FXa-activity can be measured by the Prothrombinase induced Clotting time (PiCT). The manufactured assay uses bovine FXa as component and employs a incubation period before re-calcification. Its use with new direct FXa-inhibitors is challenged by reports on decreased sensitivity.
Blood was incubated with 3 investigational, structurally related (oxazolidinones) direct FXa-inhibitors including the recently approved agent rivaroxaban (0 - 2.0 microM), with the structurally distinct direct FXa-inhibitor DX 9065a (0 - 18 microM) and with the indirect inhibitor fondaparinux (0 - 0.6 microM). We tested modifications of PiCT regarding the source of FXa (bovine or human) and the incubation step (incubation before re-calcification=2-step, no incubation =1-step), and compared results with inhibition of human or bovine FXa-activity.
The bovine 2-step PiCT showed a paradoxical decrease with all direct FXa-inhibitors, this effect is surmounted only at high concentrations and is not seen with the bovine 1-step PiCT. The decrease in PiCT is not observed in antithrombin-depleted plasma. The humanized PiCT (1 or 2 step) showed a consistent prolongation under all direct inhibitors. Fondaparinux prolonged PiCT with either assay. The correlation between PiCT and corresponding FXa-activity was significant both for humanized 2-step PiCT or bovine 1 step PiCT (r2=0.80), but the 95% prediction interval was large and covered a span of 40% FXa-activity between one agent and another.
The customary bovine PiCT should only be used to monitor direct FXa-inhibitors when modified as 1-step procedure. PiCT is not suitable to assess similarity of FXa-inhibition when different agents are interchanged.
"Similarly, the APTT is not a suitable method as it is largely insensitive to these two anticoagulants. The PiCT has been evaluated by a number of groups for measurement of LMWH and fondaparinux activity (Calatzis et al, 2008; Harder et al, 2008). Although PiCT is sufficiently sensitive to LMWH, it can be influenced by other inhibitors and is therefore not specific for LMWH. "
"Rivaroxaban prolongs clotting times concentration-dependently in the activated partial thromboplastin time , HepTest (Sekisui Diagnostics, Stamford, CT, USA ) [15,20] and prothrombinase-induced clotting time (PiCT) test [24,26,28]. However, for the HepTest and PiCT test, there is a paradoxical shortening of clotting time at low rivaroxaban concentrations when bovine Factor Xa is used . "
[Show abstract][Hide abstract] ABSTRACT: Research into new anticoagulants for preventing and treating thromboembolic disorders has focused on targeting single enzymes in the coagulation cascade, particularly Factor Xa and thrombin, inhibition of which greatly decreases thrombin generation. Based on the results of phase III clinical trials, rivaroxaban, a direct Factor Xa inhibitor, has been approved in many countries for the management of several thromboembolic disorders. Owing to its predictable pharmacokinetic and pharmacodynamic characteristics, fixed-dose regimens are used without the need for routine coagulation monitoring. In situations where assessment of rivaroxaban exposure may be helpful, anti-Factor Xa chromogenic assays (in tandem with standard calibration curves generated with the use of rivaroxaban calibrators and controls) could be used. It is important to note that test results will be affected by the timing of blood sampling after rivaroxaban intake. In addition, the anti-Factor Xa method measures the drug concentration and not the intensity of the drug's anticoagulant activity, and a higher than expected rivaroxaban plasma level does not necessarily indicate an increased risk of bleeding complications. Therefore, clinicians need to consider test results in relation to the pharmacokinetics of rivaroxaban and other patient risk factors associated with bleeding.
"The direct thrombin inhibitors lepirudin, argatroban, melagatran, as well as unfractionated and low-molecular weight heparins and fondaparinux prolong coagulation time dose dependently . The effects of rivaroxaban are measured using a one-step incubation procedure in contrast to two-step incubation procedure for the other coagulation inhibitors . Dabigatran also prolongs coagulation time of PiCT more using the one step-incubation procedure than with the two-step incubation procedure . "
[Show abstract][Hide abstract] ABSTRACT: New oral anticoagulants are given at fixed daily doses without laboratory dose adjustment for prevention of venous thromboembolism following elective total knee- and hip replacement, for treatment and prevention of recurrent events of acute venous thromboembolism, and for prevention of embolic events in atrial fibrillation. However, it may be necessary to determine the anticoagulant effect of new oral anticoagulants in special patient populations such as in elderly, for renal impairment, before operation, bleeding or thrombotic episodes and to monitor self-compliance. Oral factor Xa and oral thrombin inhibitors influence dose dependently global and specific coagulation assays. Standardization of assays is currently undertaken. Determination of the new oral anticoagulants in serum samples would facilitate blood sampling and analysis from samples taken and stored for creatinine or other biochemical parameters. Point of care methods from plasma or urine for the new oral anticoagulants would improve patient care. First data demonstrate the feasibility of such assays in urine.
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