Inside the Coagulation Cascade: Why FXIa Is Emerging as a Promising Target

About the author: Carolyn S.P. Lam, MBBS, PhD, FRCP, is Senior Consultant Cardiologist at the National Heart Centre Singapore, and Professor at Duke-National University of Singapore Graduate Medical School Singapore, and Chief of Asia-Pacific Research & AI Innovation at Baim Institute.

Disclosures: Dr. Lam has received research grants from the National Medical Research Council of Singapore, Novo Nordisk, and Roche Diagnostic; has served in advisory, consulting and trial leadership roles for Alnylam Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, BridgeBio, Corteria, CPC Clinical Research, Cytokinetics, Eli Lilly, EvlaBio, ICON Clinical Research, Impulse Dynamics, Intellia Therapeutics, Janssen Research & Development LLC, Klyv Therapeutics, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Pfizer, Radcliffe Group, Ribocure, Roche, Tenax and Us2.ai; has patent PCT/SG2016/050217 pending and patent US Patent No. US 10,702,247 B2; 10,631,828 B1; US 11,301,996 B2; US 11,446,009 B2; US 11,931,207 B2; US 12,001,939; US 12,400,762 B2; and is a co-founder and non-executive director of Us2.ai.

Sponsored by Johnson & Johnson and Bristol Myers Squibb

Thromboembolic disorders remain a leading cause of morbidity and mortality worldwide and represent a significant global health burden.ⁱ Atrial fibrillation (AFib), a highly prevalent cardiac arrhythmia that predisposes to thrombus formation, is responsible for nearly one in five ischemic strokes.ⁱⁱ

For years, managing AFib with anticoagulation therapy has required balancing stroke prevention with bleeding risk.ⁱⁱⁱ

The introduction of direct oral anticoagulants (DOACs), previously known as novel oral anticoagulants or NOACs, transformed the prevention and treatment of thromboembolic events, according to a review of preclinical and clinical data, including epidemiological studies, animal model experiments, human genetic studies, and clinical trial results.^iv Nevertheless, a bleeding risk remains, particularly among elderly patients, and those with severe renal dysfunction or comorbidities.^v

The clinician’s concern about risk of bleeding is the primary reason why people with AFib who should be treated for stroke prevention are not.^vi Worse still, it's the people who need it most.

In my practice, I see this tension play out almost daily. Patients who need anticoagulation may choose to forego it because they’re concerned about bleeding risk. Or they start therapy, experience what is categorized as a minor bleed, such as blood in their stool or prolonged bleeding from a small cut, and stop treatment, leaving themselves exposed to the risk of stroke, the very risk we were trying to prevent.

Now research on a new class of therapies targeting Factor XI or its activated form, FXIa (FXI/FXIa) is reopening this question: Can thromboembolism be prevented without raising bleeding rates?

Rethinking the Coagulation Cascade

Traditional anticoagulants, including factor X/Xa and thrombin inhibitors, work by directly suppressing central drivers of clot formation. While effective at preventing stroke, these agents may also interfere with normal clotting needed to stop bleeding after injury or surgery.^iv

FXI/FXIa occupies a unique position within the intrinsic pathway of coagulation. It contributes to amplification of thrombin generation and stabilization of clot formation but appears to be less essential for everyday hemostasis than other components of the cascade.^vii This profile has made FXI/FXIa an especially attractive therapeutic target.

FXI/FXIa inhibition works by interfering with thrombus formation within vessels, while leaving normal hemostasis intact. This separation between thrombosis and bleeding represents a potential breakthrough for antithrombotic options with a potentially lower risk of bleeding.^iv

Genetic data suggest that people with reduced FXI levels appear to have lower rates of thrombotic events and a potentially lower risk of bleeding.^viii,ix,x Patients with severe FXI deficiency (hemophilia C, FXI levels below 1%) typically experience no spontaneous bleeding and only mild post-surgical bleeding.^xi A retrospective cohort study using an electronic medical record database of more than 10,000 patients with FXI deficiency found about half the risk of stroke compared with individuals with normal FXI activity, with no increase in major bleeding or intracranial hemorrhage.^xii Conversely, in a prospective nested cohort study from two established general population cohorts genetic variants associated with higher FXI levels were linked to increased thrombotic risk.^xiii

The genetic and epidemiologic evidence supports a compelling hypothesis: FXI/FXIa inhibition can uncouple stroke prevention from bleeding risk. Through clinical trials, we can test whether this biological principle translates into therapeutic benefit at scale.

Addressing Persistent Treatment Gaps

Oral anticoagulation remains the pharmacotherapy cornerstone of stroke prevention for patients with AFib. However, despite the availability of DOACs, a retrospective cross-sectional registry-based cohort study analyzing data from the National Cardiovascular Data Registry (NCDR) PINNACLE (Practice Innovation and Clinical Excellence) Registry found that many eligible AFib patients either never start anticoagulation or discontinue treatment.^xiv

Key barriers include clinician concern about bleeding risk, patient refusal^xv or other related concerns associated with the risk of bleeding, such as advanced age, chronic kidney disease, high fall risk, or history of prior bleeding.^xiv,vii

In real-world settings, bleeding risk can impact clinical decision-making, leaving many patients undertreated or entirely untreated. According to the NCDR PINNACLE Registry (n=655,000; 2008–2014), which captured real-world cardiovascular care patterns across hundreds of U.S. outpatient practices, oral anticoagulant use rose after DOACs were introduced, yet ~40% of patients remain untreated.^xvi

A More Favorable Risk-Benefit Profile?

The promise of FXI/FXIa inhibition lies in "uncoupling" antithrombotic benefit from potential bleeding risk -- separating the benefit from the risk for the first time.^iv

There are animal and human data evaluating FXI/FXIa and stroke risk.^{xvii, xviii}

• Animal studies in FXI‑deficient mice and primates, and experiments with FXIa inhibitors, showed reduced thrombosis without increased bleeding.^{xx, xxi}
• Phase 2 trials in venous thromboembolism (VTE) prevention after orthopedic surgery have demonstrated dose-dependent efficacy with minimal increases in bleeding.^xxii

Phase 3 data are now available for secondary stroke prevention^xix, with additional clinical development underway for stroke prevention in AFib as well as other indications.^xvii

An important caveat: while positive results have been reported in Phase 2 studies, some investigational agents have failed in Phase 3 trials, potentially due to patient selection, dose selection, and unidentified biological basis.

Selective inhibition of FXI/FXIa that does not increase major bleeding while providing stroke prevention that is non-inferior to currently approved DOACs could extend to patient populations with AFib whom clinicians feel comfortable treating. This class could be beneficial particularly if approved to include patients who are older and have a history of bleeding events -- precisely the groups where clinicians struggle most to balance the risks and benefits of treatment.

The Importance of Global Clinical Evidence

The global burden of AFib has been and is projected to continue growing due to the increasing burden of chronic illnesses in an aging world population.^xxiii

Different regions exhibit substantial variations in AFib prevalence and management. Global Burden of Disease 2017 data show AFib prevalence increasing worldwide, with marked regional and sociodemographic differences.^xxiv As such, clinical trials investigating FXI/FXIa inhibition are being conducted globally to understand impact of these agents on ischemic stroke and bleeding outcomes across ethnic backgrounds, regions, and care settings.

Looking Ahead: What Could Change in Practice?

If ongoing studies confirm that FXI/FXIa inhibition can reduce the risk of ischemic strokes without increasing bleeding rates, anticoagulation with these new agents could be a viable option for patients who currently remain untreated or undertreated.

For patients with AFib, particularly those at a high bleeding risk whom I care for, FXI/FXIa inhibition could fundamentally change the conversation.

Instead of viewing anticoagulation as a tradeoff between bleeding risk and stroke prevention, clinicians may be able to approach treatment decisions with greater confidence and reassurance, especially for patients hesitant about current treatment options.

FXI/FXIa inhibition represents a promising advancement in anticoagulation research since the introduction of DOACs and may mark the beginning of a new chapter in stroke prevention.^vii

References

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