean factor XIa level ± SD in a group of healthy individuals, n = 30 (B). Horizontal lines indicate means ± SD (B), or medians ± IQR (A). Differences between baseline and follow-up measurements were established by repeated measured ANOVA or Friedman test with multiple comparison analysis. * p<0.05.