Abstract
The effect of direct oral anticoagulants (DOACs) on turbidimetric measurements of plasma clot formation and susceptibility to fibrinolysis may facilitate a comparison between different classes of anticoagulants in plasma samples. We obtained 424 citrate plasma samples from 226 atrial fibrillation patients on anticoagulation and 24 samples without anticoagulation serving as controls. As comparators, we measured the international normalized ratio (INR) for phenprocoumon samples (N = 166), anti-Xa for low molecular weight heparin (LMWH) samples (N = 42), and DOAC levels with mass spectrometry (dabigatran N = 40, rivaroxaban N = 110, apixaban N = 42). Plasma clot formation and lysis were recorded continuously on a photometer after addition of an activation mix (tissue factor 2 pmol/l and tissue plasminogen activator 333 ng/ml). We used linear regression and ANCOVA for correlation analysis. Clot formation lag phase was prolonged in the presence of anticoagulants in a concentration-dependent manner for DOACs (dabigatran Spearman r = 0.74; rivaroxaban r = 0.78; apixaban r = 0.72, all p < 0.0001), INR dependent for phenprocoumon (r = 0.59, p < 0.0001), anti-Xa level dependent in LMWH samples (r = 0.90, p < 0.0001). Maximum rate of clot formation and peak clot turbidity were reduced in the presence of anticoagulants, but correlated only moderately with the comparator measures of anticoagulation. The clot lysis time was inversely correlated with DOAC concentrations in the presence of recombinant thrombomodulin. A direct ex vivo comparison between the effects of different classes of anticoagulants is possible with turbidimetric measurement of plasma clot formation and lysis. Anticoagulation inhibited clot formation in a plasma concentration manner for DOACs, INR dependent for phenprocoumon, and anti-Xa dependent for LMWH. Susceptibility to fibrinolysis increased with increasing DOAC concentrations.
Highlights
Since the introduction of novel direct oral anticoagulants (DOACs) into clinical practice for stroke prevention in atrial fibrillation (AF), the measurement of the intensity of anticoagulation has been challenging
The clot lysis time was only dependent on anticoagulation intensity in the presence of thrombomodulin because anticoagulants reduced the generation of thrombin, which is required for thrombin-activatable fibrinolysis inhibitor (TAFI) activation and fibrinolysis inhibition
We found that the parameters of clot formation, the lag phase, were strongly correlated with the specific tests for anticoagulation, including plasma concentration of DOACs, international normalized ratio (INR) values in vitamin K antagonists (VKA) samples, and anti-Xa levels in low molecular weight heparin (LMWH) samples
Summary
Since the introduction of novel direct oral anticoagulants (DOACs) into clinical practice for stroke prevention in atrial fibrillation (AF), the measurement of the intensity of anticoagulation has been challenging. A precise determination of anticoagulation intensity is vital in the clinical management of vitamin K antagonists (VKA), which dominated the landscape of anticoagulation for the past decades, to find the ideal therapeutic window between efficacious prevention of stroke and systemic embolism and safety from bleeding complications [1]. The specific assays that exist to determine the drug concentrations while on treatment with DOACs in patient plasma, including chromogenic anti-Xa assays and diluted thrombin time assays [2,3,4,5], neither indicate the effect of anticoagulation on hemostatic capacity nor are. The kinetics of clot formation and lysis in samples from “real-world” patients on anticoagulation may give better insights into hemostatic capacity than global clotting assays and specific assays for drug concentration measurements. Ex vivo susceptibility to fibrinolysis after addition of recombinant tissue-type plasminogen activator has further been suggested as a potential biomarker for thromboembolic [8, 9] and bleeding complications [10]
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