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. 2026 Jul 13;10(5):106832. doi: 10.1016/j.rpth.2026.106832

In vitro comparison of the effects of abelacimab, dalteparin, and apixaban on catheter-induced clotting and thrombin generation

Ruiqi Yin 1,2,3, Xinyi Guo 1,2, James C Fredenburgh 1,3, Jeffrey I Weitz 1,2,3,4,∗
PMCID: PMC13448019  PMID: 42568786

Abstract

Background

Abelacimab is a fully human monoclonal antibody that binds factor XI, blocking its activation and activity. It is being compared with apixaban and dalteparin in patients with cancer-associated venous thromboembolism. Patients with cancer often have central venous catheters, which are prone to clotting. How abelacimab compares with apixaban and dalteparin for preventing catheter thrombosis is unknown.

Objectives

The aim of this study was to compare the effects of abelacimab, apixaban, and dalteparin on the activated partial thromboplastin time (aPTT) and catheter-induced clotting and thrombin generation using an established plate-based catheter thrombosis model.

Methods

The effect of abelacimab, apixaban, and dalteparin on the aPTT was determined. Human plasma containing abelacimab, apixaban, or dalteparin was added to wells of 96-well plates, with or without catheter segments. After incubation and recalcification, the time to clot formation and thrombin generation was measured.

Results

All 3 anticoagulants prolonged the aPTT and suppressed catheter-induced clotting and thrombin generation in a concentration-dependent manner. At clinically relevant concentrations, dalteparin and abelacimab exerted more potent effects on the aPTT, catheter-induced clotting, and thrombin generation than apixaban.

Conclusion

Abelacimab and dalteparin suppress catheter-induced clotting more effectively than apixaban. Clinical trials are needed to determine whether abelacimab prevents catheter-induced clotting in patients with cancer.

Keywords: antibodies, catheter, dalteparin, factor XI, thrombosis

Essentials

  • •

    Central venous catheters contribute to thrombotic risk in patients with cancer.

  • •

    Abelacimab is being compared with apixaban and dalteparin in ongoing trials.

  • •

    We examined the effects of these agents on catheter-induced coagulation.

  • •

    Abelacimab and dalteparin showed greater anticoagulant activity than apixaban.

1. Introduction

Factor (F)XI has emerged as a target for new anticoagulants that could be safer than currently available agents because FXI is crucial for thrombosis but largely unnecessary for hemostasis [1]. Abelacimab is a fully-human monoclonal antibody that binds to the catalytic domain of FXI and exerts dual mechanisms of action. Thus, it locks FXI in the zymogen conformation, thereby preventing its activation by FXIIa and thrombin, and it attenuates FXIa activity, providing comprehensive inhibition of the contact pathway [2]. Catheters trigger clotting by activating both FXII and FXI [[2], [3], [4]]. Therefore, inhibiting FXI activation and activity could be particularly effective in preventing catheter-induced thrombosis.

Using a microplate-based catheter thrombosis model, we previously demonstrated that clot formation was attenuated in plasma deficient in FXII or FXI, but not in plasma deficient in FVII, and that corn trypsin inhibitor, a potent and specific inhibitor of FXIIa, completely prevented catheter-induced clotting [5]. The pivotal role of FXII as the initiator of catheter thrombosis was further confirmed in a rabbit jugular vein model, where corn trypsin inhibitor-coated catheters exhibited markedly reduced thrombosis, and antisense oligonucleotide-mediated knockdown of FXII or FXI, but not FVII, prolonged the time to catheter occlusion [6]. By contrast, in the same assay system, direct oral anticoagulants such as apixaban and rivaroxaban were less effective than enoxaparin in preventing catheter clotting [7]. Together, these findings suggest that by blocking both FXI activation and FXIa activity, abelacimab may inhibit catheter-induced thrombosis driven by the contact system.

Abelacimab is currently undergoing phase 3 evaluation for stroke prevention in patients with atrial fibrillation in the LILAC-TIMI 76 trial (Study to Evaluate the Efficacy and Safety of Abelacimab in High-risk Patients with Atrial Fibrillation Who Have Been Deemed Unsuitable for Oral Anticoagulation; NCT05712200) and for the treatment of patients with cancer-associated venous thromboembolism (VTE) in 2 trials. Patients with VTE on the background of cancer are at higher risk for recurrence and for bleeding than those without cancer [8]. The ASTER trial (Abelacimab Versus Apixaban in the Treatment of Cancer Associated VTE; NCT05171049) compares the efficacy and safety of abelacimab with those of apixaban in patients eligible for a direct oral anticoagulant. In contrast, the MAGNOLIA trial (A Study Comparing Abelacimab to Dalteparin in the Treatment of Gastrointestinal/Genitourinary Cancer and Associated VTE; NCT05171075) compares the efficacy and safety of abelacimab with those of dalteparin in patients at high risk for bleeding, such as those with gastroesophageal cancer, unresected colon cancer, or genitourinary cancer.

Patients with cancer often have central venous catheters (CVCs), including peripherally-inserted central catheters, tunneled catheters, and implanted ports for venous access and delivery of chemotherapy, blood products, and parenteral nutrition. CVCs are associated with a risk of symptomatic upper-extremity deep vein thrombosis (DVT) in up to 5% of cases [9], which can cause pain, arm swelling, and a risk for pulmonary embolism [10,11]. CVC thrombosis is associated with significant morbidity because it can delay cancer treatments, necessitate CVC removal, and lead to postthrombotic syndrome [12]. Previous trials with heparin, low-molecular-weight heparin, or low-dose warfarin have yielded inconsistent results, and no prophylactic regimen has been firmly established [13]. Consequently, there is a need for effective anticoagulant regimens to prevent CVC thrombosis [14].

The purpose of this study was to use the established plate-based assay to compare the efficacy of abelacimab, apixaban, and dalteparin, the anticoagulants being evaluated in the ASTER and MAGNOLIA trials, in preventing catheter-induced clotting and thrombin generation. Based on our previous studies, we hypothesized that abelacimab and dalteparin would be more efficacious than apixaban.

2. Materials and Methods

2.1. Materials

Abelacimab was provided by Anthos Therapeutics. Apixaban and dalteparin were obtained from Pfizer Canada. For comparison purposes, dalteparin concentrations were expressed in molar units using the conversion factor 1 IU/mL = 1.28 μM. Apixaban was dissolved in 100% dimethyl sulfoxide to 10 mg/mL (21.8 mM) and further diluted with a solution of 20 mM N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES) and 150 mM NaCl, pH 7.4 to a final concentration of 10 mM. The activated partial thromboplastin time (aPTT) reagent, APTT-SP HemosIL, was purchased from Instrumentation Laboratory Co. The thrombin-directed fluorescent substrate, Z-Gly-Gly-Arg-AMC, was from Bachem. Cyber guide catheters (6 Fr) were a generous gift from Boston Scientific [5].

2.2. Preparation of pooled human platelet-poor plasma

After obtaining written informed consent, blood was collected from the antecubital veins of at least 17 healthy volunteers using a butterfly needle into 3.5% citrate (9:1 vol/vol), and platelet-poor plasma was obtained, pooled, and stored in aliquots at −80 °C, as previously described [7]. Blood donation protocol was approved by Hamilton Integrated Research Ethics Board, project 16080.

2.3. Effect of abelacimab, apixaban, and dalteparin on the dilute aPTT

Catheters were pressed flat with a hand roller, cut into 1.7-cm segments, rolled into rings, and placed in the periphery of wells of a transparent or black flat-bottom polystyrene 96-well microtiter plate (Corning Costar) as previously described [3]. To wells of a 96-well plate were added 80-μL aliquots of 20 mM HEPES, pH 7.4 (HB), containing up to 1 μM abelacimab, 1.3 μM apixaban (final dimethyl sulfoxide concentration of 1%, an amount that did not affect thrombin generation in control experiments [15]), or 2 μM dalteparin, and 100-μL aliquots of control plasma, as previously described [3]. The dilute aPTT refers to the assay performed using a 1:5 dilution of aPTT reagent in buffer to reduce the phospholipid and contact activator concentrations, thereby enhancing the assay’s sensitivity to FXI inhibition. After incubation for 15 minutes at 37 °C, clotting was initiated by adding 20 μL of 260 mM CaCl2 (final concentration, 26 mM). Absorbance was monitored at 405 nm every 10 seconds for 1 hour using an M3 plate reader (Molecular Devices). The aPTT was defined as the time to reach half-maximal absorbance as calculated by the instrument software. Experiments were repeated 3 times in duplicate.

2.4. Effect of abelacimab, apixaban, and dalteparin on catheter-induced clotting

To wells containing catheter segments, 100 μL of control plasma containing up to 1 μM abelacimab, 1.0 μM apixaban, or 1.3 μM dalteparin and 80 μL HB were added. After 15 minutes of incubation at 37 °C, clotting was initiated by adding CaCl2 and monitored as described above. Each experiment was performed in duplicate 3 times.

2.5. Effect of abelacimab, apixaban, and dalteparin on catheter-induced thrombin generation

To wells containing catheter segments, 100-μL aliquots of control plasma containing 10 μL of apixaban up to 8.5 μM, abelacimab up to 5 μM, and dalteparin up to 1.3 μM were added. These higher drug concentration ranges were selected to ensure that thrombin generation values would be lower than in the controls and to include clinically relevant drug concentrations. The clinically relevant concentrations of abelacimab, apixaban, and dalteparin are 0.1 to 0.3 μM, 75 to 250 ng/mL (0.16-0.5 μM), and 1 to 1.5 IU/mL (1.3-1.95 μM), respectively. After 15 minutes of incubation at 37 °C, 100-μL aliquots of HB containing 15 mM CaCl2 and 1 mM Z-Gly-Gly-Arg-AMC were added to the wells, and substrate hydrolysis was monitored at 1-minute intervals for 90 minutes at 37 °C in an M3 plate reader at excitation and emission wavelengths of 360 nm and 460 nm, respectively, with a cutoff filter set at 455 nm. Thrombin generation profiles were analyzed using Technothrombin TGA software, and the assay was calibrated with the Technothrombin TGA CAL SET according to the manufacturer’s instructions (Technoclone) as previously described [16]. Experiments were repeated 3 times in duplicate.

2.6. Statistical analysis

Results are presented as means ± SD. The significance of differences was determined using a 1-way analysis of variance followed by a Holm-Sidak or Tukey’s comparison test. SigmaPlot (Grafiti LLC) and SPSS (IBM) statistics software were used to create graphs and to perform the statistical analyses, respectively. For all analyses, P values < .05 were considered statistically significant.

3. Results

3.1. Catheter segments promote clotting and thrombin generation

The mean clotting time in the presence of catheter segments was 2.7-fold shorter than in their absence (681 ± 72 seconds and 1862 ± 147 seconds, respectively; P < .001, data not shown). In the thrombin generation assay, the mean peak thrombin concentration was 3.4-fold higher with catheter segments than without (146 ± 6 nM and 43 ± 2 nM, respectively; P < .001, data not shown), and the lag time was 2.8-fold longer with catheter segments than without (25 ± 8 minutes and 9 ± 2 minutes, respectively; P < .001, data not shown). Therefore, consistent with our previous studies [[3], [4], [5], [6], [7]], catheter segments are prothrombotic.

3.2. Abelacimab prolongs the dilute aPTT more than apixaban but less than dalteparin

The dilute aPTT was used to compare the anticoagulant effects of abelacimab, apixaban, and dalteparin. All 3 anticoagulants prolonged the dilute aPTT in a concentration-dependent manner (Figure 1). At a therapeutically relevant dalteparin concentration of 1.3 μM (1 U/mL), the aPTT was approximately 2- and 4-fold longer than with clinically relevant concentrations of abelacimab (0.3 μM) and apixaban (1 μM or 459 ng/mL), respectively. With abelacimab, the aPTT reached a plateau at 1 μM, and the half-maximal inhibitory concentration (IC50) value was 0.2 ± 0.05 μM.

Figure 1.

Figure 1

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Effect of abelacimab, apixaban, and dalteparin on the dilute activated partial thromboplastin time (aPTT). Plasma containing apixaban (squares), abelacimab (circles), or dalteparin (triangles) was incubated with dilute aPTT reagent. Clotting was initiated by recalcification. Clot times were plotted against drug concentration, and the data were fitted to a rectangular hyperbola (lines) to obtain the half-maximal inhibitory concentration (IC50) for abelacimab. The dashed lines reflect the medians of the ranges of therapeutic concentrations of abelacimab (black), apixaban (red), and dalteparin (blue). The symbols represent the mean of 3 experiments, each done in duplicate, whereas the bars reflect the SD.

3.3. Abelacimab and dalteparin attenuate catheter-induced clotting more effectively than apixaban

In the presence of catheter segments, apixaban, abelacimab, and dalteparin attenuated clotting in a concentration-dependent manner (Figure 2). With clinically relevant concentrations of abelacimab (0.3 μM) and dalteparin (1.3 μM), the clotting time was approximately 2500 seconds. In contrast, at a therapeutic concentration of 1 μM, apixaban produced a maximal clotting time of approximately 1000 seconds. The IC50 value with dalteparin was 0.04 ± 0.03 μM, which was significantly (P < .001) lower than the IC50 values for abelacimab (0.12 ± 0.04 μM) and apixaban (0.3 ± 0.01 μM). These findings suggest that dalteparin and abelacimab attenuate catheter-induced clotting to a greater extent than apixaban at clinically relevant concentrations.

Figure 2.

Figure 2

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Effect of abelacimab, apixaban, or dalteparin on catheter-induced clotting times. After incubating catheter segments with plasma containing apixaban (squares), abelacimab (circles), or dalteparin (triangles) at the indicated concentrations for 15 minutes at 37 °C, clotting was initiated by the addition of calcium. Clotting time plots were fitted to a rectangular hyperbola (lines) to determine the half-maximal inhibitory concentration (IC50) values for apixaban, abelacimab, and dalteparin. The dashed lines indicate the medians of the ranges of therapeutic concentrations for abelacimab (black), apixaban (red), and dalteparin (blue). The symbols represent the mean of 3 experiments, each performed in duplicate, whereas the bars reflect the SD.

3.4. Abelacimab and dalteparin attenuate catheter-induced thrombin generation more potently than apixaban

All 3 anticoagulants attenuated catheter-induced thrombin generation in a concentration-dependent manner (Figure 3A–C). At therapeutic concentrations, dalteparin was more potent than abelacimab or apixaban, reducing peak thrombin generation to values below those observed with the no-catheter control (Figure 3D). Abelacimab suppressed thrombin generation to levels comparable to those of no-catheter control and exerted effects greater than those of apixaban. The effects of these agents on endogenous thrombin potential showed a pattern similar to that on peak thrombin concentration (Figure 3E), with dalteparin being more potent, followed by abelacimab and apixaban. All 3 agents prolonged the lag time and time to peak in a concentration-dependent manner (data not shown).

Figure 3.

Figure 3

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Effect of apixaban, abelacimab, or dalteparin on catheter-induced thrombin generation. Catheter segments were incubated with plasma containing varying concentrations of apixaban, abelacimab, and dalteparin. Representative thrombin generation profiles for (A) apixaban up to 8.5 μM, (B) abelacimab up to 5 μM, or (C) dalteparin up to 1.3 μM are shown. Values for peak thrombin and endogenous thrombin potential of apixaban, abelacimab, and dalteparin are shown in (D) and (E), respectively. Thrombin generation values without catheter segments (control) are shown on the y-axis (green circle). The symbols represent the mean of 3 separate experiments, each performed in duplicate, and the bars reflect the SD.

4. Discussion

The ASTER and MAGNOLIA trials are evaluating abelacimab for the treatment of cancer-associated VTE. Because cancer patients frequently have CVCs, device-mediated thrombosis is an ongoing concern [8,9]. Although the ASTER and MAGNOLIA trials were recently stopped, the findings of this study remain relevant because abelacimab is being evaluated for stroke prevention in patients with atrial fibrillation in the ongoing LILAC-TIMI 76 trial, and apixaban is a mainstay for stroke prevention in this population. Patients with atrial fibrillation may undergo percutaneous coronary intervention if they develop acute coronary syndrome. Heparin or low-molecular-weight heparin is routinely administered during percutaneous coronary intervention to prevent catheter thrombosis. Therefore, understanding how abelacimab and apixaban compare with dalteparin in preventing catheter thrombosis remains relevant.

Previous work has established that catheters induce clotting via the intrinsic pathway by activating FXII and FXI [[2], [3], [4], [5], [6], [7]]. The relative potency of abelacimab, apixaban, and dalteparin in suppressing catheter-induced clotting likely reflects their mechanisms of action. Dalteparin is an indirect anticoagulant consisting of polydisperse heparin chains with a mean molecular weight of ∼5000 Da that potentiates antithrombin-mediated irreversible inhibition of FXa and thrombin, as well as enzymes of the intrinsic pathway, including FXIIa, FXIa, and FIXa [17]. In contrast, abelacimab and apixaban are direct anticoagulants that target FXI and FXa, respectively. Because it has multiple targets in the intrinsic and common pathways of coagulation, it is not surprising that dalteparin has a more potent effect on the aPTT, catheter-induced clotting, and thrombin generation. Conversely, by blocking FXI activation and FXIa activity, abelacimab prolongs the aPTT and attenuates catheter-induced clotting and thrombin generation. As previously reported [18], the effect of abelacimab on the aPTT plateaus, likely reflecting the extremely tight binding of FXI by the antibody. Catheter-induced clotting and thrombin generation are almost completely suppressed at an abelacimab concentration of about 0.3 μM, which is the concentration achieved with a monthly abelacimab dose of 150 mg [19]. Consistent with the potency of abelacimab and dalteparin observed in our study, a recent publication reported greater suppression of catheter-induced thrombin generation with abelacimab than with asundexian or milvexian, which are oral FXIa inhibitors, but less potent suppression with abelacimab than with enoxaparin [18]. Consistent with our previous observations that apixaban has a less pronounced effect on the aPTT and thrombin generation than rivaroxaban [20] and attenuates catheter-induced clotting less potently than rivaroxaban and enoxaparin [7], the reversible inhibitor apixaban is the least potent of the 3 anticoagulants for prolonging the aPTT and attenuating catheter-induced clotting and thrombin generation. Therefore, the results of this study suggest that dalteparin and abelacimab may be more effective than apixaban at preventing catheter clotting.

A limitation of using the thrombin generation assay to compare these agents is that they have different mechanisms of action: dalteparin and abelacimab affect thrombin generation upstream, whereas apixaban, as a direct FXa inhibitor, attenuates it downstream. Therefore, comparisons of thrombin generation readouts across these mechanistically distinct agents should be interpreted as functional in vitro observations rather than as evidence of mechanistic equivalence.

Findings from a static, plate-based catheter thrombosis model may not recapitulate the complex events that occur in humans. Additionally, all experiments were performed in platelet-poor plasma; studies in platelet-rich plasma may provide complementary information. Nonetheless, our previous demonstration that fondaparinux was less effective than enoxaparin at attenuating catheter thrombosis in platelet-poor plasma using this plate-based assay [4] was consistent with catheter thrombosis observed during percutaneous coronary intervention in patients randomized to fondaparinux in the Fifth and Sixth Organization to Assess Strategies in Ischemic Syndromes (OASIS-5 and OASIS-6 trials) [21]. In addition, we previously demonstrated that high concentrations of dabigatran were needed to suppress catheter clotting in this plate-based model and in a rabbit jugular vein catheter thrombosis model [22]. Finally, in a plate-based assay, we demonstrated that dabigatran and apixaban were less effective than warfarin at attenuating mechanical heart valve-induced thrombin generation [15]. These findings may explain why there were more strokes with dabigatran and apixaban than with warfarin in the RE-ALIGN (Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients after Heart Valve Replacement) and PROACT Xa (A Trial to Determine if Participants With an On-X Aortic Valve Can be Maintained Safely on Apixaban) trials [23,24]. Therefore, our in vitro findings in these plate-based assays may be clinically significant.

REGN9933 and REGN7508 are monoclonal antibodies that bind distinct domains of FXI. REGN9933 binds the apple 2 domain and blocks FXI activation by FXIIa, whereas REGN7508, like abelacimab, binds the catalytic domain and blocks FXI activation by FXIIa and thrombin, as well as FXIa activity [25]. The ongoing phase 2 ROXI-Cath trial (A Trial to Learn How Well REGN9933 and REGN7508 Work for Preventing Blood Clots, and How Safe They Are, in Adults Who Have a Peripherally Inserted Central Catheter; NCT06299111) is comparing each of these antibodies with a placebo to prevent catheter-induced clotting.

In summary, abelacimab and dalteparin are more potent than apixaban at reducing catheter-induced clotting and thrombin generation in vitro. A dedicated placebo-controlled trial, ROXI-Cath (NCT06299111), is underway to compare 2 FXI inhibitors, REGN9933 and REGN7508, with placebo in patients with peripherally inserted central catheters. Based on our study results, a similar trial with abelacimab may be warranted.

Acknowledgments

J.I.W. holds the Heart and Stroke Foundation J. Fraser Mustard Chair in Cardiovascular Research and the Canada Research Chair (Tier 1) in Thrombosis.

Funding

This work was supported, in part, by grants-in-aid from the Canadian Institutes of Health Research (FDN-159928) and the Heart and Stroke Foundation of Canada (G-16-00013163).

Author contributions

R.Y. designed the research, performed experiments, analyzed and interpreted the data, and wrote the manuscript. X.G. performed experiments and analyzed the data. J.C.F. and J.I.W. designed the experiments, analyzed and interpreted the data, and wrote the manuscript.

Relationship Disclosure

J.I.W. has served as a consultant and received honoraria from Anthos, Bristol-Myers Squibb, Johnson and Johnson, and Novartis. The other authors declare no competing financial interests.

Footnotes

Handling Editor: Professor Michael Makris

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