Rivaroxaban Causes Missed Diagnosis of Protein S Deficiency but Not of Activated Protein C Resistance (Factor V Leiden)

Abstract

Context.— Rivaroxaban causes a false increase in activated protein C resistance (APCR) ratios and protein S activity. Objective.— To investigate whether this increase masks a diagnosis of factor V Leiden (FVL) or protein S deficiency in a “real-world” population of patients undergoing rivaroxaban treatment and hypercoagulation testing. Design.— During a 2.5-year period, we compared 4 groups of patients (n = 60): FVL heterozygous (FVL-HET)/taking rivaroxaban, wild-type/taking rivaroxaban, FVL-HET/no rivaroxaban, and normal APCR/no rivaroxaban. Patients taking rivaroxaban were tested for protein S functional activity and free antigen (n = 32). Results.— The FVL-HET patients taking rivaroxaban had lower APCR ratios than wild-type patients (P < .001). For FVL-HET patients taking rivaroxaban, mean APCR was 1.75 ± 0.12, versus 1.64 ± 0.3 in FVL-HET patients not taking rivaroxaban (P = .005). Activated protein C resistance in FVL-HET patients fell more than 3 SDs below the cutoff of 2.2 at which the laboratory reflexes FVL DNA testing. No cases of FVL were missed despite rivaroxaban. In contrast, rivaroxaban falsely elevated functional protein S activity, regardless of the presence or absence of FVL (P < .001). A total of 4 of 32 patients (12.5%) had low free protein S antigen (range, 58%–67%), whereas their functional protein S activity appeared normal (range 75%–130%). Rivaroxaban would have caused a missed diagnosis of all cases of protein S deficiency during the study if testing relied on the protein S activity assay alone. Conclusions.— Despite rivaroxaban treatment, APCR testing can distinguish FVL-HET from normal patients, rendering indiscriminate FVL DNA testing of all patients on rivaroxaban unnecessary. Free protein S should be tested in patients taking rivaroxaban to exclude hereditary protein S deficiency.