title: Thrombin generation and other coagulation parameters in a patient with homozygous congenital protein S deficiency on treatment with rivaroxaban.
abstract: Rivaroxaban, which targets factor Xa and does not reduce proteins C/S, was chosen to treat a 6-year-old girl with homozygous protein S (PS) deficiency who developed skin necrosis while on warfarin. Owing to the lack of experience with rivaroxaban in children, the girl was started with 5 mg once-daily, which was gradually increased to 40 mg daily. The increasing dosage was driven by the need to avoid recurrence of skin necrosis. During dose-escalation, four pharmacokinetics assays were carried out measuring drug plasma concentrations and their effect on hemostatic parameters. We report the laboratory work-up, with special reference to parameters of thrombin-generation. Rivaroxaban concentrations by HPLC were correlated with those by the anti-factor Xa assay (r(2) = 0.92, p < 0.01), but there was an overestimation by HPLC. Thrombin-generation parameters, such as the area under the curve (referred to as ETP), peak-thrombin, and velocity-index, when measured after addition of thrombomodulin, showed unexpected changes: ETP decreased, but peak-thrombin and velocity-index increased. Similar patterns were obtained in a PS-depleted plasma and in plasma from patients with heterozygous PS deficiency, but not in plasma from controls. In conclusion, these preliminary results suggest that PS may be a determinant of velocity and peak-thrombin, but not of the total amount of thrombin generated.
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Università degli Studi di Milano, Via Pace 9, 20122, Milan, Italy. armando.tripodi@unimi.it.|Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy. armando.tripodi@unimi.it.|IRCCS Cà Granda Maggiore Hospital Foundation, Milan, Italy. armando.tripodi@unimi.it.
authors.forename: Armando
authors.initials: A
authors.lastname: Tripodi
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Università degli Studi di Milano, Via Pace 9, 20122, Milan, Italy.|Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.|IRCCS Cà Granda Maggiore Hospital Foundation, Milan, Italy.
authors.forename: Ida
authors.initials: I
authors.lastname: Martinelli
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Università degli Studi di Milano, Via Pace 9, 20122, Milan, Italy.|Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.|IRCCS Cà Granda Maggiore Hospital Foundation, Milan, Italy.
authors.forename: Veena
authors.initials: V
authors.lastname: Chantarangkul
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Università degli Studi di Milano, Via Pace 9, 20122, Milan, Italy.|Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.|IRCCS Cà Granda Maggiore Hospital Foundation, Milan, Italy.
authors.forename: Marigrazia
authors.initials: M
authors.lastname: Clerici
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Università degli Studi di Milano, Via Pace 9, 20122, Milan, Italy.|Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.|IRCCS Cà Granda Maggiore Hospital Foundation, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Artoni
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Università degli Studi di Milano, Via Pace 9, 20122, Milan, Italy.|Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.|IRCCS Cà Granda Maggiore Hospital Foundation, Milan, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Passamonti
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Università degli Studi di Milano, Via Pace 9, 20122, Milan, Italy.|Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.|IRCCS Cà Granda Maggiore Hospital Foundation, Milan, Italy.
authors.forename: Flora
authors.initials: F
authors.lastname: Peyvandi
mesh_terms: D001777:Blood Coagulation; D002648:Child; D065427:Factor Xa Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006720:Homozygote; D006801:Humans; D018455:Protein S Deficiency / Q000097:blood* / Q000151:congenital / Q000188:drug therapy* / Q000235:genetics; D000069552:Rivaroxaban / Q000008:administration & dosage / Q000627:therapeutic use*; D013917:Thrombin / Q000378:metabolism*
chemical_list: D065427:Factor Xa Inhibitors; D000069552:Rivaroxaban; D013917:Thrombin
keywords: Anticoagulation; Direct oral anticoagulants; Purpura fulminans; Skin necrosis; Thrombosis