We report a case of supratherapeutic international normalized ratio values in a hospitalized patient started on warfarin to prevent recurrent deep vein thrombosis. Her medical history showed a failed course of apixaban and so warfarin therapy was initiated during this admission but quickly stopped after sudden, significant increases in international normalized ratio for several days after termination of therapy. A review of any drug-drug interaction did not expose any reported interactions between warfarin and her current medications at that time. However, the concurrent administration of cupric chloride did raise the possibility of an undocumented interaction between these two entities. The pharmacokinetic/pharmacodynamic properties of both drugs provided a study into the consequences of a combination therapy, beyond the anticipated outcome, which is normally based on previously observed results.
References
[1]
Ofek, F., Bar Chaim, S., Kronenfeld, N., et al. (2017) International Normalized Ratio Is Significantly Elevated with Rivaroxaban and Apixaban Drug Therapies: A Retrospective Study. Clinical Therapeutics, 39, 1003-1010. https://doi.org/10.1016/j.clinthera.2017.04.007
[2]
Holbrook, A., Pereira, J., Labiris, R., et al. (2005) Systematic Overview of Warfarin and Its Drug and Food Interactions. Archives of Internal Medicine, 165, 1095-1096. https://doi.org/10.1001/archinte.165.10.1095
[3]
Schmidt, S., Gonzalez, D. and Derendorf, H. (2010) Significance of Protein Binding in Pharmacokinetics and Pharmacodynamics. Journal of Pharmaceutical Sciences, 99, 1107-1122. https://doi.org/10.1002/jps.21916
[4]
Fender, A. and Dobrev, D. (2019) How Altered Albumin Binding May Dictate Warfarin Treatment Outcome. IJC Heart & Vasculature, 22, 214-215. https://doi.org/10.1016/j.ijcha.2019.02.007
[5]
Petitpas, I., Bhattacharya, A., Twine, S., et al. (2001) Crystal Structure Analysis of Warfarin Binding to Human Serum Albumin: Anatomy of Drug Site I. Journal of Biological Chemistry, 276, 22804-22809. https://doi.org/10.1074/jbc.m100575200
[6]
Kawai, M., Harada, M., Motoike, Y., et al. (2019) Impact of Serum Albumin Levels on Supratherapeutic PT-INR Control and Bleeding Risk in Atrial Fibrillation Patients on Warfarin: A Prospective Cohort Study. IJC Heart & Vasculature, 22, 111-116. https://doi.org/10.1016/j.ijcha.2019.01.002
[7]
Henry, R. and Woslait, W. (1975) Drug Displacement of Warfarin from Human Serum Albumin: A Fluorometric Analysis. Toxicology and Applied Pharmacology, 33, 267-275. https://doi.org/10.1016/0041-008x(75)90093-9
[8]
Mullokandov, E., Ahn, J., Szalkiewicz, A. and Babayeva, M. (2014) Protein Binding Drug-Drug Interaction between Warfarin and Tizoxanide in Human Plasma. Austin Journal of Pharmacology and Therapeutics, 2, 1-3.
[9]
de Medeiros, J., Macedo, M., Contancia, J., et al. (2000) Antithrombin Activity of Medicinal Plants of the Azores. Journal of Ethnopharmacology, 72, 157-165. https://doi.org/10.1016/s0378-8741(00)00226-9
[10]
Li, C., Schwarz, U.I., Ritchie, M.D., Roden, D.M., Stein, C.M. and Kurnik, D. (2009) Relative Contribution of CYP2C9 and VKORC1 Genotypes and Early INR Response to the Prediction of Warfarin Sensitivity during Initiation of Therapy. Blood, 113, 3925-3930. https://doi.org/10.1182/blood-2008-09-176859
[11]
Sands, C., Chan, E. and Welty, T. (2002) Revisiting the Significance of Warfarin Protein-Binding Displacement Interactions. Annals of Pharmacotherapy, 36, 1642-1644. https://doi.org/10.1345/aph.1a208
[12]
Gemmati, D., Burini, F., Talarico, A., et al. (2016) The Active Metabolite of Warfarin (3’-Hydroxywarfarin) and Correlation with INR, Warfarin and Drug Weekly Dosage in Patients under Oral Anticoagulant Therapy: A Pharmacogenetic Study. PLOS ONE, 11, e0162084. https://doi.org/10.1371/journal.pone.0162084
[13]
Tarantino, G., Citro, V., Capone, D., et al. (2021) Copper Concentrations Are Prevalently Associated with Antithrombin III, but Also with Prothrombin Time and Fibrinogen in Patients with Liver Cirrhosis: A Cross-Sectional Retrospective Study. Journal of Trace Elements in Medicine and Biology, 68, Article ID: 126802. https://doi.org/10.1016/j.jtemb.2021.126802
[14]
Nielsen, V., Ward, T. and Ford, P. (2018) Effects of Cupric Chloride on Coagulation in Human Plasma: Role of Fibrinogen. Journal of Thrombosis and Thrombolysis, 46, 359-364. https://doi.org/10.1007/s11239-018-1704-4
