NOACs and routine coagulation assays. How to interpret?

Türkoğlu, Ebru

doi:10.1016/j.ijcac.2015.10.004

Cited by 7 publications

(13 citation statements)

References 17 publications

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“…Compound 1 is a very weak inhibitor of coagulation in both the PT and aPTT assays. These clotting assays are often used as biomarkers for anticoagulants [ 39 , 40 ]. Most of the known anticoagulants, including warfarin, heparin, and the DOACs, have potency in these assays at clinically relevant efficacious concentrations.…”

Section: Discussionmentioning

confidence: 99%

Reversible covalent direct thrombin inhibitors

et al. 2018

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IntroductionIn recent years, the traditional treatments for thrombotic diseases, heparin and warfarin, are increasingly being replaced by novel oral anticoagulants offering convenient dosing regimens, more predictable anticoagulant responses, and less frequent monitoring. However, these drugs can be contraindicated for some patients and, in particular, their bleeding liability remains high.MethodsWe have developed a new class of direct thrombin inhibitors (VE-DTIs) and have utilized kinetics, biochemical, and X-ray structural studies to characterize the mechanism of action and in vitro pharmacology of an exemplary compound from this class, Compound 1.ResultsWe demonstrate that Compound 1, an exemplary VE-DTI, acts through reversible covalent inhibition. Compound 1 inhibits thrombin by transiently acylating the active site S195 with high potency and significant selectivity over other trypsin-like serine proteases. The compound inhibits the binding of a peptide substrate with both clot-bound and free thrombin with nanomolar potency. Compound 1 is a low micromolar inhibitor of thrombin activity against endogenous substrates such as fibrinogen and a nanomolar inhibitor of the activation of protein C and thrombin-activatable fibrinolysis inhibitor. In the thrombin generation assay, Compound 1 inhibits thrombin generation with low micromolar potency but does not increase the lag time for thrombin formation. In addition, Compound 1 showed weak inhibition of clotting in PT and aPTT assays consistent with its distinctive profile in the thrombin generation assay.ConclusionCompound 1, while maintaining strong potency comparable to the current DTIs, has a distinct mechanism of action which produces a differentiating pharmacological profile. Acting through reversible covalent inhibition, these direct thrombin inhibitors could lead to new anticoagulants with better combined efficacy and bleeding profiles.

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Section: Discussionmentioning

confidence: 99%

Reversible covalent direct thrombin inhibitors

et al. 2018

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“…Prolongation of aPTT occurs in a curvilinear fashion in patients taking both IIa and Xa inhibitors; however, the degree of prolongation is dependent upon the reagent used. 3 , 4 , 5 …”

Section: Coagulation Assaysmentioning

confidence: 99%

“…Recognize that there may still be clinical anticoagulation effects of dabigatran with a normal aPTT; however, the patient’s serum levels would fall below the therapeutic range (<80μg/L). 4 , 5 …”

Section: Coagulation Assaysmentioning

confidence: 99%

“…The degree of elevation is specific to the reagent as well as the calibration of the laboratory equipment. 3 – 5 …”

Section: Coagulation Assaysmentioning

confidence: 99%

“…At therapeutic serum concentrations, one would expect both rivaroxaban and edoxaban to cause elevation of the PT/INR. 3 , 5 , 6 Apixaban weakly affects the PT/INR levels. 5 Similar to stated above, a normal PT/INR does not exclude some degree of anticoagulant effect, but merely indicates a level below that expected at therapeutic dosing.…”

Section: Coagulation Assaysmentioning

confidence: 99%

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