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Rivaroxaban Effects Illustrate the Underestimated Importance Of Journal of Clinical Medicine Article Rivaroxaban Effects Illustrate the Underestimated Importance of Activated Platelets in Thrombin Generation Assessed by Calibrated Automated Thrombography Stephanie Makhoul 1, Marina Panova-Noeva 1,2,Véronique Regnault 3,4 , Wolfram Ruf 1,2,5, Philip Wenzel 1,2,6 and Jeremy Lagrange 1,3,* 1 Center for Thrombosis and Hemostasis, University Medical Center Mainz, 55131 Mainz, Germany; [email protected] (S.M.); [email protected] (M.P.-N.); [email protected] (W.R.); [email protected] (P.W.) 2 DZHK (German Center for Cadiovascular Research), Partner Site Rhine Main, University Medical Center Mainz, 55131 Mainz, Germany 3 Université de Lorraine, INSERM U1116, DCAC, 54505 Nancy, France; [email protected] 4 CHRU Nancy, Vandœuvre-lès-Nancy, 54511 Nancy, France 5 Department of Immunology and Microbial Science, The Scripps Research institute, La Jolla, CA 92037, USA 6 Center for Cardiology—Cardiology I, University Medical Center Mainz, 55131 Mainz, Germany * Correspondence: [email protected] Received: 19 September 2019; Accepted: 12 November 2019; Published: 15 November 2019 Abstract: Background: The direct oral anticoagulant rivaroxaban inhibiting specifically activated factor X (FXa) causes delayed thrombin generation (TG) as measured by calibrated automated thrombography (CAT). The implications of these changes for assessing bleeding or residual prothrombotic risks of patients are unclear in the absence of a better understanding of the underlying mechanism. Methods: We compared platelet rich plasma (PRP) without or with prior collagen-induced platelet aggregation (agPRP) in the CAT assay to better characterize TG in the presence of rivaroxaban. Results: In the presence of rivaroxaban, TG curves in agPRP showed a distinct profile with a rapidly ascending phase followed with a protracted phase. Inhibition of tissue factor pathway inhibitor amplified the first phase of the curve which was also modulated by procoagulant phospholipids. Inhibition of FXIIa-dependent FXI activation revealed that aggregated platelets influenced the first phase by a combination of extrinsic and intrinsic coagulation pathway initiations. Thrombin-dependent amplification of TG (even prior collagen activation) was responsible for the second phase of the TG curve. Conclusions: AgPRP fully includes platelet ability to support TG and reveal distinct TG phases in the presence of direct FXa inhibitors highlighting its potential use in an anticoagulated setting. Keywords: thrombin; platelets; factor Xa inhibitor; phospholipids 1. Introduction Direct oral anticoagulants (DOACs) are increasingly used as first line treatment for venous thromboembolism (VTE) and for prevention of ischemic stroke in atrial fibrillation, but regular assessment of their anticoagulant effects remains challenging. The coagulation system leads to the formation of thrombin and fibrin and its polymerization that will form a clot. Most of the thrombin generation (TG) occurs after the clot formation and total TG potential of a plasma can be assessed with calibrated automated thrombography (CAT), which gives a better overview of the coagulation J. Clin. Med. 2019, 8, 1990; doi:10.3390/jcm8111990 www.mdpi.com/journal/jcm J. Clin. Med. 2019, 8, 1990 2 of 13 system than clotting times (prothrombin time or activated partial thromboplastin time) [1–4]. The CAT assay uses a fluorogenic substrate to measure prothrombin conversion to thrombin in a recalcified plasma in the presence of phospholipids (PL). In patients with acute VTE, the use of TG assays becomes challenging once an antithrombotic treatment, including DOACs, has been initiated. It is well established that anticoagulants impair dramatically thrombin generation, making it difficult to monitor the bleeding or residual prothrombotic risk. The COMPASS study (Cardiovascular Outcomes for Peoples Using Anticoagulant Strategies) included patients with stable atherosclerotic disease treated with rivaroxaban plus aspirin compared to rivaroxaban or aspirin alone and showed a lower risk of cardiovascular death, stroke, myocardial infarction, fatal bleeding, or symptomatic bleeding into a critical organ with dual therapy [5]. However, major bleeding events occurred in 3.1% (rivaroxaban plus aspirin patients) vs. 1.9% (patients under aspirin) pointing out that even if the combination of anticoagulation with antiplatelet therapy on the overall cardiovascular risk is beneficial, stratification needs to be improved. Current clinical guidelines recommend assessment of bleeding and thrombotic risks when making a decision to start anticoagulation, principally by using the clinical risk scores, such as ABC-bleeding [6], HAS-BLED [7], or CHA2DS2-VASc risk score [8]. In addition to clinical characteristics, biomarkers shown to improve bleeding and/or stroke risk estimates are also part of the clinical scores, such as NT-proBNP, high-sensitivity cardiac troponin T (hsTnT), growth differentiation factor-15 (GDF-15), hemoglobin level and platelet count [6,9]. However, risk scores may present limitations depending on cohort recruitment and follow-up and parameters selected [10]. In addition, to date no hemostatic functional assays are routinely used to estimate patients’ bleeding risk. The evaluation of bleeding risk in patients receiving both anticoagulant and antiplatelet agents, e.g., rivaroxaban and aspirin, poses a greater challenge. The reason is that the hemostasis inhibition includes both inhibition of platelets and of coagulation, and most laboratory tests evaluate these processes separately. The presence of rivaroxaban in plasma can change the appearance of the TG curve with the formation of camel-back shaped instead of normal curves [11]. Endogenous thrombin potential (ETP), representing the total amount of thrombin formed, and the peak height of TG, representing the maximum thrombin formed, are the most widely used parameters to evaluate the thrombin potential of a plasma. However, the presence of DOACs seems to affect more the parameters related to the kinetics of TG such as the lag time, the velocity and the time to peak, often not reported in the literature [12]. Not only the amount (ETP) but also the kinetic of thrombin formation and its inhibition are important for hemostasis. After a systemic review using the words (thrombin generation) and (rivaroxaban) in PubMed, from the 54 publications released over the past 10 years in which the CAT assay was performed only 26 presented curves of TG and no more than 17 of these publications showed camel-back shaped curves. These curves were also described with other Xa inhibitors as apixaban [13]; however, to date this effect has not been clarified. To the best of our knowledge, no specific studies reported on the impact of rivaroxaban on the shape of TG curves. In the present work, we aimed to explore the origin and determinants of camel-back shaped TG curves in the presence of new oral anticoagulants, in particular rivaroxaban. We took advantage of the use of aggregated platelet rich plasma (PRP/agPRP) in the CAT [14] which fully includes platelet procoagulant activity since modified TG kinetics in particular faster TG could compensate the slow TG often observed after rivaroxaban treatment. 2. Experimental Section 2.1. Blood Sampling and PRP Preparation Studies using human platelets were approved by the ethics committee of the University Mainz (study no. 837.302.12; 25.07.12). Blood from 16 healthy volunteers (8 women, 8 men, mean age 30 2.6 years) was obtained after informed consent by venipuncture via a 21-gauge ± needle and collected in S-monovette tubes containing sodium citrate (3.2%) (Sarstedt, Nümbrecht, J. Clin. Med. 2019, 8, 1990 3 of 13 Germany). Complete blood counts and hematocrit were determined with a cell counter (KX-21N, Sysmex Corporation, Kobe, Japan). PRP was prepared within 1 h following blood sampling with a centrifugation at 200 g for 10 min at 20 C. The supernatant was removed and the platelet count × ◦ was adjusted to 200 109/L with platelet poor plasma (PPP) prepared with a 10 min centrifugation at × 2000 g at 20 C. Platelet free plasma (PFP) was prepared by centrifuging PPP at 13,000 g for 30 min × ◦ × at 4 C. The collected PFP was stored at 80 C until use. ◦ − ◦ 2.2. Platelet Aggregation Platelet aggregation was monitored for 10 min by measuring light transmission through stirred PRP at 37 ◦C using a platelet aggregometer (APACT 4S plus aggregometer, Diasys Greiner, Holzheim, Germany). Platelet aggregation was triggered by 2 µg/mL equine collagen fibrils type I (Chrono-log Corp, Havertown, PA, USA). Aggregated PRP was used directly after aggregation for CAT measurement [14]. 2.3. Thrombin Generation Assay CAT was performed with PRP and agPRP or PFP (Figure S1). CAT in PRP and PFP was performed in a microtiter plate fluorometer (Fluoroskan Ascent, ThermoLabsystems, Helsinki, Finland) using dedicated software (Thrombinoscope BV, Maastricht, The Netherlands) as reported previously [15,16]. All reagents were used as follows: 80 µL PRP, homogenous agPRP or PFP, 20 µL of PRP-Reagent or PPP-Reagent low (Thrombinoscope BV, Maastricht, The Netherlands), and 20 µL of a mix of fluorogenic substrate and calcium (FluCa-Kit reagent). In specific experiments with PRP or agPRP TG was triggered with 0.1 U/mL human thrombin (Roche Diagnostics, Mannheim, Germany) instead of PRP-Reagent. Rivaroxaban, PAR 1 (vorapaxar) and PAR 4 (BMS 986120) inhibitors were purchased from Cayman Chemical (Ann Arbor, MI, USA) and reconstituted in DMSO. Vorapaxar
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