Increased FXIa Levels In Patients With a First Acute Myocardial Infarction: The Introduction Of a New Thrombin Generation Based FXIa Assay
Authors: Loeffen Rinske , Spronk Henri M.H. , van Oerle Rene , Crijns Harry J , Veenstra Leo , Cate Hugo ten 
Published: October 2019

Abstract

Introduction
Acute myocardial infarction (AMI) is still an important cause of morbidity and mortality. One of the contributing mechanisms in AMI is plasma hypercoagulability, with recent studies suggesting activation of factor (F) XI to play a role in the onset of the thrombotic event. By serving as an amplification loop that enhances thrombin generation (TG), FXIa is thought to be involved in thrombotic diseases. To quantify FXIa levels in plasma, we developed a new TG based assay and hypothesized that in AMI patients FXIa plasma levels are increased at the time of the thrombotic event, as compared to 6 months after and compared to healthy controls.

Methods
A prospective cohort study was performed including patients with a first AMI. Citrated blood samples were collected upon admission (before administration of heparin) and after 6 months. Citrated blood samples from apparently healthy individuals served as a control population. FXIa TG was measured by means of the Calibrated Automated Thrombogram. All plasma samples were diluted at a 1:5 ratio in FXI deficient plasma and triggering was by addition of 4 µM phospholipids (without tissue factor). Active site-inhibited factor VII (30 nM) was added to inhibit the extrinsic coagulation pathway. FXIa plasma concentrations were established using a FXIa reference curve, which was obtained by addition of varying concentrations of FXIa (0-100 pM) to a corn trypsin inhibitor (CTI) pool-FXI deficient plasma mixture. The established FXIa concentrations were related to the 1-year outcome: cardiovascular death, recurrent MI, a second coronary intervention and ischemic stroke.

Results
A total of 56 consecutive AMI patients (71% men), with a mean age on admission of 60 (SD ±12) years, were included. The healthy control population consisted of 30 subjects (67% men) with a mean age of 50 (SD ±6) years. FXIa plasma concentrations were significantly increased in AMI patients at day 0 compared to 6 months after the event (4.8 pM [3.6-6.9] vs. 3.9 pM [2.4-5.7], median ± IQR; P=0.0015), and also compared to the FXIa levels in apparently healthy subjects (4.8 pM [3.6-6.9] vs. 3.8 pM [2.4-4.9], median ± IQR; P=0.0075). No significant difference in FXIa concentrations was demonstrated between AMI patients at 6 months follow-up and apparently healthy controls. In the 12-month follow-up period, 11 patients reached an endpoint. However, FXIa concentrations in the highest quartile were not significantly associated with the development of a recurrent thrombotic cardiovascular event (OR 3.2 [95%CI 0.4-28.2], P=0.29).

Conclusions
This study presents the first application of a new TG based FXIa assay. Results showed that in AMI patients at the time of the thrombotic event there is a significantly increased FXIa plasma concentration, compared to 6 months after the event and compared to healthy controls. However, no significant association could be established between the FXIa concentration and the risk of recurrent ischemic cardiovascular complications.

Acknowledgment
This research was supported by the Center for Translational Molecular Medicine and the Dutch Heart Foundation (INCOAG).

Disclosures:
No relevant conflicts of interest to declare.