Thrombin generation and other coagulation parameters in a patient with homozygous congenital protein S deficiency on treatment with rivaroxaban

• Published in: International journal of hematology Vol. 103; no. 2; pp. 165 - 172
• Main Authors: Tripodi, Armando, Martinelli, Ida, Chantarangkul, Veena, Clerici, Marigrazia, Artoni, Andrea, Passamonti, Serena, Peyvandi, Flora
• Format: Journal Article
• Language: English
• Published: Tokyo Springer Japan 01-02-2016; Springer Nature B.V
• Subjects: Blood Coagulation; Child; Factor Xa Inhibitors - administration & dosage; Factor Xa Inhibitors - therapeutic use; Female; Hematology; Homozygote; Humans; Medicine; Medicine & Public Health; Oncology; Original Article; Protein S Deficiency - blood; Protein S Deficiency - congenital; Protein S Deficiency - drug therapy; Protein S Deficiency - genetics; Rivaroxaban - administration & dosage; Rivaroxaban - therapeutic use; Thrombin - metabolism; Purpura fulminans; Skin necrosis; Anticoagulation; Direct oral anticoagulants; Thrombosis
• ISSN: 0925-5710; 1865-3774
• DOI: 10.1007/s12185-015-1898-6

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.