title: Global coagulation tests: their applicability for measuring direct factor Xa- and thrombin inhibition and reversal of anticoagulation by prothrombin complex concentrate.
abstract: BACKGROUND
  Specific mass spectrometry and direct activated factor X (Xa)- and thrombin inhibition assays do not allow determination of the reversal of anticoagulant effects of non-vitamin K direct oral anticoagulants (NOACs) by prothrombin complex concentrate (PCC). The objective of this study was the evaluation of the applicability of a variety of commercially available global coagulation assays in analyzing the reversal of NOAC anticoagulation by PCC.
  
  
  METHODS
  Plasma and whole blood were spiked with apixaban or dabigatran and PCC was added to these samples. Prothrombin time (PT), modified PT (mPT), activated partial prothrombin time (APTT), thrombography (CAT method) and thromboelastography (ROTEM, TEG) were performed.
  
  
  RESULTS
  Assays triggered by contact activation (APTT, INTEM) did not show inhibitor reversal by PCC. Assays triggered by tissue factor (TF) showed NOAC type and NOAC concentration dependent anticoagulation reversal effects of PCC ranging from partial normalization to overcorrection of the following parameters: clotting or reaction time (PT, mPT TEG-TF, EXTEM, FIBTEM); angle in thromboelastography (TEG-TF); thrombin generation (CAT) lag time, endogenous thrombin potential (ETP) and peak thrombin. Extent of reversal was assay reagent dependent. ETP (5 pM TF) was the only parameter showing complete reversal of anticoagulation by PCC for all NOACs ranging from 200 to 800 μg/L.
  
  
  CONCLUSIONS
  ETP fits with the concept that reversal assessment of NOAC anticoagulation by PCC should be based on measurements on the clotting potential or thrombin generating potential of the plasma or whole blood patient sample. Low sensitivity of ETP for NOACs and its correlation with bleeding are issues that remain to be resolved.
authors.forename: Jasper
authors.initials: J
authors.lastname: Dinkelaar
authors.forename: Sanne
authors.initials: S
authors.lastname: Patiwael
authors.forename: Job
authors.initials: J
authors.lastname: Harenberg
authors.forename: Anja
authors.initials: A
authors.lastname: Leyte
authors.forename: Herm Jan M
authors.initials: HJ
authors.lastname: Brinkman
mesh_terms: D000925:Anticoagulants / Q000737:chemistry*; D001562:Benzimidazoles / Q000737:chemistry; D001779:Blood Coagulation Factors / Q000737:chemistry*; D001780:Blood Coagulation Tests / Q000379:methods*; D000069604:Dabigatran; D015951:Factor Xa / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D011720:Pyrazoles / Q000737:chemistry; D011728:Pyridones / Q000737:chemistry; D013916:Thrombelastography; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: D000925:Anticoagulants; D001562:Benzimidazoles; D001779:Blood Coagulation Factors; D011720:Pyrazoles; D011728:Pyridones; D015091:beta-Alanine; C025667:prothrombin complex concentrates; C522181:apixaban; D013917:Thrombin; D015951:Factor Xa; D000069604:Dabigatran