title: Tissue Factor As a Predictor of Recurrent Venous Thromboembolism in Malignancy: Biomarker Analyses of the CATCH Trial.
abstract: Purpose Circulating tissue factor (TF) has been studied as a biomarker for predicting initial, but not recurrent, venous thromboembolism (VTE) in cancer, a setting in which predictors are incompletely understood. We evaluated the association of TF, clinical risk factors, and other biomarkers measured at the time of initial VTE with recurrent VTE in a prespecified analysis of the CATCH (Comparison of Acute Treatments in Cancer Hemostasis) trial. Methods CATCH was a randomized, multicenter trial that investigated tinzaparin 175 IU/kg once daily or dose-adjusted warfarin for 6 months in patients with cancer and acute, symptomatic VTE. TF ELISA, soluble P-selectin, d-dimer, FVIII, and C-reactive protein were assayed. Fisher's exact test was used to screen for association with VTE; competing risk regression analysis of time to recurrent VTE was conducted, accounting for multiple variables. Results The study population comprised 900 patients (recurrent VTE, n = 76; 8.4%). Of these patients, 805 had samples available for TF assay. Mean and median TF levels were 72.5 pg/mL and 50.3 pg/mL, respectively (range, 15.6 pg/mL to 4,798 pg/mL). Patients in the highest quartile of TF experienced the greatest VTE recurrence (> 64.6 pg/mL; 38 [19%] of 203 patients v 34 [6%] of 602 patients; relative risk, 3.3; 95% CI, 2.1 to 5.1; P < .001). In competing risk regression analysis of time to recurrent VTE, TF remained strongly associated with recurrent VTE (subdistribution hazard ratio [SHR], 3.3; 95% CI, 1.7 to 6.4). Other significant variables included venous compression from mass (SHR, 3.1; 95% CI, 1.4 to 6.5) and hepatobiliary cancer (SHR, 5.5; 95% CI, 2.3 to 13.6). Conclusion This is the first report, to our knowledge, to describe TF as a potential biomarker of recurrent VTE in patients with cancer who are on anticoagulation treatment. A risk-adapted strategy could help identify high-risk patients who may benefit from more intensive anticoagulation approaches.
authors.affiliation: Alok A. Khorana, The Cleveland Clinic, Cleveland, OH; Pieter W. Kamphuisen, Tergooi, Hilversum; Pieter W. Kamphuisen, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Guy Meyer, Georges Pompidou European Hospital, Université Paris Descartes Sorbonne Paris Cité, Institut National de la Santé et de la Recherche Médicale, Unité mixte de recherche 970, Centres d'Investigation Clinique 1418, Paris, France; Rupert Bauersachs, Darmstadt Hospital, Darmstadt; Rupert Bauersachs, University Medical Center Mainz, Mainz, Germany; Mette S. Janas and Mikala F. Jarner, LEO Pharma, Ballerup, Denmark; Agnes Y.Y. Lee, University of British Columbia; and Agnes Y.Y. Lee, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Alok A
authors.initials: AA
authors.lastname: Khorana
authors.affiliation: Alok A. Khorana, The Cleveland Clinic, Cleveland, OH; Pieter W. Kamphuisen, Tergooi, Hilversum; Pieter W. Kamphuisen, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Guy Meyer, Georges Pompidou European Hospital, Université Paris Descartes Sorbonne Paris Cité, Institut National de la Santé et de la Recherche Médicale, Unité mixte de recherche 970, Centres d'Investigation Clinique 1418, Paris, France; Rupert Bauersachs, Darmstadt Hospital, Darmstadt; Rupert Bauersachs, University Medical Center Mainz, Mainz, Germany; Mette S. Janas and Mikala F. Jarner, LEO Pharma, Ballerup, Denmark; Agnes Y.Y. Lee, University of British Columbia; and Agnes Y.Y. Lee, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Pieter W
authors.initials: PW
authors.lastname: Kamphuisen
authors.affiliation: Alok A. Khorana, The Cleveland Clinic, Cleveland, OH; Pieter W. Kamphuisen, Tergooi, Hilversum; Pieter W. Kamphuisen, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Guy Meyer, Georges Pompidou European Hospital, Université Paris Descartes Sorbonne Paris Cité, Institut National de la Santé et de la Recherche Médicale, Unité mixte de recherche 970, Centres d'Investigation Clinique 1418, Paris, France; Rupert Bauersachs, Darmstadt Hospital, Darmstadt; Rupert Bauersachs, University Medical Center Mainz, Mainz, Germany; Mette S. Janas and Mikala F. Jarner, LEO Pharma, Ballerup, Denmark; Agnes Y.Y. Lee, University of British Columbia; and Agnes Y.Y. Lee, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Guy
authors.initials: G
authors.lastname: Meyer
authors.affiliation: Alok A. Khorana, The Cleveland Clinic, Cleveland, OH; Pieter W. Kamphuisen, Tergooi, Hilversum; Pieter W. Kamphuisen, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Guy Meyer, Georges Pompidou European Hospital, Université Paris Descartes Sorbonne Paris Cité, Institut National de la Santé et de la Recherche Médicale, Unité mixte de recherche 970, Centres d'Investigation Clinique 1418, Paris, France; Rupert Bauersachs, Darmstadt Hospital, Darmstadt; Rupert Bauersachs, University Medical Center Mainz, Mainz, Germany; Mette S. Janas and Mikala F. Jarner, LEO Pharma, Ballerup, Denmark; Agnes Y.Y. Lee, University of British Columbia; and Agnes Y.Y. Lee, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Rupert
authors.initials: R
authors.lastname: Bauersachs
authors.affiliation: Alok A. Khorana, The Cleveland Clinic, Cleveland, OH; Pieter W. Kamphuisen, Tergooi, Hilversum; Pieter W. Kamphuisen, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Guy Meyer, Georges Pompidou European Hospital, Université Paris Descartes Sorbonne Paris Cité, Institut National de la Santé et de la Recherche Médicale, Unité mixte de recherche 970, Centres d'Investigation Clinique 1418, Paris, France; Rupert Bauersachs, Darmstadt Hospital, Darmstadt; Rupert Bauersachs, University Medical Center Mainz, Mainz, Germany; Mette S. Janas and Mikala F. Jarner, LEO Pharma, Ballerup, Denmark; Agnes Y.Y. Lee, University of British Columbia; and Agnes Y.Y. Lee, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Mette S
authors.initials: MS
authors.lastname: Janas
authors.affiliation: Alok A. Khorana, The Cleveland Clinic, Cleveland, OH; Pieter W. Kamphuisen, Tergooi, Hilversum; Pieter W. Kamphuisen, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Guy Meyer, Georges Pompidou European Hospital, Université Paris Descartes Sorbonne Paris Cité, Institut National de la Santé et de la Recherche Médicale, Unité mixte de recherche 970, Centres d'Investigation Clinique 1418, Paris, France; Rupert Bauersachs, Darmstadt Hospital, Darmstadt; Rupert Bauersachs, University Medical Center Mainz, Mainz, Germany; Mette S. Janas and Mikala F. Jarner, LEO Pharma, Ballerup, Denmark; Agnes Y.Y. Lee, University of British Columbia; and Agnes Y.Y. Lee, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Mikala F
authors.initials: MF
authors.lastname: Jarner
authors.affiliation: Alok A. Khorana, The Cleveland Clinic, Cleveland, OH; Pieter W. Kamphuisen, Tergooi, Hilversum; Pieter W. Kamphuisen, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Guy Meyer, Georges Pompidou European Hospital, Université Paris Descartes Sorbonne Paris Cité, Institut National de la Santé et de la Recherche Médicale, Unité mixte de recherche 970, Centres d'Investigation Clinique 1418, Paris, France; Rupert Bauersachs, Darmstadt Hospital, Darmstadt; Rupert Bauersachs, University Medical Center Mainz, Mainz, Germany; Mette S. Janas and Mikala F. Jarner, LEO Pharma, Ballerup, Denmark; Agnes Y.Y. Lee, University of British Columbia; and Agnes Y.Y. Lee, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Agnes Y Y
authors.initials: AY
authors.lastname: Lee
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D005169:Factor VIII / Q000378:metabolism; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D006495:Heparin, Low-Molecular-Weight / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000150:complications* / Q000628:therapy; D019007:P-Selectin / Q000097:blood; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012008:Recurrence; D012307:Risk Factors; D013925:Thromboplastin / Q000378:metabolism*; D013997:Time Factors; D000078222:Tinzaparin; D054556:Venous Thromboembolism / Q000097:blood* / Q000188:drug therapy / Q000209:etiology
chemical_list: D015415:Biomarkers; D005338:Fibrin Fibrinogen Degradation Products; D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D019007:P-Selectin; C036309:fibrin fragment D; D000078222:Tinzaparin; D005169:Factor VIII; D002097:C-Reactive Protein; D013925:Thromboplastin