Is there any literature on treatment of enoxaparin resistant VTE? What treatments should be considered for a patient who has failed DOAC and is not a compliant with warfarin follow-up?

Comment by InpharmD Researcher

Literature on confirmed enoxaparin failure indicates a higher risk in intensive care unit (ICU) patients with elevated body mass index (BMI), personal/family venous thromboembolism (VTE) history, or vasopressor use, and while cancer patients may require 20 to 25% dose escalation, recurrence still occurs, with weight-based dosing in pregnancy and obesity also unreliable. When direct oral anticoagulant (DOAC) therapy fails, the 2026 AHA/ACC guidelines suggest switching to an alternative anticoagulant class, commonly a parenteral agent such as low molecular weight heparin (LMWH) or fondaparinux, while a recent case series also describes combining an anti-Xa DOAC with dabigatran as a potential option for highly refractory thrombosis, although evidence remains limited. However, data specifically addressing DOAC failure when a patient refuses warfarin INR monitoring are lacking, and retrospective data show no significant difference in second recurrent thrombosis or bleeding rates among subsequent anticoagulant choices. An additional literature search identified one study finding success with LMWH dose escalation following initial treatment resistant to standard dosing, as well as a case series where recurrent thrombosis was successfully treated with fondaparinux in high-risk patients. Please refer to Tables 7 and 8.

PubMed and Google Scholar were searched using combinations of terms for enoxaparin or low-molecular-weight heparin failure, recurrent venous thromboembolism despite therapeutic anticoagulation, and direct oral anticoagulant failure, including subsequent treatment with warfarin, dabigatran, enoxaparin, fondaparinux, or combination anticoagulation. The search identified 6 relevant publications, including case reports/series, retrospective analyses, and studies evaluating risk factors for thromboprophylaxis failure.

Background

The 2026 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for management of acute pulmonary embolism (PE) in adult patients do not specifically address failure of enoxaparin therapy. However, cancer patients frequently experience recurrent PE despite therapeutic low molecular weight heparin (LMWH) treatment, which may require dose escalation by 20% to 25%. However, the cited study for this recommendation still reported 3 of 15 patients still developing recurrent venous thromboembolism (VTE). Weight-based dosing in special populations like pregnant and obese patients can be unreliable, and can lead to treatment failure or increased bleed risk. [1]

For recurrent PE when patients are on a direct oral anticoagulant (DOAC), the guidelines recommend switching to an alternative drug class may be reasonable, which is usually a parenteral drug like LMWH or fondaparinux. However, ensure patients are on the normal dose of DOAC rather than a reduced dose. [1]

Background References: [1] Writing Committee Members, Creager MA, Barnes GD, et al. 2026 AHA/ACC/ACCP/ACEP/CHEST/SCAI/SHM/SIR/SVM/SVN Guideline for the Evaluation and Management of Acute Pulmonary Embolism in Adults: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2026;153(12):e977-e1051.
Literature Review

A search of the published medical literature revealed 8 studies investigating the researchable question:

Is there any literature on treatment of enoxaparin resistant VTE? What treatments should be considered for a patient who has failed DOAC and is not a compliant with warfarin follow-up?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-8 for your response.

Factors associated with venous thromboembolic disease due to failed thromboprophylaxis
Design

Case-control study nested in a historical cohort

N= 612 (204 cases, 408 controls)
Objective To evaluate which clinical factors are associated with the development of failed thromboprophylaxis in hospitalized patients
Study Groups

Failed thromboprophylaxis (n= 204)

Effective thromboprophylaxis (n= 408)
Inclusion Criteria Patients over 18 years old, hospitalized for more than 24 hours, receiving pharmacological thromboprophylaxis with enoxaparin, unfractionated heparin, or dalteparin
Exclusion Criteria Patients with an indication for full anticoagulation prior to hospital admission
Methods Patients were identified using institutional databases and matched on a 1:2 basis for age, sex, type of thromboprophylaxis, and hospitalization date. Data on clinical variables were collected from electronic medical records. Univariate and multivariate regression analyses were performed to identify factors associated with failed thromboprophylaxis.
Duration 1 January 2019 to 31 December 2021
Outcome Measures

Primary: Factors associated with failed thromboprophylaxis 
Baseline Characteristics   Failed thromboprophylaxis (n= 204) Effective thromboprophylaxis (n= 408) p value
Male, n (%) 107 (52.45) 214 (52.45) 1
Age, years (IQR) 63 (51–74) 63 (51–74) 1
BMI, kg/m2 (IQR) 26.3 (23.6–30.1) 25.2 (22.2–29.0) <0.001
Leukocytosis, n (%) 55 (27.0) 77 (18.9) 0.022
ICU requirement, n (%) 98 (48.0) 101 (24.8) <0.001
Results   Univariate analysis OR (95%CI) p-Value Multivariate analysis OR (95%CI) p-Value
BMI, kg/m2 1.05 (1.01–1.09) 0.011 1.04 (1.00-1.09) 0.039
Active cancer 1.01 (0.68–1.48) 0.969 1.63 (1.03–2.57) 0.036
Leukocytosis 1.68 (1.23–2.53) 0.012 1.64 (1.05–2.57) 0.031
ICU requirement 3.31 (2.23–4.90) <0.001 3.67 (2.31–5.83) <0.001
Adverse Events Not applicable
Study Author Conclusions Our study suggests that BMI, active cancer, leukocytosis, and need for intensive care are significantly and independently associated with thromboprophylaxis failure. The coexistence of these factors may suggest the use of alternative therapies to minimize this risk.
Critique The study provides valuable insights into factors associated with failed thromboprophylaxis, particularly in medical patients. However, the case-control design may introduce selection bias, and residual confounding due to unmeasured variables could affect the results. The retrospective nature limits the ability to establish causality, and findings may not be generalizable to obstetric patients. Future prospective studies are needed to confirm these associations and explore potential interventions.
Table 1 References:
[2] Prez SG, Ruiz-Talero P, Velandia OMM. Factors associated with venous thromboembolic disease due to failed thromboprophylaxis. Thromb J. 2023;21(1):120. Published 2023 Dec 6. doi:10.1186/s12959-023-00566-4

 

Enoxaparin Failure in Patient With Cerebral Venous Sinus Thrombosis and Prothrombin G20210A Mutation: Case Report

Design

 Case report

Case presentation

A 19-year-old Caucasian woman diagnosed with cerebral venous sinus thrombosis (CVST) exhibited an unusual resistance to enoxaparin. The patient, initially presenting with severe headaches, was diagnosed through MRI and MRV imaging, which disclosed thrombi in multiple cerebral sinuses. Despite the administration of low-molecular-weight heparin (LMWH) therapy, her condition deteriorated, as evidenced by worsening symptoms and increasing thrombus size, prompting a switch to unfractionated heparin (UFH). Remarkably, the patient's symptoms and cerebral imaging results improved dramatically within 24 hours of UFH initiation, and subsequent bridging to warfarin ensured stabilization. Further genetic testing unveiled a heterozygous prothrombin G20210A mutation, implicating it as a contributory factor to the thrombotic events and possibly to the observed enoxaparin resistance.  

Study Author Conclusions

 This case report highlights the potential for LMWH resistance in patients with CVST and prothrombin gene mutations. These ndings also emphasize the importance of close monitoring of coagulation parameters and clinical response in patients with CVST receiving LMWH.
Table 2 References:
[3] Polavarapu A, Bhushan A, Duarte-Celada W, Windisch T, Bhushan B. Enoxaparin Failure in Patient With Cerebral Venous Sinus Thrombosis and Prothrombin G20210A Mutation: Case Report. Neurologist. 2025;30(3):175-181. Published 2025 May 1. doi:10.1097/NRL.0000000000000591
Failure of Anticoagulant Thromboprophylaxis: Risk Factors in Medical-Surgical Critically Ill Patients
Design

Multivariable regression analysis of thrombosis predictors from a randomized thromboprophylaxis trial

N= 3,746
Objective To identify risk factors for failure of anticoagulant thromboprophylaxis in critically ill patients in the ICU
Study Groups All patients (n= 3,746)
Inclusion Criteria Patients 18 years old or older, weighing ≥45 kg, expected to be in ICU for ≥72 hours
Exclusion Criteria Contraindication to heparin, need for therapeutic heparin, ICU admission diagnosis following trauma, cardiac surgery, orthopedic surgery, or neurosurgery
Methods Patients received anticoagulant thromboprophylaxis with low-molecular-weight heparin or unfractionated heparin at standard doses. Independent predictors for venous thromboembolism, proximal leg deep vein thrombosis, and pulmonary embolism were assessed using multivariable Cox regression analysis.
Duration Not specified
Outcome Measures

Primary: Development of venous thromboembolism

Secondary: Development of proximal leg deep vein thrombosis, pulmonary embolism
Baseline Characteristics   All patients (n= 3,746)
Age, mean (sd) 61.4 (16.5)
Body mass index, mean (sd) 28.3 (7.7)
Acute Physiology and Chronic Health Evaluation II, mean (sd) 21.5 (7.8)
Medical admission 3,046 (81.3%)
Female sex 1,614 (43.3%)
End-stage renal disease 118 (3.2%)
Personal/family history of venous thromboembolism 120 (3.2%)
Cancer 150 (4.0%)
Hospitalized for 1 wk previously 730 (19.6%)
Results   Hazard Ratio (95% CI) p-Value
Venous thromboembolism - Personal/family history of VTE 1.64 (1.03–2.59) 0.04
Venous thromboembolism - Body mass index (10-point increase) 1.18 (1.04–1.35) 0.01
Proximal leg deep vein thrombosis - Body mass index (10-point increase) 1.25 (1.06–1.46) 0.007
Proximal leg deep vein thrombosis - Statin use 0.46 (0.27–0.77) 0.004
Pulmonary embolism - Body mass index (10-point increase) 1.37 (1.02–1.83) 0.035
Pulmonary embolism - Vasopressor use 1.84 (1.01–3.35) 0.046
Pulmonary embolism - Low-molecular-weight heparin vs unfractionated heparin 0.51 (0.27–0.95) 0.034
Adverse Events Not specified
Study Author Conclusions

Failure of standard thromboprophylaxis using low-molecular-weight heparin or unfractionated heparin is more likely in ICU patients with elevated body mass index, those with a personal or family history of venous thromboembolism, and those receiving vasopressors. Alternate management or incremental risk reduction strategies may be needed in such patients.
Critique

The study's strengths include a large sample size and rigorous analysis, which enhance the robustness of the findings. However, limitations include potential underreporting of personal or family history of VTE and lack of post-ICU discharge follow-up. The study did not account for mobility factors directly, and the primary outcome was based on a composite measure of VTE, which may not capture all nuances of thrombotic risk in critically ill patients.

 

Table 3 References:
[4] Lim W, Meade M, Lauzier F, et al. Failure of anticoagulant thromboprophylaxis: risk factors in medical-surgical critically ill patients*. Crit Care Med. 2015;43(2):401-410. doi:10.1097/CCM.0000000000000713

Failure of pharmacological DVT prophylaxis due to cold chain disruption: a six-month audit from a tertiary surgical ward in Cairo
Design

Retrospective clinical audit in Egypt

N= 212
Objective To investigate the unexpected rise in deep vein thrombosis (DVT) incidence in a tertiary surgical ward and evaluate the compliance with venous thromboembolism (VTE) prophylaxis protocols, focusing on the impact of cold chain integrity on enoxaparin efficacy
Study Groups All patients (N= 212)
Inclusion Criteria All consecutive adult patients (≥18 years) admitted for elective or emergency general surgical procedures during the audit period
Exclusion Criteria Pre-existing DVT or pulmonary embolism at the time of admission, therapeutic anticoagulation for other indications, or incomplete records regarding perioperative prophylaxis
Methods Retrospective review of patient records for demographic details, surgical urgency, procedure type, perioperative prophylaxis, and use of mechanical prophylaxis. Cold chain integrity of enoxaparin storage was reviewed. Clinically suspected DVTs were identified using Wells Score criteria and confirmed by duplex Doppler ultrasonography. The audit evaluated compliance with international VTE prophylaxis guidelines and investigated factors contributing to an unexpectedly high incidence of postoperative DVT. Records of the hospital’s pharmacy and ward medication refrigerators were audited to identify potential breaches in cold chain storage of low molecular weight heparin (LMWH, enoxaparin). Drug storage temperatures were compared against manufacturer storage recommendations (2-8°C).
Duration December 2024 to June 2025
Outcome Measures

Primary: Incidence of radiologically confirmed postoperative DVT within 30 days of surgery

Secondary: Incidence of clinically suspected but unconfirmed cases, evaluation of potential systemic contributors to prophylaxis failure
Baseline Characteristics  

DVT

(n= 14)

No DVT

(n= 198)

 p-value
Age, median (IQR), years 59 (53–67) 55 (44–63) 0.28
Male sex, n (%) 9 (64.3%) 113 (57.1%) 0.62
Emergency surgery, n (%) 8 (57.1%) 84 (42.4%) 0.32
Elective surgery, n (%) 6 (42.9%) 114 (57.6%) -
Mechanical prophylaxis applied, n (%) 4 (28.6%) 90 (45.5%) 0.21
Enoxaparin from affected fridge, n (%) 11 (78.6%) 62 (31.3%) 0.002*
Results   Suspected DVT Cases* Temperature Breaches
Week 1 0 0
Week 2 1 1
Week 3 0 0
Week 4 1 2
Week 5 2 2
Week 6 1 1
Week 7 0 0
Week 8 1 2
Week 9 0 0
Week 10 0 0
Week 11 1 1
Week 12 2 3
Week 13 0 0
Week 14 1 1
Week 15 1 1
Week 16 0 0
Week 17 0 0
Week 18 1 2
Week 19 0 0
Week 20 2 3
Week 21 1 2
Week 22 0 0
Week 23 1 1
Week 24 0 0
Week 25 1 1
Week 26 1 1
*Eighteen patients were suspected to have developed postoperative DVT within 30 days, but only 14 were confirmed by Doppler ultrasonography.
Adverse Events Not reported
Study Author Conclusions Cold chain failure was strongly associated with prophylaxis failure and is the most plausible contributor to the unexpected rise in DVT incidence. Infrastructure monitoring and mechanical prophylaxis adherence are essential to effective thromboprophylaxis.
Critique The study highlights a critical systems failure in cold chain management, providing valuable insights into infrastructure's role in pharmacological efficacy. However, the retrospective design, lack of baseline audit for comparison, and absence of pharmacological testing limit the ability to definitively attribute drug degradation to the observed DVT rates. The single-center setting also limits generalizability, and the lack of systematic recording of bleeding events is a notable limitation. Therapeutic alternatives used to manage patients who developed DVTs while on enoxaparin were not described in this report, however. 
Table 4 References:
[5] Shafik A Jr, Elessawy H, Gobrial YK, Lotfy A. Failure of pharmacological DVT prophylaxis due to cold chain disruption: a six-month audit from a tertiary surgical ward in Cairo. BMC Surg. 2025;26(1):62. Published 2025 Dec 17. doi:10.1186/s12893-025-03326-5

Direct Oral Anticoagulant Failure in Patients with Venous Thromboembolism—Why And What Next?

Design

 Case series

Case presentation 1

A 45-year-old male with no prior medical history presented with a 6-month history of recurrent abdominal cramping, loose stools, and unintentional weight loss. Colonoscopy demonstrated erosions, mucosal atrophy, epithelial dysplasia, and granulomas suggestive of inflammatory bowel disease, for which corticosteroid therapy was initiated.

During hospitalization, he developed a painful left leg, and Doppler ultrasonography confirmed a femoral deep vein thrombosis; apixaban was started, and he was discharged after improvement in his gastrointestinal symptoms. One month later, he returned with shortness of breath and was diagnosed with a segmental pulmonary embolism despite reporting no missed apixaban doses, although he had experienced increasing bowel-movement frequency during the preceding 2 weeks.

The recurrent VTE was attributed to impaired apixaban absorption during an active inflammatory bowel disease flare, in addition to the thromboinflammatory state associated with active disease. He was transitioned to therapeutic-dose low-molecular-weight heparin and subsequently bridged to warfarin after the inflammatory bowel disease flare resolved.

Case presentation 2

A 32-year-old female presented with exertional dyspnea and pleuritic chest pain and was diagnosed with pulmonary embolism, initially considered provoked by an 8-hour flight. Her relevant history included 2 unexplained miscarriages.

Rivaroxaban was initiated, and she was discharged with planned follow-up; however, 6 weeks later, she developed worsening shortness of breath requiring intensive care admission for respiratory support. Given the recurrent thrombosis and obstetric history, antiphospholipid syndrome was suspected, and testing demonstrated high-titer immunoglobulin G anticardiolipin and anti-β2-glycoprotein antibodies, with persistent positivity confirmed after 12 weeks.

She was treated initially with once-daily low-molecular-weight heparin and subsequently transitioned to warfarin with a target international normalized ratio of 2 to 3. Lupus anticoagulant testing was not performed because she declined interruption of anticoagulation.

Case presentation 3

A 41-year-old female receiving dabigatran for a VTE diagnosed 2 months earlier presented with abdominal pain, hypotension, renal impairment, and anemia and was found to have an intraperitoneal hematoma caused by rupture of a clear cell ovarian tumor.

Anticoagulation was changed to unfractionated heparin because of cardiovascular instability, renal impairment, and the need for surgery, after which she was transitioned to apixaban. Four months into a bevacizumab-containing treatment regimen, restaging imaging showed a partial oncologic response but incidentally identified pulmonary emboli involving multiple bilateral lung segments.

After adherence, drug interactions, and absorption were reviewed, the recurrent cancer-associated thrombosis was considered to have occurred despite therapeutic apixaban, and she was switched to once-daily low-molecular-weight heparin.

Study Author Conclusions
The majority of patients with VTE can be managed adequately with either fixed-duration or long-term DOAC therapy. Recurrent VTE, despite therapeutic anticoagulation, affects a minority of patients but may be associated with significant morbidity and mortality.
 
The general approach to such patients involves switching from a DOAC to LMWH, fondaparinux, or warfarin. Another potential strategy for refractory thrombosis is to combine DOACs with differing mechanisms of action, ie, an anti-Xa inhibitor (apixaban, rivaroxaban, or edoxaban) with a direct thrombin inhibitor (dabigatran). A retrospective review of 8 patients with refractory thrombosis managed in this fashion reported no recurrent VTE or bleeding episodes during therapy. This approach requires further assessment but poses an interesting additional possibility for patients with highly refractory thrombotic states. Whether other novel agents, such as FXI inhibitors, could play a role in these patients is also not known.
 
Consensus guidelines regarding patients with DOAC failure alongside randomized controlled data comparing anticoagulation strategies are lacking and urgently needed to improve care of these patients.
Table 5 References:
[6] Swan D, Turner R, Grove EL, Schulman S, Thachil J. Direct oral anticoagulant failure in patients with venous thromboembolism-why and what next?. J Thromb Haemost. 2025;23(6):1774-1786. doi:10.1016/j.jtha.2025.03.026

Equivalent thrombotic risk with Warfarin, Dabigatran, or Enoxaparin after failure of initial direct oral anticoagulation (DOAC) therapy
Design

Retrospective analysis

N= 166
Objective To describe and compare outcomes with second line anticoagulants used after DOAC failure
Study Groups

Warfarin (n= 60)

Dabigatran (n= 42)

Enoxaparin (n= 64)
Inclusion Criteria Patients seen at an urban hospital system for an episode of acute VTE initially treated with either apixaban or rivaroxaban who experienced a subsequent recurrent thrombosis while on anticoagulation
Exclusion Criteria Patients on DOAC therapy for less than two weeks or who had antiphospholipid syndrome
Methods Patients with recurrent thrombosis while on apixaban or rivaroxaban were subsequently treated with warfarin, dabigatran, or enoxaparin. Outcomes such as 2nd recurrent thrombosis and major bleeding were recorded. Statistical analysis included Kaplan-Meier method and multivariable Cox-proportional hazards modeling
Duration January 1, 2010 to September 1, 2022
Outcome Measures

Primary: 2nd recurrent thrombosis-free survival

Secondary: Risk for major bleeding event
Baseline Characteristics   All Dabigatran Enoxaparin Warfarin p-value
Age, years, median (IQR) 62 (48–71) 60 (45–69) 62 (50–71) 63 (50–73) 0.42
Male sex, n (%) 80 (48) 25 (60) 25 (39) 30 (50) 0.11
BMI, median (IQR) 29 (25–33) 27 (24–31) 29 (25–32) 31 (26–35) 0.20
Race - Black 57 (34) 17 (40) 20 (31) 20 (33) 0.76
Race - Hispanic 40 (24) 7 (17) 19 (30) 14 (23) 0.76
Race - White 59 (36) 16 (38) 22 (34) 21 (35) 0.76
Initial anticoagulation - Apixaban 85 (51) 27 (64) 31 (48) 27 (45) 0.14
Initial anticoagulation - Rivaroxaban 81 (49) 15 (36) 33 (52) 33 (55) 0.14
Location of recurrent thrombosis - PE 38 (23) 8 (19) 16 (25) 14 (23) 0.93
Location of recurrent thrombosis - Extremity DVT 95 (57) 25 (60) 35 (55) 35 (58) 0.93
Location of recurrent thrombosis - Other VTE 17 (10) 6 (14) 6 (9) 5 (8) 0.93
Location of recurrent thrombosis - Arterial thrombus 16 (10) 3 (7) 7 (11) 6 (10) 0.93
Follow-up, months, median (IQR) 16 (4–34) 17 (7–34) 12 (2–25) 22 (6–47) 0.02
Results

Enoxaparin was preferentially prescribed in patients with a malignancy-associated etiology for 1st recurrent thrombosis (p< 0.01).

There was no difference in 2nd recurrent thrombosis-free survival (p= 0.72) or risk for major bleeding event (p=0.30) among patients treated with dabigatran, warfarin, or enoxaparin.
Adverse Events Major bleeding occurred in 17 patients (10.2%), with no significant difference in risk among dabigatran, warfarin, or enoxaparin (p= 0.30)
Study Author Conclusions In this retrospective analysis of patients failing first line DOAC therapy, rates of 2nd recurrent thrombosis and bleeding did not differ among subsequently chosen anticoagulants. Our study provides evidence that the optimal 2nd anticoagulant is not clear, and the choice of 2nd anticoagulant should continue to balance patient preference, cost, and provider experience
Critique The study is limited by its retrospective nature and small sample size, which may not capture all patients with DOAC failure. The lack of randomization and potential for selection bias could affect the results. Additionally, the study does not account for all possible anticoagulation strategies, such as alternative anticoagulants or ancillary therapies, which limits the generalizability of the findings
Table 6 References:
[7] Shyu M, Liu A, Srikureja A, et al. Equivalent thrombotic risk with Warfarin, Dabigatran, or Enoxaparin after failure of initial direct oral anticoagulation (DOAC) therapy. J Thromb Thrombolysis. 2024;57(5):871-876. doi:10.1007/s11239-024-02978-z

 

Dose escalation of low molecular weight heparin to manage recurrent venous thromboembolic events despite systemic anticoagulation in cancer patients
Design

Retrospective cohort study

N= 70
Objective To evaluate the benefit and risk of low molecular weight heparin (LMWH) dose escalation in cancer patients with recurrent VTE
Study Groups Cancer patients with recurrent VTE (n= 70)
Inclusion Criteria Documented active malignancy; objectively proven first episode of VTE; objectively documented recurrent VTE while taking systemic anticoagulation medication (LMWH or a VKA)
Exclusion Criteria Not specified
Methods Retrospective cohort study of cancer outpatients with recurrent VTE while on anticoagulation. Patients on LMWH had their dose escalated by 20-25% for at least 4 weeks. Patients on VKA were switched to therapeutic dose LMWH. Follow-up was for a minimum of 3 months
Duration July 2004 to June 2008 (Ottawa); April 2003 to June 2007 (Hamilton)
Outcome Measures

Primary: Incidence of a second recurrent VTE within 3 months

Secondary: Minor and major bleeding, overall and VTE-related death
Baseline Characteristics   LMWH (N = 47) Vitamin K antagonist (N = 23) Study population (N = 70)
Female 25 (53.2%) 13 (56.5%) 38 (54.3%)
Age, years (median; range) 58 (27-83) 64 (49-90) 60 (27-90)
Cancer location - Lung 15 (31.9%) 6 (26.1%) 21 (30.0%)
Cancer location - Colon 9 (19.2%) 1 (4.3%) 10 (14.3%)
Cancer stage - Non-metastatic 18 (38.3%) 6 (26.1%) 24 (34.3%)
Cancer stage - Metastatic 28 (59.6%) 16 (69.6%) 44 (62.9%)
Results   Study population (N = 70)
Second recurrent VTE 6 (8.6%; 95% CI 4.0-17.5%)
Bleeding complications 3 (4.3%; 95% CI 1.5-11.9%)
Median time to second recurrence 1.9 months (range, 0.6-3.0 months)
Median survival after index recurrent VTE 11.4 months (range, 0-83.9 months)
Adverse Events Three patients (4.3%) had bleeding complications, including one intracranial bleed. Two patients had minor bleeding episodes while on therapeutic LMWH
Study Author Conclusions Escalating the dose of LMWH can be effective for treating recurrent VTE in cancer patients resistant to standard doses of LMWH or a VKA
Critique The study provides valuable insights into managing recurrent VTE in cancer patients, but its retrospective nature and lack of a control group limit the ability to draw definitive conclusions. The small sample size and lack of routine anti-FXa measurements are additional limitations
Table 7 References:
[8] Carrier M, Le Gal G, Cho R, Tierney S, Rodger M, Lee AY. Dose escalation of low molecular weight heparin to manage recurrent venous thromboembolic events despite systemic anticoagulation in cancer patients. J Thromb Haemost. 2009;7(5):760-765. doi:10.1111/j.1538-7836.2009.03326.x

 

Recurrent thrombosis rescued by fondaparinux in high-risk patients: A case series

Design

 Case series

Case presentation 1

A woman in her 20s with triple-positive antiphospholipid syndrome developed a transient ischemic attack at 33 weeks of pregnancy despite aspirin and therapeutic dalteparin 200 units/kg, prompting a 20% dose increase. After delivery, she developed cerebral microinfarcts despite a further increase to 280 units/kg, followed by a large 21 × 9 mm mitral valve thrombus with worsening neurologic symptoms. Fondaparinux was initiated with a 10-mg loading dose, followed by 7.5 mg daily for 25 days while bridging to warfarin. The thrombus decreased to 3.4 mm after 1 month and had completely resolved by 5 months, with no recurrent thrombosis or bleeding during 2 years of follow-up.

 
Case presentation 2

A woman in her 30s with homozygous factor V Leiden and suspected May-Thurner syndrome developed thrombosis within a left common iliac vein stent while receiving therapeutic warfarin. She was switched to dalteparin 200 units/kg, but the left-leg DVT progressed after 30 days. Dalteparin was increased by 25% to 250 units/kg, yet she developed a new right common femoral DVT 7 days later. Fondaparinux 10 mg daily was administered for 14 months, followed by warfarin with a higher INR target. At 5 months, the right-leg veins were patent and the left-leg thrombosis had partially regressed. No recurrent thrombosis or bleeding occurred during 4 years of follow-up.
Case presentation 3

 A man in his 50s with metastatic testicular germ-cell cancer developed bilateral proximal DVTs and was treated with dalteparin 230 units/kg, approximately 15% above the standard weight-adjusted dose. Seven months later, he developed acute bilateral above-knee DVTs despite this supratherapeutic regimen. He was switched to fondaparinux 7.5 mg daily for 5 months and subsequently transitioned to apixaban. Follow-up ultrasonography at 5 months showed bilateral partial recanalization with post-thrombotic changes. He experienced no recurrent thrombosis or bleeding during 3 years of follow-up.
Case presentation 4

 A man in his 50s with stage IV pancreatic cancer developed a right above-knee DVT and was started on dalteparin 200 units/kg. Three weeks later, he developed an acute left above-knee DVT, prompting a 30% dose increase to 260 units/kg. Despite this escalation, bilateral pulmonary emboli occurred 2 months later. He was switched to fondaparinux 7.5 mg daily. After 1 month, ultrasonography demonstrated partial recanalization of the bilateral DVTs. He received fondaparinux for 40 days without thrombosis progression or bleeding but subsequently died from his underlying cancer.
Case presentation 5

 A woman in her 60s with Hodgkin lymphoma developed a catheter-related subclavian DVT and was treated with unfractionated heparin, requiring approximately 40,000 units per day to achieve a therapeutic partial thromboplastin time. After 3 days, her arm pain and edema worsened, and ultrasonography showed thrombus extension into the axillary vein. She was switched to fondaparinux 7.5 mg daily for 8 months. Repeat imaging after 2 months showed partial recanalization, with no recurrent thrombosis or bleeding during 4 years of follow-up.
Case presentation 6

 A man in his 70s with multiple myeloma was receiving dalteparin 200 units/kg for a right proximal DVT and pulmonary emboli. Ten months later, he developed a spontaneous thigh hematoma requiring transfusion, while imaging simultaneously showed a new acute right above-knee DVT. Anticoagulation was stopped and an inferior vena cava filter was placed. Two weeks later, he developed an extensive left above-knee DVT and was started on unfractionated heparin, requiring approximately 28,000 units per day for a therapeutic partial thromboplastin time. After 4 days, the bilateral DVTs progressed and became limb-threatening. Fondaparinux 7.5 mg daily was administered for 16 months, followed by apixaban. D-dimer levels nearly normalized within 1 week, and ultrasonography at 3 months showed bilateral partial recanalization. No recurrent thrombosis or bleeding occurred during 4 years of follow-up.

Study Author Conclusions

 In conclusion, fondaparinux was a limb-­ saving and possibly life-saving option when other standard methods of anticoagulation failed in six patients. Our findings may provide clinicians facing a clinical dilemma with a potentially safe treatment option. Larger studies are needed to validate our findings. 
Table 8 References:
[9] Tanguay M, Sguin C. Recurrent thrombosis rescued by fondaparinux in high-risk patients: A case series. Res Pract Thromb Haemost. 2022;6(5):e12773. Published 2022 Jul 29. doi:10.1002/rth2.12773