Koudriavtseva and colleagues measured levels of different biomarkers in healthy controls, patients with remitting multiple sclerosis (MS), and patients with relapsing MS. The Quantikine enzyme-linked immunosorbent assay (ELISA) (R&D Systems, Minneapolis,MN, Cat. No. DCF300) was used to measure plasma tissue factor (TF) (S. Lorenzano, personal communication). The authors found that patients with relapsing MS had lower levels of plasma TF compared to either patients with remitting MS or the control group. It was concluded that plasma TF is a promising biomarker and possible therapeutic target in relapsing-remitting MS

Mackman N.

Sachetto A.T.A.

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Frontiers in ImmunologyOPEN ACCESSEDITED BYUday Kishore,United Arab Emirates University,United Arab EmiratesREVIEWED BYPaolo Ragonese,University of Palermo, Italy*CORRESPONDENCENigel Mackmannmackman@med.unc.eduRECEIVED 11 October 2023ACCEPTED 15 November 2023PUBLISHED 01 December 2023CITATIONMackman N and Sachetto ATA (2023)Commentary: Tissue factor as a potentialcoagulative/vascular marker in relapsing-remitting multiple sclerosis.Front. Immunol. 14:1320179.doi: 10.3389/fimmu.2023.1320179COPYRIGHT© 2023 Mackman and Sachetto. This is anopen-access article distributed under theterms of the Creative Commons AttributionLicense (CC BY). The use, distribution orreproduction in other forums is permitted,provided the original author(s) and thecopyright owner(s) are credited and thatthe original publication in this journal iscited, in accordance with acceptedacademic practice. No use, distribution orreproduction is permitted which does notcomply with these terms.TYPE General CommentaryPUBLISHED 01 December 2023DOI 10.3389/fimmu.2023.1320179Commentary: Tissue factor as apotential coagulative/vascularmarker in relapsing-remittingmultiple sclerosisNigel Mackman* and Ana T.A. SachettoDepartment of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesKEYWORDSmultiple sclerosis, tissue factor, inflammation, biomarker, coagulationA Commentary onTissue factor as a potential coagulative/vascular marker in relapsing-remitting multiple sclerosisby Koudriavtseva T, Lorenzano S, Cellerino M, Truglio M, Fiorelli M, Lapucci C, D’Agosto G,Conti L, Stefanile A, Zannino S, Filippi MM, Cortese A, Piantadosi C, Maschio M, Maialetti A, GalièE, Salvetti M and Inglese M (2023) Front. Immunol. 14:1226616. doi: 10.3389/fimmu.2023.1226616Koudriavtseva and colleagues (1) measured levels of different biomarkers in healthycontrols, patients with remitting multiple sclerosis (MS), and patients with relapsing MS. TheQuantikine enzyme-linked immunosorbent assay (ELISA) (R&D Systems, Minneapolis, MN,Cat. No. DCF300) was used to measure plasma tissue factor (TF) (S. Lorenzano, personalcommunication). The authors found that patients with relapsing MS had lower levels ofplasma TF compared to either patients with remitting MS or the control group. It wasconcluded that plasma TF is a promising biomarker and possible therapeutic target inrelapsing-remitting MS.A previous clinical study called Comparison of Acute Treatments in CancerHemostasis (CATCH) used the same Quantikine ELISA to measure plasma TF levels in805 patients with cancer and acute symptomatic venous thromboembolism treated withanticoagulants (2). The mean and median values for TF were 72.5 pg/mL and 50.3 pg/mL,respectively. Plasma TF was identified as a biomarker of recurrent venousthromboembolism in this group of patients. We were invited to write a commentary onthe paper (understanding the pathway), in which we raised concerns about the ability of theQuantikine ELISA to accurately measure levels of TF in human plasma (3).Recently, we assessed the ability of four commercial human TF ELISAs, including theQuantikine ELISA, to detect TF in various biological samples, including human plasma (4).frontiersin.org01Mackman and Sachetto 10.3389/fimmu.2023.1320179Two of the ELISAs (Quantikine and Imubind) detectedrecombinant TF and TF in extracellular vesicles from a TF-expressing human pancreatic cell line. However, the ELISAs failedto detect TF in plasma that contained TF-positive extracellularvesicles (1.2–2.6 pg/mL) (determined using a factor Xa generationassay). The only plasma samples that had a signal above thebackground of plasma from healthy controls were from threepatients with acute leukemia, who had very high levels ofextracellular vesicle TF activity (151–696 pg/mL). We concludedthat, except for some patients with leukemia, the Quantikine ELISAcould not detect TF in human plasma.There are two significant challenges withmeasuring TF in humanplasma. First, the concentration of this potent procoagulant protein isvery low. Secondly, plasma contains multivalent substances, such asheterotypic antibodies, that can generate signals in ELISAsindependently of the target protein by simply bridging assayantibodies. Such heterotypic antibodies may increase in differentFrontiers in Immunology 02disease states. The datasheet for the Quantikine ELISA states that themean value for plasma from healthy controls is 33.3 pg/mL (Table 1).We and others (4–7) have observed similar low values for healthyindividuals (mean, 23.5–45.1 pg/mL; median, 39.1–52.4 pg/mL)(Table 1). In contrast, Koudriavtseva and colleagues (1) reportmuch higher values of TF in healthy controls (mean, 110.85 pg/mL; median, 120.69 pg/mL) (Table 1). Patients with remitting MShad similarly high values (mean, 94.06 pg/mL; median, 99.23 pg/mL),whereas patients with relapsing MS had low values (mean, 45.03 pg/mL; median, 22.72 pg/mL). These low values are more consistentwith healthy controls than a disease group.We found that the Quantikine ELISA could not detect low levelsof TF in human plasma. We believe that additional methods shouldbe used to demonstrate changes in TF levels in the plasma, such asmeasuring extracellular vesicle TF activity, before concluding thatplasma TF is a biomarker of relapsing-remitting MS.Author contributionsNM: Writing – original draft. AS: Writing – review & editing.FundingThe author(s) declare that no financial support was received forthe research, authorship, and/or publication of this article.Conflict of interestThe authors declare that the research was conducted in theabsence of any commercial or financial relationships that could beconstrued as a potential conflict of interest.Publisher’s noteAll claims expressed in this article are solely those of the authorsand do not necessarily represent those of their affiliated organizations,or those of the publisher, the editors and the reviewers. Any productthat may be evaluated in this article, or claim that may be made by itsmanufacturer, is not guaranteed or endorsed by the publisher.References1. Koudriavtseva T, Lorenzano S, Cellerino M, Truglio M, Fiorelli M, Lapucci C, et al.Tissue factor as a potential coagulative/vascular marker in relapsing-remitting multiplesclerosis. Front Immunol (2023) 14:1226616. doi: 10.3389/fimmu.2023.12266162. Khorana AA, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF,et al. Tissue factor as a predictor of recurrent venous thromboembolism in Malignancy:biomarker analyses of the CATCH trial. J Clin Oncol (2017) 35(10):1078–85. doi:10.1200/JCO.2016.67.45643. Ay C, Mackman N. Tissue factor: catch me if you can! J Clin Oncol (2017) 35(10):1128–30. doi: 10.1200/JCO.2016.70.67884. Sachetto ATA, Archibald SJ, Bhatia R, Monroe D, Hisada Y, Mackman N.Evaluation of four commercial ELISAs to measure tissue factor in humanplasma. Res Pract Thromb Haemostasis (2023) 100133. doi: 10.1016/j.rpth.2023.1001335. Talar-Wojnarowska R, Woźniak M, Borkowska A, Cypryk K, Olakowski M,Małecka-Panas E. Procoagulant disorders in patients with newly diagnosed pancreaticadenocarcinoma. Medicina (2020) 56(12):677. doi: 10.3390/medicina561206776. Kobayashi S, Koizume S, Takahashi T, Ueno M, Oishi R, Nagashima S, et al.Tissue factor and its procoagulant activity on cancer-associated thromboembolism inpancreatic cancer. Cancer Sci (2021) 112(11):4679–91. doi: 10.1111/cas.151067. Cacciola R, Gentilini Cacciola E, Vecchio V, Cacciola E. Cellular and molecularmechanisms in COVID-19 coagulopathy: role of inflammation and endotheliopathy. JThromb Thrombolysis (2022) 53(2):282–90. doi: 10.1007/s11239-021-02583-4TABLE 1 Measurement of the levels of plasma tissue factor in healthycontrols and patients with multiple sclerosis using the quantikineTF ELISA.Mean (SD)(pg/mL)Median (IQR)(pg/mL)Ref.Healthy control(n = 36)33.3 (6.6) R&DdatasheetHealthy control(n = 20)– 52.4 (28.4–72.4) (5)Healthy control(n = 41)– 39.1 (16.8–87.3) (6)Healthy control(n = 40)23.5 (5) – (7)Healthy control(n = 5)45.1 (14.7) 40.6 (33.4–59.0) (4)Healthy control(n = 30)110.85 (56.31) 120.69a (1)Remitting MS (n= 30)94.06 (55.83) 99.23a (1)Relapsing MS (n= 30)45.03 (37.66) 22.72a (1)SD, standard deviation; IQR, interquartile range.aA single value was reported for the IQR instead of a range.frontiersin.org

Commentary: Tissue factor as a potential coagulative/vascular marker in relapsing-remitting multiple sclerosis

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