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Thromb Haemost
DOI: 10.1055/a-2546-2581
Invited Editorial Focus

Factor XI Measurement in Acute Coronary Syndrome

Diana A. Gorog 
1   Faculty of Medicine, National Heart and Lung Institute, Imperial College, London, United Kingdom
2   Centre for Health Services and Clinical Research, Postgraduate Medical School, University of Hertfordshire, Hatfield, Hertfordshire, United Kingdom
3   East and North Hertfordshire NHS Trust, Hertfordshire, United Kingdom
4   School of Cardiovascular and Metabolic Medicine and Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
,
Young-Hoon Jeong 
5   Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Republic of Korea
6   CAU Thrombosis and Biomarker Center, Chung-Ang University Gwangmyeong Hospital, Gwangmyeong, Republic of Korea
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The interest in factor XI (FXI) stems from epidemiological data showing that congenital FXI deficiency is associated with significantly reduced cardiovascular and venous thromboembolic risk. Although the greatest reduction is in the risk of venous thromboembolism in those with FXI deficiency (activity <50%) (adjusted hazard ratio [HRadj] 0.26, 95% confidence interval [CI] 0.08–0.84]), the risk of cardiovascular events is also significantly lower in individuals with mild (HRadj 0.52, 95% CI 0.31–0.87) or moderate–severe FXI deficiency (HR 0.57, 95% CI 0.35–0.93) compared with individuals with normal FXI activity.[1]

However, in contrast to the understanding of the impact of congenital FXI deficiency, the impact of elevated FXI levels on cardiovascular risk in individuals with normal coagulation profile has not been extensively studied and the results of observational studies have been conflicting. Generally, the impact of FXI on cardiovascular risk has predominantly been studied in longitudinal cohort studies.

In the Study of Myocardial Infarctions Leiden (SMILE), which evaluated 560 men with a first myocardial infarction under the age of 70 years and 646 control subjects, the risk of myocardial infarction, adjusted for age, in those in the highest quintile of FXI compared with those in the lowest quintile was 1.8-fold increased (adjusted odds ratio [OR], 1.8, 95% CI 1.2–2.7).[2] However, in the Atherosclerosis Risk In Communities (ARIC) study, which followed 11,439 individuals over a median period of 18 years,[3] FXI levels were not associated with cardiovascular events. In a substudy of the REasons for Geographic And Racial Differences in Stroke (REGARDS) study, FXI antigen levels were measured in 609 participants with incident coronary heart disease, patients with incident ischemic stroke, and in a random cohort. After adjusting for cardiac risk factors, higher FXI level was associated with a small increase in the risk of stroke (HR 1.15, 95% CI 0.97–1.36), which was further attenuated after adjustment for risk factors.[4] In the Prospective Cohort with Incident Stroke Berlin (PROSCIS-B) study, which followed 576 individuals with ischemic stroke for up to 3 years, high FXI activity was associated with an increased risk of recurrent stroke, myocardial infarction, or all-cause mortality after adjustment for confounders (HR 1.80, 95% CI 1.09–2.98).[5]

More recently, a large case control study evaluated the prognostic impact of baseline FXI levels in 1,846 individuals recruited into a large prospective registry in China who were followed for the occurrence of ACS or stroke.[6] After adjustment for cardiovascular risk factors, individuals with a high FXI level had an increased risk of stroke (OR 1.72, 95% CI 1.14–2.60), predominantly ischemic stroke, but not of ACS (OR 0.96, 95% CI 0.68–1.36), compared with individuals with middle range FXI.

The recent study by Spagnollo, Capodano, and colleagues, reported in this issue of Thrombosis and Haemostasis, builds on this limited understanding of FXI levels in patients with CAD, but this time in the acute phase of myocardial infarction ([Fig. 1]). In a prospective study in 54 patients presenting with a working diagnosis of ST-segment elevation myocardial infarction (STEMI), FXIa levels were measured at presentation before primary percutaneous intervention (PPCI) and prior to hospital discharge. They observed that the median plasma FXIa level before discharge was significantly higher than the level at admission (1.161 IU/mL [IQR 0.982–1.317] versus 0.865 IU/mL [IQR 0.554–0.978], p < 0.001). All patients were treated with conventional DAPT after PPCI.

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Fig. 1 Measurement of factor XI (FXI) level in patients presenting with ST-segment elevation myocardial infarction undergoing percutaneous intervention (PCI) may identify individuals at increased cardiovascular risk. (Created in BioRender. Gorog, D. (2025) https://BioRender.com/v04r556.)

Based on the median change in FXIa levels between admission and discharge (delta change), the patient cohort was divided into two groups, those with delta FXIa level above and those with delta FXIa level below the median. There was no difference in clinical variables of patients in the two groups, including with respect to clinical risk factors, angiographic variables including coronary flow at presentation and after PPCI, thrombus burden, or myocardial injury. However, patients with greater change in FXI level had a greater time interval between the first and second FXIa measurements compared with those with lower variability (5 [IQR 4–5] days versus 3 [IQR 3–4] days, p = 0.016).

This is the first study to report an increase in FXIa levels from admission to discharge in STEMI patients undergoing PCI. The level of FXIa at presentation was not related to angiographic thrombus burden, indicating that acutely, FXIa levels may not reflect the overall thrombotic milieu.

FXI is synthesized in hepatocytes and circulates with a mean plasma half-life of approximately 52 hours. Therefore, the rising levels from admission to discharge in the present study may reflect an acute activation of coagulation but which is only maximally manifest later. Furthermore, in the present study, 17 of 54 patients received heparin prior to admission sampling, which may have reduced baseline FXIa levels. In keeping with this, a prior prospective cohort study of 56 patients with STEMI in which samples were taken at admission and after 6 months showed that FXIa concentrations were significantly increased at admission compared with 6 months after the event (3.7 pm [2.7–5.5] versus 2.8 [1.9–4.3], median ± IQR; p = 0.001) and compared with healthy controls (3.7 pm [2.7–5.5] versus 2.7 [1.6–4.2], median ± IQR; p = 0.004).[7] An acute elevation in activated FXI–antithrombin (FXIa-AT) complex was documented in 114 patients with out-of-hospital cardiac arrest (OHCA) of assumed cardiac origin, who had blood samples taken immediately after resuscitation, and at 8 to 12 hours and 24 to 48 hours after admission.[8] A significant increase in 30-day all-cause mortality was observed through increasing quartiles of FXIa-AT, with acute levels falling more quickly within 48 hours in survivors compared with non-survivors.

Whether elevated FXIa levels post-infarct, or the relative magnitude of change in FXI level from baseline, can identify a cohort of patients at increased risk of arterial thrombotic events is unclear and larger studies are clearly required. However, it is increasingly recognized that a prothrombotic milieu, driven by activation of procoagulant pathways[9] [10] and impaired endogenous fibrinolysis,[9] [11] [12] is an independent risk factor for cardiovascular events in patients after an ACS despite potent platelet inhibition.

Dual antiplatelet therapy, comprising of aspirin with a P2Y12-receptor inhibitor, represents the standard antithrombotic strategy for patients with an ACS. However, despite this, some 5 to 15% of patients experience a recurrent thrombotic event in the subsequent year. Although the addition of anticoagulation with very low dose rivaroxaban has been shown to reduce adverse CV events, this is counterbalanced by a higher risk of bleeding that may outweigh the benefit.[13] Novel antithrombotic strategies that reduce thrombosis risk without excessive bleeding are much needed.[14] [15] [16]

The concept of inhibiting FXI as a strategy to reduce adverse cardiovascular events in patients with ACS was explored in the PACIFIC-AMI study.[17] This phase 2, randomized, placebo-controlled trial explored the safety and efficacy of three oral doses of the small molecule FXIa inhibitor asundexian (10, 20, or 50 mg) in addition to dual antiplatelet therapy in 1,601 patients with recent AMI. The primary safety outcome was the composite of Bleeding Academic Research Consortium type 2, 3, or 5 bleeding, while the primary efficacy outcome was the composite of cardiovascular death, recurrent myocardial infarction, stroke, or stent thrombosis. The trial demonstrated near-complete dose-dependent suppression of FXIa activity with asundexian 50 mg. Over a median follow-up of 1 year, there was no significant increase in bleeding events or significant differences in the efficacy outcome with asundexian compared with standard of care alone. Although a subsequent phase 3 trial was planned, this was not initiated after the premature termination of the phase 3 OCEANIC-AF trial, which showed that compared with apixaban, treatment of patients with atrial fibrillation (AF) with asundexian was associated with a higher incidence of stroke or systemic embolism, albeit with fewer major bleeding events.[18] However, another small molecule FXIa inhibitor, milvexian, is currently being evaluated in the Librexia-ACS trial, in which it is compared with placebo and given to patients within 7 days of the ACS event, on top of standard-of-care antiplatelet medication.

The current study is hypothesis generating and provides more questions than answers about the role of FXI in AMI. Does FXI rise in all patients following STEMI? If so, when does it peak and for how long is it elevated? Is it simply an acute phase response or a marker of increased thrombotic risk? Does inhibition of FXI activity reduce cardiovascular risk post MI? When would be the optimal time to start treatment with an FXI inhibitor, and for how long?

The more we know, the more we realize we do not know… (orig. Plato, attr. paraphrased to Albert Einstein).



Publication History

Article published online:
31 March 2025

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