Next Article in Journal
Role of Regulatory T Cells and Their Potential Therapeutic Applications in Celiac Disease
Next Article in Special Issue
Tissue Injury Protection: The Other Face of Anticoagulant Treatments in the Context of Ischemia and Reperfusion Injury with a Focus on Transplantation
Previous Article in Journal
Size-Controlled Silver Nanoparticles Supported by Pyrolytic Carbon from Microcrystalline Cellulose
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 24
Issue 19
10.3390/ijms241914433
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Inhibition of Factor XI: A New Era in the Treatment of Venous Thromboembolism in Cancer Patients?

by
Géraldine Poenou
1,2,
Marco Heestermans
2,3,
Ludovic Lafaie
2,4,
Sandrine Accassat
1,5,
Nathalie Moulin
1,
Alexandre Rodière
1,
Bastien Petit
1,
Cécile Duvillard
1,
Patrick Mismetti
1,2,5,6 and
Laurent Bertoletti
1,2,5,6,*
1
Therapeutic and Vascular Medecine Department, Saint-Etienne Universitary Hospital Center, F-42270 Saint-Priest en Jarez, France
2
INSERM, U 1059 SAINBIOSE, Jean Monnet University, Mines Saint-Étienne, F-42023 Saint Priest en Jarez, France
3
French Blood Establishement Auvergne-Rhône-Alpes, Research Department, F-42023 Saint-Etienne, France
4
Geriatry Department, Saint-Etienne Universitary Hospital Center, F-42000 Saint-Etienne, France
5
INSERM, CIC-1408, Saint-Etienne Universitary Hospital Center, F-42055 Saint Priest en Jarez, France
6
F-CRIN INNOVTE Network, F-42000 Saint-Etienne, France
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(19), 14433; https://doi.org/10.3390/ijms241914433
Submission received: 6 August 2023 / Revised: 3 September 2023 / Accepted: 13 September 2023 / Published: 22 September 2023
(This article belongs to the Special Issue New Insight into Anticoagulants)
Browse Figures
Review Reports Versions Notes

Abstract

:
Direct oral anticoagulants against activated factor X and thrombin were the last milestone in thrombosis treatment. Step by step, they replaced antivitamin K and heparins in most of their therapeutic indications. As effective as the previous anticoagulant, the decreased but persistent risk of bleeding while using direct oral anticoagulants has created space for new therapeutics aiming to provide the same efficacy with better safety. On this basis, drug targeting factor XI emerged as an option. In particular, cancer patients might be one of the populations that will most benefit from this technical advance. In this review, after a brief presentation of the different factor IX inhibitors, we explore the potential benefit of this new treatment for cancer patients.

1. Introduction

From the beginning of the 20th century to the present day, we have experienced significant advancements in antithrombotic drugs [1]. The first anticoagulants (vitamin K antagonists and heparins) non-specifically targeted the procoagulant serine proteases of coagulation [2,3]. Then, at the dawn of the 21st century, the development of oral medications specifically targeting thrombin (FIIa) and activated factor X (FXa), formerly referred to as DOACs for direct oral anticoagulants, improved the management of patients with indication for anticoagulant therapy [4,5]. Over time, these specific antithrombotics have become the first-line treatment for most thrombosis patients [6,7]. However, there remain situations, such as thrombosis associated with cancer, where these drugs can be ineffective with a risk of recurrence, can be overly effective with a risk of iatrogenic bleeding, or can simply be inappropriate (severe renal failure or impossible oral intake in palliative situations) [8,9]. Driven by the search for an antithrombotic that would guarantee efficacy, not inferior to current anticoagulants but with a greater safety, the inhibition factor XI (FXI) has emerged as a very interesting hypothesis [10]. FXI appears to play an auxiliary role in physiological hemostasis but a predominant role in pathological thrombosis [11]; see Figure 1.
Ijms 24 14433 g001
Figure 1. Factor XIa in the coagulation cascade. The coagulation cascade is represented as a pyramid where the closer you get to fibrin the higher is the risk of coagulation. In physiological state FXIa does not play a major role in the balance between bleeding and thrombosis. However, in cancer associated thrombosis several conditions activate FXI such as the cancer itself, surgery, catheter and inflammation. Black arrows represent the traditional pathway of coagulation. The red arrows represent the different pathway of activation of thrombosis in cancer associated thrombosis. Indeed, epidemiological data in patients with constitutional FXI deficiencies and experimental data in animals have strongly supported this hypothesis, with few prothrombotic events and almost no increased risk of bleeding in the central nervous system or gastrointestinal tract [12]. Phase II trials seem to confirm the interest in this strategy [13]. Parallel data on the pathophysiology of thrombotic events during cancer appear to support a prominent role of the contact path way via FXI in thrombus formation. Thus, the advent of FXI inhibitors, which have the potential to attenuate the response to prothrombotic stimuli with little or no disruption of hemostasis, could provide a safer anticoagulant [10]; see Figure 2.
Figure 1. Factor XIa in the coagulation cascade. The coagulation cascade is represented as a pyramid where the closer you get to fibrin the higher is the risk of coagulation. In physiological state FXIa does not play a major role in the balance between bleeding and thrombosis. However, in cancer associated thrombosis several conditions activate FXI such as the cancer itself, surgery, catheter and inflammation. Black arrows represent the traditional pathway of coagulation. The red arrows represent the different pathway of activation of thrombosis in cancer associated thrombosis. Indeed, epidemiological data in patients with constitutional FXI deficiencies and experimental data in animals have strongly supported this hypothesis, with few prothrombotic events and almost no increased risk of bleeding in the central nervous system or gastrointestinal tract [12]. Phase II trials seem to confirm the interest in this strategy [13]. Parallel data on the pathophysiology of thrombotic events during cancer appear to support a prominent role of the contact path way via FXI in thrombus formation. Thus, the advent of FXI inhibitors, which have the potential to attenuate the response to prothrombotic stimuli with little or no disruption of hemostasis, could provide a safer anticoagulant [10]; see Figure 2.
Ijms 24 14433 g001
Several FXI inhibitors are under development. These include the following: I/small molecules that bind to the active site of activated FXI (FXIa) and inhibit its activity (Asundexian and Milvexian), II/antibodies directed against FXI that inhibit the activation of FXI or the activity of FXIa (Osocimab, Abelacimab, and Xisomab), III/antisense oligonucleotides (ASOs, e.g., fesomersen) which reduce the synthesis of FXI by binding to the messenger RNA of FXI in hepatocytes and induce its degradation, and IV/natural inhibitors [13]. This review summarizes current progress and highlights how FXI inhibitors could be prescribed and used in the future treatment of patients with cancer-associated thrombosis.

2. General Information about FXI Inhibitors

2.1. The Inhibition of Contact Pathway as a New Therapeutic Target

In the classic portrayal of the coagulation cascade, which consists of the intrinsic, extrinsic, and common pathways, FXI is positioned within the intrinsic or contact activation arm of coagulation [14]. Given that deficiencies in contact activation proteins (like coagulation factor XII (FXII), prekallikrein (PK), and high-molecular-weight kininogen) are not associated with a bleeding tendency in humans, the role of contact activation in thrombin generation and plasma clotting was long considered separate from thrombosis, being seen primarily as a laboratory artifact, e.g., used to measure activated partial thromboplastin time (aPTT) tests. The aPTT test, which uses artificial contact activators like silica or ellagic acid to activate FXII and measure plasma clotting time, helps physicians identify anomalies concerning the plasma levels of certain coagulation factors [15]. Despite its deficiency causing a mild bleeding disorder known as hemophilia C, FXI was similarly deemed irrelevant for preventing venous thromboembolism (VTE), very similar to other contact factors [16]. However, recent times have seen a surge in interest in FXI, as it is now believed that it is more significant for thrombosis than for hemostasis. Accordingly, compounds inhibiting FXI function, like ASOs or blocking antibodies, reduced thrombosis in preclinical animal studies [16,17,18]. Recently, several contact activators linked to the onset of VTE, such as DNA, RNA, platelet polyphosphates, and misfolded proteins, have been suggested as physiological FXII activators [19,20,21]. According to data from these preclinical studies, FXI appears to serve solely as a substrate of FXIIa and is thus involved in coagulation only due to contact activation [22]. Nevertheless, this does not fully represent the human scenario where FXI deficiency, unlike FXII and PK, aligns with a bleeding phenotype and, unlike for FXI plasma levels, FXII and PK levels are not linked with the risk of VTE. The specific activation of FXI by thrombin in thrombotic events will be developed further [23]. Multiple therapeutic strategies for targeting the FXI protein have been suggested and the essential pharmacological attributes of each drug class are outlined in Table 1.
ASOs (fesomersen) and monoclonal antibodies (like Xisomab 3G3/AB023, Osocimab/BAY1213790, or Abelacimab/MAA868) have longer half-lives in humans of up to 30 days, facilitating less-frequent dosing, which could potentially improve patient adherence and compliance [24,25]. Small peptidomimetic molecules, such as Milvexian/BMS-986177 or BAY 2433334, are currently the sole drug class available for oral administration [26,27]. These compounds have a shorter half-life (one day versus weeks) and renal clearance. Natural inhibitors like Ir-CPI (Ixodes ricinus contact phase inhibitor) appear to be the least-viable therapeutic option due to their slow onset and offset, coupled with a relatively high risk of adverse side effects. The impact of antibodies and ASOs on FXI differ in their time to effect; monoclonal antibodies reduce FXI function within hours post administration, whereas the effect of ASOs only becomes noticeable after several weeks [13]. In addition, ASOs may cause thrombocytopenia [28]. This time difference in onset likely explains why the development of FXI-inhibiting monoclonal antibodies is currently more prevalent and why they would be more interesting for cancer patients. Finally, antibodies do not seem to suffer from drug–drug interactions, another crucial difference from direct oral anticoagulants.

2.2. FXI Inhibitor Monitoring

For patients with a congenital FXIa deficiency or an FXIa deficiency acquired from treatment, routine coagulation tests are not very relevant [29]. The prothrombin time is a reflection of coagulation initiated by the FVIIa/TF complex; thus, there is no expected interference from resulting low levels of FXIa in this assay. On the contrary, on those same patients, when using the aPTT, which explores factors belonging to the intrinsic pathway such as FVIII, FIX, FXII, and FXI, an elongation of the aPTT might be observed [29]. However, while the aPTT could be useful for detecting the presence of an FXI inhibitor, it cannot serve as a tool for assessing the effectiveness or safety in relation to the risk of bleeding from a congenital or acquired FXIa deficiency [30]. Indeed, FXI is not an initiator of coagulation in the aPTT test; thus, the effect of FXI inhibition on the test will vary for the same anti-FXI depending on the patient and between different anti-FXIs. As the FXI assay is a test based on the principle of the aPTT, the rate found will not be indicative. Finally, global coagulation tests such as thrombin generation, which evaluates both the initiation and propagation of coagulation, could be interesting to test FXI inhibitor levels [31]. However, their lack of standardization and their non-ubiquitous nature in all diagnostic laboratories are factors to be considered before envisioning routine use.

2.3. Antidote

Given that FXI inhibition can potentially disrupt the activation of TAFI (thrombin-activatable fibrinolysis inhibitor), tranexamic acid seems to be a powerful candidate in the prevention and treatment of bleeding in patients receiving FXI inhibitors [32]. It is commonly administered to FXI-deficient patients requiring surgical intervention or urgent procedures associated with a high risk of bleeding. In the event of severe bleeding with fesomersen, replacement with an FXI concentrate or fresh-frozen plasma may be beneficial [33]. This type of replacement therapy is likely to be insufficient with other FXI inhibitors. Instead, treatment with low doses of recombinant FVIIa, an approach successfully used in patients with congenital FXI deficiency, or with a prothrombotic complex concentrate, may be necessary [34]. Fortunately, recombinant FVIIa has not been required in the completed phase II trials so far, and patients have undergone major surgery such as kidney transplantation without excessive bleeding. Therefore, the need for reversal may be less with FXI inhibitors than with FXa or FIIa inhibitors. Among other antidotes on the market, andexanet alfa and idarucizumab, both highly specific, will assuredly not have any effect on FXI inhibitors [35,36]. What remains is understanding whether the mysterious universal antidote, Ciraparantag (PER977), a small cationic molecule whose development has not seen any updates for several years, will have an effect [37].

3. Potential of FXI Inhibitors in Venous Thromboembolic Events

3.1. Physiopathology of Venous Thrombosis

Thrombosis, the formation of blood clots within venous blood vessels, primarily occurs due to the exposure of tissue factor (TF) on the surface of an injured vascular endothelium [11]. TF binds with activated factor VII (FVIIa) to form the FVIIa/TF complex, otherwise known as the extrinsic pathway [11]. This complex enables the activation of FX, which subsequently leads to the activation of thrombin [11]. This reaction is confined to the TF exposure area, and FXI plays a role in propagating intraluminal thrombus growth by aiding in the formation of the intrinsic pathway after activation by thrombin, which in turn enables the activation of FX and subsequently thrombin [11]. Cancer induces a systemic hypercoagulable state that raises the baseline thrombotic risk among affected patients. Cancer-associated thrombosis, like all venous thrombosis, is initiated by endothelial activation (e.g., catheter-related thrombosis), increased blood hypercoagulability, and blood stasis (e.g., compressive-metastasis-related thrombosis) [38]. The presence of a malignancy often amplifies the activation of the coagulation cascade, as well as the activation of blood cells, such as platelets and leukocytes [39,40,41]. Neutrophils can enhance thrombosis by releasing neutrophil extracellular traps (NETs) and by secreting proteases that target the Tissue Factor Pathway Inhibitor (TFPI) [42,43]. The reduction in the concentration of TFPI leads to increased TF activity and coagulation activation [42,43]. The contact pathway is activated by the elevation of circulating cell-free DNA and extracellular vesicles [44]. Furthermore, fibrinolysis is impaired due to an elevated concentration of Plasminogen activator inhibitor 1 [45]. In addition, cancer treatments, including chemotherapy and new targeted therapies, may increase thrombosis through mechanisms that are not yet fully understood [46]. Lastly, patient characteristics, such as age, sex, and previous history of thrombosis, as well as co-morbidities, such as anemia, renal and liver impairment, and sepsis, are also determinants of hypercoagulability in cancer patients [39].

3.2. Management of Cancer-Associated Thrombosis

Amongst patients with cancer-associated thrombosis, there is no differentiation with respect to the indication of anticoagulation, regardless of whether the patient has developed a pulmonary embolism or a deep-vein thrombosis. Cancer patients consistently receive treatment for a minimum duration of 6 months. (Guidelines are summarized in Table 2.) If the cancer remains active beyond this timeframe, as indicated by ongoing treatment or the presence of detectable cancer masses, the anticoagulation regimen is extended. Managing thrombosis in cancer patients presents unique challenges compared to non-cancer patients, primarily due to the delicate balance between the heightened risk of recurrent thrombosis and the elevated susceptibility to major bleeding resulting from anticoagulant therapy. In 2003, the guidelines established by the CLOT trial endorsed the use of LMWH monotherapy as the standard-of-care treatment for VTE in cancer patients [45]. With the advent of the new generation of anticoagulants, specifically direct oral anticoagulants, numerous randomized controlled trials were initiated to evaluate the efficacy and safety of this novel therapeutic class in the initial management of VTE among cancer patients. In Figure 3, the collective findings from these studies consistently affirm the favorable attributes of DOACs for the treatment of thrombosis when compared to LMWHs [46].

3.3. FXI Inhibitors to Prevent Venous Thromboembolic Events

A compelling way to ascertain the effectiveness of a new anticoagulant treatment in VTE is through post-orthopedic surgery prevention, given the high incidence of VTE events without thromboprophylaxis [47]. As such, several phase II randomized trials have assessed the safety and efficacy of FXI inhibitors in preventing thromboembolic events post orthopedic surgery, especially in knee surgery (Table 3) [48,49,50,51].
In a meta-analysis by Nopp et al., irrespective of the FXI inhibitor treatment (antibody or small molecule) compared to 40 mg of enoxaparin, there was a reduction in the risk of VTE with a relative risk (RR) of 0.59 (95% CI, 0.37–0.94) [2]. Furthermore, a reduced RR of developing clinically relevant bleeding in patients treated with an FXI inhibitor compared to enoxaparin was observed with 0.41 (95% CI, 0.19–0.92) [52]. A second meta-analysis published by Presume et al. corroborates these findings, with an evaluation of clinically significant bleeding, id est, an association of major bleeding and clinically significant non-major bleeding. The risk of recurrence had an RR of 0.50 (95% CI, 0.36–0.65), and, for the risk of clinically significant bleeding, an OR (odd ratio) of 0.41 (95% CI, 0.22–0.75) [53]. Of note, these trials did not include patients with active cancer, and consequentially patients with cancer-associated thrombosis. Reducing the risk of thrombus with thromboprophylaxis appears to be an option in cancer patients. Indeed, several trials in cancer patients treated with chemotherapy demonstrated that thromboprophylaxis decreases the global risk of VTE. Khorana et al. published a study in 2017 showing a non-significant reduction in the risk of thrombosis (12% on dalteparin vs. 21% on placebo, hazard ratio of 6.9) with a statistically significantly increased risk of clinically relevant bleeding, in cancer patients on chemotherapy with a Khorana score ≥ 3 after 12 weeks of prophylactic Dalteparin [54]. The AVERT and CASSINI studies evaluated FXa inhibitors in cancer patients. Despite a hazard ratio in favor of thromboprophylaxis with FXa inhibitors, they drew the same conclusions regarding the risk of bleeding [55,56]. Thus, thromboprophylaxis should be prescribed only to cancer patients at high risk of VTE [39]. For thromboprophylaxis, the promising lower risk of bleeding could lead to an interesting use of FXI inhibitors for thromboprophylaxis; however, to our knowledge, no study has been designed to explore that therapeutic option in cancer patients.

3.4. FXI Inhibitors to Treat Venous Thromboembolic Events

The management of VTE in cancer patients poses a unique challenge compared to non-cancer individuals, due to the delicate balance between the heightened risk of recurrences and the increased risk of clinically relevant bleeding, under anticoagulant treatment. In 2003, based on the CLOT trial, guidelines promoted low-molecular-weight heparin (LMWH) monotherapy as the primary treatment for cancer patients with VTE [48]. However, the advent of FXa inhibitors prompted several randomized controlled trials to evaluate their safety and efficacy in cancer patients. All studies concluded that FXa inhibitors are as beneficial for thrombosis treatment as LMWHs [57,58,59,60,61,62]. A meta-analysis by Planquette et al. incorporated five randomized controlled trials, i.e., the Hokusai VTE cancer, ADAM-VTE, SELECT-D, CASTA DIVA, and CARAVAGGIO trials, comparing FXa inhibitors and LMWHs [62]. The conclusion was that FXa inhibitors were as effective in preventing VTE, although an elevated risk of clinically significant bleeding with FXa inhibitors was identified. Further research is needed to evaluate the applicability of these randomized controlled trials to everyday practice, where patients with more comorbidities are often encountered [63]. Today, an increasing number of cancer patients are favoring oral treatment with FXa inhibitors as the first choice for anticoagulation, because of an expected better adherence and more convenient usage (tablets versus injections), provided their risk of bleeding permits it.
However, there are certain restrictions to the use of FXa inhibitors. International guidelines for patients with thrombosis and cancer mention a significant risk associated with the use of FXa inhibitors in patients without a high risk of bleeding. Hence, for patients with gastrointestinal cancer and urinary tract cancer, the usage of FXa inhibitors (and thrombin inhibitors) should be avoided [57,64]. Buoyed by the satisfactory results of thromboprophylaxis in non-cancer patients, phase III trials have directly commenced in the therapeutic treatment of thrombosis associated with cancer. In this population, the hemorrhagic risk and the thrombotic risk are competing and failures to demonstrate their effectiveness have been observed with all available molecules, both on the prothrombotic and hemorrhagic sides. Notably, on the hemorrhagic side the type of cancer plays a role, with a predominance of unremoved gastrointestinal and genitourinary sites in patients most at risk of bleeding. Given these findings, two trials have been designed. The first, ASTER NCT05171049, compares Abelacizumab at a dose of 150 mg with Apixaban at a dose of 5 mg twice a day in patients suffering from cancer whose tumor mass is not in contact with the mucosa. The second, MAGNOLIA NCT05171075, compares Abelacizumab at a dose of 150 mg with Dalteparin at a dose of 200 IU/kg per day for one month, followed by 150 IU/kg per day.

3.5. FXI Inhibitors to Prevent Catheter-Related Thrombosis

In catheter-related thrombosis, inhibition of FXI could facilitate the dissolution of the fibrin sheath conducive to thrombotic events. A common situation outside of intensive care, where patient management involves the insertion of a catheter, is dialysis. Due to kidney failure and the use of a heparinized dialysis circuit, dialysis patients are at a high risk of bleeding. Several studies using FXI inhibitors in dialysis have been conducted and published with small molecules, ASOs, and antibodies and concluded with encouraging results (Table 4) [25,65].
In a canine model of veno-venous extracorporeal membrane oxygenation (ECMO) using EP-7041, Pollack et al. demonstrated a prolongation of the aPTT and a reduction in bleeding associated with ECMO in this model [66]. Unsurprisingly, given the established interrelation between FXI activation and the presence of material, a phase II clinical trial has begun assessing Xisomab 3G3 (AB023) versus placebo for the prevention of catheter-related thrombosis in cancer patients. It is noteworthy that Xisomab 3G3 (AB023) has not been evaluated in other clinical situations requiring thromboprophylaxis.

4. Other Clinical Needs of Cancer Patients

4.1. FXI Inhibitors to Prevent Arterial Thromboembolic Events

An increasing number of studies have examined the link between VTE events and atherothrombosis, including in patients with cancer [67,68]. As with VTE, arterial thrombosis also involves exposure to TF during the rupture of an atherosclerotic plaque or its expression on activated monocytes or TF-bearing microvesicles, triggering the generation of small amounts of thrombin [68,69]. Thrombus expansion depends on the amplification of coagulation via thrombin-mediated activation facilitated by FXI, as well as thrombin itself, a potent platelet agonist [70]. The management of atheromatous diseases such as myocardial ischemia, carotid stenosis or occlusions, and lower-limb obliterating arteriopathy relies on platelet inhibition by single or dual antiplatelet treatments [71,72]. Despite this approach, up to 11% of patients suffering from an atheromatous pathology experience recurrent ischemic events each year. In these patients, it appears that suppression of platelet activity is not sufficient to avoid thrombosis [72,73]. Since thrombin has a dual effect on coagulation and platelets, this could explain the failure of antiplatelet agents. And thrombin-activated platelets are likely more frequent in cancer patient groups [74]. In the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial, 27,395 patients with coronary artery disease or stable peripheral arterial disease were assigned to one of three treatment arms: rivaroxaban 2.5 mg twice daily with 100 mg aspirin once daily; rivaroxaban 5 mg twice daily alone; or aspirin 100 mg once daily [75]. The primary outcome, a composite of cardiovascular death, stroke, or non-fatal myocardial infarction, was significantly lower with rivaroxaban plus aspirin than with aspirin alone (4.1% and 5.4%, respectively; hazard ratio = 0.76; 95% CI (0.66–0.86)). However, the rate of major bleeding was significantly higher in the rivaroxaban plus aspirin group than in the aspirin-alone group (3.1% and 1.9%, respectively; hazard ratio = 1.70; 95% CI (1.40–2.05)) [60]. While the rate of net clinical benefit (the occurrence of a composite of cardiovascular death, stroke, myocardial infarction, and fatal or symptomatic bleeding in a critical organ) was 4.7% in the rivaroxaban plus aspirin group and 5.9% in the aspirin-alone group (HR = 0.80; 95% CI (0.70–0.91)) is in favor of the combination, the incidence of major bleeding favors the exploration of safer solutions such as FXI inhibitors [75]. On the other hand, when we look at the included population of patients who developed cancer during follow-up, we observe that this combination is less favorable [76]. Major gastrointestinal bleeding was associated with a 20-fold increase in new diagnoses of gastrointestinal cancer (9.3% versus 0.7%; HR = 22.6; 95% CI (14.9–34.3)) and hematuria was associated with a 98-fold increase in new diagnoses of urinary cancer (14.2% versus 0.2%; hazard ratio = 98.5; 95% CI (68.0–142.7). In 66 cases, gastrointestinal bleeding also occurred for cancers of other types, with a hazard ratio of almost 2 (3.8% versus 3.1%; hazard ratio = 1.70; 95% CI (1.20–2.40)) [76]. These results suggest the importance of developing an anticoagulant able to prevent atherothrombosis in combination with an antiplatelet drug with a lower risk of bleeding for cancer patients, due to their bleeding sensitivity. In Table 5 the studies regarding arterial thrombosis in the general population are summarized. So far, no study dedicated to cancer patients exists regarding their arterial risk of thrombosis.

4.2. Chronic Complications of Cancer-Associated Thrombosis (Post-Thrombotic Syndrome, Chronic Thromboembolic Pulmonary Hypertension, and Recurrence)

Although we are able to effectively prevent deaths post VTE, there is currently no therapeutic arsenal to prevent sequels such as chronic thromboembolic pulmonary hypertension (CTEPH) or post-thrombotic syndrome (PTS) [77]. From a recent murine model, it appears that a reduction in macrophage activity through the inhibition of FXI would allow for a faster resolution of clot formation [78]. Catella-Chatron et al. observed that the medical evaluation of CTEPH may be lower for patients with cancer, despite some of them having a reasonable survival expectancy [79]. Direct inhibitors of FXa are about to become the drugs most used in cancer patients, but are not recommended for CTEPH patients. If FXa inhibitors are increasingly used in cancer patients, their potential impact on the development of CTEPH and their use in CTEPH cancer patients will deserve further research. A follow up of the cancer patients that developed thrombosis included in the studies with Abelacizumab and Xisomab may be very informative for understanding both CTEPH and PTS development under FXI inhibitors.

5. Conclusions

The pathophysiologic approach to the inhibition of FXI make it a promising target to solve the prothrombotic situations encountered with patients with a cancer-mediated procoagulant state (e.g., during chemotherapy, malignancy, or catheter placement). Subject to the results of ongoing trials, the factor XI inhibition pathway appears to be an encouraging way of improving the management of patients suffering from cancer-associated thrombosis.

Author Contributions

G.P.: writing—original draft preparation, all authors: writing—review, L.B.: supervision. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Heestermans, M.; Poenou, G.; Hamzeh-Cognasse, H.; Cognasse, F.; Bertoletti, L. Anticoagulants: A Short History, Their Mechanism of Action, Pharmacology, and Indications. Cells 2022, 11, 3214. [Google Scholar] [CrossRef]
  2. Link, K.P. The discovery of dicumarol and its sequels. Circulation 1959, 19, 97–107. [Google Scholar] [CrossRef]
  3. Mclean, J. The Discovery of Heparin. Circulation 1959, 19, 75–78. [Google Scholar] [CrossRef]
  4. Svendsen, E.; Karwinski, B. Prevalence of pulmonary embolism at necropsy in patients with cancer. J. Clin. Pathol. 1989, 42, 805–809. [Google Scholar] [CrossRef]
  5. Perzborn, E.; Roehrig, S.; Straub, A.; Kubitza, D.; Misselwitz, F. The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor. Nat. Rev. Drug Discov. 2011, 10, 61–75. [Google Scholar] [CrossRef]
  6. Sanchez, O.; Benhamou, Y.; Bertoletti, L.; Constans, J.; Couturaud, F.; Delluc, A.; Elias, A.; Fischer, A.-M.; Frappé, P.; Gendron, N.; et al. Recommandations de bonne pratique pour la prise en charge de la maladie veineuse thromboembolique chez l’adulte—Version longue. Rev. Mal. Respir. 2021, 38, e1–e6. [Google Scholar] [CrossRef]
  7. Ortel, T.L.; Neumann, I.; Ageno, W.; Beyth, R.; Clark, N.P.; Cuker, A.; Hutten, B.A.; Jaff, M.R.; Manja, V.; Schulman, S.; et al. American Society of Hematology 2020 Guidelines for Management of Venous Thromboembolism: Treatment of Deep Vein Thrombosis and Pulmonary Embolism. Blood Adv. 2020, 4, 4693–4738. [Google Scholar] [CrossRef]
  8. Pengo, V.; Denas, G.; Zoppellaro, G.; Jose, S.P.; Hoxha, A.; Ruffatti, A.; Andreoli, L.; Tincani, A.; Cenci, C.; Prisco, D.; et al. Rivaroxaban vs Warfarin in High-Risk Patients with Antiphospholipid Syndrome. Blood 2018, 132, 1365–1371. [Google Scholar] [CrossRef]
  9. Eikelboom, J.W.; Weitz, J.I. Warfarin faring better: Vitamin K antagonists beat rivaroxaban and apixaban in the INVICTUS and PROACT Xa trials. J. Thromb. Haemost. 2023, S1538783623005238. [Google Scholar] [CrossRef]
  10. Mackman, N.; Bergmeier, W.; Stouffer, G.A.; Weitz, J.I. Therapeutic strategies for thrombosis: New targets and approaches. Nat. Rev. Drug Discov. 2020, 19, 333–352. [Google Scholar] [CrossRef]
  11. Hsu, C.; Hutt, E.; Bloomfield, D.M.; Gailani, D.; Weitz, J.I. Factor XI Inhibition to Uncouple Thrombosis From Hemostasis. J. Am. Coll. Cardiol. 2021, 78, 625–631. [Google Scholar] [CrossRef]
  12. Sharman Moser, S.; Chodick, G.; Ni, Y.G.; Chalothorn, D.; Wang, M.-D.; Shuldiner, A.R.; Morton, L.; Salomon, O.; Jalbert, J.J. The Association between Factor XI Deficiency and the Risk of Bleeding, Cardiovascular, and Venous Thromboembolic Events. Thromb. Haemost. 2022, 122, 808–817. [Google Scholar] [CrossRef] [PubMed]
  13. Poenou, G.; Dimitru Dimitru, T.; Lafaie, L.; Mismetti, V.; Heestermans, M.; Bertoletti, L. Factor XI Inhibition for the Prevention of Venous Thromboembolism: An Update on Current Evidence and Future Perspectives. Vasc. Health Risk Manag. 2022, 18, 359–373. [Google Scholar] [CrossRef] [PubMed]
  14. Davie, E.W.; Ratnoff, O.D. Waterfall Sequence for Intrinsic Blood Clotting. Science 1964, 145, 1310–1312. [Google Scholar] [CrossRef]
  15. Ignjatovic, V. Activated partial thromboplastin time. Methods Mol. Biol. Clifton NJ 2013, 992, 111–120. [Google Scholar]
  16. Renné, T.; Pozgajová, M.; Grüner, S.; Schuh, K.; Pauer, H.-U.; Burfeind, P.; Gailani, D.; Nieswandt, B. Defective Thrombus Formation in Mice Lacking Coagulation Factor XII. J. Exp. Med. 2005, 202, 271–281. [Google Scholar] [CrossRef]
  17. Zhang, Z.; Lei, J.; Zhai, Z.; Yang, Y.; Wan, J.; Xie, W.; Wang, C. Comparison of Prediction Value of Four Bleeding Risk Scores for Pulmonary Embolism with Anticoagulation: A Real-World Study in Chinese Patients. Clin. Respir. J. 2019, 13, 139–147. [Google Scholar] [CrossRef]
  18. Cheng, Q.; Tucker, E.I.; Pine, M.S.; Sisler, I.; Matafonov, A.; Sun, M.; White-Adams, T.C.; Smith, S.A.; Hanson, S.R.; McCarty, O.J.T.; et al. A Role for Factor XIIa–Mediated Factor XI Activation in Thrombus Formation in Vivo. Blood 2010, 116, 3981–3989. [Google Scholar] [CrossRef]
  19. Maas, C.; Oschatz, C.; Renné, T. The Plasma Contact System 2.0. Semin. Thromb. Hemost. 2011, 37, 375–381. [Google Scholar] [CrossRef]
  20. Müller, F.; Mutch, N.J.; Schenk, W.A.; Smith, S.A.; Esterl, L.; Spronk, H.M.; Schmidbauer, S.; Gahl, W.A.; Morrissey, J.H.; Renné, T. Platelet Polyphosphates Are Proinflammatory and Procoagulant Mediators In Vivo. Cell 2009, 139, 1143–1156. [Google Scholar] [CrossRef]
  21. Fuchs, T.A.; Brill, A.; Duerschmied, D.; Schatzberg, D.; Monestier, M.; Myers, D.D.; Wrobleski, S.K.; Wakefield, T.W.; Hartwig, J.H.; Wagner, D.D. Extracellular DNA Traps Promote Thrombosis. Proc. Natl. Acad. Sci. USA 2010, 107, 15880–15885. [Google Scholar] [CrossRef]
  22. Mailer, R.K.; Rangaswamy, C.; Konrath, S.; Emsley, J.; Renné, T. An Update on Factor XII-Driven Vascular Inflammation. Biochim. Biophys. Acta Mol. Cell Res. 2022, 1869, 119166. [Google Scholar] [CrossRef]
  23. Gailani, D.; Broze, G.J. Factor XI Activation in a Revised Model of Blood Coagulation. Science 1991, 253, 909–912. [Google Scholar] [CrossRef]
  24. Yi, B.A.; Freedholm, D.; Widener, N.; Wang, X.; Simard, E.; Cullen, C.; Al-Saady, N.M.; Lepor, N.E.; Coulter, S.; Lovern, M.; et al. Pharmacokinetics and Pharmacodynamics of Abelacimab (MAA868), a Novel Dual Inhibitor of Factor XI and Factor XIa. J. Thromb. Haemost. 2022, 20, 307–315. [Google Scholar] [CrossRef] [PubMed]
  25. Walsh, M.; Bethune, C.; Smyth, A.; Tyrwhitt, J.; Jung, S.W.; Yu, R.Z.; Wang, Y.; Geary, R.S.; Weitz, J.; Bhanot, S.; et al. Phase 2 Study of the Factor XI Antisense Inhibitor IONIS-FXIRx in Patients With ESRD. Kidney Int. Rep. 2022, 7, 200–209. [Google Scholar] [CrossRef] [PubMed]
  26. Perera, V.; Wang, Z.; Luettgen, J.; Li, D.; DeSouza, M.; Cerra, M.; Seiffert, D. First-in-Human Study of Milvexian, an Oral, Direct, Small Molecule Factor XIa Inhibitor. Clin. Transl. Sci. 2021, 15, 330–342. [Google Scholar] [CrossRef] [PubMed]
  27. Kubitza, D.; Heckmann, M.; Distler, J.; Koechel, A.; Schwers, S.; Kanefendt, F. Pharmacokinetics, Pharmacodynamics and Safety of BAY 2433334, a Novel Activated Factor XI Inhibitor, in Healthy Volunteers: A Randomized Phase 1 Multiple-dose Study. Br. J. Clin. Pharmacol. 2022, bcp.15230. [Google Scholar] [CrossRef]
  28. Zaslavsky, A.; Adams, M.; Coa, X.; Yamaguchi, A.; Henderson, J.; Busch-Østergren, P.; Udager, A.; Sethuramasundaram Pitchiaya, S.; Tourdot, B.; Kasputis, T.; et al. Antisense Oligonucleotides and Nucleic Acids Generate Hypersensitive Platelets. Thromb. Res. 2021, 200, 64–71. [Google Scholar] [CrossRef]
  29. Ragni, M.V.; Sinha, D.; Seaman, F.; Lewis, J.H.; Spero, J.A.; Walsh, P.N. Comparison of Bleeding Tendency, Factor XI Coagulant Activity, and Factor XI Antigen in 25 Factor XI-Deficient Kindreds. Blood 1985, 65, 719–724. [Google Scholar] [CrossRef]
  30. Bertaggia Calderara, D.; Zermatten, M.G.; Aliotta, A.; Alberio, L. How to Capture the Bleeding Phenotype in FXI-Deficient Patients. Hamostaseologie 2020, 40, 491–499. [Google Scholar] [CrossRef]
  31. Depasse, F.; Binder, N.B.; Mueller, J.; Wissel, T.; Schwers, S.; Germer, M.; Hermes, B.; Turecek, P.L. Thrombin Generation Assays Are Versatile Tools in Blood Coagulation Analysis: A Review of Technical Features, and Applications from Research to Laboratory Routine. J. Thromb. Haemost. 2021, 19, 2907–2917. [Google Scholar] [CrossRef] [PubMed]
  32. Livnat, T.; Tamarin, I.; Mor, Y.; Winckler, H.; Horowitz, Z.; Korianski, Y.; Bar-Zakay, B.; Seligsohn, U.; Salomon, O. Recombinant Activated Factor VII and Tranexamic Acid Are Haemostatically Effective during Major Surgery in Factor XI-Deficient Patients with Inhibitor Antibodies. Thromb. Haemost. 2009, 102, 487–492. [Google Scholar] [CrossRef] [PubMed]
  33. Bauduer, F.; de Raucourt, E.; Boyer-Neumann, C.; Trossaert, M.; Beurrier, P.; Faradji, A.; Peynet, J.; Borg, J.-Y.; Chamouni, P.; Chatelanaz, C.; et al. Factor XI Replacement for Inherited Factor XI Deficiency in Routine Clinical Practice: Results of the HEMOLEVEN Prospective 3-Year Postmarketing Study. Haemoph. Off. J. World Fed. Hemoph. 2015, 21, 481–489. [Google Scholar] [CrossRef]
  34. Salomon, O.; Gailani, D. A Proposal for Managing Bleeding in Patients on Therapeutic Factor XI(a) Inhibitors. J. Thromb. Haemost. 2022, 20, 32–38. [Google Scholar] [CrossRef] [PubMed]
  35. Lu, G.; DeGuzman, F.R.; Hollenbach, S.J.; Karbarz, M.J.; Abe, K.; Lee, G.; Luan, P.; Hutchaleelaha, A.; Inagaki, M.; Conley, P.B.; et al. A Specific Antidote for Reversal of Anticoagulation by Direct and Indirect Inhibitors of Coagulation Factor Xa. Nat. Med. 2013, 19, 446–451. [Google Scholar] [CrossRef] [PubMed]
  36. Pollack, C.V.; Reilly, P.A.; Eikelboom, J.; Glund, S.; Verhamme, P.; Bernstein, R.A.; Dubiel, R.; Huisman, M.V.; Hylek, E.M.; Kamphuisen, P.W.; et al. Idarucizumab for Dabigatran Reversal. N. Engl. J. Med. 2015, 373, 511–520. [Google Scholar] [CrossRef]
  37. Ansell, J.E.; Bakhru, S.H.; Laulicht, B.E.; Steiner, S.S.; Grosso, M.; Brown, K.; Dishy, V.; Noveck, R.J.; Costin, J.C. Use of PER977 to Reverse the Anticoagulant Effect of Edoxaban. N. Engl. J. Med. 2014, 371, 2141–2142. [Google Scholar] [CrossRef]
  38. Wolberg, A.S.; Rosendaal, F.R.; Weitz, J.I.; Jaffer, I.H.; Agnelli, G.; Baglin, T.; Mackman, N. Venous thrombosis. Nat. Rev. Dis. Prim. 2015, 1, 15006. [Google Scholar]
  39. Falanga, A.; Russo, L.; Milesi, V.; Vignoli, A. Mechanisms and risk factors of thrombosis in cancer. Crit. Rev. Oncol. Hematol. 2017, 118, 79–83. [Google Scholar] [CrossRef]
  40. Levin, J.; Conley, C.L. Thrombocytosis associated with malignant disease. Arch. Intern. Med. 1964, 114, 497–500. [Google Scholar] [CrossRef]
  41. Shoenfeld, Y.; Gurewich, Y.; Gallant, L.A.; Pinkhas, J. Leukocytosis in non hematological malignancies—A possible tumor-associated marker. J. Cancer Res. Clin. Oncol. 1986, 111, 54–58. [Google Scholar] [CrossRef] [PubMed]
  42. Edwards, R.L.; Rickles, F.R.; Moritz, T.E.; Henderson, W.G.; Zacharski, L.R.; Forman, W.B.; Cornell, C.J.; Forcier, R.J.; O’Donnel, J.F.; Headley, E. Abnormalities of blood coagulation in patients with cancer. Mononuclear cell tissue factor generation. J. Lab. Clin. Med. 1987, 98, 917–928. [Google Scholar]
  43. Thalin, C.; Hisada, Y.; Lundstrom, S.; Mackmen, N.; Wallen, H. Neutrophil extracellular traps: Villains and targets in arterial, venous, and cancer-associated thrombosis. Arterioscler. Thromb. Vasc. Biol. 2019, 39, 1724–1738. [Google Scholar] [CrossRef] [PubMed]
  44. Almeida, V.H.; Rondon, A.M.R.; Gomes, T.; Monteiro, R. Q Novel Aspects of Extracellular Vesicles as Mediators of Cancer-Associated Thrombosis. Cells 2019, 8, 716. [Google Scholar] [CrossRef] [PubMed]
  45. Kubala, M.H.; DeClerck, Y.A. The plasminogen activator inhibitor-1 paradox in cancer: A mechanistic understanding. Cancer Metastasis Rev. 2019, 38, 483–492. [Google Scholar] [CrossRef] [PubMed]
  46. Herrmann, J.; Yang, E.H.; Iliescu, C.; Cilingiroglu, M.; Charitakis, K.; Hakeem, A.; Toutouzas, K.; Leesar, M.A.; Grines, C.L.; Marmagkiolis, K. Vascular toxic effects of cancer therapies. Nat. Rev. Cardiol. 2020, 17, 503–522. [Google Scholar] [CrossRef] [PubMed]
  47. Geerts, W.H.; Pineo, G.F.; Heit, J.A.; Bergqvist, D.; Lassen, M.R.; Colwell, C.W.; Ray, J.G. Prevention of Venous Thromboembolism. Chest 2004, 126, 338S–400S. [Google Scholar] [CrossRef]
  48. Weitz, J.I.; Bauersachs, R.; Becker, B.; Berkowitz, S.D.; Freitas, M.C.S.; Lassen, M.R.; Metzig, C.; Raskob, G.E. Effect of Osocimab in Preventing Venous Thromboembolism Among Patients Undergoing Knee Arthroplasty: The FOXTROT Randomized Clinical Trial. JAMA 2020, 323, 130. [Google Scholar] [CrossRef]
  49. Weitz, J.I.; Strony, J.; Ageno, W.; Gailani, D.; Hylek, E.M.; Lassen, M.R.; Mahaffey, K.W.; Notani, R.S.; Roberts, R.; Segers, A.; et al. Milvexian for the Prevention of Venous Thromboembolism. N. Engl. J. Med. 2021, 385, 2161–2172. [Google Scholar] [CrossRef]
  50. Verhamme, P.; Yi, B.A.; Segers, A.; Salter, J.; Bloomfield, D.; Büller, H.R.; Raskob, G.E.; Weitz, J.I. Abelacimab for Prevention of Venous Thromboembolism. N. Engl. J. Med. 2021, 385, 609–617. [Google Scholar] [CrossRef]
  51. Büller, H.R.; Bethune, C.; Bhanot, S.; Gailani, D.; Monia, B.P.; Raskob, G.E.; Segers, A.; Verhamme, P.; Weitz, J.I. Factor XI Antisense Oligonucleotide for Prevention of Venous Thrombosis. N. Engl. J. Med. 2015, 372, 232–240. [Google Scholar] [CrossRef]
  52. Nopp, S.; Kraemmer, D.; Ay, C. Factor XI Inhibitors for Prevention and Treatment of Venous Thromboembolism: A Review on the Rationale and Update on Current Evidence. Front. Cardiovasc. Med. 2022, 9, 903029. [Google Scholar] [CrossRef]
  53. Presume, J.; Ferreira, J.; Ribeiras, R.; Mendes, M. Achieving Higher Efficacy without Compromising Safety with Factor XI Inhibitors versus Low Molecular Weight Heparin for the Prevention of Venous Thromboembolism in Major Orthopedic Surgery—Systematic Review and Meta-analysis. J. Thromb. Haemost. 2022, 20, 2930–2938. [Google Scholar] [CrossRef] [PubMed]
  54. Khorana, A.A.; Francis, C.W.; Kuderer, N.M.; Carrier, M.; Ortel, T.L.; Wun, T.; Rubens, D.; Hobbs, S.; Iyer, R.; Peterson, D.; et al. Dalteparin Thromboprophylaxis in Cancer Patients at High Risk for Venous Thromboembolism: A Randomized Trial. Thromb. Res. 2017, 151, 89–95. [Google Scholar] [CrossRef] [PubMed]
  55. Khorana, A.A.; Soff, G.A.; Kakkar, A.K.; Vadhan-Raj, S.; Riess, H.; Wun, T.; Streiff, M.B.; Garcia, D.A.; Liebman, H.A.; Belani, C.P.; et al. Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer. N. Engl. J. Med. 2019, 380, 720–728. [Google Scholar] [CrossRef] [PubMed]
  56. Carrier, M.; Abou-Nassar, K.; Mallick, R.; Tagalakis, V.; Shivakumar, S.; Schattner, A.; Kuruvilla, P.; Hill, D.; Spadafora, S.; Marquis, K.; et al. Apixaban to Prevent Venous Thromboembolism in Patients with Cancer. N. Engl. J. Med. 2019, 380, 711–719. [Google Scholar] [CrossRef]
  57. Key, N.S. Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update. J. Clin. Oncol. 2020, 38, 496–520. [Google Scholar] [CrossRef]
  58. Lee, A.Y.Y. Low-Molecular-Weight Heparin versus a Coumarin for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer. N. Engl. J. Med. 2003, 349, 146–153. [Google Scholar] [CrossRef]
  59. Raskob, G.E.; van Es, N.; Verhamme, P.; Carrier, M.; Di Nisio, M.; Garcia, D.; Grosso, M.A.; Kakkar, A.K.; Kovacs, M.J.; Mercuri, M.F.; et al. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. N. Engl. J. Med. 2018, 378, 615–624. [Google Scholar] [CrossRef]
  60. Ageno, W.; Vedovati, M.C.; Cohen, A.; Huisman, M.; Bauersachs, R.; Gussoni, G.; Becattini, C.; Agnelli, G. Bleeding with Apixaban and Dalteparin in Patients with Cancer-Associated Venous Thromboembolism: Results from the Caravaggio Study. Thromb. Haemost. 2021, 121, 616–624. [Google Scholar] [CrossRef]
  61. McBane, R.D.; Wysokinski, W.E.; Le-Rademacher, J.G.; Zemla, T.; Ashrani, A.; Tafur, A.; Perepu, U.; Anderson, D.; Gundabolu, K.; Kuzma, C.; et al. Apixaban and Dalteparin in Active Malignancy-associated Venous Thromboembolism: The ADAM VTE Trial. J. Thromb. Haemost. 2020, 18, 411–421. [Google Scholar] [CrossRef] [PubMed]
  62. Planquette, B.; Bertoletti, L.; Charles-Nelson, A.; Laporte, S.; Grange, C.; Mahé, I.; Pernod, G.; Elias, A.; Couturaud, F.; Falvo, N.; et al. Rivaroxaban vs Dalteparin in Cancer-Associated Thromboembolism. Chest 2021, S0012369221040794. [Google Scholar] [CrossRef] [PubMed]
  63. Poénou, G.; Tolédano, E.; Helfer, H.; Plaisance, L.; Happe, F.; Versini, E.; Diab, N.; Djennaoui, S.; Mahé, I. In Search of the Appropriate Anticoagulant-Associated Bleeding Risk Assessment Model for Cancer-Associated Thrombosis Patients. Cancers 2022, 14, 1937. [Google Scholar] [CrossRef] [PubMed]
  64. Lyman, G.H.; Carrier, M.; Ay, C.; Di Nisio, M.; Hicks, L.K.; Khorana, A.A.; Leavitt, A.D.; Lee, A.Y.Y.; Macbeth, F.; Morgan, R.L.; et al. American Society of Hematology 2021 Guidelines for Management of Venous Thromboembolism: Prevention and Treatment in Patients with Cancer. Blood Adv. 2021, 5, 927–974. [Google Scholar] [CrossRef] [PubMed]
  65. Eikelboom, J.; Floege, J.; Thadhani, R.; Weitz, J.I.; Winkelmayer, W.C. Anticoagulation in Patients with Kidney Failure on Dialysis: Factor XI as a Therapeutic Target. Kidney Int. 2021, 100, 1199–1207. [Google Scholar] [CrossRef]
  66. Pollack, C.V.; Kurz, M.A.; Hayward, N.J. EP-7041, a Factor XIa Inhibitor as a Potential Antithrombotic Strategy in Extracorporeal Membrane Oxygenation: A Brief Report. Crit. Care Explor. 2020, 2, e0196. [Google Scholar] [CrossRef]
  67. Prandoni, P.; Bilora, F.; Marchiori, A.; Bernardi, E.; Petrobelli, F.; Lensing, A.W.A.; Prins, M.H.; Girolami, A. An Association between Atherosclerosis and Venous Thrombosis. N. Engl. J. Med. 2003, 348, 1435–1441. [Google Scholar] [CrossRef]
  68. Naschitz, J.E. Cancer-Associated Atherothrombosis: The Challenge. Int. J. Angiol. 2021, 30, 249–256. [Google Scholar] [CrossRef]
  69. Grover, S.P.; Mackman, N. Tissue Factor: An Essential Mediator of Hemostasis and Trigger of Thrombosis. Arterioscler. Thromb. Vasc. Biol. 2018, 38, 709–725. [Google Scholar] [CrossRef]
  70. Zilberman-Rudenko, J.; Itakura, A.; Wiesenekker, C.P.; Vetter, R.; Maas, C.; Gailani, D.; Tucker, E.I.; Gruber, A.; Gerdes, C.; McCarty, O.J.T. Coagulation Factor XI Promotes Distal Platelet Activation and Single Platelet Consumption in the Bloodstream Under Shear Flow. Arterioscler. Thromb. Vasc. Biol. 2016, 36, 510–517. [Google Scholar] [CrossRef]
  71. Arockiam, S.; Staniforth, B.; Kepreotis, S.; Maznyczka, A.; Bulluck, H. A Contemporary Review of Antiplatelet Therapies in Current Clinical Practice. Int. J. Mol. Sci. 2023, 24, 11132. [Google Scholar] [CrossRef] [PubMed]
  72. Yusuf, S.; Zhao, F.; Mehta, S.R.; Chrolavicius, S.; Tognoni, G.; Fox, K.K. Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators Effects of Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndromes without ST-Segment Elevation. N. Engl. J. Med. 2001, 345, 494–502. [Google Scholar] [CrossRef] [PubMed]
  73. Steg, P.G.; Bhatt, D.L.; Wilson, P.W.F.; D’Agostino, R.; Ohman, E.M.; Röther, J.; Liau, C.-S.; Hirsch, A.T.; Mas, J.-L.; Ikeda, Y.; et al. One-Year Cardiovascular Event Rates in Outpatients with Atherothrombosis. JAMA 2007, 297, 1197–1206. [Google Scholar] [CrossRef] [PubMed]
  74. Palacios-Acedo, A.L.; Mège, D.; Crescence, L.; Dignat-George, F.; Dubois, C.; Panicot-Dubois, L. Platelets, Thrombo-Inflammation, and Cancer: Collaborating With the Enemy. Front. Immunol. 2019, 10, 1805. [Google Scholar] [CrossRef] [PubMed]
  75. Eikelboom, J.W.; Connolly, S.J.; Bosch, J.; Dagenais, G.R.; Hart, R.G.; Shestakovska, O.; Diaz, R.; Alings, M.; Lonn, E.M.; Anand, S.S.; et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N. Engl. J. Med. 2017, 377, 1319–1330. [Google Scholar] [CrossRef]
  76. Eikelboom, J.W.; Connolly, S.J.; Bosch, J.; Shestakovska, O.; Aboyans, V.; Alings, M.; Anand, S.S.; Avezum, A.; Berkowitz, S.D.; Bhatt, D.L.; et al. Bleeding and New Cancer Diagnosis in Patients With Atherosclerosis. Circulation 2019, 140, 1451–1459. [Google Scholar] [CrossRef]
  77. Klok, F.A.; Ageno, W.; Ay, C.; Bäck, M.; Barco, S.; Bertoletti, L.; Becattini, C.; Carlsen, J.; Delcroix, M.; van Es, N.; et al. Optimal Follow-up after Acute Pulmonary Embolism: A Position Paper of the European Society of Cardiology Working Group on Pulmonary Circulation and Right Ventricular Function, in Collaboration with the European Society of Cardiology Working Group on Atherosclerosis and Vascular Biology, Endorsed by the European Respiratory Society. Eur. Heart J. 2022, 43, 183–189. [Google Scholar] [CrossRef]
  78. Jordan, K.R.; Wyatt, C.R.; Fallon, M.E.; Woltjer, R.; Neuwelt, E.A.; Cheng, Q.; Gailani, D.; Lorentz, C.; Tucker, E.I.; McCarty, O.J.T.; et al. Pharmacological Reduction of Coagulation Factor XI Reduces Macrophage Accumulation and Accelerates Deep Vein Thrombosis Resolution in a Mouse Model of Venous Thrombosis. J. Thromb. Haemost. 2022, 20, 2035–2045. [Google Scholar] [CrossRef]
  79. Catella-Chatron, J.; Merah, A.; De Magalhaes, E.; Moulin, N.; Accassat, S.; Duvillard, C.; Mismetti, P.; Bertoletti, L. Chronic Thromboembolic Pulmonary Hypertension Suspicion after Pulmonary Embolism in Cancer Patients. Respir. Med. Res. 2019, 76, 34–37. [Google Scholar] [CrossRef]
Ijms 24 14433 g002
Figure 2. FXI inhibitors and other anticoagulants. The coagulation cascade is represented as a pyramid where the closer you get to fibrin the higher is the risk of coagulation. Therefore regarding anticoagulant the inhibition of thrombin is at a higher risk than the inhibition of FXIa. VKA stands for vitamin K antagonist. Black arrows represent the traditional pathway of coagulation.
Figure 2. FXI inhibitors and other anticoagulants. The coagulation cascade is represented as a pyramid where the closer you get to fibrin the higher is the risk of coagulation. Therefore regarding anticoagulant the inhibition of thrombin is at a higher risk than the inhibition of FXIa. VKA stands for vitamin K antagonist. Black arrows represent the traditional pathway of coagulation.
Ijms 24 14433 g002
Ijms 24 14433 g003
Figure 3. Randomized controlled trials for thromboprophylaxis treatment and secondary prevention in cancer-associated thrombosis.
Figure 3. Randomized controlled trials for thromboprophylaxis treatment and secondary prevention in cancer-associated thrombosis.
Ijms 24 14433 g003
Table 1. FXI inhibitors.
Table 1. FXI inhibitors.
Drug TypeMoleculeTargetMechanismOral Route AvailableHalf LifeActionRenal ExcretionCytochrome p450 MetabolismPotential for Drug-Drug InteractionNeed for Reversion StrategyIs It a Suitable Option for Cancer Associated Thrombosis
Antisense oligonucleotides or ASOFesomersen
IONIS FXI-LRx (ISIS 416858) FXI-ASO (ISIS416858)		FXI mRNASpecific protein synthesis blockingNoLong: weekly administrationSlow and long actingNoNoNoYes: FXI replacement The slow setting makes it less likely;
however, it can be interesting for the prevention of CAT
Aptamers/FXIaSpecific protein bindingNoShort: daily administrationFast and short actingNoNoNoNoThere is not enough evidence to make an opinion
Monoclonal antibodiesAbelacimab (MAA868), Osocimab (BAY1213790), FXI-175, FXI-203 (preclinical), 14E11 (preclinical), Xisomab 3G3 (AB023), MK 2060FXI or FXI synthesisSpecific protein binding and decreases its concentrationNoLong: monthly administrationFast and long actingNoNoNoYes: no existing failure of FXI replacementYes
Natural inhibitorsIrCPIFXIa or FXIa + FXIIaSpecific protein bindingNoShort: daily administrationFast and short actingUnknownNoUnknownNoThere is not enough evidence to make an opinion
Small peptidomimetic moleculesAsundexian (oral). Milvexian (oral)/Frunexian EP-7041a, BMS-962212, ONO-7684 (oral), BMS-654457 (preclinical), ONO-5450598 (preclinical),BMS-262084 (preclinical), SHR2285 (oral)FXIa or FXI + plasma kallicreinSpecific protein bindingYesShort: daily administrationFast and short actingBiliary and 15% renal excretionCYP3A4Midazolam Rifampicin Verapamil, Ketoconazole… NoThe risk of interaction makes it less likely
Table 2. Current guidelines regarding the management of cancer-associated thrombosis.
Table 2. Current guidelines regarding the management of cancer-associated thrombosis.
RecommendationThromboprophylaxisIntital TreatmentLong-Term Treatement
ACCP 2016/LMWHLMWH or DOAC or VKA
ASCO 2019LMWH or DOACLMWH, Fondaparinux or DOACLMWH or DOAC
ISTH 2019Khorana ≥ 2
LMWH or DOAC
Khorana ≥ 2 LMWH
ITAC 2019LMWH or FondaparinuxUFH, LMWH, DOAC or VKA
ASH 2021LMWHLMWH or DOAC
French recommendations
2021		No thromboprophylaxisLMWHLMWH or DOAC or VKA
ACCP = American College of Chest Physicians
ASCO = American Society of Clinical Oncology		ASH = American Society of Hematology
ISTH = International Society on Thrombosis and Haemostasis		ITAC = International Initiative on Thrombosis and Cancer
Table 3. Studies with FXI inhibitors in venous thrombosis on https://clinicaltrials.gov and https://eudract.ema.europa.eu (accessed on 20 August 2023).
Table 3. Studies with FXI inhibitors in venous thrombosis on https://clinicaltrials.gov and https://eudract.ema.europa.eu (accessed on 20 August 2023).
Venous ThromboembolismStudy NameRegistration NumberDrug NameComparatorStatus
Orthopedic-surgery-related thrombosis preventionFXI-ASO TKA trialNCT01713361IONIS FXI-LRx (ISIS 416858) 200 mg or 300 mg SCEnoxaparin 40 mg COMPLETED
AXIOMATIC-TKR trialNCT03891524 Milvexian (BMS-986177) (JNJ70033093) oral 5 mg, 50 mg, 100 mg, or 200 mg twice daily or 25 mg, 50 mg, or 200 mg once dailyEnoxaparin 40 mg COMPLETED
FOXTROT trialNCT03276143Osocimab (BAY1213790) Single IV postoperative doses of 0.3 mg/kg, 0.6 mg/kg, 1.2 mg/kg, or 1.8 mg/kg Single IV preoperative doses of 0.3 mg/kg or 1.8 mg/kgEnoxaparin 40 mg COMPLETED
ANT-005 TKA trialEudraCT number, 2019-003756-37Abelacimab (MAA868) 30 mg, 75 mg, or 150 mgEnoxaparin 40 mg COMPLETED
COVID-19-related thrombosis preventionCOVID-19 ThromboprophylaXIsNCT05040776Frunexian EP-7041aClinician choice of thromboprophylaxisONGOING
Cancer-associated thrombosis treatmentMAGNOLIA trialNCT05171075 Abelacimab (MAA868) 150 mgDalteparin 20 mgONGOING
ASTER trialNCT05171049 Abelacimab (MAA868) 150 mgApixaban 5 mg bidONGOING
Table 4. Studies with FXI inhibitors in catheter-related thrombosis.
Table 4. Studies with FXI inhibitors in catheter-related thrombosis.
Catheter-Related ThrombosisName of the Study Registration NumberDrug NameComparatorStatus
End-stage renal disease/NCT04534114Factor XI LICA (BAY 2976217)PlaceboUPCOMING
ESMERALD trialNCT03358030IONIS FXI-LRx (ISIS 416858) 200 mg, 250 mg or 300 mg PlaceboONGOING
/NCT02553889IONIS FXI-LRx (ISIS 416858)PlaceboCOMPLETED
/NCT03196206Milvexian (BMS-986177) EnoxaparinCOMPLETED
NCT02902679Milvexian (BMS-986177)NoneCOMPLETED
MK-2060-004NCT03873038MK-2060PlaceboCOMPLETED
MK-2060-007NCT05027074MK-2060PlaceboON GOING
/NCT03787368Osocimab (BAY1213790)PlaceboCOMPLETED
/NCT04523220Osocimab (BAY1213790)PlaceboUPCOMING
/NCT04510987BAY2433334 (Asundexian)NoneCOMPLETED
Catheter-related thrombosis prevention NCT04465760Xisomab 3G3 (AB023)PlaceboONGOING
Table 5. Studies with FXI inhibitors in arterial thrombosis.
Table 5. Studies with FXI inhibitors in arterial thrombosis.
ArterialRegistration NumberStudyDrug NameComparatorStatus
AOMIAXIOMATIC-SSPtrialNCT03766581Oral Milvexian (BMS-986177) (JNJ70033093) in association with aspirin and clopidogrelPlaceboCOMPLETED
FAPACIFIC-AFNCT04218266Asundexian 20 or 50 mgApixaban 5 or 2.5 mgCOMPLETED
StrokeOCEANIC-STROKENCT04304508Asundexian 10, 20 or 50 mgPlaceboCOMPLETED
IDMPACIFIC-AMINCT04304534Asundexian in association with aspirineand clopidogrelPlaceboCOMPLETED
OCEANIC-AFNCT05643573AsundexianApixaban 5 or 2.5 mgONGOING
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Poenou, G.; Heestermans, M.; Lafaie, L.; Accassat, S.; Moulin, N.; Rodière, A.; Petit, B.; Duvillard, C.; Mismetti, P.; Bertoletti, L. Inhibition of Factor XI: A New Era in the Treatment of Venous Thromboembolism in Cancer Patients? Int. J. Mol. Sci. 2023, 24, 14433. https://doi.org/10.3390/ijms241914433

AMA Style

Poenou G, Heestermans M, Lafaie L, Accassat S, Moulin N, Rodière A, Petit B, Duvillard C, Mismetti P, Bertoletti L. Inhibition of Factor XI: A New Era in the Treatment of Venous Thromboembolism in Cancer Patients? International Journal of Molecular Sciences. 2023; 24(19):14433. https://doi.org/10.3390/ijms241914433

Chicago/Turabian Style

Poenou, Géraldine, Marco Heestermans, Ludovic Lafaie, Sandrine Accassat, Nathalie Moulin, Alexandre Rodière, Bastien Petit, Cécile Duvillard, Patrick Mismetti, and Laurent Bertoletti. 2023. "Inhibition of Factor XI: A New Era in the Treatment of Venous Thromboembolism in Cancer Patients?" International Journal of Molecular Sciences 24, no. 19: 14433. https://doi.org/10.3390/ijms241914433

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop