Therapeutic efficacy of heparin and direct factor Xa inhibitors in cancer-associated cryptogenic ischemic stroke with venous thromboembolism

Yamaura, Genpei; Ito, Takeshi; Miyaji, Yoshiyuki; Ueda, Naohisa; Nakae, Yoshiharu; Momoo, Takayuki; Nakano, Tatsu; Johmura, Yuji; Higashiyama, Yuichi; Joki, Hideto; Doi, Hiroshi; Takeuchi, Hideyuki; Takahashi, Tatsuya; Koyano, Shigeru; Yamaguchi, Shigeki; Yokoyama, Mutsumi; Tanaka, Fumiaki

doi:10.1016/j.thromres.2021.08.016

Cited by 10 publications

(8 citation statements)

References 22 publications

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“…Compared to cerebral ischemia with conventional risk factors, paraneoplastic ischemic stroke often involves multiple territories and is associated with a high stroke-associated morbidity and mortality. 9 – 12 However, unfractionated subcutaneous heparin 13 , 14 may reduce the risk of stroke recurrence in these patients. Low-molecular-weight heparin also corrects cancer-associated hypercoagulability, 15 and this correction was found to be associated with a better prognosis.…”

Section: Introductionmentioning

confidence: 99%

Development of an algorithm for identifying paraneoplastic ischemic stroke in association with lung, pancreatic, and colorectal cancer

Kassubek,

Winter,

Dreyhaupt

et al. 2024

Ther Adv Neurol Disord

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Background: Paraneoplastic ischemic stroke has a poor prognosis. We have recently reported an algorithm based on the number of ischemic territories, C-reactive protein (CRP), lactate dehydrogenase (LDH), and granulocytosis to predict the underlying active cancer in a case-control setting. However, co-occurrence of cancer and stroke might also be merely incidental. Objective: To detect cancer-associated ischemic stroke in a large, unselected cohort of consecutive stroke patients by detailed analysis of ischemic stroke associated with specific cancer subtypes and comparison to patients with bacterial endocarditis. Methods: Retrospective single-center cohort study of consecutive 1612 ischemic strokes with magnetic resonance imaging, CRP, LDH, and relative granulocytosis data was performed, including identification of active cancers, history of now inactive cancers, and the diagnosis of endocarditis. The previously developed algorithm to detect paraneoplastic cancer was applied. Tumor types associated with paraneoplastic stroke were used to optimize the diagnostic algorithm. Results: Ischemic strokes associated with active cancer, but also endocarditis, were associated with more ischemic territories as well as higher CRP and LDH levels. Our previous algorithm identified active cancer-associated strokes with a specificity of 83% and sensitivity of 52%. Ischemic strokes associated with lung, pancreatic, and colorectal (LPC) cancers but not with breast and prostate cancers showed more frequent and prominent characteristics of paraneoplastic stroke. A multiple logistic regression model optimized to identify LPC cancers detected active cancer with a sensitivity of 77.8% and specificity of 81.4%. The positive predictive value (PPV) for all active cancers was 13.1%. Conclusion: Standard clinical examinations can be employed to identify suspect paraneoplastic stroke with an adequate sensitivity, specificity, and PPV when it is considered that the association of ischemic stroke with breast and prostate cancers in the stroke-prone elderly population might be largely incidental.

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Section: Introductionmentioning

confidence: 99%

Development of an algorithm for identifying paraneoplastic ischemic stroke in association with lung, pancreatic, and colorectal cancer

Kassubek,

Winter,

Dreyhaupt

et al. 2024

Ther Adv Neurol Disord

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“…However, the neutral result of TEACH pilot trial (Navi, Marshall, et al, 2018) suggested that compared with antiplatelet therapy, anticoagulation did not show obvious advantages in preventing stroke recurrence and bleeding. Unfortunately, the results of other clinical trials of anticoagulant therapy in CRS patients are not very optimistic, either (Nam, Kim, Kim, An, Oh, et al, 2017;Yamaura et al, 2021). Therefore, the effectiveness of anticoagulation therapy needs to be evaluated further.…”

Section: Introductionmentioning

confidence: 99%

Cancer‐related stroke: Exploring personalized therapy strategies

et al. 2022

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Background: Cancer and ischemic stroke are two common diseases that threaten human health and have become the main causes of death in the world. It is estimated that one-in-ten patients with ischemic stroke have concomitant cancer, and this incidence is expected to increase as improvements in medical technology extends the life expectancy of cancer patients.Discussion: Cancer-related stroke (CRS) refers to unexplained ischemic stroke in patients with active cancer that cannot be explained by current stroke mechanisms.Available evidence suggests that CRS accounts for 5-10% of embolic stroke of undetermined source (ESUS). Although the incidence of CRS is gradually increasing, its underlying pathogenesis remains unclear. Also, there is no consensus on acute treatment and secondary prevention of stroke. Conclusion:In this review, we retrospectively analyzed the incidence, mechanisms of CRS, its potential as a new stroke subtype, options for acute treatment, secondary prevention strategies, and disease progression, with the aim of attempting to explore personalized therapy strategies.

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“…7 In addition to this serious adverse effect, UFH is clinically employed by intravenous route, making it unfeasible for long-term outpatient treatments. 8 Although LMWHs and some UFH mimetics obtained through extensive chemical/enzymatic processes have already proven to be effective and pose reduced risk of bleeding, different stakeholders involved in the production and research of heparins are still looking for new and more feasible UFH derivatives that somehow preserve the physical-chemical features required for aiming new therapeutic targets but with decreased anticoagulant activity nonetheless. 9 All UFHs currently available for clinical use and production of LMWHs are produced using heparin porcine intestine (Heparin Porcine Intestine; HPI) (Heparin Bovine Intestine; HBI) Hepatocyte Growth Factor (HGF) as raw material, except in some countries, including Brazil, Argentina, and India, which also employ UFH products obtained from heparin bovine intestine (HBI).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic, Hemostatic, and Anticancer Properties of a Low-Anticoagulant Bovine Heparin

Santos

Tovar

Oliveira

et al. 2022

TH Open

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Heparin is a centennial anticoagulant drug broadly employed for treatment and prophylaxis of thromboembolic conditions. Although unfractionated heparin (UFH) has already been shown to have remarkable pharmacological potential for treating a variety of diseases unrelated with thromboembolism, including cancer, atherosclerosis, inflammation, and virus infections, its high anticoagulant potency makes the doses necessary to exert non-hemostatic effects unsafe due to an elevated bleeding risk. Our group recently developed a new low-anticoagulant bovine heparin (LABH) bearing the same disaccharide building blocks of the UFH gold standard sourced from porcine mucosa (HPI) but with anticoagulant potency approximately 85% lower (approximately 25 and 180 Heparin International Units [IU]/mg). In the present work, we investigated the pharmacokinetics profile, bleeding potential, and anticancer properties of LABH administered subcutaneous into mice. LABH showed pharmacokinetics profile similar to HPI but different from the low-molecular weight heparin (LMWH) enoxaparin and diminished bleeding potential, even at high doses. Subcutaneous treatment with LABH delays the early progression of Lewis lung carcinoma, improves survival, and brings beneficial health outcomes to the mice, without the advent of adverse effects (hemorrhage/mortality) seen in the animals treated with HPI. These results demonstrate that LABH is a promising candidate for prospecting new therapeutic uses for UFH.

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Therapeutic efficacy of heparin and direct factor Xa inhibitors in cancer-associated cryptogenic ischemic stroke with venous thromboembolism

Cited by 10 publications

References 22 publications

Development of an algorithm for identifying paraneoplastic ischemic stroke in association with lung, pancreatic, and colorectal cancer

Development of an algorithm for identifying paraneoplastic ischemic stroke in association with lung, pancreatic, and colorectal cancer

Cancer‐related stroke: Exploring personalized therapy strategies

Pharmacokinetic, Hemostatic, and Anticancer Properties of a Low-Anticoagulant Bovine Heparin

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