A narrative literature review on the clinical utility of activated partial thromboplastin time and anti-factor Xa activity assays in cancer patients with anticoagulant therapy

Introduction

Thromboembolic events represent one of the most common complications in cancer patients, drawing widespread attention due to their high incidence and mortality rates, which ranks second only to cancer progression itself (1,2). Venous thromboembolism (VTE), as the most prevalent thromboembolic event, affects 4–20% of cancer patients (1,3). Compared to the general population, malignancy patients face a 4–7-fold elevated risk of developing VTE (4). VTE is the most common cause of death during postoperative 30-day follow-up in cancer patients; it accounts for approximately 9% of deaths among hospitalized malignancy patients and has become the primary cause of mortality beyond cancer progression in this population (5,6). The pathogenesis of cancer-associated thromboembolic events involves multiple risk factors, broadly categorized as patient-related factors (including a history of VTE, advanced age, obesity, infection, inherited thrombophilia, pre-chemotherapy thrombocytosis, leukocytosis, and hemoglobin levels <100 g/L—the latter also predicting VTE risk in chemotherapy-treated patients), cancer-related factors (such as tumor type, primary site, and stage), and treatment-related factors (encompassing surgical interventions such as major abdominal or pelvic surgery, central venous catheter placement, chemotherapy, and other systemic therapies), all collectively contributing to thrombotic risk (7-9).

For all patients with malignant tumors, it is essential to discuss both the risk of VTE and the bleeding risk associated with anticoagulation, and conduct regular dynamic assessments during treatment to ensure benefits outweigh risks (10). The evidence base for primary VTE prevention with prophylactic anticoagulation in cancer patients receiving chemotherapy continues to mature (3,5). The updated 2023 American Society of Clinical Oncology (ASCO) guideline suggests using prophylactic doses of anticoagulants such as rivaroxaban or apixaban for chemotherapy patients with a Khorana score ≥2, but recommends against the routine use of prophylactic-dose non-vitamin K antagonist oral anticoagulants (NOAC) (5). It is noteworthy that when using direct oral anticoagulants (DOACs), particularly in patients with gastrointestinal malignancies or underlying urogenital malignancies, there is an increased risk of bleeding (10-12). Although a meta-analysis of multiple recent randomized controlled trials (RCTs) demonstrated that DOACs significantly reduce the risk of cancer-associated thrombosis (CAT) recurrence [risk ratio (RR) =0.67; 95% confidence interval (CI): 0.52–0.85] compared to low-molecular-weight heparins (LMWHs), they also show a non-significant increase in the risk of major bleeding (MB) (RR =1.17; 95% CI: 0.82–1.67) (13). In addition, another meta-analysis demonstrated that extended thromboprophylaxis fails to significantly reduce the risk of VTE [odds ratio (OR) =0.85; 95% CI: 0.61–1.18] in medically ill patients with cancer, while approximately doubling the bleeding rate (OR =2.10; 95% CI: 1.33–3.35) (14). In a study of cancer patients, the cumulative incidences of clinically relevant bleeding (CRB) and MB were 14.4% (95% CI: 11.2–17.5%) and 7.0% (95% CI: 4.7–9.2%), respectively, in the non-anticoagulated subgroup. In contrast, the overall cohort demonstrated higher incidences of 16.6% (95% CI: 13.7–19.6%) for CRB and 9.1% (95% CI: 6.8–11.3%) for MB. These findings indicate that anticoagulant therapy is associated with an increased risk of bleeding in this population, as evidenced by the elevated event rates observed in anticoagulated patients (15). Current clinical consensus holds that during anticoagulant therapy, subtherapeutic dosing may elevate thrombotic risk while supratherapeutic dosing can increase bleeding risk (16,17). Following endoscopic submucosal dissection (ESD) for gastrointestinal tumors, the overall risk of bleeding is estimated at 5–8%. However, this risk substantially increases to 8.7–20.8% in patients receiving DOACs, representing a significantly higher incidence compared to patients not on anticoagulant therapy (18). Therefore, the implementation of therapeutic drug monitoring is particularly crucial for cancer patients receiving anticoagulation to ensure an optimal balance between thrombosis prevention and hemorrhage control.

Unfractionated heparin (UFH), LMWHs, oral vitamin K antagonists (e.g., warfarin), and targeted activated factor Xa inhibitors (e.g., rivaroxaban) are currently the predominant anticoagulants used clinically (17,19-21). Among these, UFH and warfarin exhibit complex pharmacokinetics and pharmacodynamics, resulting in highly variable dosing requirements and narrow therapeutic ranges that necessitate frequent laboratory monitoring and dose adjustments (22). Prothrombin time (PT) and international normalized ratio (INR) monitoring for warfarin have been well-validated and are widely implemented (23-25). Conversely, conventional activated partial thromboplastin time (aPTT) monitoring for UFH is increasingly challenged by anti-factor Xa (anti-Xa) activity assays, particularly for LMWHs and DOACs such as rivaroxaban, where anti-Xa assays demonstrate superior suitability compared to aPTT (26-28). A direct linear relationship between anti-Xa activity and plasma levels has been validated for both apixaban and rivaroxaban (18). With advancements in the understanding of anticoagulation, anti-Xa activity testing has gained broader clinical adoption as a novel monitoring approach. However, correlating anti-Xa results with clinical outcomes remains challenging and requires validation through large-scale RCTs. This review comprehensively analyzes the characteristics of anticoagulants suitable for aPTT versus anti-Xa monitoring and synthesizes recent clinical advancements in both monitoring methodologies in cancer patients. We present this article in accordance with the Narrative Review reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1944/rc).

Methods

A comprehensive narrative literature review was conducted to evaluate the clinical utility of aPTT and anti-Xa assays in cancer patients receiving anticoagulant therapy. The search strategy adhered to the Scale for the Assessment of Narrative Review Articles (SANRA) framework to ensure methodological rigor. Literature searches spanned from January 2010 to August 2025, covering PubMed, MEDLINE, Embase, and the Cochrane Library as primary databases, with Web of Science and Scopus as supplementary sources. Included publications were restricted to: Peer-reviewed original research, systematic reviews, meta-analyses, and clinical guidelines, English-language publications, human studies encompassing RCTs, cohort studies, case-control studies, and cross-sectional analyses. Case reports were explicitly excluded.

Combinations of controlled vocabulary (MeSH terms) and free-text keywords were used as (“neoplasms” OR “cancer” OR “malignancy”) AND (“anticoagulant therapy” OR “low molecular weight heparin” OR “direct oral anticoagulants” OR “unfractionated heparin”) AND (“activated partial thromboplastin time” OR “aPTT” OR “anti-factor Xa” OR “anti-Xa”) AND (“monitoring” OR “dose adjustment” OR “bleeding risk” OR “thrombosis recurrence”).

Study selection was performed independently by two investigators (H.X.L. and L.H.S.), both trained in systematic review methodology. A two-phase screening process was implemented: Phase 1 (Title/Abstract Screening): articles were included if they investigated the correlation between aPTT/anti-Xa assays and clinical outcomes (bleeding, thrombosis, mortality) in anticoagulated cancer patients. The exclusion criteria were as follows: animal studies, non-English publications, and studies involving non-relevant populations (e.g., non-cancer patients). Phase 2 (Full-Text Assessment): eligible publications underwent thorough evaluation with focused data extraction on aPTT and anti-Xa assays in cancer patients receiving anticoagulant therapy (Table 1).

Discussion and summary

Principles of aPTT and anti-Xa assays

Principles of aPTT assay

Blood coagulation constitutes a sophisticated physiological mechanism essential for hemorrhage control and wound repair, mediated through intricate biochemical processes culminating in clot formation. Initial hemostatic responses to vascular injury involve two sequential phases: Primary hemostasis initiates immediately post-injury via vasoconstriction reducing local blood flow, platelet adhesion to exposed subendothelial collagen, and the formation of a provisional platelet plug sealing the damaged vessel. Secondary hemostasis subsequently stabilizes this plug through fibrin deposition, comprising a proteolytic cascade that converts fibrinogen to insoluble fibrin with the intrinsic and extrinsic pathways.

aPTT, a clot-based coagulation assay, demonstrates specific sensitivity to intrinsic pathway and common pathway factor deficiencies (29). The intrinsic coagulation pathway initiates when blood contacts negatively charged surfaces such as exposed collagen in damaged vessels, triggering factor XII activation; this subsequently induces sequential proteolytic reactions wherein factor XIIa catalyzes the conversion of XI to XIa, which then complexes with cofactor VIII to activate IX to IXa, culminating in IXa assembling with VIII and Ca²⁺ to form the tenase complex that cleaves factor X into its active form (Xa). The extrinsic coagulation pathway initiates when extravascular tissue damage releases tissue factor (TF), which forms a catalytic complex with factor VII that induces its proteolytic activation to VIIa. This VIIa-TF complex subsequently activates Factor X to Xa, representing the critical convergence point with the intrinsic pathway. Ultimately, Xa assembles with factor V and Ca2+ to constitute the prothrombinase complex, executing thrombin generation through cleavage of prothrombin (II) to thrombin (IIa). As the terminal protease in coagulation cascades, thrombin catalyzes the proteolytic conversion of fibrinogen to fibrin. Clinically, global hemostatic function is evaluated through complementary gold standard assays: PT quantifies extrinsic pathway integrity by measuring clot latency in citrated plasma following TF stimulation, specifically interrogating factors I (fibrinogen), II, V, VII, and X; concurrently, aPTT assesses intrinsic pathway competence via clot formation kinetics triggered by contact phase activators, with diagnostic sensitivity spanning factors I, II, V, VIII, IX, X, XI, and XII (Figure 1A) (29,30).

Figure 1 Principles of aPTT and anti-Xa assays. Schematic diagrams depict the operational workflows for aPTT (A) and anti-Xa assays (B). anti-Xa, anti-factor Xa; aPTT, activated partial thromboplastin time; AT, antithrombin; CS, chromogenic substrate; PT, prothrombin time; rXa, residual Xa.

Principles of anti-Xa assay

The anti-Xa assay is primarily utilized for monitoring the anticoagulant efficacy of anti-Xa agents, including UFH, LMWHs, and direct anti-Xa inhibitors (e.g., rivaroxaban). Its methodology involves incubating test specimens with excess Xa reagent, during which target anti-Xa drugs neutralize the reagent’s Xa activity. Calibration is performed using corresponding anti-Xa drug standards, followed by quantification of residual Xa activity via chromogenic substrate hydrolysis or clotting time measurement. This allows precise quantification of anticoagulant drug levels to determine therapeutic effectiveness (Figure 1B) (31).

As a pharmacodynamic assay, anti-Xa activity testing must incorporate the pharmacokinetic profiles of anticoagulants. UFH typically achieves peak plasma concentrations 3–6 hours post-administration with trough levels at 12–16 hours, necessitating anti-Xa monitoring at 4 hours during deep venous thrombosis (DVT) treatment (therapeutic range: 0.3–0.7 kU/L). Similarly, LMWHs require testing 4 hours post-subcutaneous injection: for twice-daily enoxaparin or nadroparin, targets are 0.6–1.0 kU/L; once-daily regimens require enoxaparin >1.0 kU/L, nadroparin 1.3 kU/L, dalteparin 1.05 kU/L, and tinzaparin 0.85 kU/L (32). Clinician-guided dose adjustments are indicated based on anti-Xa results.

aPTT and anti-Xa monitoring in patients with cancer

aPTT monitoring in patients with cancer

A prospective multicenter Japanese study involving VTE patients treated with edoxaban demonstrated consistent anticoagulant effects between cancer and non-cancer cohorts, as evidenced by comparable PT and aPTT measurements (e.g., log-transformed aPTT: 3.55 vs. 3.55; P=0.45). These findings confirm that edoxaban exerts equivalent therapeutic efficacy in cancer-associated VTE and non-cancer VTE cases (33). In patients with abnormally prolonged aPTT who lack bleeding manifestations, factor XII deficiency should be highly suspected (34). Patients developing central venous catheter-associated VTE during cancer treatment demonstrated significantly shorter aPTT than those without VTE [25.6 s (95% CI: 23.2–27.9) vs. 28.1 s (95% CI: 26.9–29.3); P=0.001] (35). Preoperative elevations in PT and aPTT predicted poorer overall survival (OS) and disease-free survival (DFS) in colorectal cancer (CRC) patients, with significant outcome differences observed across risk strata: low-risk (PT <11.85 s and aPTT <25.85 s), medium-risk (PT ≥11.85 s or aPTT ≥25.85 s), and high-risk (PT ≥11.85 s and aPTT ≥25.85 s) (36). Multiple myeloma patients with prolonged coagulation times (PT or aPTT) demonstrated significantly reduced survival outcomes versus those with normal parameters: median OS 37.5 vs. 73.8 months [hazard ratio (HR) =2.100; 95% CI: 1.525–2.893; P<0.001] and progression-free survival (PFS) 23.1 vs. 31.6 months (P=0.001) (37). In patients with hematologic malignancies such as acute lymphoblastic leukemia (ALL), dynamic changes in aPTT during treatment correlate significantly with survival outcomes. Persistently abnormal aPTT levels throughout therapy indicate greater disease severity and predict comparatively poorer OS (38). The aforementioned studies (33-39) demonstrate that aPTT holds significant clinical utility for monitoring applications in malignancy management, spanning diagnosis, prognostic implications, and anticoagulation regimens.

Patients with malignancies exhibit elevated risks for VTE. Current anticoagulants for VTE prevention and treatment in this population primarily include LMWH, vitamin K antagonists (VKAs), and DOACs, each presenting unique challenges (5,40). LMWH requires daily subcutaneous administration, which may compromise patient adherence and cause injection-site adverse reactions with prolonged use. VKAs possess a narrow therapeutic window necessitating frequent INR monitoring for dose adjustment, a particularly complex undertaking in malignancy patients due to comorbidities, polypharmacy, and dynamic disease states. DOACs offer convenient oral administration without routine monitoring but demonstrate contested safety and efficacy profiles in oncology settings, with studies suggesting potentially elevated bleeding risks in certain tumor subtypes (20,41). Furthermore, significant interpatient heterogeneity in tumor types, disease stages, treatment modalities, and comorbid conditions critically influences anticoagulation selection and therapeutic outcomes. Consequently, developing individualized anticoagulation strategies with tailored efficacy monitoring protocols constitutes a pressing clinical challenge in contemporary oncological practice. In a single-center retrospective study comparing anticoagulation regimens in lung cancer patients undergoing video-assisted lobectomy, significant differences emerged between LMWH [4,000 IU, quaque die (QD)] and UFH [5,000 IU, bis in die (BID)]. The heparin group demonstrated clinically significant elevations in both intraoperative blood loss (105.11 vs. 50.26 mL; P<0.001) and postoperative mean drainage volume (251.52 vs. 216.90 mL; P=0.03) compared to the LMWH cohort. Furthermore, postoperative aPTT measurements were significantly prolonged in the heparin group (30.17 vs. 28.20 s; P=0.02), indicating enhanced anticoagulant effects (42). Significant aPTT prolongation has been reported following prophylactic-dose UFH administration in benign or malignant brain tumors (43). In lung cancer patients undergoing video-assisted thoracoscopic lobectomy, the LMWH treatment group exhibited significantly prolonged aPTT on postoperative day 1 compared to the non-LMWH group. However, no significant intergroup differences were observed preoperatively, perioperatively, or on postoperative day 2. These findings do not support aPTT as a reliable monitoring parameter for LMWH efficacy, necessitating the implementation of additional clinical markers for therapeutic assessment (44). A small-scale Chinese cohort study demonstrated comparable clinical efficacy between preoperative (12-hour pre-surgery, n=56) and postoperative (24-hour post-surgery, n=506) administration of prophylactic-dose LMWH for thromboprophylaxis (45). The analysis revealed no statistically significant intergroup differences in key coagulation parameters, including PT (11.5±3.9 vs. 11.4±1.4 s), aPTT (27.8±3.5 vs. 28.3±4.0 s), or INR (0.96±0.06 vs. 0.98±0.07). Critically, this research framework intentionally avoided reliance on single-parameter aPTT monitoring for therapeutic assessment. Instead, a multidimensional evaluation protocol was implemented incorporating, such as in comprehensive coagulation profiles, perioperative blood loss quantification, postoperative drainage volume measurement, and pulmonary embolism incidence tracking (45). Furthermore, the majority of studies indicated that aPTT exhibits considerable dose- and reagent-dependent variability in response to DOACs. Consequently, aPTT cannot be safely used to determine the degree of anticoagulation achieved with DOAC therapy (46,47).

Anti-Xa monitoring in patients with cancer

The anti-Xa assay can be utilized for monitoring UFH, LMWH, and rivaroxaban (18,48-50). Although anti-Xa testing is not fully standardized, it provides more reliable monitoring for heparins compared to aPTT. Research has demonstrated that when anti-Xa levels reach 0.3 IU/mL, corresponding aPTT values show significant variability (47–108 s), and patients within the conventional aPTT therapeutic range frequently exhibit subtherapeutic anti-Xa levels and protamine titration assays. Due to the poor dose-dependent correlation between aPTT and plasma heparin concentrations, laboratory-specific calibration of aPTT ranges against anti-Xa activity is required to align the aPTT monitoring window (target anti-Xa equivalent: 0.3–0.7 IU/mL) (51,52). Given that multiple biologic variables can affect aPTT independently of UFH effects, many institutions have transitioned to monitoring anti-Xa levels (target range, 0.3–0.7 IU/mL) as a replacement for aPTT-guided heparin management (48-50). Clinical evidence over the past 10–20 years has demonstrated that switching from aPTT to anti-Xa monitoring achieves a flatter dose-response curve, resulting in more stable anticoagulation levels, reduced blood sampling frequency, and fewer dose adjustments (48-50). Considering the only marginally higher cost for anti-factor Xa reagents, this approach represents an economical method for monitoring heparin activity (48-50).

In non-oncological brain-injured patients, the use of anti-Xa-guided dosing for LMWH may reduce the incidence of DVT [adjusted odds ratio (aOR): 0.52; 95% CI: 0.40–0.69], pulmonary embolism (aOR: 0.48; 95% CI: 0.30–0.78), or any VTE (aOR: 0.54; 95% CI: 0.42–0.69) compared to fixed-dose regimens. However, all effect estimates are derived from evidence of low certainty (53). Pharmacokinetic profiling of LMWH in patients with locally advanced or metastatic malignancies revealed significantly reduced anti-Xa activity compared to historical controls: Pre-injection median anti-Xa levels measured 0.24 IU/mL (range, 0.07–0.70 IU/mL) versus 0.52 IU/mL in controls. At 4 hours post-administration, median anti-Xa activity reached 0.58 IU/mL (range, 0.22–1.23 IU/mL), substantially lower than the control value of 1.2 IU/mL. This preliminary investigation demonstrated that a clinically significant proportion of cancer patients with venous thrombosis receiving therapeutic LMWH regimens exhibited subtherapeutic anti-Xa states (54). The study by Shin et al. (55) demonstrated a strong correlation (R=0.97) between UFH-calibrated anti-Xa activity and plasma rivaroxaban concentration in patients with CAT. The UFH-calibrated anti-Xa assay exhibited sufficient sensitivity for rivaroxaban detection, supporting its utility in assessing anticoagulant levels during critical clinical events. When rivaroxaban-specific anti-Xa testing is unavailable, the chromogenic anti-Xa assay calibrated for UFH serves as a viable alternative for monitoring rivaroxaban anticoagulation (55). A study of patients with VTE and VTE complicated by concomitant malignancy revealed that anti-Xa levels were not correlated with the presence of cancer, age, sex, or estimated glomerular filtration rate (eGFR). Anti-Xa concentrations exclusively reflected bemiparin treatment concentrations. These findings indicate anti-Xa activity as a robust monitoring parameter for anticoagulation management in cancer patients (56). A study investigating enoxaparin dose adjustment guided by anti-Xa activity versus weight-based dosing found no significant difference in recurrent VTE or MB rates among cancer patients receiving initial treatment for VTE. The composite endpoint (recurrent VTE, major bleed, or all-cause death) occurred in 102 of 283 patients (36%) in the anti-Xa monitored cohort versus 166 of 391 patients (42.5%) in the weight-based cohort (HR =0.73; 95% CI: 0.57–0.93; P=0.01). However, when mortality was excluded from the composite outcome, no statistically significant difference persisted between the cohorts for recurrent VTE or MB alone (HR =1.18; P=0.38) (57). In a prostate cancer patient receiving enoxaparin therapy at 1 mg/kg every 12 hours, deterioration of renal function (estimated creatinine clearance of 30 mL/min) developed after 4 weeks, accompanied by extensive hematomas in the back and flank regions. Following stabilization of hemoglobin and renal parameters, anticoagulation was resumed with a 25% dose reduction. Subsequent serial peak anti-Xa level monitoring demonstrated values consistently ranging between 0.7 and 0.9 IU/mL. No further hemorrhagic or thrombotic complications occurred during the observation period. This evidence synthesis, incorporating both the presented case and extant literature, supports the recommendation that in patients with severe renal impairment (creatinine clearance ≤30 mL/min), anti-Xa activity monitoring should be instituted when LMWH therapy is clinically indicated (58). Conversely, a lack of standardized methodology demonstrated a consistent correlation between anti-Xa testing and clinical outcomes. Anti-Xa assays are most frequently performed (57.4%) in patients with active malignancy receiving therapeutic-dose anticoagulation for VTE. Patients with out-of-range anti-Xa levels exhibit a fourfold higher likelihood of LMWH regimen modification compared to those within therapeutic range (OR =4.16; 95% CI: 2.53–6.84). However, despite abnormal results, LMWH dosing remains unchanged in one-third to one-half of cases. The majority of tests fall within therapeutic thresholds, suggesting limited necessity for routine monitoring even in high-risk populations. Moreover, most out-of-range results do not precipitate therapeutic adjustments. Future multicenter trials are warranted to establish whether anti-Xa-guided LMWH dosing translates into improved clinical endpoints (59). In cancer patients, particularly those post-gastrectomy, DOACs, specifically factor Xa inhibitors, exhibit adequate systemic absorption, as evidenced by measurable increases in anti-Xa activity following administration. However, caution is warranted in this subpopulation, as evidenced by an observed recurrent thromboembolic event in a patient receiving dabigatran. This suggests that although pharmacokinetic exposure is achievable, therapeutic efficacy may be compromised in certain surgical cohorts, necessitating individualized risk–benefit assessment (60). In a gynecologic oncology surgery postoperative thromboprophylaxis protocol, 63% of patients receiving a fixed-dose LMWH regimen had peak anti-Xa levels below the target range (0.2–0.4 IU/mL), indicating that monitoring anti-Xa levels is significant for adjusting LMWH doses (61). Among the 83 patients who underwent lower extremity ultrasound during the perioperative period for CRC, enoxaparin was administered for 5 days from postoperative day 1 to day 5. Three patients (3.6%) had hemorrhagic events; however, there was no significant trend for anti-Xa factor activity (62). Sayar et al. (63) found that the use of poly(ADP-ribose) polymerase inhibitors (PARPi) in cancer patients leads to elevated anti-Xa levels, consequently necessitating DOAC dose adjustment. The primary reason is that the PARPi increases plasma levels of rivaroxaban in some patients, presumably via cytochrome P450 3A4 (CYP3A4)/P-glycoprotein inhibition. In patients with head and neck or breast cancer receiving standard fixed-dose enoxaparin for VTE prophylaxis, peak anti-Xa levels are frequently subprophylactic. This is evidenced by mean anti-Xa levels of 0.13±0.09 IU/mL in VTE patients and 0.11±0.07 IU/mL in bleeding patients, which were significantly below the target prophylactic range of 0.2–0.5 IU/mL (64). These findings indicate that relying solely on anti-Xa monitoring may mask underlying bleeding risks during thromboprophylaxis. Overall, current guidelines predominantly recommend anti-Xa monitoring for routine coagulation management in cancer patients. However, its accuracy may be compromised by interference from targeted therapies (e.g., PARPi) or transitions between anticoagulants. Notably, when switching to UFH, supplemental aPTT analysis becomes essential due to UFH’s distinct monitoring requirements.

The association of aPTT and anti-Xa assays

In coagulation testing, aPTT and anti-Xa assays play complementary roles. aPTT primarily reflects the overall status of the intrinsic pathway, whereas anti-Xa specifically quantifies the inhibitory effect of anticoagulant drugs on factor Xa. Their combined use provides a more comprehensive assessment of hemostatic status (65). Numerous institutions have explored discontinuing aPTT monitoring. However, the widespread adoption of oral Xa inhibitors has introduced new challenges for anti-Xa-based protocols. In response, May et al. (47) implemented a stratified approach: anti-Xa assays remain the preferred method for most patients, but aPTT monitoring is reintroduced specifically for individuals transitioning from oral Xa inhibitors to enoxaparin. Shusterman et al. (43) proposed a stepwise monitoring protocol for UFH therapy: when aPTT exceeds the upper limit of normal and is >1.5 times the patient’s baseline value with a persistent upward trend, anti-Xa monitoring should be initiated (Table 2). Subsequent UFH dosing should be maintained if anti-Xa levels are ≥0.3 IU/mL, whereas dose reduction may be considered only when anti-Xa falls below 0.3 IU/mL. In cirrhosis patients, impaired hepatic synthesis of coagulation factors causes discordant laboratory findings that aPTT becomes elevated while anti-Xa levels decrease. Consequently, clinical decision-making requires simultaneous assessment of both parameters to establish safe and effective anticoagulation strategies (66). In addition, the sensitivity and specificity of aPTT and anti-Xa assays remain clinically debated. aPTT often demonstrates insufficient sensitivity for monitoring certain anticoagulants or coagulation abnormalities. For instance, research on edoxaban-treated patients revealed aPTT’s inadequacy in quantifying edoxaban’s anticoagulant activity. Conversely, anti-Xa assays exhibit linear correlations across wide edoxaban concentrations but show significant variability at supratherapeutic levels (67). Similarly, both PT and aPTT poorly detect apixaban concentrations, whereas anti-Xa assays demonstrate strong plasma concentration correlations, though methodological heterogeneity and confounding variables affect their reliability (68). Research of neonatal UFH further highlights inconsistent correlations between aPTT and anti-Xa measurements, complicating accurate anticoagulation monitoring (69). Collectively, these limitations in sensitivity and specificity necessitate methodological refinements or multi-parameter integration for comprehensive clinical assessment.

Limitations

This narrative review has several inherent limitations: (I) restriction to English-language publications may have introduced selection bias against significant non-English evidence; (II) as a narrative review, the methodology lacks formal systematic assessment of study quality, which may affect conclusions about assay reliability; (III) the findings highlight insufficient evidence linking anti-Xa levels to clinical outcomes, a critical knowledge gap that inherently limits the review’s ability to establish evidence-based monitoring thresholds; (IV) despite advocating for combined assay use, the review could not resolve fundamental standardization challenges due to heterogeneous primary data.

Conclusions

In summary, anti-Xa activity assays are increasingly recognized as the gold standard for monitoring anti-Xa agents among clinicians. Both LMWHs and NOACs require rigorous monitoring in specific clinical contexts to achieve individualized anticoagulation, a clinically critical challenge demanding the precise management of subtherapeutic dosing and overdosing. Although aPTT remains the preferred method for routine UFH monitoring, special circumstances such as cancer patients undergoing targeted therapies or during transitions between anticoagulants, may necessitate switching from anti-Xa monitoring to aPTT measurements, or potentially concurrent monitoring of both parameters. Moreover, current evidence insufficiently establishes direct causal relationships between aPTT/anti-Xa results and clinical outcomes. The poor correlation between these methodologies further complicates clinicians’ ability to formulate evidence-based anticoagulation regimens, particularly highlighted in studies of anticoagulated patients with cancer.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1944/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1944/prf

Funding: This work was supported by the Health Commission of Hebei Province (No. 20211135).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1944/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Khorana AA, Mackman N, Falanga A, et al. Cancer-associated venous thromboembolism. Nat Rev Dis Primers 2022;8:11. [Crossref] [PubMed]
2. Farge D, Frere C, Connors JM, et al. 2022 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer, including patients with COVID-19. Lancet Oncol 2022;23:e334-47. [Crossref] [PubMed]
3. Guntupalli SR, Spinosa D, Wethington S, et al. Prevention of venous thromboembolism in patients with cancer. BMJ 2023;381:e072715. [Crossref] [PubMed]
4. Prouse T, Mohammad MA, Ghosh S, et al. Pancreatic Cancer and Venous Thromboembolism. Int J Mol Sci 2024;25:5661. [Crossref] [PubMed]
5. Key NS, Khorana AA, Kuderer NM, et al. Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Guideline Update. J Clin Oncol 2023;41:3063-71. [Crossref] [PubMed]
6. Trujillo-Santos J, Casas JM, Casado I, et al. Thirty-day mortality rate in women with cancer and venous thromboembolism. Findings from the RIETE Registry. Thromb Res 2011;127:S1-4. [Crossref] [PubMed]
7. Mahé I, Mayeur D, Couturaud F, et al. Anticoagulant treatment of cancer-associated thromboembolism. Arch Cardiovasc Dis 2024;117:29-44. [Crossref] [PubMed]
8. Falanga A, Marchetti M. Cancer-associated thrombosis: enhanced awareness and pathophysiologic complexity. J Thromb Haemost 2023;21:1397-408. [Crossref] [PubMed]
9. Girardi L, Wang TF, Ageno W, et al. Updates in the Incidence, Pathogenesis, and Management of Cancer and Venous Thromboembolism. Arterioscler Thromb Vasc Biol 2023;43:824-31. [Crossref] [PubMed]
10. Key NS, Khorana AA, Kuderer NM, et al. Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update. J Clin Oncol 2020;38:496-520. [Crossref] [PubMed]
11. Schaefer JK, Elshoury A, Nachar VR, et al. How to Choose An Appropriate Anticoagulant for Cancer-Associated Thrombosis. J Natl Compr Canc Netw 2021;19:1203-10. [Crossref] [PubMed]
12. Fioretti AM, Leopizzi T, La Forgia D, et al. Abelacimab in Cancer-Associated Thrombosis: The Right Drug at the Right Time for the Right Purpose. A Comprehensive Review. Rev Cardiovasc Med 2023;24:295. [Crossref] [PubMed]
13. Frere C, Farge D, Schrag D, et al. Direct oral anticoagulant versus low molecular weight heparin for the treatment of cancer-associated venous thromboembolism: 2022 updated systematic review and meta-analysis of randomized controlled trials. J Hematol Oncol 2022;15:69. [Crossref] [PubMed]
14. Osataphan S, Patell R, Chiasakul T, et al. Extended thromboprophylaxis for medically ill patients with cancer: a systemic review and meta-analysis. Blood Adv 2021;5:2055-62. [Crossref] [PubMed]
15. Englisch C, Moik F, Steiner D, et al. Bleeding events in patients with cancer: incidence, risk factors, and impact on prognosis in a prospective cohort study. Blood 2024;144:2349-59. [Crossref] [PubMed]
16. Mahé I, Carrier M, Mayeur D, et al. Extended Reduced-Dose Apixaban for Cancer-Associated Venous Thromboembolism. N Engl J Med 2025;392:1363-73. [Crossref] [PubMed]
17. Douketis JD, Spyropoulos AC. Perioperative Management of Patients Taking Direct Oral Anticoagulants: A Review. JAMA 2024;332:825-34. [Crossref] [PubMed]
18. Sugimoto M, Murata M, Kawai T. Assessment of delayed bleeding after endoscopic submucosal dissection of early-stage gastrointestinal tumors in patients receiving direct oral anticoagulants. World J Gastroenterol 2023;29:2916-31. [Crossref] [PubMed]
19. Martins MA, Silva TF, Fernandes CJ. An Update in Anticoagulant Therapy for Patients with Cancer-Associated Venous Thromboembolism. Curr Oncol Rep 2023;25:425-32. [Crossref] [PubMed]
20. Schrag D, Uno H, Rosovsky R, et al. Direct Oral Anticoagulants vs Low-Molecular-Weight Heparin and Recurrent VTE in Patients With Cancer: A Randomized Clinical Trial. JAMA 2023;329:1924-33. [Crossref] [PubMed]
21. Falanga A, Ay C, Di Nisio M, et al. Venous thromboembolism in cancer patients: ESMO Clinical Practice Guideline. Ann Oncol 2023;34:452-67. [Crossref] [PubMed]
22. Yong BSJ, Ling RR, Li R, et al. Pharmacotherapy for Venous Thromboprophylaxis following Total Hip or Knee Arthroplasty: A Systematic Review and Network Meta-analysis. Semin Thromb Hemost 2025;51:290-300. [Crossref] [PubMed]
23. Hirai T, Aoyama T, Tsuji Y, et al. Kinetic-pharmacodynamic model of warfarin for prothrombin time-international normalized ratio in Japanese patients. Br J Clin Pharmacol 2024;90:828-36. [Crossref] [PubMed]
24. Munir R, Schapkaitz E, Noble L, et al. A Comprehensive Clinical Assessment of the LumiraDx International Normalized Ratio (INR) Assay for Point-of-Care Monitoring in Anticoagulation Therapy. Diagnostics (Basel) 2024;14:2683. [Crossref] [PubMed]
25. Van Beek A, Moeyaert M, Ragheb B, et al. Outcomes of Warfarin Home INR Monitoring vs Office-Based Monitoring: a Retrospective Claims-Based Analysis. J Gen Intern Med 2024;39:1127-34. [Crossref] [PubMed]
26. Dean CL. An Overview of Heparin Monitoring with the Anti-Xa Assay. Methods Mol Biol 2023;2663:343-53. [Crossref] [PubMed]
27. Xu L, Sun Y, Wang S, et al. Anti-Xa level monitoring of low-molecular-weight heparin during intermittent venovenous hemofiltration. Ann Hematol 2023;102:2251-6. [Crossref] [PubMed]
28. Zhu E, Yuriditsky E, Raco V, et al. Anti-factor Xa as the preferred assay to monitor heparin for the treatment of pulmonary embolism. Int J Lab Hematol 2024;46:354-61. [Crossref] [PubMed]
29. Santoro RC, Molinari AC, Leotta M, et al. Isolated Prolongation of Activated Partial Thromboplastin Time: Not Just Bleeding Risk! Medicina (Kaunas) 2023;59:1169. [Crossref] [PubMed]
30. Adcock DM, Moore GW, Montalvão SL, et al. Activated Partial Thromboplastin Time and Prothrombin Time Mixing Studies: Current State of the Art. Semin Thromb Hemost 2023;49:571-9. [Crossref] [PubMed]
31. Douxfils J, Ageno W, Samama CM, et al. Laboratory testing in patients treated with direct oral anticoagulants: a practical guide for clinicians. J Thromb Haemost 2018;16:209-19. [Crossref] [PubMed]
32. Garcia DA, Baglin TP, Weitz JI, et al. Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e24S-43S.
33. Yoshida M, Ejiri K, Matsuo N, et al. Anticoagulant effects of edoxaban in cancer and noncancer patients with venous thromboembolism. Thromb J 2025;23:36. [Crossref] [PubMed]
34. Haining L, Chunyan Z, Xiaopei L, et al. Prolonged APTT secondary to factor XII deficiency in a patient with prostate cancer: A case report. Asian J Surg 2023;46:5182-3. [Crossref] [PubMed]
35. Senthil M, Chaudhary P, Smith DD, et al. A shortened activated partial thromboplastin time predicts the risk of catheter-associated venous thrombosis in cancer patients. Thromb Res 2014;134:165-8. [Crossref] [PubMed]
36. Zhang L, Ye J, Luo Q, et al. Prediction of Poor Outcomes in Patients with Colorectal Cancer: Elevated Preoperative Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT). Cancer Manag Res 2020;12:5373-84. [Crossref] [PubMed]
37. Geng C, Yang G, Wang H, et al. The Prognostic Role of Prothrombin Time and Activated Partial Thromboplastin Time in Patients with Newly Diagnosed Multiple Myeloma. Biomed Res Int 2021;2021:6689457. [Crossref] [PubMed]
38. Betticher C, Bertaggia Calderara D, Matthey-Guirao E, et al. Global coagulation assays detect an early prothrombotic state in children with acute lymphoblastic leukemia. J Thromb Haemost 2024;22:2482-94. [Crossref] [PubMed]
39. Lei H, Li X, Hu Z, et al. A nomogram predicting venous thromboembolism risk in primary liver cancer patients. J Thromb Thrombolysis 2025;58:145-56. [Crossref] [PubMed]
40. Streiff MB, Abutalib SA, Farge D, et al. Update on Guidelines for the Management of Cancer-Associated Thrombosis. Oncologist 2021;26:e24-40. [Crossref] [PubMed]
41. Al-Tourah L, Mithoowani S, Lim W, et al. The incidence of major bleeding in adult patients with urogenital and gynecological cancer being treated with direct oral anticoagulants (DOACs): a systematic review. J Thromb Thrombolysis 2024;57:630-7. [Crossref] [PubMed]
42. A-Lai GH. Preoperative thromboprophylactic administration of low-molecular-weight-heparin significantly decreased the risk of intraoperative bleeding compared with heparin in patients undergoing video-assisted lobectomy for lung cancer. Ann Transl Med 2019;7:90. [Crossref] [PubMed]
43. Shusterman M, Grassl N, Berger K, et al. Prolonged activated partial thromboplastin time after prophylactic-dose unfractionated heparin in the post-operative neurosurgical setting: case series and management recommendations. J Thromb Thrombolysis 2020;49:153-8. [Crossref] [PubMed]
44. Christensen TD, Vad H, Pedersen S, et al. Coagulation profile in patients undergoing video-assisted thoracoscopic lobectomy: A randomized, controlled trial. PLoS One 2017;12:e0171809. [Crossref] [PubMed]
45. Xu H, Liao H, Che G, et al. Clinical Value Evaluation of Perioperative Prophylactic Anticoagulation Therapy for Lung Cancer Patients. Zhongguo Fei Ai Za Zhi 2018;21:767-72. [Crossref] [PubMed]
46. Volod O, Rollins-Raval M, Goodwin AJ, et al. Interlaboratory Performance in Measurement of Dabigatran and Rivaroxaban. Arch Pathol Lab Med 2022;146:145-53. [Crossref] [PubMed]
47. May JE, Siniard RC, Taylor LJ, et al. From Activated Partial Thromboplastin Time to Antifactor Xa and Back Again. Am J Clin Pathol 2022;157:321-7. [Crossref] [PubMed]
48. Vandiver JW, Vondracek TG. Antifactor Xa levels versus activated partial thromboplastin time for monitoring unfractionated heparin. Pharmacotherapy 2012;32:546-58. [Crossref] [PubMed]
49. Frugé KS, Lee YR. Comparison of unfractionated heparin protocols using antifactor Xa monitoring or activated partial thrombin time monitoring. Am J Health Syst Pharm 2015;72:S90-7. [Crossref] [PubMed]
50. Halawi H, Sabawi MM, Rizk E, et al. Bleeding outcomes in critically ill patients on heparin with discordant aPTT and anti-Xa activity. J Thromb Thrombolysis 2025;58:210-9. [Crossref] [PubMed]
51. Bates SM, Weitz JI, Johnston M, et al. Use of a fixed activated partial thromboplastin time ratio to establish a therapeutic range for unfractionated heparin. Arch Intern Med 2001;161:385-91. [Crossref] [PubMed]
52. Byun JH, Jang IS, Kim JW, et al. Establishing the heparin therapeutic range using aPTT and anti-Xa measurements for monitoring unfractionated heparin therapy. Blood Res 2016;51:171-4. [Crossref] [PubMed]
53. Tran A, Fernando SM, Gates RS, et al. Efficacy and Safety of Anti-Xa-Guided Versus Fixed Dosing of Low Molecular Weight Heparin for Prevention of Venous Thromboembolism in Trauma Patients: A Systematic Review and Meta-Analysis. Ann Surg 2023;277:734-41. [Crossref] [PubMed]
54. Nasser NJ, Na'amad M, Weinberg I, et al. Pharmacokinetics of low molecular weight heparin in patients with malignant tumors. Anticancer Drugs 2015;26:106-11. [Crossref] [PubMed]
55. Shin H, Koh EH, Lee GW, et al. Can an anti-Xa assay for unfractionated heparin be used to assess the presence of rivaroxaban in critical situations? J Vasc Surg Venous Lymphat Disord 2020;8:741-7. [Crossref] [PubMed]
56. Galeano-Valle F, Pérez-Rus G, Demelo-Rodríguez P, et al. Monitoring anti-Xa levels in patients with cancer-associated venous thromboembolism treated with bemiparin. Clin Transl Oncol 2020;22:1312-20. [Crossref] [PubMed]
57. Hart K, Andrick B, Grassi S, et al. Cancer-Associated Venous Thromboembolism Treatment With Anti-Xa Versus Weight-Based Enoxaparin: A Retrospective Evaluation of Safety and Efficacy. Ann Pharmacother 2021;55:1120-6. [Crossref] [PubMed]
58. Kreuziger LB, Streiff M. Anti-Xa monitoring of low-molecular-weight heparin in adult patients with cancer. Hematology Am Soc Hematol Educ Program 2016;2016:206-7. [Crossref] [PubMed]
59. Lin A, Vazquez SR, Jones AE, et al. Description of anti-Xa monitoring practices during low molecular weight heparin use. J Thromb Thrombolysis 2019;48:623-8. [Crossref] [PubMed]
60. Puhr HC, Ilhan-Mutlu A, Preusser M, et al. Absorption of Direct Oral Anticoagulants in Cancer Patients after Gastrectomy. Pharmaceutics 2022;14:662. [Crossref] [PubMed]
61. Abu Saadeh F, Marchocki Z, O'Toole SA, et al. Extended thromboprophylaxis post gynaecological cancer surgery; the effect of weight adjusted and fixed dose LMWH (Tinzaparin). Thromb Res 2021;207:25-32. [Crossref] [PubMed]
62. Aoki J, Sakamoto K, Takahashi R, et al. Current status of venous thromboembolism development during the perioperative period for colorectal cancer, its prevention with enoxaparin, and monitoring methods. Ther Clin Risk Manag 2019;15:791-802. [Crossref] [PubMed]
63. Sayar Z, Weatherill A, Gates C, et al. Use of anti-factor Xa levels in cancer patients taking direct oral anticoagulants. Thromb Res 2021;200:81-2. [Crossref] [PubMed]
64. Ambani SW, Bengur FB, Varelas LJ, et al. Standard Fixed Enoxaparin Dosing for Venous Thromboembolism Prophylaxis Leads to Low Peak Anti-Factor Xa Levels in Both Head and Neck and Breast Free Flap Patients. J Reconstr Microsurg 2022;38:749-56. [Crossref] [PubMed]
65. Kanji R, Vandenbriele C, Arachchillage DRJ, et al. Optimal Tests to Minimise Bleeding and Ischaemic Complications in Patients on Extracorporeal Membrane Oxygenation. Thromb Haemost 2022;122:480-91. [Crossref] [PubMed]
66. Ha NB, Regal RE. Anticoagulation in Patients With Cirrhosis: Caught Between a Rock-Liver and a Hard Place. Ann Pharmacother 2016;50:402-9. [Crossref] [PubMed]
67. Cuker A, Husseinzadeh H. Laboratory measurement of the anticoagulant activity of edoxaban: a systematic review. J Thromb Thrombolysis 2015;39:288-94. [Crossref] [PubMed]
68. Skeppholm M, Al-Aieshy F, Berndtsson M, et al. Clinical evaluation of laboratory methods to monitor apixaban treatment in patients with atrial fibrillation. Thromb Res 2015;136:148-53. [Crossref] [PubMed]
69. Bhatt MD, Paes BA, Chan AK. How to use unfractionated heparin to treat neonatal thrombosis in clinical practice. Blood Coagul Fibrinolysis 2016;27:605-14. [Crossref] [PubMed]

(English Language Editor: J. Jones)