title: A novel, rapid method to compare the therapeutic windows of oral anticoagulants using the Hill coefficient.
abstract: A central challenge in designing and administering effective anticoagulants is achieving the proper therapeutic window and dosage for each patient. The Hill coefficient, nH, which measures the steepness of a dose-response relationship, may be a useful gauge of this therapeutic window. We sought to measure the Hill coefficient of available anticoagulants to gain insight into their therapeutic windows. We used a simple fluorometric in vitro assay to determine clotting activity in platelet poor plasma after exposure to various concentrations of anticoagulants. The Hill coefficient for argatroban was the lowest, at 1.7 ± 0.2 (95% confidence interval, CI), and the Hill coefficient for fondaparinux was the highest, at 4.5 ± 1.3 (95% CI). Thus, doubling the dose of fondaparinux from its IC50 would decrease coagulation activity by nearly a half, whereas doubling the dose of argatroban from its IC50 would decrease coagulation activity by merely one quarter. These results show a significant variation among the Hill coefficients, suggesting a similar variation in therapeutic windows among anticoagulants in our assay.
authors.affiliation: Department of Biomedical Informatics, Columbia University Medical Center, New York, New York, USA.
authors.forename: Jeremy B
authors.initials: JB
authors.lastname: Chang
authors.affiliation: Department of Biomedical Informatics, Columbia University Medical Center, New York, New York, USA.
authors.forename: Kayla M
authors.initials: KM
authors.lastname: Quinnies
authors.affiliation: Columbia Genome Center, Columbia University Medical Center, New York, New York, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Realubit
authors.affiliation: Columbia Genome Center, Columbia University Medical Center, New York, New York, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Karan
authors.affiliation: Department of Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medical Center, New York, New York, USA.
authors.forename: Jacob H
authors.initials: JH
authors.lastname: Rand
authors.affiliation: Department of Biomedical Informatics, Columbia University Medical Center, New York, New York, USA.|Departments of Systems Biology and Medicine, Columbia University Medical Center, New York, New York, USA.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Tatonetti
mesh_terms: D000284:Administration, Oral; D000925:Anticoagulants / Q000008:administration & dosage*; D001120:Arginine / Q000031:analogs & derivatives; D001777:Blood Coagulation; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005470:Fluorometry; D000077425:Fondaparinux; D006801:Humans; D020128:Inhibitory Concentration 50; D010875:Pipecolic Acids / Q000008:administration & dosage*; D010949:Plasma / Q000187:drug effects; D011134:Polysaccharides / Q000008:administration & dosage*; D013449:Sulfonamides; D013917:Thrombin / Q000737:chemistry
chemical_list: D000925:Anticoagulants; D010875:Pipecolic Acids; D011134:Polysaccharides; D013449:Sulfonamides; D001120:Arginine; D013917:Thrombin; C031942:argatroban; D000077425:Fondaparinux