Differential effects of direct thrombin inhibitors and antithrombin-dependent anticoagulants on the dynamics of clot formation

Abstract

New anticoagulants, including the direct thrombin inhibitors (DTIs) and fondaparinux, are increasingly replacing unfractionated heparin and enoxaparin. We examined the effects of argatroban (n = 60), bivalirudin (n = 44), heparin (n = 14), enoxaparin (n = 22), and fondaparinux (n = 24) on clot formation utilizing thromboelastography. Blood samples containing anticoagulants at clinically relevant concentrations were prepared ex vivo and analyzed using kaolin or tissue factor activation. Thromboelastography parameters of clot initiation (R), clot propagation (K and angle), clot rigidity (maximum amplitude) and clot elasticity (G) were compared between anticoagulants. Thromboelastography was also performed on blood from eight patients receiving anticoagulants. Each anticoagulant exerted significant concentration-dependent effects on R, K and angle. Only heparin, enoxaparin, and fondaparinux significantly affected maximum amplitude and G. Significant differences existed for all parameters between heparin and each anticoagulant and between fondaparinux and each DTI (P < 0.001), and for angle, maximum amplitude, and G between enoxaparin and each DTI (P < 0.008). Thromboelastography responses in ex-vivo samples and patient samples were comparable. In conclusion, whereas argatroban, bivalirudin, heparin, enoxaparin and fondaparinux each delay clot formation, the DTIs do not alter clot rigidity or elasticity. The reduced bleeding reported with DTIs versus heparin may relate to the fact that clots form with normal rigidity and elasticity.

Novel method using rotational thromboelastography analysis for intraoperative management of device patient with heparin-induced thrombocytopenia

“…Currently, in the clinical setting clotting assays such as activated clotting time (ACT) and activated partial thromboplastin time (aPTT) are used to guide dosing and monitor patient anticoagulation [2][3][4]8]. These assays provide a measure of clot initiation and therefore only account for a small fraction of the coagulation pathway [2,3]. Rotational thromboelastography (ROTEM) can offer additional information regarding intrinsic and extrinsic coagulation properties as well as fibrin polymerization and fibrinolysis [2,9].…”

“…Heparin-induced thrombocytopenia (HIT) is an immune-mediated prothrombotic disease in response to previous heparin exposure [1] Direct thrombin inhibitors (DTIs) are suitable candidates for the prophylaxis of thrombosis in patients with HIT [2][3][4][5][6]. Bivalirudin, a common DTI, can be considered as a therapeutic alternative to heparin [3,[5][6][7].…”

“…Bivalirudin, a common DTI, can be considered as a therapeutic alternative to heparin [3,[5][6][7]. Currently, in the clinical setting clotting assays such as activated clotting time (ACT) and activated partial thromboplastin time (aPTT) are used to guide dosing and monitor patient anticoagulation [2][3][4]8].…”

Evaluation of coagulation kinetics using thromboelastometry—methodologic influence of activator and test medium

“…As of today, the tissue factor pathway is largely acknowledged as the physiological trigger for in vivo generation of a sufficient haemostatic plug [15,16]. Nevertheless, several interesting studies adopted traditional contact activation [17][18][19][20]. The final concentration of the activating reagent, whether tissue factor or contact activator, may also influence the characteristics of coagulation kinetics in various coagulopathies.…”

Introduction to haemostasis from a pharmacodynamic perspective

“…[33,34]. Similarly to the TGT tests the various variants require validation for their relevance as PD methods and addition to diagnosis [35,36] Lupus anticoagulant tests As is well known, lupus testing relies on the determination of prolongation of clotting tests, while 'by contrast' the feared complication is thrombotic.This indicates that the clotting tests utilized are pharmacokinetic rather than functional. More recently Rand et al [37] proposed other tests which seem to reflect the (patho-)physiology better as they study increased coagulation in relation to thrombosis.…”