Mechanisms of Ischemic Stroke in Patients with Cancer: A Prospective Study

Navi, Babak B.; Sherman, Carla; Genova, Richard; Mathias, R. G.; Lansdale, Kelsey N; LeMoss, Natalie M.; Wolfe, J. M.; Skakodub, Anna; Kamel, Hooman; Tagawa, Scott T.; Saxena, Ashish; Ocean, Allyson J.; Soff, Gerald A.; DeSancho, Maria T.; Iadecola, Costantino; Elkind, Mitchell S.V.; Peerschke, Ellinor I.B.; Zhang, Cenai; DeAngelis, Lisa M.

doi:10.1002/ana.26129

Cited by 49 publications

(70 citation statements)

References 30 publications

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“…Moreover, the presence of multiple infarcts on DWI was independently associated with poor outcomes and mortality in the present study. The high prevalence of lesions involving multiple vascular territories found in the present study has been reported as a characteristic finding of cancer-related ischemic stroke ( 8 , 14 , 16 – 18 , 29 ).…”

Section: Discussionsupporting

confidence: 79%

“…Cancer-associated stroke is attracting attention as an emerging subtype of ischemic stroke with unique pathomechanisms ( 11 , 12 ). High plasma D-dimer levels are seen in patients with cancer-associated ischemic stroke, suggesting the importance of hypercoagulability as the etiology of the stroke ( 13 – 18 ). Accumulating data suggest that the plasma D-dimer level, a marker of activated coagulation and fibrinolysis, is a useful biomarker for the diagnosis of cancer-associated stroke and the evaluation of recurrent stroke risk ( 19 , 20 ).…”

Section: Introductionmentioning

confidence: 99%

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Post-Treatment Plasma D-Dimer Levels Are Associated With Short-Term Outcomes in Patients With Cancer-Associated Stroke

et al. 2022

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Background and ObjectiveHypercoagulability is associated with increased risks of ischemic stroke and subsequent mortality in patients with active cancer. This study investigated the relationships between plasma D-dimer levels after stroke treatment and short-term outcomes in patients with cancer-associated stroke.MethodsThis retrospective, observational, multicenter study analyzed consecutive patients with cancer-associated ischemic stroke. Hypercoagulability was assessed by plasma D-dimer levels before and after stroke treatment. Short-term outcomes were assessed in terms of poor outcomes (a modified Rankin Scale score >3), cumulative rates of recurrent ischemic stroke, and mortality at 30 days after admission.ResultsOf 282 patients, 135 (47.9%) showed poor outcomes. Recurrent ischemic stroke was observed in 28 patients (9.9%), and the cumulative mortality rate was 12.4%. Multivariate analysis showed that post-treatment plasma D-dimer levels ≥10 μg/ml were independently associated with both poor outcomes (adjusted odds ratio [OR], 9.61; 95% confidence interval [CI], 3.60–25.70; P < 0.001) and mortality (adjusted OR, 9.38; 95% CI, 3.32–26.44; P < 0.001). Pre-treatment plasma D-dimer levels ≥10 μg/ml were not associated with these outcomes. Patients who received heparin had higher pre-treatment plasma D-dimer levels than those treated with other anticoagulants. Heparin produced a significant reduction in D-dimer levels from pre- to post-treatment without increasing the incidence of hemorrhagic events.ConclusionA high plasma D-dimer level after stroke treatment was associated with poor short-term outcomes in patients with cancer-associated stroke. Using anticoagulants to reduce D-dimer levels may improve short-term outcomes in these patients.

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Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Post-Treatment Plasma D-Dimer Levels Are Associated With Short-Term Outcomes in Patients With Cancer-Associated Stroke

et al. 2022

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“…It is not clear what role that CEA plays in the generation of ECIS. However, animal experiments have confirmed that mucins secreted by cancer cells into the blood may 482 first bind to platelets with P-selectin, 21,22 which is an adhesion molecule on the membrane surface of neutrophils, and then the mucins activate platelets and release soluble P-selectin, finally leading to hypercoagulability and thrombosis. [23][24][25] Moreover, elevated levels of plasma CA125, another mucin factor that is secreted into the blood by cancer cells, were found to increase blood coagulation and thus lead to cancer-related stroke.…”

Section: Discussionmentioning

confidence: 99%

The Index of Esophageal Cancer Related Ischemic Stroke: A Retrospective Patient Control Study

Liu¹,

LiZhi²,

Cheng³

et al. 2022

NDT

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To investigate independent risk factors for esophageal cancer-related ischemic stroke (ECIS) and to use them to develop an index of ECIS to help clinicians identify patients at high risk for ECIS or to identify ECIS from other types of ischemic stroke. Methods: We retrospectively enrolled active esophageal cancer (EC) patients with acute ischemic stroke (ECIS group) and patients with active EC without ischemic stroke (EC group), age-and sex-matched with ECIS patients, at seven centers from January 2011 to December 2020. Clinical data and laboratory and imaging findings were collected. Univariate and multivariate analyses were performed to analyze the independent risk factors for ECIS. Optimal cutoffs for sensitivities and specificities were obtained by Youden's J statistic following a receiver operator characteristic (ROC) analysis of each risk factor and the product of the risk factors. Results: A total of 91 ECIS patients and 91 EC patients were included. Elevated levels of carcinoembryonic antigen (CEA) [odds ratio (OR) = 0.105, 95% confidence interval (CI): 1.051-1.174, P < 0.001], D-dimer (DD) (OR = 0.003, 95% CI: 1.002-1.004, P < 0.001), and neutrophil count (OR = 0.857, 95% CI: 1.628-3.407, P < 0.001) were independent risk factors for ECIS. The area under the curve (AUC) of each independent risk factor and the product of the three independent risk factors were calculated by a receiver operator characteristic (ROC) curve, and the cutoff value from the largest AUC was called the ECIS index. Conclusion: It was suggested that elevated plasma DD and CEA levels and increased neutrophils in EC patients may altogether contribute to the development of ECIS. The index of ECIS may facilitate clinicians to identify patients at high risk for ECIS or to identify ECIS from other etiologic types of ischemic stroke.

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“…The expression level of sPselectin is considered a biomarker of inflammation, platelet activation, and vascular and thrombotic diseases. [42][43][44] To reveal the correlation of THCMA's P-selectin inhibition activity with its antithrombosis, anti-inflammation, and antitumor activity, in vivo expression levels of sP-selectin and TNFα were examined. Figure 8A-D show that expression levels of sP-selectin in arterial thrombosis rats, venous thrombosis rats, S180 mice, and ear-edema mice had similar patterns.…”

Section: Downregulation Of Sp-selectin and Tnfα Expression By Thcma In Vivomentioning

confidence: 99%

“…(D) Molecular interactions and binding energies between P-selectin (ribbon model) and PSI-697 (cyan stick model) and THCMA (wheat stick model), with detailed interactions presented in 2-D. Figures rendered with PDB 1G1S and docking results and plotted with PyMol and APBS plugins 44.…”

mentioning

confidence: 99%

Nanoparticles of a New Small-Molecule P-Selectin Inhibitor Attenuate Thrombosis, Inflammation, and Tumor Growth in Two Animal Models

Feng¹,

Wang²,

Muhtar³

et al. 2021

IJN

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Purpose: To assess whether the newly designed small-molecule oral P-selectin inhibitor 3S-1,2,3,4-tetrahydro-β-carboline-3-methyl aspartyl ester (THCMA) as a nanomedicine enhances antithrombosis, anti-inflammation, and antitumor activity more than the clinical trial drug PSI-697. Methods: THCMA was designed as an amphiphile containing pharmacophores of PSI-697. Its nanofeatures were explored with TEM, SEM, Tyndall effect, ζ-potential, FT-ICR-MS, and NOESY 2D 1 H NMR. The P-selectin inhibitory effect of THCMA was demonstrated with molecular docking, ultraviolet (UV) spectra, and competitive ELISA. In vivo and in vitro assays -anti-arterial thrombosis, anti-venous thrombosis, anti-inflammation, antitumor growth, anti-platelet aggregation, rat-tail bleeding time, anticoagulation index, soluble P-selectin (sP-selectin) expression, and serum TNFα expression -were performed to explore bioactivity and potential mechanisms. Water solubility of THCMA was measured using UV-absorption spectra. Results: THCMA self-assembled into nanorings of approximately 100 nm in diameter. Its water solubility was about 1,030-fold that of PSI-697. THCMA exhibited more potent P-selectin inhibitory effect than PSI-697. The oral efficacy of THCMA was 100-fold that of PSI-697 in inhibiting arterial and venous thrombosis and tenfold in inhibiting inflammation. THCMA inhibited thrombosis at a dose that produces no coagulation disorders and no bleeding risk. THCMA exhibited enhanced antitumor activity over PSI-697 without systemic chemotherapy toxicity. THCMA significantly inhibited platelet aggregation in vitro and downregulated the expression levels of serum sP-selectin and TNFα in vivo. Conclusion:A new small-molecule P-selectin inhibitor, THCMA, has been successfully designed as a nanomedicine with largely enhanced oral efficacy compared to the clinical trial drug PSI-697, and thus might be developed for the oral treatment of arterial thrombosis, venous thrombosis, inflammation, and cancer-associated thrombosis.

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Mechanisms of Ischemic Stroke in Patients with Cancer: A Prospective Study

Cited by 49 publications

References 30 publications

Post-Treatment Plasma D-Dimer Levels Are Associated With Short-Term Outcomes in Patients With Cancer-Associated Stroke

Post-Treatment Plasma D-Dimer Levels Are Associated With Short-Term Outcomes in Patients With Cancer-Associated Stroke

The Index of Esophageal Cancer Related Ischemic Stroke: A Retrospective Patient Control Study

Nanoparticles of a New Small-Molecule P-Selectin Inhibitor Attenuate Thrombosis, Inflammation, and Tumor Growth in Two Animal Models

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