Delayed Thrombin Generation Is Associated with Minor Bleedings in Venous Thromboembolism Patients on Rivaroxaban: Usefulness of Calibrated Automated Thrombography.

Jaroslaw Zalewski,Konrad Stepien,Sandi Caus,Karol Nowak,Saulius Butenas,Anetta Undas

doi:10.3390/jcm9072018

Abstract

Bleeding is the most feared and difficult to predict adverse event of anticoagulation. We sought to investigate whether calibrated automated thrombography (CAT) parameters are associated with minor bleeding (MB) in anticoagulated patients following venous thromboembolism (VTE). Enrolled were 132 patients on rivaroxaban, 145 on vitamin K antagonists (VKA) and 31 controls who stopped anticoagulation. Prior to the next dose of the anticoagulant, we measured CAT parameters, along with rivaroxaban concentration and INR. During a median follow-up of 10 months, we recorded minor and major bleedings. On rivaroxaban, 27 (20.5%) patients with MB had longer time to start thrombin generation, lower peak thrombin generation and lower endogenous thrombin potential compared with subjects without MB (all p < 0.001). All CAT parameters, except for peak thrombin generation (p = 0.049), were similar in VKA patients with (n = 25, 17.2%) vs. without MBs. By logistic regression, time to start thrombin generation (p = 0.007) and unprovoked VTE (p = 0.041) independently predicted MBs on rivaroxaban. Major bleedings were more frequent in patients with MBs (17.3% vs. 1.8%, p < 0.001). Abnormal CAT parameters characterize VTE patients prone to MBs on rivaroxaban, but not on VKA. Time to start thrombin generation measured about 24 h since the last rivaroxaban dose might help predict MBs.

Highlights

Minor bleeding (MB) is usually defined, based on the International Society on Thrombosis and Hemostasis (ISTH) guidance, as a clinically overt event not meeting the criteria of major or clinically relevant non-major (CRNM) bleeding [1,2]
The Dresden non-vitamin K antagonist oral anticoagulants (NOAC) registry [11] showed that ISTH-defined MBs occur with the frequency of 37.8 per 100 person-years in real-life venous thromboembolism (VTE) subjects treated with rivaroxaban and they accounted for 58.9% of all observed bleedings
132 (42.8%) were on rivaroxaban, and 145 (47.1%) on vitamin K antagonist (VKA) (77 on warfarin and 68 on acenocoumarol), while 31 (10.1%) patients following provoked VTE who stopped anticoagulation at least three months before inclusion served as controls

Summary

Introduction

Minor bleeding (MB) is usually defined, based on the International Society on Thrombosis and Hemostasis (ISTH) guidance, as a clinically overt event not meeting the criteria of major or clinically relevant non-major (CRNM) bleeding [1,2]. In VTE patients treated mostly with non-vitamin K antagonist oral anticoagulants (NOAC) MBs were frequently found including heavy menstrual bleeding in 23.2%, easy bruising in 15.4% and gingival bleeding in 8.8% of subjects [9,10]. The Dresden NOAC registry [11] showed that ISTH-defined MBs occur with the frequency of 37.8 per 100 person-years in real-life VTE subjects treated with rivaroxaban and they accounted for 58.9% of all observed bleedings. MBs in VTE patients on apixaban or rivaroxaban defined as outpatient claims not requiring hospital admission were reported in 20 or 34 per 100 person-years, respectively [12]

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Discussion

Conclusion