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The Role of Factor Xa-Independent Pathway and Anticoagulant Therapies in Cancer-Related Stroke.

ABSTRACT: The optimal strategy for stroke prevention in cancer patients is unknown. We compared the underlying mechanisms of coagulopathy and the effects of anticoagulants in patients with active cancer and atrial fibrillation (AF). We retrospectively enrolled 46 consecutive patients with embolic stroke of unknown source and active cancer (cancer stroke). We consecutively screened patients with cancer patients without stroke (n = 29), AF stroke (n = 52), and healthy subjects (n = 28), which served as controls. Patients with cancer stroke were treated with either enoxaparin (a low-molecular-weight heparin) or a factor Xa inhibitor, and those with AF stroke were treated with factor Xa inhibitors. D-dimer, factor Xa, and circulating cell-free DNA (cfDNA), a marker of neutrophil extracellular traposis, were measured at both before and after anticoagulation. In AF stroke, factor Xa activity and cfDNA and D-dimer levels were decreased by treatment with factor Xa inhibitors. In contrast, in cancer stroke, factor Xa activity was decreased, D-dimer levels were unchanged, and cfDNA levels were increased by treatment with factor Xa inhibitors. In cancer stroke patients treated with enoxaparin, D-dimer levels were decreased (p = 0.011) and cfDNA levels were unchanged. The anticoagulation effects of factor Xa inhibitors differed between cancer stroke and AF stroke.

SUBMITTER: Kim HJ

PROVIDER: S-EPMC8745325 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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The Role of Factor Xa-Independent Pathway and Anticoagulant Therapies in Cancer-Related Stroke.

Kim Hyung Jun HJ Chung Jong-Won JW Bang Oh Young OY Cho Yeon Hee YH Lim Yun Jeong YJ Hwang Jaechun J Seo Woo-Keun WK Kim Gyeong-Moon GM Kim Hee-Jin HJ Ahn Myung-Ju MJ

Journal of clinical medicine 20211227 1

<h4>Background</h4>The optimal strategy for stroke prevention in cancer patients is unknown. We compared the underlying mechanisms of coagulopathy and the effects of anticoagulants in patients with active cancer and atrial fibrillation (AF).<h4>Methods</h4>We retrospectively enrolled 46 consecutive patients with embolic stroke of unknown source and active cancer (cancer stroke). We consecutively screened patients with cancer patients without stroke (<i>n</i> = 29), AF stroke (<i>n</i> = 52), and ...[more]

PMID: 35011864

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Project description:Introduction Certain low-molecular-weight heparins have been reported to reduce tumor growth and metastasis in tumor cell-inoculated mouse models and cancer patients. Recently, direct oral anticoagulants (DOACs) have been widely used in patients with thromboembolism. This study was aimed at investigating the effect of DOACs, which target thrombin or factor Xa, on tumor growth in a syngeneic mouse model comprising BALB/c mice inoculated with colon cancer Colon26 cells. Materials and Methods DOACs targeting thrombin (dabigatran etexilate [DABE]) or factor Xa (rivaroxaban [RVX] and edoxaban [EDX]) were orally administered daily to male BALB/c mice inoculated with Colon26 cells, followed by analyses of tumor growth and plasma levels of coagulation- and tumor-related factors such as tissue factor (TF), plasminogen activator inhibitor-1 (PAI-1), interleukin-6 (IL-6), and matrix metalloproteinase-2 (MMP-2). Results Colon26 cells expressed significant amounts of functionally active TF. Tumor growth in Colon26-inoculated mice was significantly suppressed in DABE- or RVX-treated mice ( p <0.05) and was suppressed more significantly in EDX-treated mice ( p <0.01). Therefore, the antitumor mechanism of action of EDX was investigated next. Plasma levels of TF, PAI-1, IL-6, and MMP-2 were elevated in Colon26-inoculated mice but were significantly reduced in EDX-treated mice ( p <0.01). The expression of protease-activated receptor (PAR)1, PAR2, signal transducer and activator of transcription-3 (STAT3), cyclin D1, and Ki67 was increased in tumor tissue of Colon26-inoculated mice but (except for PAR1) was significantly decreased in tumor tissues of EDX-treated mice ( p <0.01). In addition, apoptotic cells and p53 protein levels were significantly increased in tumor tissues of EDX-treated mice. Conclusion The data suggest that among the tested DOACs, EDX significantly suppresses tumor cell proliferation via the factor Xa-PAR2 pathway, which is activated by coagulation and inflammation in Colon26-inoculated mice and induces tumor cell apoptosis.

Dataset Information

The Role of Factor Xa-Independent Pathway and Anticoagulant Therapies in Cancer-Related Stroke.

Publications

The Role of Factor Xa-Independent Pathway and Anticoagulant Therapies in Cancer-Related Stroke.

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