TY - JOUR
T1 - Role of circulating mitochondria in venous thrombosis in glioblastoma
AU - Gonzalez-Delgado, Ricardo
AU - Muñoz, Nina M.
AU - Carlos-Alcalde, Wendolyn
AU - Cho, Min Soon
AU - Lee, Hani
AU - Jin, Jeff
AU - Serpas, Victoria
AU - Gorlova, Olga
AU - Sheth, Rahul A.
AU - Afshar-Kharghan, Vahid
N1 - Funding Information:
This study was supported, in part, by the National Institutes of Health grant CA231141 to V.A.-K. and O.G., the National Institutes of Health grant CA177909 to V.A.-K., the Liz Tilberis Early Career Development Award from the Ovarian Cancer Research Alliance, Ovarian Cancer Research in honor of Liza Chance from the Foundation of Women Cancer, and the National Institutes of Health grant P50 CA217685 (to M.S.C.). We acknowledge the Brain Tumor Center and the Neuropathology Satellite Tumor Bank of the University of Texas MD Anderson Cancer Center for providing the plasma specimens. In addition, the authors gratefully acknowledge the assistance of Katherine Dixon, Malea Williams, and Crystal Dupuis for the in vivo inferior vena cava stenosis model generation and angiography experiments, Cancer Center Support Grant (CCSG) NIH P30CA016672, and High-Resolution Electron Microscopy Facility for transmission electron microscopy studies.
Funding Information:
Funding information This study was supported, in part, by the National Institutes of Health grant CA231141 to V.A.-K. and O.G., the National Institutes of Health grant CA177909 to V.A.-K., the Liz Tilberis Early Career Development Award from the Ovarian Cancer Research Alliance, Ovarian Cancer Research in honor of Liza Chance from the Foundation of Women Cancer, the National Institutes of Health grant P50 CA217685 (to M.S.C.), and Cancer Center Support Grant (CCSG) grant NIH P30CA016672.This study was supported, in part, by the National Institutes of Health grant CA231141 to V.A.-K. and O.G. the National Institutes of Health grant CA177909 to V.A.-K. the Liz Tilberis Early Career Development Award from the Ovarian Cancer Research Alliance, Ovarian Cancer Research in honor of Liza Chance from the Foundation of Women Cancer, and the National Institutes of Health grant P50 CA217685 (to M.S.C.). We acknowledge the Brain Tumor Center and the Neuropathology Satellite Tumor Bank of the University of Texas MD Anderson Cancer Center for providing the plasma specimens. In addition, the authors gratefully acknowledge the assistance of Katherine Dixon, Malea Williams, and Crystal Dupuis for the in vivo inferior vena cava stenosis model generation and angiography experiments, Cancer Center Support Grant (CCSG) NIH P30CA016672, and High-Resolution Electron Microscopy Facility for transmission electron microscopy studies. R.G.-D. and N.M.M. conducted the experiments, analyzed and interpreted the data, and edited the manuscript. W.C.-A. M.S.C. and H.L. conducted the experiments. J.J. analyzed the database, and V.S. reviewed the medical records and confirmed the presence or absence of venous thromboembolism. O.G. analyzed and interpreted the data, and R.A.S. designed and conducted the experiments, analyzed and interpreted the data, and edited the manuscript. V.A.-K. designed the experiments, analyzed and interpreted the data, wrote the manuscript, and supervised the study. There are no competing interests to disclose.
Funding Information:
Funding information This study was supported, in part, by the National Institutes of Health grant CA231141 to V.A.-K. and O.G., the National Institutes of Health grant CA177909 to V.A.-K., the Liz Tilberis Early Career Development Award from the Ovarian Cancer Research Alliance, Ovarian Cancer Research in honor of Liza Chance from the Foundation of Women Cancer, the National Institutes of Health grant P50 CA217685 (to M.S.C.), and Cancer Center Support Grant (CCSG) grant NIH P30CA016672.
Publisher Copyright:
© 2023 International Society on Thrombosis and Haemostasis
PY - 2023/8
Y1 - 2023/8
N2 - Background: Many patients with glioblastoma multiforme (GBM) develop deep venous thrombosis or pulmonary emboli. Cell-free circulating mitochondria increase after brain injury and are associated with coagulopathy. Objectives: This study evaluated whether mitochondria play a role in the GBM-induced hypercoagulable state. Methods: We examined the correlation between cell-free circulating mitochondria and venous thrombosis in patients with GBM and the impact of mitochondria on venous thrombosis in mice with inferior vena cava stenosis. Results: Using plasma samples of 82 patients with GBM, we found that patients with GBM had a higher number of mitochondria in their plasma (GBM with venous thromboembolism [VTE],: 2.8 × 107 mitochondria/mL; GBM without VTE, 1.9 × 107 mitochondria/mL) than that in healthy control subjects (n = 17) (0.3 × 107 mitochondria/mL). Interestingly, patients with GBM and VTE (n = 41) had a higher mitochondria concentration than patients with GBM without VTE (n = 41). In a murine model of inferior vena cava stenosis, intravenous delivery of mitochondria resulted in an increased rate of venous thrombosis compared with that in controls (70% and 28%, respectively). Mitochondria-induced venous thrombi were neutrophil-rich and contained more platelets than those in control thrombi. Furthermore, as mitochondria are the only source of cardiolipin in circulation, we compared the concentration of anticardiolipin immunoglobulin G in plasma samples of patients with GBM and found a higher concentration in patients with VTE (optical density, 0.69 ± 0.04) than in those without VTE (optical density, 0.51 ± 0.04). Conclusion: We concluded that mitochondria might play a role in the GBM-induced hypercoagulable state. We propose that quantifying circulating mitochondria or anticardiolipin antibody concentrations in patients with GBM might identify patients at increased risk of VTE.
AB - Background: Many patients with glioblastoma multiforme (GBM) develop deep venous thrombosis or pulmonary emboli. Cell-free circulating mitochondria increase after brain injury and are associated with coagulopathy. Objectives: This study evaluated whether mitochondria play a role in the GBM-induced hypercoagulable state. Methods: We examined the correlation between cell-free circulating mitochondria and venous thrombosis in patients with GBM and the impact of mitochondria on venous thrombosis in mice with inferior vena cava stenosis. Results: Using plasma samples of 82 patients with GBM, we found that patients with GBM had a higher number of mitochondria in their plasma (GBM with venous thromboembolism [VTE],: 2.8 × 107 mitochondria/mL; GBM without VTE, 1.9 × 107 mitochondria/mL) than that in healthy control subjects (n = 17) (0.3 × 107 mitochondria/mL). Interestingly, patients with GBM and VTE (n = 41) had a higher mitochondria concentration than patients with GBM without VTE (n = 41). In a murine model of inferior vena cava stenosis, intravenous delivery of mitochondria resulted in an increased rate of venous thrombosis compared with that in controls (70% and 28%, respectively). Mitochondria-induced venous thrombi were neutrophil-rich and contained more platelets than those in control thrombi. Furthermore, as mitochondria are the only source of cardiolipin in circulation, we compared the concentration of anticardiolipin immunoglobulin G in plasma samples of patients with GBM and found a higher concentration in patients with VTE (optical density, 0.69 ± 0.04) than in those without VTE (optical density, 0.51 ± 0.04). Conclusion: We concluded that mitochondria might play a role in the GBM-induced hypercoagulable state. We propose that quantifying circulating mitochondria or anticardiolipin antibody concentrations in patients with GBM might identify patients at increased risk of VTE.
KW - anticardiolipin antibody
KW - glioblastoma
KW - mitochondria
KW - neutrophils
KW - venous thrombosis
UR - http://www.scopus.com/inward/record.url?scp=85161062579&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85161062579&partnerID=8YFLogxK
U2 - 10.1016/j.jtha.2023.04.036
DO - 10.1016/j.jtha.2023.04.036
M3 - Article
C2 - 37178770
AN - SCOPUS:85161062579
SN - 1538-7933
VL - 21
SP - 2202
EP - 2212
JO - Journal of Thrombosis and Haemostasis
JF - Journal of Thrombosis and Haemostasis
IS - 8
ER -