Elevated Microparticle Tissue Factor Activity Differentiates Patients With Venous Thromboembolism in Anti-neutrophil Cytoplasmic Autoantibody Vasculitis

Carmen E. Mendoza; Elizabeth J. Brant; Matthew L. McDermott; Anne Froment; Yichun Hu; Susan L. Hogan; J. Charles Jennette; Ronald J. Falk; Patrick H. Nachman; Vimal K. Derebail; Donna O.Dell Bunch

doi:10.1016/j.ekir.2019.07.006

Elevated Microparticle Tissue Factor Activity Differentiates Patients With Venous Thromboembolism in Anti-neutrophil Cytoplasmic Autoantibody Vasculitis

Carmen E. Mendoza, Elizabeth J. Brant, Matthew L. McDermott, Anne Froment, Yichun Hu, Susan L. Hogan, J. Charles Jennette, Ronald J. Falk, Patrick H. Nachman, Vimal K. Derebail, Donna O.Dell Bunch

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

Introduction: Venous thromboembolism (VTE) is a life-threatening complication of anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis whose mechanism remains incompletely elucidated. We tested the hypothesis that elevated microparticle tissue factor activity (MPTFa) or anti-plasminogen antibodies (anti-Plg) may identify patients at risk for VTE. Methods: In this prospective study, patients were enrolled during active disease and followed longitudinally. Twelve patients who experienced a VTE (VTE^pos) were compared with patients without VTE (VTE^neg, n = 29) and healthy controls (HC, n = 70). MPTFa, anti-Plg, interleukin-6, high-sensitivity C-reactive protein (hs-CRP), D-dimer, serum creatinine, and serum albumin were assessed. Fisher's exact tests and Wilcoxon tests compared categorical and continuous variables, respectively. Cox regression for time to VTE or last follow-up was performed. Results: VTE^pos patients had higher MPTFa (peak median = 14.0, interquartile range = 4.3–36.6) than HC (0, 0–3.5) and VTE^neg patients (0, 0–1.4). In time-to-event analysis, MPTFa was associated with VTE when measured during both active disease (hazard ratio [HR]; 95% confidence interval [CI]: 1.04; 1.01–1.08) and remission (1.4; 1.11–1.77). Anti-Plg during remission was also associated with VTE (1.17; 1.03–1.33). Each g/dl decrease of serum albumin was associated with a 4-fold increase in VTE risk (4.4; 1.5–12.9). Adjusting for estimated glomerular filtration rate (eGFR), anti-Plg during remission remained significantly associated with VTE. Conclusion: Elevated MPTFa and increased anti-Plg in remission are strong indicators of VTE independent of renal function. Association of anti-Plg during remission with VTE implies hypercoagulability even during disease quiescence. Hypoalbuminemia strongly portends VTE risk, which is a novel finding in ANCA vasculitis. A thrombotic signature would allow improved management of patients to minimize VTE risk and complications of anticoagulation.

Original language	English (US)
Pages (from-to)	1617-1629
Number of pages	13
Journal	Kidney International Reports
Volume	4
Issue number	11
DOIs	https://doi.org/10.1016/j.ekir.2019.07.006
State	Published - Nov 2019
Externally published	Yes

Bibliographical note

Funding Information:
We thank Elizabeth McInnis for IgG purification and Jean Brown for editorial assistance. Nigel Mackman, Nigel Key, Dougald Monroe, Micah Mooberry, Robert Bradford, and Mark Piegore provided expert advice regarding the MPTFa assay. These studies were supported by National Institutes of Health (NIH) / National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) PO1 DK 058335 . EJB received a Vasculitis Foundation Clinical Research Fellowship. VKD was supported by the Nephrotic Syndrome Study Network Consortium (NEPTUNE), NIDDK U-54-DK-083912, and Duke–University of North Carolina Clinical Hematology Research Career Development Program Grant 5K12 HL087097–05 (NIH/National Heart, Lung, and Blood Institute). The UNC Flow Cytometry Core Facility is supported by P30 CA016086 Cancer Center Core Support Grant to the UNC Lineberger Comprehensive Cancer Center.

Funding Information:
We thank Elizabeth McInnis for IgG purification and Jean Brown for editorial assistance. Nigel Mackman, Nigel Key, Dougald Monroe, Micah Mooberry, Robert Bradford, and Mark Piegore provided expert advice regarding the MPTFa assay. These studies were supported by National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) PO1 DK 058335. EJB received a Vasculitis Foundation Clinical Research Fellowship. VKD was supported by the Nephrotic Syndrome Study Network Consortium (NEPTUNE), NIDDK U-54-DK-083912, and Duke–University of North Carolina Clinical Hematology Research Career Development Program Grant 5K12 HL087097–05 (NIH/National Heart, Lung, and Blood Institute). The UNC Flow Cytometry Core Facility is supported by P30 CA016086 Cancer Center Core Support Grant to the UNC Lineberger Comprehensive Cancer Center. DOB, PHN, VKD, RJF, and JCJ designed the study. AF consented patients and acquired data. EJB, CEM, and DOB performed experiments. DOB, CEM, EJB, VKD, MLM, YH, and SLH analyzed data. DOB and CEM prepared figures. DOB, CEM, EJB, and VKD drafted the paper. All authors revised and approved the final version of manuscript.

Publisher Copyright:
© 2019 International Society of Nephrology

Keywords

autoimmunity
biomarkers
plasminogen
thrombosis
tissue factor
venous thrombosis

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Mendoza, C. E., Brant, E. J., McDermott, M. L., Froment, A., Hu, Y., Hogan, S. L., Jennette, J. C., Falk, R. J., Nachman, P. H., Derebail, V. K., & Bunch, D. O. D. (2019). Elevated Microparticle Tissue Factor Activity Differentiates Patients With Venous Thromboembolism in Anti-neutrophil Cytoplasmic Autoantibody Vasculitis. Kidney International Reports, 4(11), 1617-1629. https://doi.org/10.1016/j.ekir.2019.07.006

Mendoza, CE, Brant, EJ, McDermott, ML, Froment, A, Hu, Y, Hogan, SL, Jennette, JC, Falk, RJ, Nachman, PH, Derebail, VK & Bunch, DOD 2019, 'Elevated Microparticle Tissue Factor Activity Differentiates Patients With Venous Thromboembolism in Anti-neutrophil Cytoplasmic Autoantibody Vasculitis', Kidney International Reports, vol. 4, no. 11, pp. 1617-1629. https://doi.org/10.1016/j.ekir.2019.07.006

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title = "Elevated Microparticle Tissue Factor Activity Differentiates Patients With Venous Thromboembolism in Anti-neutrophil Cytoplasmic Autoantibody Vasculitis",

abstract = "Introduction: Venous thromboembolism (VTE) is a life-threatening complication of anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis whose mechanism remains incompletely elucidated. We tested the hypothesis that elevated microparticle tissue factor activity (MPTFa) or anti-plasminogen antibodies (anti-Plg) may identify patients at risk for VTE. Methods: In this prospective study, patients were enrolled during active disease and followed longitudinally. Twelve patients who experienced a VTE (VTEpos) were compared with patients without VTE (VTEneg, n = 29) and healthy controls (HC, n = 70). MPTFa, anti-Plg, interleukin-6, high-sensitivity C-reactive protein (hs-CRP), D-dimer, serum creatinine, and serum albumin were assessed. Fisher's exact tests and Wilcoxon tests compared categorical and continuous variables, respectively. Cox regression for time to VTE or last follow-up was performed. Results: VTEpos patients had higher MPTFa (peak median = 14.0, interquartile range = 4.3–36.6) than HC (0, 0–3.5) and VTEneg patients (0, 0–1.4). In time-to-event analysis, MPTFa was associated with VTE when measured during both active disease (hazard ratio [HR]; 95% confidence interval [CI]: 1.04; 1.01–1.08) and remission (1.4; 1.11–1.77). Anti-Plg during remission was also associated with VTE (1.17; 1.03–1.33). Each g/dl decrease of serum albumin was associated with a 4-fold increase in VTE risk (4.4; 1.5–12.9). Adjusting for estimated glomerular filtration rate (eGFR), anti-Plg during remission remained significantly associated with VTE. Conclusion: Elevated MPTFa and increased anti-Plg in remission are strong indicators of VTE independent of renal function. Association of anti-Plg during remission with VTE implies hypercoagulability even during disease quiescence. Hypoalbuminemia strongly portends VTE risk, which is a novel finding in ANCA vasculitis. A thrombotic signature would allow improved management of patients to minimize VTE risk and complications of anticoagulation.",

keywords = "autoimmunity, biomarkers, plasminogen, thrombosis, tissue factor, venous thrombosis",

author = "Mendoza, {Carmen E.} and Brant, {Elizabeth J.} and McDermott, {Matthew L.} and Anne Froment and Yichun Hu and Hogan, {Susan L.} and Jennette, {J. Charles} and Falk, {Ronald J.} and Nachman, {Patrick H.} and Derebail, {Vimal K.} and Bunch, {Donna O.Dell}",

note = "Funding Information: We thank Elizabeth McInnis for IgG purification and Jean Brown for editorial assistance. Nigel Mackman, Nigel Key, Dougald Monroe, Micah Mooberry, Robert Bradford, and Mark Piegore provided expert advice regarding the MPTFa assay. These studies were supported by National Institutes of Health (NIH) / National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) PO1 DK 058335 . EJB received a Vasculitis Foundation Clinical Research Fellowship. VKD was supported by the Nephrotic Syndrome Study Network Consortium (NEPTUNE), NIDDK U-54-DK-083912, and Duke–University of North Carolina Clinical Hematology Research Career Development Program Grant 5K12 HL087097–05 (NIH/National Heart, Lung, and Blood Institute). The UNC Flow Cytometry Core Facility is supported by P30 CA016086 Cancer Center Core Support Grant to the UNC Lineberger Comprehensive Cancer Center. Funding Information: We thank Elizabeth McInnis for IgG purification and Jean Brown for editorial assistance. Nigel Mackman, Nigel Key, Dougald Monroe, Micah Mooberry, Robert Bradford, and Mark Piegore provided expert advice regarding the MPTFa assay. These studies were supported by National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) PO1 DK 058335. EJB received a Vasculitis Foundation Clinical Research Fellowship. VKD was supported by the Nephrotic Syndrome Study Network Consortium (NEPTUNE), NIDDK U-54-DK-083912, and Duke–University of North Carolina Clinical Hematology Research Career Development Program Grant 5K12 HL087097–05 (NIH/National Heart, Lung, and Blood Institute). The UNC Flow Cytometry Core Facility is supported by P30 CA016086 Cancer Center Core Support Grant to the UNC Lineberger Comprehensive Cancer Center. DOB, PHN, VKD, RJF, and JCJ designed the study. AF consented patients and acquired data. EJB, CEM, and DOB performed experiments. DOB, CEM, EJB, VKD, MLM, YH, and SLH analyzed data. DOB and CEM prepared figures. DOB, CEM, EJB, and VKD drafted the paper. All authors revised and approved the final version of manuscript. Publisher Copyright: {\textcopyright} 2019 International Society of Nephrology",

year = "2019",

month = nov,

doi = "10.1016/j.ekir.2019.07.006",

language = "English (US)",

volume = "4",

pages = "1617--1629",

journal = "Kidney International Reports",

issn = "2468-0249",

publisher = "Elsevier Inc.",

number = "11",

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TY - JOUR

T1 - Elevated Microparticle Tissue Factor Activity Differentiates Patients With Venous Thromboembolism in Anti-neutrophil Cytoplasmic Autoantibody Vasculitis

AU - Mendoza, Carmen E.

AU - Brant, Elizabeth J.

AU - McDermott, Matthew L.

AU - Froment, Anne

AU - Hu, Yichun

AU - Hogan, Susan L.

AU - Jennette, J. Charles

AU - Falk, Ronald J.

AU - Nachman, Patrick H.

AU - Derebail, Vimal K.

AU - Bunch, Donna O.Dell

N1 - Funding Information: We thank Elizabeth McInnis for IgG purification and Jean Brown for editorial assistance. Nigel Mackman, Nigel Key, Dougald Monroe, Micah Mooberry, Robert Bradford, and Mark Piegore provided expert advice regarding the MPTFa assay. These studies were supported by National Institutes of Health (NIH) / National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) PO1 DK 058335 . EJB received a Vasculitis Foundation Clinical Research Fellowship. VKD was supported by the Nephrotic Syndrome Study Network Consortium (NEPTUNE), NIDDK U-54-DK-083912, and Duke–University of North Carolina Clinical Hematology Research Career Development Program Grant 5K12 HL087097–05 (NIH/National Heart, Lung, and Blood Institute). The UNC Flow Cytometry Core Facility is supported by P30 CA016086 Cancer Center Core Support Grant to the UNC Lineberger Comprehensive Cancer Center. Funding Information: We thank Elizabeth McInnis for IgG purification and Jean Brown for editorial assistance. Nigel Mackman, Nigel Key, Dougald Monroe, Micah Mooberry, Robert Bradford, and Mark Piegore provided expert advice regarding the MPTFa assay. These studies were supported by National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) PO1 DK 058335. EJB received a Vasculitis Foundation Clinical Research Fellowship. VKD was supported by the Nephrotic Syndrome Study Network Consortium (NEPTUNE), NIDDK U-54-DK-083912, and Duke–University of North Carolina Clinical Hematology Research Career Development Program Grant 5K12 HL087097–05 (NIH/National Heart, Lung, and Blood Institute). The UNC Flow Cytometry Core Facility is supported by P30 CA016086 Cancer Center Core Support Grant to the UNC Lineberger Comprehensive Cancer Center. DOB, PHN, VKD, RJF, and JCJ designed the study. AF consented patients and acquired data. EJB, CEM, and DOB performed experiments. DOB, CEM, EJB, VKD, MLM, YH, and SLH analyzed data. DOB and CEM prepared figures. DOB, CEM, EJB, and VKD drafted the paper. All authors revised and approved the final version of manuscript. Publisher Copyright: © 2019 International Society of Nephrology

PY - 2019/11

Y1 - 2019/11

N2 - Introduction: Venous thromboembolism (VTE) is a life-threatening complication of anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis whose mechanism remains incompletely elucidated. We tested the hypothesis that elevated microparticle tissue factor activity (MPTFa) or anti-plasminogen antibodies (anti-Plg) may identify patients at risk for VTE. Methods: In this prospective study, patients were enrolled during active disease and followed longitudinally. Twelve patients who experienced a VTE (VTEpos) were compared with patients without VTE (VTEneg, n = 29) and healthy controls (HC, n = 70). MPTFa, anti-Plg, interleukin-6, high-sensitivity C-reactive protein (hs-CRP), D-dimer, serum creatinine, and serum albumin were assessed. Fisher's exact tests and Wilcoxon tests compared categorical and continuous variables, respectively. Cox regression for time to VTE or last follow-up was performed. Results: VTEpos patients had higher MPTFa (peak median = 14.0, interquartile range = 4.3–36.6) than HC (0, 0–3.5) and VTEneg patients (0, 0–1.4). In time-to-event analysis, MPTFa was associated with VTE when measured during both active disease (hazard ratio [HR]; 95% confidence interval [CI]: 1.04; 1.01–1.08) and remission (1.4; 1.11–1.77). Anti-Plg during remission was also associated with VTE (1.17; 1.03–1.33). Each g/dl decrease of serum albumin was associated with a 4-fold increase in VTE risk (4.4; 1.5–12.9). Adjusting for estimated glomerular filtration rate (eGFR), anti-Plg during remission remained significantly associated with VTE. Conclusion: Elevated MPTFa and increased anti-Plg in remission are strong indicators of VTE independent of renal function. Association of anti-Plg during remission with VTE implies hypercoagulability even during disease quiescence. Hypoalbuminemia strongly portends VTE risk, which is a novel finding in ANCA vasculitis. A thrombotic signature would allow improved management of patients to minimize VTE risk and complications of anticoagulation.

AB - Introduction: Venous thromboembolism (VTE) is a life-threatening complication of anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis whose mechanism remains incompletely elucidated. We tested the hypothesis that elevated microparticle tissue factor activity (MPTFa) or anti-plasminogen antibodies (anti-Plg) may identify patients at risk for VTE. Methods: In this prospective study, patients were enrolled during active disease and followed longitudinally. Twelve patients who experienced a VTE (VTEpos) were compared with patients without VTE (VTEneg, n = 29) and healthy controls (HC, n = 70). MPTFa, anti-Plg, interleukin-6, high-sensitivity C-reactive protein (hs-CRP), D-dimer, serum creatinine, and serum albumin were assessed. Fisher's exact tests and Wilcoxon tests compared categorical and continuous variables, respectively. Cox regression for time to VTE or last follow-up was performed. Results: VTEpos patients had higher MPTFa (peak median = 14.0, interquartile range = 4.3–36.6) than HC (0, 0–3.5) and VTEneg patients (0, 0–1.4). In time-to-event analysis, MPTFa was associated with VTE when measured during both active disease (hazard ratio [HR]; 95% confidence interval [CI]: 1.04; 1.01–1.08) and remission (1.4; 1.11–1.77). Anti-Plg during remission was also associated with VTE (1.17; 1.03–1.33). Each g/dl decrease of serum albumin was associated with a 4-fold increase in VTE risk (4.4; 1.5–12.9). Adjusting for estimated glomerular filtration rate (eGFR), anti-Plg during remission remained significantly associated with VTE. Conclusion: Elevated MPTFa and increased anti-Plg in remission are strong indicators of VTE independent of renal function. Association of anti-Plg during remission with VTE implies hypercoagulability even during disease quiescence. Hypoalbuminemia strongly portends VTE risk, which is a novel finding in ANCA vasculitis. A thrombotic signature would allow improved management of patients to minimize VTE risk and complications of anticoagulation.

KW - autoimmunity

KW - biomarkers

KW - plasminogen

KW - thrombosis

KW - tissue factor

KW - venous thrombosis

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Elevated Microparticle Tissue Factor Activity Differentiates Patients With Venous Thromboembolism in Anti-neutrophil Cytoplasmic Autoantibody Vasculitis

Abstract

Bibliographical note

Keywords

UN SDGs

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