Recurrent thrombosis in patients with antiphospholipid antibodies treated with vitamin K antagonists or rivaroxaban

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1 Published Ahead of Print on March 8, 2018, as doi: /haematol Copyright 2018 Ferrata Storti Foundation. Recurrent thrombosis in patients with antiphospholipid antibodies treated with vitamin K antagonists or rivaroxaban by Ida Martinelli, Maria Abbattista, Paolo Bucciarelli, Armando Tripodi, Andrea Artoni, Francesca Gianniello, Cristina Novembrino, and Flora Peyvandi Haematologica 2018 [Epub ahead of print] Citation: Ida Martinelli, Maria Abbattista, Paolo Bucciarelli, Armando Tripodi, Andrea Artoni, Francesca Gianniello, Cristina Novembrino, and Flora Peyvandi. Recurrent thrombosis in patients with antiphospholipid antibodies treated with vitamin K antagonists or rivaroxaban. Haematologica. 2018; 103:xxx doi: /haematol Publisher's Disclaimer. E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors. After having E-published Ahead of Print, manuscripts will then undergo technical and English editing, typesetting, proof correction and be presented for the authors' final approval; the final version of the manuscript will then appear in print on a regular issue of the journal. All legal disclaimers that apply to the journal also pertain to this production process.

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6 Z&ZE^ 1. Pengo V, Ruffatti A, Legnani C, et al. Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J Thromb Haemost. 2010;8(2): Cervera R, Piette J, Font J, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum. 2002;46(4): Ruiz-Irastorza, G Cuadrado M, Ruiz-Arruza I, Brey R, et al. Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: Report of a Task Force at the 13th International Congress on Antiphospholipid Antibodies. Lupus. 2011;20(2): Crowther M, Ginsberg JS, Julian J, et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med. 2003;349(12): Prandoni P, Simioni P, Girolami A. Antiphospholipid antibodies, recurrent thromboembolism, and intensity of warfarin anticoagulation. Thromb Haemost. 1996;75(5): Finazzi G, Marchioli R, Brancaccio V, et al. A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost. 2005;3(5): Haładyj E, Olesińska M. Rivaroxaban - A safe therapeutic option in patients with antiphospholipid syndrome? Our experience in 23 cases. Reumatologia. 2016;54(3): Noel N, Dutasta F, Costedoat-Chalumeau N, et al. Safety and efficacy of oral direct inhibitors of thrombin and factor Xa in antiphospholipid syndrome. Autoimmun Rev. 2015;14(8): Malec K, Goralczyk T, Undas A. The use of direct oral anticoagulants in 56 patients with antiphospholipid syndrome. Thromb Res. 2017;152: Dufrost V, Risse J, Zuily S, Wahl D. Direct Oral Anticoagulants Use in Antiphospholipid Syndrome: Are These Drugs an Effective and Safe Alternative to Warfarin? A Systematic Review of the Literature. Curr Rheumatol Rep. 2016;18(12): Kaatz S, Ahmad D, Spyropoulos A, Schulman SS; Subcommittee on Control of Anticoagulation. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost. 2015;13(11): Devreese KMJ, Pierangeli SS, de Laat B, Tripodi A, Atsumi T, Ortel TL. Testing for Antiphospholipid antibodies with Solid Phase Assays: Guidance from the SSC of the ISTH. J Thromb Haemost. 2014;12(5): Cohen H, Hunt BJ, Efthymiou M, et al. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol. 2016;3(9):e426 e436. d

7 14. Resseguier AS, Pereira B, Rieu V, Le Guenno G, Grobost V, Ruivard M. Direct oral anticoagulants: an alternative treatment for thrombotic antiphospholipid syndrome? Lupus. 2017;26(12): Anand SS, Bosch J, Eikelboom JW, et al. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebocontrolled trial. Lancet Nov 10. [Epub ahead of print]. e

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11 Supplemental material for: RECURRENT THROMBOSIS IN PATIENTS WITH ANTIPHOSPHOLIPID ANTIBODIES TREATED WITH VITAMIN K ANTAGONISTS OR RIVAROXABAN Ida Martinelli 1, Maria Abbattista 1, Paolo Bucciarelli 1, Armando Tripodi 1-2, Andrea Artoni 1, Francesca Gianniello 1, Cristina Novembrino 1-3 and Flora Peyvandi A.Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda - Ospedale Maggiore Policlinico; 2 Department of Clinical Sciences and Community Health and 3 Laboratory of Clinical Chemistry and Microbiology, 4 Department of Pathophysiology and Transplantation, University of Milan, Italy METHODS Laboratory tests Venous blood samples were taken at the time of the first visit for thrombophilia testing and collected into vacutainer tubes containing trisodium citrate 109 mm at the 9:1 proportion (blood: anticoagulant). Platelet-poor plasma (PPP) was obtained by centrifugation at 1800g for 15 minutes at room temperature, frozen in liquid nitrogen and stored at -80 C until used. LA testing was performed on fresh plasma obtained by centrifuging blood samples at 3000g for 15 minutes. The supernatant plasma was re-centrifuged (same conditions) to minimize residual platelets and the samples were analysed within the day of collection. Thrombophilia screening included: DNA analysis (performed on citrated whole blood) for the 1691 guanine to adenine substitution in coagulation factor V gene (factor V Leiden) 1 and for the guanine to adenine substitution in the 3 -untranslated region of the prothrombin gene; 2 functional and/or antigenic assays for plasma fibrinogen, antithrombin, protein C and protein S; 3 apl were evaluated as recommended by the Subcommittee on Lupus Anticoagulant/Phospholipid/Dependent Antibodies of the ISTH. 4 LA was detected using two screening tests: silica clotting time (SCT, Werfen, Orangeburg, NY) and diluted Russel viper venom test (drvvt, Werfen). Mixing tests (patient/normal) and confirmatory tests at increasing phospholipid concentrations carried out whenever the screening test was prolonged beyond the local cut-off values (1.35 ratio for SCT and 1.23 ratio for drvvt). Patients were considered positive for LA whenever SCT and/or drvvt gave positive results for screening, mixing and confirm; 5 in patients on VKA therapy mixing studies should correct the prolonged screening studies if they are only due to the anticoagulant effect; the drvvt with confirmatory testing has been demonstrated to reliably detect LA in patients on warfarin therapy. 6,7 For acl >40 GPL or MPL and for a 2-GPI >10 U/mL, corresponding to the 99 th percentile, were determined on serum samples by Elisa (Phadia Gmbh, Thermo Fisher Scientific, Uppsala, Sweden) on Phadia 250 analyzer (Thermo Fisher Scientific), following the ISTH recommendation. 4 Patients were considered as having positive results 1

12 whenever one of the two tests (acl or aβ2-gpi) gave results higher than the local cut-off values. The presence of apl was confirmed in a second blood sample three months apart from the first detection, as recommended by international guidelines. 5 Protein C and protein S were not tested in patients on VKA at the time of blood sampling. Patients on rivaroxaban were tested only for antithrombin and protein S free antigens because of the known influence of the drug on the functional tests; functional protein C was evaluated using a chromogenic assay in order to overcome these interferences. Statistical analysis Mean and standard deviation or median and inter-quartile range were used to describe continuous variables. Count and percentage were used for demographic and clinical variables. The incidence rates (IR) of recurrent thrombosis were calculated with their 95% confidence intervals (CI) according to Poisson distribution and expressed as events per 100 patients-year (pts-yr). In case of patients shifted from VKA to DOAC or vice versa, their exposure period was concurrently partitioned to each of the two anticoagulants. Kaplan-Meier curves were used to plot the cumulative incidence of recurrent thrombosis during the followup period. The cumulative incidence of recurrent thrombosis was calculated from life table with its 95% CI with Hosmer-Lemeshow-May method for the periods of VKA intake and according to Poisson distribution for the periods of DOAC intake. Hazard ratio (HR) and its 95% CI was calculated by a Cox proportional hazard regression model as a risk estimate of recurrent thrombosis in patients with aps treated with DOAC relative to those treated with VKA (reference category). All analyses were performed with the statistical software SPSS (release 23.0, IBM SPSS Statistics for Windows, IBM Corp., Armonk, NY, USA). References 2

13 1. Bertina RM, Koeleman BPC, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3 -untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996;88(10): Tripodi A. A review of the clinical and diagnostic utility of laboratory tests for the detection of congenital thrombophilia. Semin Thromb Hemost 2005;31(1): Devreese KMJ, Pierangeli SS, de Laat B, Tripodi A, Atsumi T, Ortel TL. Testing for Antiphospholipid antibodies with Solid Phase Assays: Guidance from the SSC of the ISTH. J Thromb Haemost 2014;12(5): Pengo V, Tripodi A, Reber G, et al. Update of the guidelines for lupus anticoagulant detection. J Thromb Haemost 2009;7(10): Tripodi A, Chantarangkul V, Clerici M. Laboratory Diagnosis of Lupus Anticoagulants for Patients on Oral Anticoagulant Treatment Performance of Dilute Russell Viper Venom Test and Silica Clotting Time in. 2002; Olteanu H, Downes K, Patel J, Praprotnik D, Sarode R. Warfarin does not interfere with lupus anticoagulant detection by dilute Russell s viper venom time. Clin Lab 2009;55(3 4):