Abstract
Background
Trousseau syndrome is a cancer-associated hypercoagulable state characterized by recurrent thromboembolic events, including ischemic stroke. Optimal anticoagulation strategies remain controversial, particularly regarding the effectiveness of direct oral anticoagulants (DOACs) compared with low-molecular-weight heparin (LMWH).
Case presentation
We report two patients with Trousseau syndrome who presented with recurrent multi-territory cerebral infarctions despite ongoing DOAC therapy. Case 1 was a 66-year-old man with active intrahepatic cholangiocarcinoma who developed repeated ischemic strokes and deep vein thrombosis while receiving rivaroxaban. After switching to LMWH, D-dimer levels decreased markedly. However, anticoagulation was de-escalated in the context of apparent normalization of D-dimer, followed by recurrent stroke, subsequent discontinuation of anticoagulation, and a rapid surge in D-dimer levels, ultimately resulting in death. Case 2 was a 74-year-old man with suspected recurrent metastatic gastric adenocarcinoma who developed ischemic stroke while on rivaroxaban. Following transition to LMWH, D-dimer levels progressively declined, and the patient remained clinically stable without recurrence during follow-up. A longitudinal timeline analysis integrating biomarker dynamics, treatment transitions, and clinical events demonstrated distinct patterns between the two cases, suggesting a potential discordance between D-dimer levels and underlying hypercoagulable activity.
Conclusion
These cases highlight the dynamic nature of hypercoagulability in Trousseau syndrome. Normalization of D-dimer alone may not reliably indicate sustained control of malignancy-associated hypercoagulability and should not be used in isolation to guide anticoagulation de-escalation. LMWH may provide more consistent control in selected high-risk patients, although causal inference cannot be established from this report.
Keywords: case report, D-dimer, direct oral anticoagulants, hypercoagulability, ischemic stroke, low-molecular-weight heparin, multi-territory infarction, Trousseau syndrome
Highlights
Trousseau syndrome may present with recurrent multi-territory infarctions despite DOAC therapy.
Normalization of D-dimer does not necessarily indicate resolution of hypercoagulability.
De-escalation or interruption of anticoagulation may lead to rapid thrombotic deterioration.
Low-molecular-weight heparin may provide more consistent control of hypercoagulability in selected patients.
Timeline analysis reveals dynamic relationships between biomarkers, treatment, and outcomes.
Introduction
Trousseau syndrome is a well-recognized paraneoplastic phenomenon characterized by a systemic hypercoagulable state associated with malignancy, particularly adenocarcinomas. It commonly manifests as venous thromboembolism, arterial thrombosis, and recurrent ischemic stroke, often involving multiple vascular territories (1–4). These thrombotic events are thought to be driven by tumor-related mechanisms, including mucin secretion, activation of selectin-mediated pathways, platelet aggregation, and widespread microthrombosis (3, 5, 6).
Ischemic stroke in the context of Trousseau syndrome is clinically distinctive, frequently presenting as multifocal infarctions affecting both anterior and posterior circulations, and is often associated with markedly elevated biomarkers of hypercoagulability, such as D-dimer (7–10). Notably, the severity of thrombotic risk may not correlate with traditional vascular risk factors or initial neurological deficits, complicating early risk stratification and management (10, 11).
Optimal anticoagulation strategies for Trousseau syndrome remain controversial. While direct oral anticoagulants (DOACs) have become increasingly used in cancer-associated thrombosis because of their convenience and acceptable safety profiles, emerging evidence suggests that they may be insufficient to fully control malignancy-associated hypercoagulability in some patients, particularly in the setting of cancer-associated stroke or recurrent thrombosis (12–15). In contrast, low-molecular-weight heparin (LMWH) has been proposed to exert broader antithrombotic effects, potentially through both anticoagulant activity and interference with tumor-mediated pathways, including selectin-dependent interactions (5, 16–18). However, comparative clinical data in Trousseau syndrome remain limited, and real-world evidence regarding dynamic treatment responses is still lacking (12, 15, 19).
Furthermore, the temporal relationship between biomarker fluctuations, therapeutic adjustments, and clinical outcomes in Trousseau syndrome has not been well characterized. Serial and post-treatment D-dimer levels have been associated with recurrent stroke and poor outcomes in cancer-associated stroke, but it remains unclear whether normalization of D-dimer reliably indicates resolution of the hypercoagulable state or can safely guide de-escalation of anticoagulation therapy (15, 20–23).
Here, we report two patients with Trousseau syndrome who developed recurrent multi-territory cerebral infarctions despite ongoing DOAC therapy, yet demonstrated divergent clinical outcomes following different anticoagulation strategies. By integrating serial D-dimer measurements, treatment transitions, and clinical events within a structured longitudinal framework, this report aims to explore the potential mismatch between biomarker dynamics and true hypercoagulable activity, a phenomenon that remains insufficiently characterized.
Case presentation
Case 1
Patient information
A 66-year-old man with a history of active intrahepatic cholangiocarcinoma diagnosed approximately 6 months earlier was admitted with speech impairment persisting for 4 days. Approximately one month prior to admission, he had experienced multiple cerebral infarctions and had been treated with oral rivaroxaban. During the same period, a left popliteal deep vein thrombosis was identified. He had no history of hypertension, diabetes mellitus, or coronary artery disease.
Clinical findings
On admission, his blood pressure was 112/63 mmHg. He was conscious but exhibited impaired comprehension and answered questions irrelevantly. Neurological examination revealed sensory aphasia with relatively preserved articulation. Cranial nerve examination was largely unremarkable. Muscle strength was grade 5 in all extremities, with normal muscle tone and preserved tendon reflexes. The National Institutes of Health Stroke Scale (NIHSS) score was 6, and the modified Rankin Scale (mRS) score was 3.
Diagnostic assessment
Laboratory testing demonstrated moderate anemia (hemoglobin 88 g/L) and markedly elevated D-dimer levels (3.44–4.16 mg/L). Tumor markers were significantly elevated, including carcinoembryonic antigen (CEA) at 277.92 ng/mL and carbohydrate antigen 19-9 (CA19-9) >1,200,000 U/mL.
Brain magnetic resonance imaging (MRI) revealed multiple acute infarctions involving the corona radiata, centrum semiovale, cortical regions of the temporal and parietal lobes, and bilateral cerebellar hemispheres, consistent with a multi-territory infarction pattern involving both anterior and posterior circulations (Figure 1A). Computed tomography angiography (CTA) showed no significant large-vessel stenosis.
Figure 1.
Diffusion-weighted imaging (DWI) findings in two patients with malignancy-associated stroke. (A) Case 1: Representative supratentorial (upper) and infratentorial (lower) DWI images demonstrate multiple acute infarcts involving bilateral cortical and subcortical regions as well as the cerebellum, indicating both anterior and posterior circulation involvement. (B) Case 2: DWI images reveal numerous scattered acute infarcts in the bilateral cerebral hemispheres and cerebellum, showing a diffuse multi-territory distribution suggestive of embolic infarctions associated with malignancy-related hypercoagulability. White arrows indicate representative lesions. The diffuse multi-territory distribution involving both anterior and posterior circulations is suggestive of embolic showering associated with malignancy-related hypercoagulability.
Given the presence of active malignancy, recent venous thrombosis, recurrent multi-territory infarctions, and elevated D-dimer levels, a clinical diagnosis of Trousseau syndrome was established.
Therapeutic intervention and clinical course
Given the clinical suspicion of Trousseau syndrome and the presence of swallowing impairment, anticoagulation was transitioned from rivaroxaban to low-molecular-weight heparin (LMWH; enoxaparin 40 mg (0.4 mL) subcutaneously every 12 h), which is generally preferred in malignancy-associated hypercoagulability. Following initiation of LMWH, D-dimer levels progressively decreased and normalized, suggesting apparent but potentially transient control of the hypercoagulable state.
After clinical stabilization, anticoagulation was de-escalated in the context of overall clinical improvement, including apparent normalization of D-dimer levels, and rivaroxaban was resumed after discharge. This decision was also influenced in part by patient and family preference to avoid long-term subcutaneous injections.
Follow-up and outcomes
Approximately 3 weeks after discharge, the patient developed a third episode of cerebral infarction and was readmitted. At readmission, neurological impairment had significantly worsened (NIHSS score 17). Anticoagulation was discontinued and replaced with antiplatelet therapy (aspirin 100 mg daily) because of concerns regarding hemorrhagic risk.
This was followed by a rapid and marked increase in D-dimer levels (up to 41.96 mg/L), indicating severe exacerbation of hypercoagulability. Despite supportive management, the patient's condition deteriorated rapidly, and he ultimately died of brain herniation.
Case 2
Patient information
A 74-year-old man was admitted with left-sided weakness of more than 1 day in duration. His medical history included hypertension, type 2 diabetes mellitus, and gastrectomy for gastric cancer more than 20 years earlier. Approximately 2 weeks before admission, he had been diagnosed with deep vein thrombosis and was receiving rivaroxaban.
Clinical findings
On admission, he was conscious and cooperative. Neurological examination revealed mild left-sided weakness, with muscle strength graded as IV in the left upper limb and V− in the left lower limb. Cranial nerve examination showed left-beating nystagmus and slight tongue deviation to the right. The NIHSS score was 1, and the mRS score was 2.
Diagnostic assessment
Laboratory tests demonstrated thrombocytopenia (platelet count 77 × 109/L) and markedly elevated D-dimer levels (24.02 mg/L, later decreasing to 6.87 mg/L). Tumor markers were significantly elevated, including CEA at 798.10 ng/mL and CA19-9 >1,200,000 U/mL.
Brain MRI revealed multiple acute infarctions involving bilateral frontal, parietal, and occipital lobes, cerebellar hemispheres, thalamus, and right temporal lobe, consistent with multi-territory embolic infarctions (Figure 1B). CTA showed no large-vessel occlusion.
Whole-body PET-CT demonstrated hypermetabolic lesions in the gastric remnant, liver, and multiple lymph nodes, suggestive of recurrent metastatic malignancy. Based on these findings, a clinical diagnosis of Trousseau syndrome was made.
Therapeutic intervention and clinical course
Despite ongoing rivaroxaban therapy, the occurrence of ischemic stroke prompted a change in anticoagulation strategy. Given the clinical diagnosis of Trousseau syndrome, in which low-molecular-weight heparin is generally preferred, together with the apparent inadequate efficacy of oral anticoagulation as evidenced by stroke occurrence during treatment, anticoagulation was transitioned to low-molecular-weight heparin (enoxaparin 40 mg (0.4 mL) subcutaneously every 12 h). Following this adjustment, D-dimer levels decreased markedly and subsequently normalized, indicating apparent control of the hypercoagulable state.
During hospitalization, biopsy was considered for tumor evaluation but deferred based on multidisciplinary clinical evaluation of high procedural risk in the setting of active hypercoagulability. Anticoagulation with low-molecular-weight heparin was therefore continued.
After discharge, the patient underwent biopsy at an external institution, and histopathological examination confirmed poorly differentiated adenocarcinoma.
Follow-up and outcomes
With continued LMWH therapy, the patient remained clinically stable without recurrent thromboembolic events during follow-up, and D-dimer levels remained within the normal range.
A comparison of the clinical characteristics, diagnostic findings, treatment strategies, and outcomes of the two cases is provided in Table 1. The temporal relationships among D-dimer dynamics, treatment transitions, and clinical events are illustrated in Figure 2.
Table 1.
Comparison of the clinical characteristics of the two cases.
| Variable | Case 1 | Case 2 |
|---|---|---|
| Age (years) | 66 | 74 |
| Sex | Male | Male |
| Cancer status | Active intrahepatic cholangiocarcinoma (adenocarcinoma) | Suspected recurrent metastatic gastric adenocarcinoma |
| Time since initial cancer diagnosis | 6 months | 26 years |
| Vascular risk factors | None | Hypertension, diabetes mellitus |
| Recent venous thromboembolism | DVT (1 month) | DVT (2 weeks) |
| Prior anticoagulation | Rivaroxaban | Rivaroxaban |
| Admission NIHSS | 6 | 1 |
| Admission mRS | 3 | 2 |
| Peak D-dimer | 41.96 mg/L | 36.90 mg/L |
| Tumor markers | Elevated CEA, CA19-9 | Markedly elevated CEA, CA19-9 |
| DWI pattern | Multi-territory infarctions | Multi-territory infarctions |
| Acute anticoagulation strategy | LMWH (enoxaparin 40 mg (0.4 mL) q12h) | LMWH (enoxaparin 40 mg (0.4 mL) q12h) |
| Short-term outcome | Recurrent fatal infarction | Clinically stable |
DVT, deep vein thrombosis; NIHSS, National Institutes of Health Stroke Scale; mRS, modified Rankin Scale; CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19-9; DWI, diffusion-weighted imaging; LMWH, low-molecular-weight heparin.
Figure 2.
Longitudinal analysis of D-dimer levels, clinical events, and anticoagulation therapy. Case 1 (upper panel) illustrates a phenomenon we term “D-dimer masking,” defined as a transient reduction or normalization of D-dimer levels that does not reflect true resolution of the underlying hypercoagulable state. This pattern suggests a potential discordance between biomarker levels and ongoing prothrombotic activity. All timelines were aligned using the onset of the index stroke as day 0 to improve comparability between cases. Each case is presented across three aligned panels showing (from top to bottom) D-dimer levels, clinical events, and antithrombotic therapy. In contrast, Case 2 (lower panel) shows sustained biomarker suppression and clinical stability following the initiation of LMWH. In the antithrombotic therapy panels, solid horizontal bars represent rivaroxaban/direct oral anticoagulant (DOAC), dashed horizontal bars represent LMWH, and dotted horizontal bars represent antiplatelet therapy. DOAC, direct oral anticoagulant; DVT, deep vein thrombosis; LMWH, low-molecular-weight heparin; NIHSS, National Institutes of Health Stroke Scale.
Discussion
This report describes two patients with Trousseau syndrome who developed recurrent multi-territory cerebral infarctions despite ongoing direct oral anticoagulant (DOAC) therapy but exhibited markedly different clinical outcomes following changes in anticoagulation strategies. The integration of serial D-dimer measurements, treatment transitions, and clinical events through a structured timeline analysis highlights the dynamic and unstable nature of malignancy-associated hypercoagulability. Notably, normalization of D-dimer did not reliably indicate sustained control of the hypercoagulable state in Case 1, whereas persistent suppression of D-dimer under low-molecular-weight heparin (LMWH) was associated with clinical stabilization in Case 2. This temporal relationship is further detailed in a structured timeline (Figure 2), which integrates longitudinal biomarker trends with therapeutic adjustments and clinical outcomes. Collectively, these findings suggest a potential dissociation between biomarker normalization and true control of malignancy-associated hypercoagulability.
The pathophysiology of Trousseau syndrome is complex and involves tumor-driven activation of coagulation pathways, including mucin-mediated platelet activation, selectin-dependent interactions, and systemic thrombin generation (2, 3, 5, 6). These mechanisms contribute to widespread microthrombosis and embolic phenomena, often resulting in multi-territory cerebral infarctions (24). In this context, D-dimer serves as a surrogate marker of ongoing coagulation activation and fibrin turnover (20, 21, 23, 25). However, as illustrated in our cases, D-dimer levels may fluctuate dynamically in response to both disease activity and therapeutic interventions, and transient normalization may not necessarily reflect resolution of the underlying prothrombotic state. We propose the concept of “D-dimer masking,” defined as a transient reduction or normalization of D-dimer levels that does not reflect true resolution of the underlying hypercoagulable state. Notably, a potential discordance between markedly elevated tumor markers (e.g., CA19-9) and relatively modest D-dimer levels may reflect differential pathways of thrombogenesis, particularly platelet-rich thrombus formation that is not fully captured by fibrin-based biomarkers. In addition, DOAC therapy may partially suppress fibrin generation without adequately targeting platelet-mediated thrombogenesis, potentially leading to relatively lower D-dimer levels despite ongoing hypercoagulability, thereby creating a misleading impression of disease control. A proposed diagnostic and management workflow for Trousseau syndrome-related stroke, integrating imaging patterns, biomarker assessment, and anticoagulation strategies, is illustrated in Figure 3.
Figure 3.
Proposed diagnostic and management workflow for Trousseau syndrome-related stroke. The algorithm integrates key clinical and radiological features, including multi-territory infarctions on diffusion-weighted imaging (DWI), elevated D-dimer levels, thrombotic history, and underlying malignancy status, to guide diagnostic evaluation and therapeutic decision-making. Tumor screening and multidisciplinary assessment are recommended, and low-molecular-weight heparin (LMWH) is emphasized as a key anticoagulation strategy in malignancy-associated hypercoagulability. CT, computed tomography; DVT, deep vein thrombosis; DWI, diffusion-weighted imaging; LMWH, low-molecular-weight heparin; NBTE, nonbacterial thrombotic endocarditis; PET-CT, positron emission tomography-computed tomography.
The failure of DOACs in these cases may be attributed to their pharmacological limitations in the setting of malignancy-associated hypercoagulability. While DOACs, such as rivaroxaban, specifically inhibit Factor Xa, they do not address the broader prothrombotic environment characteristic of Trousseau syndrome, such as mucin-mediated platelet activation triggered via P- and L-selectins (5, 6). Given the exceptionally high CA19-9 levels in our patients (>1,200,000 U/mL), we hypothesize that mucin-rich tumor cells directly interact with platelets and neutrophils, effectively bypassing the classical coagulation cascade inhibited by DOACs (2, 6). Conversely, LMWH exerts pleiotropic antithrombotic effects beyond simple factor inhibition, including the blockade of selectin-mediated interactions and the neutralization of tumor-derived microparticles (16, 17). This mechanism may provide superior protection against the widespread microthrombosis driven by tumor-derived mucins, explaining the clinical stabilization observed following the transition to LMWH in our cases (18, 19). Furthermore, recent clinical observations support the concern that DOACs may fail to control the fulminant hypercoagulability encountered in patients with advanced metastatic adenocarcinomas (12, 19).
The optimal anticoagulation strategy for Trousseau syndrome remains controversial. Although DOACs are increasingly used in cancer-associated thrombosis due to their convenience and favorable safety profiles, accumulating evidence suggests that they may be insufficient to fully control malignancy-associated hypercoagulability in certain patients, particularly in the setting of cancer-related stroke (26, 27). In contrast, LMWH has been considered the preferred anticoagulant in this context, not only because of its established efficacy in cancer-associated venous thromboembolism, but also due to its potential to interfere with tumor-mediated prothrombotic pathways, including selectin-dependent interactions (13, 16–18).
Our findings provide clinically relevant insight into this therapeutic dilemma. In Case 1, de-escalation of anticoagulation in the context of apparent biochemical improvement was followed by recurrent stroke and clinical deterioration, whereas in Case 2, sustained anticoagulation with low-molecular-weight heparin (LMWH) was associated with stabilization of both D-dimer levels and clinical status. These contrasting trajectories are consistent with previous observations that malignancy-associated hypercoagulability may not be adequately controlled by DOAC therapy in certain patients (12, 15).
These observations underscore several important clinical implications. First, D-dimer should be interpreted as a dynamic biomarker reflecting ongoing coagulation activity rather than a definitive indicator of resolution, and normalization alone may not reliably justify de-escalation of anticoagulation therapy. Second, LMWH may provide more consistent control of hypercoagulability in selected patients with Trousseau syndrome, particularly in those with recurrent thromboembolic events despite DOAC therapy. Third, anticoagulation strategies should be individualized and guided by the overall clinical course, longitudinal biomarker trends, and underlying disease activity, rather than single time-point measurements. These findings highlight the importance of continuous reassessment of coagulation status in patients with Trousseau syndrome.
This study has several limitations. First, as a case report involving only two patients, the findings are inherently limited by the small sample size and observational nature, precluding causal inference. Second, not all biomarkers of coagulation activation, such as fibrin degradation products, were systematically assessed. Third, nonbacterial thrombotic endocarditis could not be definitively excluded because transesophageal echocardiography was not performed. In addition, medication adherence and potential pharmacokinetic interactions with rivaroxaban were not fully evaluated, which may confound the interpretation of apparent DOAC failure. Furthermore, treatment decisions were influenced by clinical considerations and patient-specific factors, which may limit generalizability. Finally, the follow-up duration in Case 2 was relatively limited, restricting assessment of long-term outcomes. Larger prospective studies are needed to validate these observations and to better define optimal anticoagulation strategies in Trousseau syndrome.
Conclusion
In conclusion, this report highlights the dynamic nature of malignancy-associated hypercoagulability in Trousseau syndrome and suggests that normalization of D-dimer may not reliably indicate disease control. Sustained anticoagulation with LMWH may offer advantages over DOACs in selected patients with Trousseau syndrome. Careful longitudinal monitoring and individualized treatment strategies are essential to improve clinical outcomes in this high-risk population. These findings support a cautious approach to anticoagulation de-escalation and highlight the importance of sustained and individualized strategies in patients with malignancy-associated stroke. This case report was prepared in accordance with the CARE guidelines.
Acknowledgments
We sincerely thank the patients and their family members for consenting to the publication of this case report.
Funding Statement
The author(s) declared that financial support was received for this work and/or its publication. This work was supported by the Jiading District Medical Key Specialist Construction Plan (No. JDYXZDZK-5), the Science and Technology Commission of Jiading District, China (No. JDKW-2018-W13) (Jianhua Xu). The funder had no role in the design, data collection, data analysis, and reporting of this study.
Footnotes
Edited by: Robert W. Maitta, University Hospitals Cleveland Medical Center, United States
Reviewed by: Gauranga Mahalwar, Cleveland Clinic, United States
Nobuaki Hayase, Saitama Cancer Center, Japan
Data availability statement
The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding authors.
Ethics statement
The studies involving humans were approved by the Medical Research Ethics Committee of Shanghai Jiading District Central Hospital (approval No. 20260085). The studies were conducted in accordance with local legislation and institutional requirements. Written informed consent was obtained from the patients / patient's next of kin for participation in the study. Written informed consent was obtained from the patient(s)/patient's next of kin for the publication of this case report.
Author contributions
GD: Conceptualization, Writing – review & editing, Resources, Writing – original draft. JX: Writing – review & editing, Conceptualization, Writing – original draft. MY: Resources, Writing – review & editing, Supervision, Conceptualization.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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The author(s) declared that generative AI was not used in the creation of this manuscript.
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References
- 1.Guo YJ, Chang MH, Chen PL, Lee YS, Chang YC, Liao YC. Predictive value of plasma (D)-dimer levels for cancer-related stroke: a 3-year retrospective study. J Stroke Cerebrovasc Dis. (2014) 23:e249–254. 10.1016/j.jstrokecerebrovasdis.2013.10.022 [DOI] [PubMed] [Google Scholar]
- 2.Varki A. Trousseau's syndrome: multiple definitions and multiple mechanisms. Blood. (2007) 110:1723–9. 10.1182/blood-2006-10-053736 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Ikushima S, Ono R, Fukuda K, Sakayori M, Awano N, Kondo K. Trousseau's syndrome: cancer-associated thrombosis. Jpn J Clin Oncol. (2016) 46:204–8. 10.1093/jjco/hyv165 [DOI] [PubMed] [Google Scholar]
- 4.Schwarzbach CJ, Schaefer A, Ebert A, Held V, Bolognese M, Kablau M, et al. Stroke and cancer: the importance of cancer-associated hypercoagulation as a possible stroke etiology. Stroke. (2012) 43:3029–34. 10.1161/STROKEAHA.112.658625 [DOI] [PubMed] [Google Scholar]
- 5.Wahrenbrock M, Borsig L, Le D, Varki N, Varki A. Selectin-mucin interactions as a probable molecular explanation for the association of Trousseau syndrome with mucinous adenocarcinomas. J Clin Invest. (2003) 112:853–62. 10.1172/JCI18882 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Shao B, Wahrenbrock MG, Yao L, David T, Coughlin SR, Xia L, et al. Carcinoma mucins trigger reciprocal activation of platelets and neutrophils in a murine model of Trousseau syndrome. Blood. (2011) 118:4015–23. 10.1182/blood-2011-07-368514 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Kim SJ, Park JH, Lee M-J, Park YG, Ahn MJ, Bang OY. Clues to occult cancer in patients with ischemic stroke. PLoS One. (2012) 7:e44959. 10.1371/journal.pone.0044959 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Bang OY, Chung JW, Lee MJ, Seo WK, Kim GM, Ahn MJ, et al. Cancer-related stroke: an emerging subtype of ischemic stroke with unique pathomechanisms. J Stroke. (2020) 22:1–10. 10.5853/jos.2019.02278 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Sener U, Keser Z. Ischemic stroke in patients with malignancy. Mayo Clin Proc. (2022) 97:2139–44. 10.1016/j.mayocp.2022.09.003 [DOI] [PubMed] [Google Scholar]
- 10.Navi BB, Iadecola C. Ischemic stroke in cancer patients: a review of an underappreciated pathology. Ann Neurol. (2018) 83:873–83. 10.1002/ana.25227 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Navi BB, Reiner AS, Kamel H, Iadecola C, Elkind MSV, Panageas KS, et al. Association between incident cancer and subsequent stroke. Ann Neurol. (2015) 77:291–300. 10.1002/ana.24325 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Aung ET, Hayden MW, Chouhan K, Mon YT, Skeldon L. A case of Trousseau syndrome: a report detailing recurrent ischaemic strokes associated with metastatic pancreatic cancer and pulmonary embolisms despite treatment with direct oral anticoagulation. Cureus. (2025) 17:e97696. 10.7759/cureus.97696 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Farge D, Frere C, Connors JM, Khorana AA, Kakkar A, Ay C, 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. 10.1016/S1470-2045(22)00160-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Vedovati MC, Germini F, Agnelli G, Becattini C. Direct oral anticoagulants in patients with VTE and cancer: a systematic review and meta-analysis. Chest. (2015) 147:475–83. 10.1378/chest.14-0402 [DOI] [PubMed] [Google Scholar]
- 15.Hsu JY, Liu AB. Anticoagulants for cancer-associated ischemic stroke. Tzu Chi Med J. (2019) 31:144–8. 10.4103/tcmj.tcmj_55_19 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Mousa SA, Petersen LJ. Anti-cancer properties of low-molecular-weight heparin: preclinical evidence. Thromb Haemost. (2009) 102:258–67. 10.1160/TH08-12-0832 [DOI] [PubMed] [Google Scholar]
- 17.Stevenson JL, Varki A, Borsig L. Heparin attenuates metastasis mainly due to inhibition of P- and L-selectin, but non-anticoagulant heparins can have additional effects. Thromb Res. (2007) 120(Suppl 2):S107–111. 10.1016/S0049-3848(07)70138-X [DOI] [PubMed] [Google Scholar]
- 18.Lee AYY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, et al. Randomized comparison of low-molecular-weight heparin versus oral anticoagulant therapy for the prevention of recurrent venous thromboembolism in patients with cancer (CLOT) investigators, low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. (2003) 349:146–53. 10.1056/NEJMoa025313 [DOI] [PubMed] [Google Scholar]
- 19.Zwicker JI. Trousseau syndrome: management of refractory VTE. Hematology Am Soc Hematol Educ Program. (2024) 2024:253–8. 10.1182/hematology.2024000552 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Ito S, Kikuchi K, Ueda A, Nagao R, Maeda T, Murate K, et al. Changes in serial D-dimer levels predict the prognoses of Trousseau's syndrome patients. Front Neurol. (2018) 9:528. 10.3389/fneur.2018.00528 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Fujinami J, Nagakane Y, Fujikawa K, Murata S, Maezono K, Ohara T, et al. D-dimer trends predict recurrent stroke in patients with cancer-related hypercoagulability. Cerebrovasc Dis Extra. (2024) 14:9–15. 10.1159/000535644 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Lee MJ, Chung JW, Ahn MJ, Kim S, Seok JM, Jang HM, et al. Hypercoagulability and mortality of patients with stroke and active cancer: the OASIS-CANCER study. J Stroke. (2017) 19:77–87. 10.5853/jos.2016.00570 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Nakajima S, Kawano H, Yamashiro K, Tanaka R, Kameda T, Kurita N, et al. Post-treatment plasma D-dimer levels are associated with short-term outcomes in patients with cancer-associated stroke. Front Neurol. (2022) 13:868137. 10.3389/fneur.2022.868137 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Neilson LE, Rogers LR, Sundararajan S. Evaluation and treatment of a patient with recurrent stroke in the setting of active malignancy. Stroke. (2019) 50:e9–11. 10.1161/STROKEAHA.118.022088 [DOI] [PubMed] [Google Scholar]
- 25.Wang P, Tang J, Li T, Shang L, Zhang Q, Hu M. Trousseau's syndrome caused by hepatocellular carcinoma: a case description and literature analysis. Quant Imaging Med Surg. (2024) 14:3762–7. 10.21037/qims-23-1746 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Chen A, Stecker E, Warden BA. Direct oral anticoagulant use: a practical guide to common clinical challenges. J Am Heart Assoc. (2020) 9:e017559. 10.1161/JAHA.120.017559 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Mai V, Tanguay VF, Guay CA, Bertoletti L, Magnan S, Turgeon AF, et al. DOAC compared to LMWH in the treatment of cancer related-venous thromboembolism: a systematic review and meta-analysis. J Thromb Thrombolysis. (2020) 50:661–7. 10.1007/s11239-020-02055-1 [DOI] [PubMed] [Google Scholar]
Associated Data
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Data Availability Statement
The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding authors.