Low Anti-Factor Xa Level Predicts 90-Day Symptomatic Venous Thromboembolism in Surgical Patients Receiving Enoxaparin Prophylaxis: A Pooled Analysis of Eight Clinical Trials

Ann Surg. 2022 Dec 1;276(6):e682-e690. doi: 10.1097/SLA.0000000000004589. Epub 2020 Oct 19.


Objective: To examine the relationship between enoxaparin dose adequacy, quantified with anti-Factor Xa (aFXa) levels, and 90-day symptomatic venous thromboembolism (VTE) and postoperative bleeding.

Summary background data: Surgical patients often develop "breakthrough" VTE events-those which occur despite receiving chemical anticoagulation. We hypothesize that surgical patients with low aFXa levels will be more likely to develop 90-day VTE, and those with high aFXa will be more likely to bleed.

Methods: Pooled analysis of eight clinical trials (N = 985) from a single institution over a 4 year period. Patients had peak steady state aFXa levels in response to a known initial enoxaparin dose, and were followed for 90 days. Survival analysis log-rank test examined associations between aFXa level category and 90-day symptomatic VTE and bleeding.

Results: Among 985 patients, 2.3% (n = 23) had symptomatic 90-day VTE, 4.2% (n = 41) had 90-day clinically relevant bleeding, and 2.1% (n = 21) had major bleeding. Patients with initial low aFXa were significantly more likely to have 90-day VTE than patients with adequate or high aFXa (4.2% vs 1.3%, P = 0.007). In a stratified analysis, this relationship was significant for patients who received twice daily (6.2% vs 1.5%, P = 0.003), but not once daily (3.0% vs 0.7%, P = 0.10) enoxaparin. No association was seen between high aFXa and 90-day clinically relevant bleeding (4.8% vs 2.9%, P = 0.34) or major bleeding (3.6% vs 1.6%, P = 0.18).

Conclusions: This manuscript establishes inadequate enoxaparin dosing as a plausible mechanism for breakthrough VTE in surgical patients, and identifies anticoagulant dose adequacy as a novel target for process improvement measures.

Trial registration: ClinicalTrials.gov NCT02411292 NCT02704052 NCT03212365 NCT03251963.

Publication types

  • Meta-Analysis
  • Research Support, U.S. Gov't, P.H.S.
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticoagulants / therapeutic use
  • Enoxaparin* / therapeutic use
  • Humans
  • Postoperative Complications / drug therapy
  • Postoperative Complications / epidemiology
  • Postoperative Complications / prevention & control
  • Postoperative Hemorrhage
  • Prospective Studies
  • Venous Thromboembolism* / etiology
  • Venous Thromboembolism* / prevention & control


  • Enoxaparin
  • Anticoagulants

Associated data

  • ClinicalTrials.gov/NCT02411292
  • ClinicalTrials.gov/NCT02704052
  • ClinicalTrials.gov/NCT03212365
  • ClinicalTrials.gov/NCT03251963